Robert C Bransfield, MD, DLFAPA

Robert C Bransfield, MD, DLFAPA
Chronic Infections as Aetiological Factors in Psychiatric Disorders Microbes and Mental Illness Dean Center for Tick Borne Illness Spaulding Rehabilitation Harvard Boston, MA March 14, 2016 Abstract and Learning Objectives 50 minutes Chronic Infections as Aetiological Factors in Psychiatric Disorders Robert C Bransfield, MD, DLFAPA Both past and current infections in the body, or less often in the brain, can cause direct injury and/or immune reactions that adversely impact mental functioning. Prior infections can alter brain development and have lasting brain effects leading to impairments which contribute to dysfunction causing subsequent psychiatric illnesses. In addition, there are persistent and persistent complex interactive infections which are able to avoid adaptive immunity and elimination by the immune system as a result of their capacity for immune evasion and immune suppression. These persistent infections may provoke persistent inflammatory and autoimmune immune reactions that may contribute to disease progression causing increasing severity of mental illnesses that may include anxiety, apathy, depression, autism, psychosis, dementia, other mental disorders and violence. While a number of acute infections are associated with “hit and run infections” causing residual brain injury with lasting effects, other chronic, low grade persistent infections and often complex interactive infections, such as vector-borne, viral and venereal diseases are associated with more chronic progressive conditions. Lyme and associated tick-borne diseases is one model that is used to explain disease progression associated with increasing cognitive, emotional and vegetative symptoms. A better awareness of the pathophysiology of this contributor to mental illness increases opportunities for prevention, diagnosis & effective treatment which can help prevent some cases of mental illness and violence. Learning objectives: To better understand how infections can contribute to mental illnesses. To review the data regarding how infections can have direct and indirect immune mediated effects through inflammatory and autoimmune reactions causing mental illnesses. To review relevant data regarding specific conditions including developmental disorders and autism, anxiety disorders, depression, psychosis, dementia and violence. We are requesting you provide an overview of the effects of microbes on mental illness, describing the mechanisms that disrupt brain function and cause neuropsychiatric and neurocognitive symptoms. Please focus on the impact of tick-borne infections; according to your website these include: Cell injury Inflammation Cytokine activity Immune and autoimmune mechanisms Disruption in neural transmission Disruption in blood flow Injury to associative centers Injury to modulating centers Toxins? Please also discuss common psychiatric syndromes associated with Tick-borne infections and associated nervous system dysfunction. Please include PANDAS/PANS in this piece of your discussion. Robert C Bransfield, MD, DLFAPA

Disclosure Statement Robert Bransfield, MD, DLFAPA, PC
Patients pay me money in return for trying to help them. Most of my income is paid directly from patients No Lyme, psychoimmunology or infectious disease financial interests. No research grants or patents dependent upon a disease definition. Speakers Bureau (currently): Lundbeck, Sunovion, Takeda

Microbes and Mental Illness
What causes mental illness? Is it the result of a gene and environmental interaction? If so, are microbes a significant contributor? Which microbes are most significant in causing mental illness? What are the mechanisms—inflammation, autoimmunity, other process? How might this expand our capacity to understand, prevent and treat mental illness?

Outline Pathophysiology
Chronic Stress, Insomnia, Sickness Syndrome & Fatigue Mental Illness and Tick-Borne Diseases Inflammation Autoimmunity Biochemistry Clinical Presentations Throughout the lifespan Autism Intrusive Symptoms Dementia Violence Treatment Conclusion

Pathophysiology

The History of Mental Illness
You’re possessed by demons & need punishment… Your mother caused it & you need psychoanalysis… Your serotonin is low & you need Prozac… Your genes are bad, too bad… You have chronic infections, your immune system is provoked & you need antibiotics… You have “subjective, non-specific medically unexplained symptoms,” taking antibiotics makes you and your doctor demons & you both need punishment…

Defining Mental Health
Mental health occurs when mental functioning (cognition, emotions, vegetative functioning) reflects the life situation and facilitates adaptation with: The capacity to experience well being, pleasure, fulfilling relationships & productive activities The ability to recognize and contend with adversity The mental flexibility to adapt to change Mental illness is impairment with dysregulated adaptive mechanisms.

With Emerging & Complex Diseases Think Outside the Box

Disease Models Bransfield RC. Pediatric Health. April 2009, Vol. 3, No. 2, Pages

Time Predisposing & precipitating factors Infections
immune & other reactions Pathophysiological processes Dysfunction Symptoms & Syndromes Ineffective Treatment Disease Progression

Multi-Systemic Disease Model
Progression Disease Recovery

CDC: Emerging Infectious Determinants of Chronic Diseases
Non-communicable chronic diseases can stem from infectious agents. Identifying the relationships can affect health across populations, creating opportunities to reduce the impact of chronic disease by preventing or treating infection. Infectious agents likely determine more cancers, immune-mediated syndromes, neurodevelopmental disorders, and other chronic conditions than currently appreciated. To capitalize on these opportunities, clinicians, public health practitioners, and policymakers must recognize that many chronic diseases may indeed have infectious origins. Note the date on this information and the contributors. EMERGING INFECTIOUS DISEASES Current Issue Vol. 12, No. 7 July Perspective Emerging Infectious Determinants of Chronic Diseases Siobh M. O'Connor,* Christopher E. Taylor, and James M. Hughes¡ *Centers for Disease Control and Prevention, Atlanta, Georgia, USA;National Institutes of Health, Bethesda, Maryland, USA; and Emory University, Atlanta, Georgia, USA Evidence now confirms that noncommunicable chronic diseases can stem from infectious agents. Furthermore, at least 13 of 39 recently described infectious agents induce chronic syndromes. Identifying the relationships can affect health across populations, creating opportunities to reduce the impact of chronic disease by preventing or treating infection. As the concept is progressively accepted, advances in laboratory technology and epidemiology facilitate the detection of noncultivable, novel, and even recognized microbial origins. A spectrum of diverse pathogens and chronic syndromes emerges, with a range of pathways from exposure to chronic illness or disability. Complex systems of changing human behavioral traits superimposed on human, microbial, and environmental factors often determine risk for exposure and chronic outcome. Yet the strength of causal evidence varies widely, and detecting a microbe does not prove causality. Nevertheless, infectious agents likely determine more cancers, immune-mediated syndromes, neurodevelopmental disorders, and other chronic conditions than currently appreciated. Infectious agents have emerged as notable determinants, not just complications, of chronic diseases. Not infrequently, infection may simply represent the first misstep along a continuum from health to long-term illness and disability. Preventing or treating infection or the immune response to infection offers a chance to disrupt the continuum, avoiding or minimizing a chronic outcome. To capitalize on these opportunities, clinicians, public health practitioners, and policymakers must recognize that many chronic diseases may indeed have infectious origins. A diverse spectrum of agents, pathways, outcomes, and co-factors characterize the already well-established causal associations. Together, this group affects all populations around the globe€”regardless of country, region, race/ethnicity, socioeconomic status, or culture. Expectations are that additional etiologic relationships will emerge over the coming decades, influenced by ever-evolving populations, ecology, and economies as well as by advances in science and technology (). The true potential to avoid or minimize chronic disease by preventing or treating infections may yet be substantially underestimated. Controlling infectious diseases remains paramount to the health and well-being of persons and populations worldwide. The breakdown of public health and prevention measures leads to the resurgence of old and new microbial threats. Nevertheless, implementing and maintaining infection control measures is shifting disease patterns, so that today chronic diseases represent the major health burden of established economies (>90 million people in the United States) and are a rapidly growing burden in developing economies () (). This fact implies that preventing or mitigating chronic diseases of infectious etiology could have considerable positive impact on global and domestic health. Add to this the potential benefits of minimizing infections that influence the morbidity of preexisting chronic conditions. The result is a tremendous opportunity to reduce long-term illness and disability worldwide by maximizing infection prevention and control. Siobh M. et al (CDC). Emerging Infectious Determinants of Chronic Diseases. Emerging Infectious Diseases. (2006)Vol. 12, No. 7

NIH Human Microbiome Project
A study researching all of the various microbes that live in people. The project has already established that the bacteria in the human microbiome collectively possess at least 100 times as many genes as the 20,000 or so in the human genome. Bacterial cells outnumber human cells by 10 to 1. Humans depend on their microbiome for essential functions, including digestion, leading microbiologists to conclude that a person should really be considered a superorganism. Six Tribes of Bacteria Live in Your Inner Elbow The crook of your elbow is a special ecosystem that provides a bountiful home to six tribes of bacteria. Even after you wash, there are still 1 million bacteria living on every square centimeter. These bacteria are what biologists call commensals, helpful rather than harmful organisms. They moisturize your skin by processing the raw fats that it produces. The bacteria were discovered as part of the human microbiome project, a study researching all of the various microbes that live in people. The project is in its early stages, but has already established that the bacteria in the human microbiome collectively possess at least 100 times as many genes as the 20,000 or so in the human genome. The bacterial cells also outnumber human cells by 10 to 1. Humans depend on their microbiome for essential functions, including digestion, leading microbiologists to conclude that a person should really be considered a superorganism. Sources: New York Times May 23, 2008 Genome Research May 23, 2008 Science May 22, 2008 New York Times May 23, 2008

Categories of Disease Causation
genetic (inherited alleles) noninfectious environmental (diet, lifestyle, chemicals, radiation) parasitic Paul W. Ewald. ILADS ILADS Annual Meeting. Jersey City, NJ. October 15, 2010

Research & Clinical Observation: Microbes & TBD Cause Mental Illness
Thousands of peer-reviewed journal articles demonstrate the causal association between infections and mental illness. Viral, venereal, vector-borne diseases are associated with persistent infections (Most notably arachnid, tick-borne diseases). 300+ peer reviewed scientific articles demonstrate the causal association between tick-borne disease and mental illness. Clinical observation by front line physicians also supports this view.

Go round up the usual suspects…

Some microbes associated with mental symptoms & mental illness I
Spirochetes: Borrelia afzelii (Lyme disease in UK, Europe) Borrelia burgdorferi sensu stricto (Lyme disease in USA,UK,Europe) Borrelia garinii (Lyme disease in UK, Europe) Borrelia miyamotoi Borrelia hermsii (Relapsing Fever) Borrelia turicatae (Relapsing Fever) Leptospira (Leptospirosis) Treponema pallidum pallidum (Syphilis) Bacteria: Anaplasmas phagocytophilum (Human Granulocytic Ehrlichiosis) Bartonella henselae (cat scratch fever) Bartonella quintana (trench fever) Bartonella rochalimae (Bartonellosis) Brucella (Brucellosis) Chlamydophilia pneumoniae (Chlamydia) Chlamydophila psittaci (Chlamydia) Coxiella burnetti (Q-Fever and "Post-Q Fever Fatigue Syndrome") Ehrlichia chaffeensis (Human Monocytic Ehrlichiosis) Francisella tularensis (Rabit Fever or Tularemia) Haemophilus influenzae (Haemophilus) Helicobacter pylori Listeria Meningococcus (Meningococcal Meningitis) Mycoplasma fermentans Mycoplasma pneumoniae Mycobacterium tuberculosis (Tuberculosis) Rickettsia. akari (Rickettsialpox) Rickettsia rickettsii (Rocky Mountain Spotted Fever) Rickettsia species (Eastern tick-borne Rickettsiosis) Shigella (Shigellosis) Streptococcus pneumoniae or Pneumococcus (Pneumonia) Streptococcus (PANDAS, Sydenham’s Chorea, St Vitus Dance) Bransfield RC. Pediatric Health. April 2009, Vol. 3, No. 2, Pages

Some microbes associated with mental symptoms & mental illness II
Varicella zoster virus(Chicken Pox) Viral meningitis West Nile virus XMRV/HGRV Protozoa: Plasmodium (Malaria) Babesia microti (Babesiosis) Babesia duncani (Babesiosis) Other Babesia species (Babesiosis) Leishmania (Leishmmaniasis) Toxoplasma gondii (Toxoplasmosis) Parasites: Blastocystis (Blastocystosis) Strongyloides stercoralis (Strongyloidiasis) Taenia solium (Neurocysticercosis or Cysticercosis) Fungal: Cryptocococcus Coccidiomycosis Histomycosis Yeast: Candida albicans (Candidiasis) Candida dubliniensis Prion Variant Creutzfeldt-Jakob Viruses: Borna virus Chikungunya virus Coltiviruse (Colorado Tick Fever) Coronaviruses Coxsackie virus Cytomegalovirus Enterovirus Flaviviridae virus (Japanese B encephalitis & Tick-borne encephalitis virus) Hepatitis C virus Herpes virus family Human endogenous retroviruses Human herpesvirus 4 or Epstein-Barr virus Human immunodeficiency virus Human T-Cell Lymphotropic Virus Type 1 Influenza A virus subtype H3N2 (Hong Kong Flu) Influenza virus Pandemic Influenza of 1918 Papopavirus Paramyxovirus (Measles virus) Parvo B19 Poliovirus Rabies virus Rubella Toga virus Bransfield RC. Pediatric Health. April 2009, Vol. 3, No. 2, Pages

Zika Virus Dobyns Lab, NYT
A leading pediatric neurologist who has studied the brains of babies stricken with the Zika virus says the damage is far more severe than global health officials are telling the public. Dr. William Dobyns was ed the images by a specialist in Brazil and told The Daily Beast the cases are some of the worst he’s seen in more than 30 years of study. Dobyns says images also share telltale signs of viral infection, though a definitive link from the birth defects to the Zika virus has not yet been established. These heads are six deviations below the mean, Dobyns estimates. “In these kids with Zika you see really severe microcephaly,” he said. “The heads are probably minus five to six standard deviations below the norm, and that’s really small. If the appearance of the head seems problematic, the brain is worse.” Dobyns said, based on the pictures, that some of the infants may have brains that are 10 standard deviations below the mean for age and sex. Dobyns Lab Dobyns Lab, NYT

Zika May Increase Risk of Mental Illness, Researchers Say
The Zika virus closely resembles some infectious agents that have been linked to the development of autism, bipolar disorder and schizophrenia. Schizophrenia and other debilitating mental illnesses have no single cause. The conditions are thought to arise from a combination of factors, including genetic predisposition and traumas later in life, such as sexual or physical abuse, abandonment or heavy drug use. But illnesses in utero, including viral infections, are thought to be a trigger. “The consequences of this go way beyond microcephaly,” said Dr. W. Ian Lipkin. I wouldn’t be surprised if we saw a big upswing in ADHD., autism, epilepsy and schizophrenia. We’re looking at a large group of individuals who may not be able to function in the world.” DONALD G. McNEIL Jr. NYT FEB. 18, 2016

Most, but Not All Tick-Borne Disease Symptoms Are Immune Mediated
Tick-Borne Infections Pathophysiology Causing Symptoms Immune Effects Th1 (Innate) & Th2 (Acquired) Bransfield RC.

Is Trauma from Infection from Infection or from the Host’s Immune Reaction?
Parasite Cell penetration Toxin release Incorporation of parasite genes into host genome Host Cytokine release Antibodies Inflammation Other cellular response

Schizophrenia and immunity. In: Adler R, ed. Psychoneuroimmunology.
July 10, Psychiatric Times. Vol. 26 No. 7 Tatiana Falcone, MD, Erin Carlton, MS, Kathleen Franco, MD, and Damir Janigro, PhD Inflammation, Psychosis, and the Brain New Research When the solution to a clinical or scientific puzzle eludes us for more than a century, as with schizophrenia, we need new methods to examine the pathology. If we want to make an impact on the disease we must shift research paradigms and focus on the early detection, early intervention, and new avenues of treatment that address different symptoms of schizophrenia. Immunological and blood-brain barrier (BBB) abnormalities in patients with psychosis have been repeatedly noted. Hundreds of studies of schizophrenic illness in adults have documented immunological abnormalities in these patients, and an increasing number of studies have shown a link between S100b, a marker of BBB function, and schizophrenic illness (Table).1-3 In looking at the possible causes of schizophrenia, earlier studies focused on neurons. Increasing evidence now suggests that the glia, cerebral vasculature, and the BBB may be involved. Two postmortem studies reported activated glial cells in a subgroup of patients with schizophrenia.4,5 Using the marker PK11195 to label glial cells in patients with psychosis, Hirsch6 found activation throughout the cortex using positron emission tomographic accentuation in the frontal lobes. Here we present evidence linking inflammation, immunological abnormalities, BBB disruption, and neurological disorders. BBB in health and disease The BBB is a physical and metabolic barrier that regulates and protects the brain. This barrier is composed of tight junctions between endothelial cells in CNS vessels that restrict the passage of solutes. Several lines of evidence have pointed to a link between CNS problems—such as psychiatric disorders and inflammation—that occur in response to pathogens. Impairment of the BBB may be the consequence of immunopathogenic mechanisms.7 Little is known about the microvascular endothelial cells that form the BBB. Technical difficulties and lack of specific markers for BBB endothelial cells have made this research difficult. However, with recent advances in methodological techniques, it is becoming possible to identify important characteristics of BBB endothelial cells. Integrity of the BBB reduces entry of immunocompetent cells and antibodies and is necessary for the immune system to attack infectious agents. A highly specialized tight endothelium isolates the brain from immune surveillance and allows only a few mononuclear cells, activated T cells, and macrophages to migrate into the CNS.8 During inflammation, extensive leukocyte migration occurs at the BBB.9 Both endothelial cells and astrocytes act as antigen-presenting cells to facilitate entry of T lymphocytes and antibodies. The BBB itself plays an active role in mediating the neuro-immune response. Cytokines, or cellular hormones, include neurotrophins, neuropoietic factors, interleukin (IL)-1 and IL-6, interferons (IFNs), colony-stimulating factors, growth factors, and thymic hormones that are released following stress. Perivascular macrophages, microglial cells, astrocytes, and cerebral endothelial cells can produce cyto-kines on activation.10 Cytokines influence the transport of compounds into the brain by altering the permeability of the BBB. In vitro studies reveal that the administration of IL-1, IL-6, tumor necrosis factor (TNF)-a, and IFN-g increases endothelial permeability TNF-a can induce the production of matrix metalloproteinases—in particular gelatinase B—that attack the basal lamina macromolecule-like type 4 collagen that surrounds the brain microvessels. Modulation of adhesion molecules may promote leukocyte adhesion to the cerebral endothelium and permit the migration of lymphocytes across the BBB via a transcellular route (Figure 1). Serum and cerebrospinal fluid S100b protein, inflammation, and schizophrenia There is increasing interest in the brain-specific protein S100b and its physiological roles and behavior in various neuropathological conditions. Levels of S100b, a small astrocytic calcium-binding protein, are increased in some neurological conditions, such as brain trauma, ischemia, epilepsy, and brain tumors. Increased serum levels of S100b help rule out BBB disruption as reliably as contrast-enhanced MRI and can be identified in seconds to minutes after BBB disruption. Elevated serum levels of S100b also predict the presence of neoplasms in the CNS. S100b thus serves as a noninvasive measurement of BBB function in patients and healthy persons. S100b levels are elevated in first-episode psychosis, chronic schizophrenia, and acute psychosis (Table). In 14 studies that evaluated 399 adults with schizophrenia and 389 controls, S100b concentrations were above normal: average levels were ng/mL in patients who have schizophrenia and 0.02 ng/mL in healthy controls. In a larger sample, Rothermundt and colleagues3 demonstrated the association of negative symptoms of schizophrenia with continuously elevated S100b for 24 weeks after an acute episode. Findings indicate that patients with initially elevated S100b concentrations show significantly slower improvement. Monocytosis in patients with schizophrenia Monocytosis has been reported in 5 studies. In their original observations of catatonia, Bruce and Peebles15 reported 12 cases of adolescents with psychosis and leukocytosis—particularly monocytosis. Zorrilla and colleagues16 reported monocytosis in symptomatic schizophrenic patients. Nikkila and associates17 compared cerebrospinal fluid samples obtained from schizophrenic patients and controls. The proportion of mononuclear/macrophages was significantly higher in samples taken from patients who had schizophrenia. Wilke and coworkers18 detected a statistically significant increase in leukocyte numbers, particularly monocytes (P < .05), in patients compared with controls. Kowalski and colleagues19 demonstrated activation of monocytes in 20 patients with paranoid schizophrenia and an increased serum concentration of IL-1b and TNF-a that normalized with antipsychotic treatment. Infections with different pathogens, viruses, retroviruses, and bacteria are increased across the life span of schizophrenic patients with a specific genotype. Fellerhoff and colleagues9 reported that Chlamydia stimulated the transmigration of monocytes through the BBB in 40.3% of 72 schizophrenic patients. This is a possible mechanism for monocyte activation and the inflammatory cascade.20 For example, the presence of this infection activates the inflammatory response and increases production of cytokines associated with schizophrenia. It is perhaps genotype HLA-A10 in addition to the infection that may be associated with psychotic symptoms in some schizophrenic patients. In our pilot study to analyze white blood cell abnormalities in children with psychosis, conducted from 2003 through 2006, we enrolled 102 inpatients admitted to the Cleveland Clinic Child and Adolescent Psychiatry unit. Sixteen patients who were taking anti-biotics or lithium, who had a fever on admission, or who had bipolar disorder were excluded from the sample. A total of 86 patients with a median age of 14 years participated in the study. In those patients, 2 child psychiatrists diagnosed psychosis using DSM-IV-TR criteria for psychosis not otherwise specified (NOS), schizophreniform disorder, schizoaffective disorder, or new-onset schizophrenia. Active psychosis included hallucinations, delusions, or peculiar fantasies. A group of 86 nonpsychotic patients, recruited from the same inpatient unit, served as controls. In the psychotic group, most patients had monocyte counts that were well above what is considered normal for children. The percentage of monocytes was particularly high. These findings did not correlate with drug use before admission or with therapeutic and pharmacological interventions. When comparing hematological results of these patients with those of controls, monocytosis was the most common and statistically significant finding (P < .01) (Figure 2). Prospective study of inflammatory markers in children with psychosis To further assess the role of inflammation in the pathogenesis of psychosis, we studied the relationship between S100b serum concentrations and acute psychosis in children and adolescents. Participants had been admitted to the child and adolescent inpatient psychiatry unit with a diagnosis of acute psychosis. (Psychosis NOS, schizophreniform disorder, or schizophrenia had been diagnosed in the past 6 months.) Parent(s) or guardian(s) gave consent for us to obtain blood samples. Our hypothesis was that proinflammatory changes were responsible for observed differences in the monocyte counts of the psychotic patients and that a downstream effect of monocytosis was damaging to the endothelial cells constituting the BBB. Serum samples of 10 psychotic children were compared with those of 9 healthy children. In the healthy control group, a preliminary interview had ruled out psychosis, any neurodegenerative disorder, fever, current infection, or current use of antibiotics. S100b levels were significantly higher in children with psychosis than in controls (P < .05) (Figure 3). Most psychotic children had S100b levels above normal. Nonetheless, S100b is a nonspecific measure of BBB permeability. Elevated S100b does not give insight into the mechanism of BBB disruption, and it does not prove a causal link to psychotic symptoms. Psychosis may precede elevations of S100b and BBB dysfunction. From this standpoint, S100b can still serve as a biomarker of BBB disruption. Conclusion First-episode psychosis in children is associated with evidence of increased inflammation (eg, monocytosis) and elevated serum concentrations of S100b. Several cytokines—TNF-a, IL-1b, and IL-6, among others—have been reported to be elevated in patients with schizophrenia. These inflammatory mediators are often associated with BBB leakage, which is consis-tent with animal models of schizophrenia Curiously, some antipsychotic medications have immunomodulatory effects.25 Future research may determine whether serum factors are causally related or only associated with transendothelial leakage of S100b. Our results support the inflammatory theory of schizophrenia that was formulated over a 100 years ago and perhaps offer hope that prevention of chronicity can occur if the first episode of psychosis is rapidly and effectively controlled.26 Although there are mixed results in 6 studies using anti-inflammatory medications in schizophrenic patients, Müller and colleagues27,28 believe that these agents are more likely to be effective in first-episode patients than in those with chronic schizophrenia. The missing images can be viewed on the website: Rothermundt M, Arolt V. Schizophrenia and immunity. In: Adler R, ed. Psychoneuroimmunology. Burlington, MA: Elsevier Academic Press; 2007:

Pathophysiology: What Causes Mental Symptoms in Tick-Borne Disease?
Ticks live in filth, suck blood from rodents and other wild animals and may inject multiple unidentifiable pathogens in a tick bite.

Tick-borne Pathogens Borreliosis: Borrelia burgdorferi (multiple species and strains) also B. americana, B. andersonii, B. bissettii, B. carolinensis, B. afzelii, B. garinii, B. spielmanii, B. lonestari, B. bissetti, B. kurtenbachii, B. chilensis, B. lusitaniae, B. valaisiana, B. sinica, B. bavariensis, B. finlandensis, B. japonica, B. miyamoti, B. Yangtze, B. tanukii, B. turdi Babesiosis: Babesia microti, Babesia duncani, etc. Other Piroplasm Diseases: Theileria and Cytauxzoon Ehrlichiosis: Ehrlichia chaffeensis, Anaplasma phagocytophilum, and Ehrlichia ewingii. Human Monocytic Ehrlichiosis: Ehrlichia chaffeensis Rocky Mountain Spotted Fever: Rickettsia rickettsii Tick-borne Relapsing Fever: Borrelia turicatae, B. hermsi Tularemia: Francisella tularensis Q Fever: coxiella burnetii Tick Paralysis (Tick Toxicosis): Unknown Powassan/Deer Tick Virus Encephalitis: Powassan and deer tick viruses Colorado Tick Fever: Colorado tick fever virus Southern Tick-Associated Rash Illness (STARI) or Master’s Disease : unknown Bartonellosis: Bartonella species Mycoplasosis: Mycoplasma species Tick-borne Encephalitis: Flavivirus Maculatum Disease: Rickettsia parkeri Relapsing Fever: Borrelia hermsii Rickettsia philipii Bourbom virus Who knows what else? In addition to Bb, the I. scapularis, I. pacificus and I. ricinus ticks may harbor Ehrlichiosis, Babesia microti (B. microti), and tick-borne encephalitis viruses.37 Ehrlichiosis is a generic name for a series of obligate intracellular bacteria in the family Anaplasmataceae, the best studied species consisting of Ehrlichia chaffeensis (E. chaffeensis), Anaplasma phagocytophilum (A. phagocytophilum), and Ehrlichia ewingii.37 E. chaffeensis infecting human monocytes leads to human monocytic ehrlichiosis (HME).37 A. phagocytophilum infecting human granulocytes leads to granulocytic anaplasmosis (HGA).37 E. ewingii, similar to E. chaffeensis, leads to human ewingii ehrlichiosis.37 Babesia inclusive of B. microti, WA-1 in California and Washington State, MO-1 in Missouri and and occasional cases in Europe, Africa, Asia, and South America All three tick species may simultaneous carry combinations of these same pathogens.7,34,35,478 Studies of I. scapularis demonstrated the presence of B. microti, A. phagocytophilum, and Bartonella spp.478 I. pacificus can also carry A. phagocytophilum, B. microti, and Bartonella spp..34 I. ricinus is known to harbor A. phagocytophilum, spotted fever group Rickettsia spp., Babesia spp., Bartonella birtlesii and Francisella tularensis.7,35 PCR analysis revealed Bartonella spp. in 34.5% of the ticks in northern New Jersey.36 More research is needed to determine if Bartonella spp. and other organisms found in ticks are pathogenic. Lyme borreliosis: Borrelia burgdorferi (Ixodes scapularis, Ix. pacificus) Babesiosis: Babesia microti (Ix. Scapularis) Rocky Mountain spotted fever: Rickettsia rickettsii (Dermacentor variabilis, D. andersoni, Rhipicephalus sanguineus) Maculatum disease: R. parkeri (Amblyomma maculatum, A. americanum) Human monocytotropic ehrlichiosis: Ehrlichia chaffeensis (A. americanum, D. variabilis, Ix. Pacificus) Ewingii ehrlichiosis E. ewingii (A. americanum, D. variabilis) Human granulocytotropic: anaplasmosis (Anaplasma phagocytophilum Ix. scapularis, Ix. Pacificus) Tick-borne relapsing fever: Borrelia turicatae, B. hermsi (Ornithodoros turicatae, O. hermsi) Tularemia: Francisella tularensis (D. andersoni, D. variabilis, A. americanum) Q Fever: Tick paralysis (tick toxicosis): Unknown Powassan/Deer tick virus encephalitis: Powassan and deer tick viruses (Ix. scapularis, D. andersoni) Colorado tick fever: Colorado tick fever virus (D. Andersoni) Southern tick-associated rash illness (STARI): unknown (A. americanum) Bartonellosis: Bartonella species Mycoplasosis: Mycoplasma species Who knows what else? Bransfield, Burrascano

Tick-Borne Coinfections
In addition other known and unknown tick-borne diseases such as Babesia,[1] Bartonella,[2] Ehrlichia,[3,4] Mycoplasma,[5] etc. have immune and metabolic effects that further add to the complexity of the pathophysiology of tick-borne infections. [1] Shimamoto Y et al. J Vet Med Sci Feb;74(2):241-5. [2] Maritsi DN et al. Case Rep Pediatr. 2013;2013: [3] Jarefors S, Karlsson M, Forsberg P, et al. Reduced number of interleukin-12 secreting cells in patients with Lyme borreliosis previously exposed to Anaplasma phagocytophilum. Clin Exp Immunol. 2006;143(2): [4] Grab DJ et al. Anaplasma phagocytophilum-Borrelia burgdorferi coinfection enhances chemokine, cytokine, and matrix metalloprotease expression by human brain microvascular endothelial cells. Clin Vaccine Immunol Nov;14(11): [5] Meyer Sauteur PM, Streuli JC, Iff T, Goetschel P. Klin Padiatr Jul;223(4):

Complex Interactive Infections: An Interaction of Multiple Species

Immunosupression and Co-pathogens
Luc Montagnier, the Nobel laureate, says he has never seen AIDS without secondary (apparently causative) pathogens. And neither has he seen Lyme without pathogens other than Borrelia. The secondary causative pathogens reside in the tissue Microbiome, where 99.9% of species cannot be detected with PCR or culture. Because the suppression of some innate pathways in these diseases is so complete, the co-infections can be viewed a result of the disease process, rather than the cause. To date, every penny of Lyme research money has disappeared down a deep dark hole. The only treatments available for folk with a Lyme diagnosis have come from the anecdotal observations and experience of physicians. The reason for this is that the Biologists and epidemiologists are looking in the wrong place for the pathogens causing the symptoms of Chronic Lyme. This community has told them to look at Borrelia, yet everything they come up with fails to cure the disease. Perhaps it is because Borrelia alone is not the pathogen? Luc Montagnier, the Nobel laureate, discussed this with me last October. He says he has never seen AIDS without secondary (apparently causative) pathogens. And neither has he seen Lyme without pathogens other than Borrelia. Which is exactly what I and my colleagues have been saying for over a decade now. The secondary causative pathogens are not Bartonella, or any of the microbes you can currently tests for. They reside in the tissue Microbiome, where 99.9% of species cannot be detected with PCR or culture. Targeting Borrelia nutrients is a dead-end project. It cannot result in a treatment for the disease we know as Chronic Lyme. Sincerely Trevor As Carl Tuttle remarked: "Viral load and immune suppression are other pieces of the puzzle." Almost complete innate immune suppression is necessary to allow the pathogens to persist. The more seriously ill a patient, the more seriously compromised their innate immune response, and the greater likelihood of detectable opportunistic pathogens. Because the suppression of some innate pathways in these diseases is so complete, the co-infections can be viewed a result of the disease process, rather than the cause. Trevor Marshall

Three Basic Types of Borrelia burgdorferi Infections
Three basic types of Borrelia burgdorferi infections cause neuropsychiatric symptoms: The meningovascular form associated with cerebrovascular infarcts.[1,2] The atrophic form of Lyme meningoencephalitis, associated with cortical atrophy, gliosis and dementia.[1] Infections outside the CNS causing effects within the CNS associated with neuropsychiatric symptoms. [3] [1] Miklossy J. Chronic or late lyme neuroborreliosis: analysis of evidence compared to chronic or late neurosyphilis. Open Neurol J. 2012;6: [2] Back T, et al. Neuroborreliosis-associated cerebral vasculitis: long-term outcome and health-related quality of life. J Neurol Jun;260(6): [3] Bransfield RC. The Psychoimmunology of Lyme/Tick-Borne Diseases and its Association with Neuropsychiatric Symptoms. Open Neurol J. 2012;

Progressive Infection & Inflammation is Associated with Increasing Encephalopathy & Increasing Mental Symptoms Mild Moderate Severe Executive dysfunction Increasing cognitive deficits Dementia Reduced frustration tolerance, irritability, dysthymia Anxiety disorders, major depression, impulsivity, personality disorders Major psychiatric disorders, psychosis, suicide, homicide Insomnia, decreased appetite & libido Moderately impaired sleep, eating & sexual functioning Severely impaired sleep, eating & sexual functioning Increasing Neurological, Multisystemic Symptoms & Fatigue

Lyme/TBD vs. IDSA Lyme Disease
Lyme/Tick-Borne Disease IDSA Lyme Disease Constantly evolving definition based on clinical observations & science. Pathophysiology is complex, interactive infection of multiple pathogens, opportunistic infections & other contributors. Diagnose with comprehensive clinical exam & pattern recognition. Recognition of limitations of current testing. Can be severe & chronic. Regional variability. Clinically relevant to all physicians globally. Defined by highly restrictive clinical and laboratory criteria, based on symptoms seen in a 1975 juvenile arthritis epidemic in Lyme CT & Bbsl. B-31 Shelter Island, NY USA laboratory reference strain & two-tiered testing with restrictive Dearborn criteria, “mild, never chronic & easily treated.” Limited clinical relevance. Burgdorfer, Cameron, Stricker, Philips, Liegner, Bransfield, Johnson, et al. Wormser, Steere, Shapiro, McSweegan et al.

Nomenclature Borrelia Broad Definition
IDSA Lyme Restrictive Definition Persistent Complex Interactive Infections Borrelia Broad Definition Persistent Tick-Borne Infections

Psychiatric Syndromes & Infections
The same syndrome may be caused by different infections in different individuals The same infection can cause different syndromes in different individuals Tick-borne disease can cause any psychiatric syndrome in the DSM-5

Tick Borne Diseases Peer Reviewed Articles
26,757 273 persistent infection 123 autopsies documenting persistent infection 5 psychoimmunology 300+ psychiatric illness 60 dementia 30 congenital 15 autism spectrum 5 violence

Borrelia burgdorferi: More formidable than Syphilis
132 genes plasmids 90% genes unrelated to any other know bacteria Able to adapt to many different hosts Perhaps the most complex bacteria known Borrelia: 15 million years old Treatment is challenging Only 22 genes Limited adaptive capabilities No evidence it existed before 1492 Can be effectively treated

Higher prevalence of antibodies to Borrelia burgdorferi in psychiatric patients than in healthy subjects. Hajek T, Paskova B, Janovska D, Bahbouh R, Hajek P, Libiger J, Hoschl C. Am J Psychiatry 2002 Feb;159(2): CONCLUSIONS: These findings support the hypothesis that there is an association between Borrelia burgdorferi infection and psychiatric morbidity. In countries where this infection is endemic, a proportion of psychiatric inpatients may be suffering from neuropathogenic effects of Borrelia burgdorferi. Am J Psychiatry 2002 Feb;159(2): Related Articles, Links Higher prevalence of antibodies to Borrelia burgdorferi in psychiatric patients than in healthy subjects. Hajek T, Paskova B, Janovska D, Bahbouh R, Hajek P, Libiger J, Hoschl C. Prague Psychiatric Center, Department of Epidemiology, Charles University, Third Faculty of Medicine, Czech Republic. OBJECTIVE: Borrelia burgdorferi infection can affect the CNS and mimic psychiatric disorders. It is not known whether Borrelia burgdorferi contributes to overall psychiatric morbidity. The authors compared the prevalence of antibodies to Borrelia burgdorferi in groups of psychiatric patients and healthy subjects to find out whether there is an association between this infection and psychiatric morbidity. METHOD: Between 1995 and 1999 the authors screened for antibodies to Borrelia burgdorferi in 926 psychiatric patients consecutively admitted to Prague Psychiatric Center. They compared the results of this screening with findings from 884 consecutive healthy subjects who took part in an epidemiological survey of antibodies to Borrelia burgdorferi in the general population of the Czech Republic. Sera were tested by means of enzyme-linked immunosorbent assay. Circulating immune complexes were isolated by polyethylene glycol precipitation. To control for potential confounders, the two groups of patients and healthy subjects were matched according to gender and age. Results were obtained in a sample of 499 matched pairs. RESULTS: Among the matched pairs, 166 (33%) of the psychiatric patients and 94 (19%) of the healthy comparison subjects were seropositive in at least one of the four assays. CONCLUSIONS: These findings support the hypothesis that there is an association between Borrelia burgdorferi infection and psychiatric morbidity. In countries where this infection is endemic, a proportion of psychiatric inpatients may be suffering from neuropathogenic effects of Borrelia burgdorferi. PMID: [PubMed - indexed for MEDLINE]

A Sequence of Brain Symptoms
Early symptoms are mediated by proinflammatory cytokines and include brain fog and fatigue. Another wave of symptoms are mediated by autoimmune processes and may include obsessive symptoms, tics, irritability and other symptoms. The next group of symptoms are associated with altered tryptophan metabolism, decreased serotonin, increased quinolinic acid and are associated with depression. Late stage symptoms are associated with brain inflammation and neurodegenerative changes.

Chronic Tick Borne Disease & Mental Symptoms
Encephalopathy 89%, Memory Loss 81%, Fatigue 74%, Depression 37%, Extreme irritability, 26% [Logigian EL et al. 1990] Attention/Concentration, 77%, Memory Complaints 65%, Mental Fatigue 70%, Depression 37%, Anger/Irritability 53%, Rages/ Explosive Behavior 25%, Anxiety/Panic Attacks 54% [Shea 2013] Cognitive impairment 92%, fatigue 94%, sleep impairment 92%, depression 64%, [Johnson L, Wilcox S, Mankoff J, Stricker RB. 2014] Memory loss 63%, Poor concentration 60%, Difficulty finding words 46%, Confusion 44%, Inattention 44%, Fatigue 88%, Sleep disturbances 66%, Mood swings 47%, Irritability 47%. [Lobraico J et al. 2014] Impairments of reasoning (93%), memory (92%) and attention (91%), with speaking (75%), listening (73%), reading and/or writing (79%) [Molrine CJ 2015]

What Provokes & Weakens the Immune System?
Infections Cancer Allergens Stress Early life stress Sleep deprivation Vaccinations Trauma Toxins Degenerative changes T cell dysfunction Smoking Foehn, barometric pressure drops Molecular mimicry Low glutathione levels Increased oxidative stress Metal toxicity Elevated leptin levels Obesity Sedentary lifestyle Poor diet Leaky gut Some medical treatments

What Supports the Association?
Inflammatory agents induce mental symptoms Inflammatory markers are elevated in mental disorders. Biochemistry Immune dysfunction adversely impact brain development. Psychotropics are anti-inflammatory. Boorman E et al. Psychiatric Annals. 2015;45(5):

Neuroinflammation Definition
The inflammatory response is an early, non-specific immune reaction to tissue damage or pathogen invasion. Inflammation of the central nervous system (CNS) is characterized by increased glial activation, pro-inflammatory cytokine concentration, blood-brain-barrier permeability, and leukocyte invasion. Interleukin (IL)-1 is up-regulated in neurodegenerative disorders leading to NFkB-dependent transcription of pro-inflammatory cytokines (tumor necrosis factor (TNF)-alpha, IL-6, and interferons) and neutrophil-recruiting chemokines (CXCL1 and CXCL2) in glia.

Hepatitis C & Interferon Treatment
A good model for inflammation mediated mental symptoms Cognitive impairments Symptoms include depression, anxiety, mania, irritability, impulsiveness, hostility, relapse of substance abuse & lassitude.[1] [1] Henry, Castera, Demotes-Mainard

Sickness Syndrome Resembles Depression
(Mediated by Proinflammatory Cytokines IL-1, IL-6, and TNF) Anhedonia Malaise Weakness Cytokines Induce Sickness Behavior Hypersomnia Poor Concentration Anorexia Social Withdrawal Musselman DL, et al. N Engl J Med 2001;344:

Are Mood and Anxiety Disorders Inflammatory Diseases?
Studies demonstrate increases in inflammatory markers in: Sleep deprivation: IL-6 [1] Stress: IL-1 beta, TNF-alpha, IL-6 [2] PTSD: IL-1 beta, IL-6, TNF-alpha [3] Depression: IL-6, CRP, IL-1, TNF-alpha [3] Bipolar: IL-6, TNF-alpha, CRP, sIL-2R, sIL-6R [3] Schizophrenia: IL-6, IL-1 beta [4] Autism: IL-6, autoimmune mechanisms [5] Alzheimer’s: IL-6, TNF-, IL-1, TGF-, IL-12 and IL-18 [6] [1] M. Haack, E. Sanchez, J. Broussard, M. Regan, J. Mullington. J Pain. 2004;5(3) [2] Raison et al, Arch Gen Psychiatry. 2010;67(12): [3] Boorman E et al. Psychiatric Annals. 2015;45(5): [4] Schwieler L, et al. J Psychiatry Neurosci Mar;40(2):126-33 [5] Bransfield R. Pediatric Health. 3(2): (2009) [6] Swardfager W, et al. BIOL PSYCHIATRY 2010.

Cytokine Activation Causes Psychiatric Symptoms
Interleukin-6 Is Elevated in the Cerebrospinal Fluid of Suicide Attempters and Related to Symptom Severity (1) Interluken-1Beta & Self-Inflicted Aggressive Behavior (2) Interluken-1Beta Causes Fatigue (3) (1) Lindqvist D, Janelidze S, Hagell P, Erhardt S, Samuelsson M, Minthon L, Hansson O, Björkqvist M, Träskman-Bendz L, Brundin L. Biol Psychiatry Mar 6. [Epub] Lindqvist D. 10th Psychoimmunology Expert’s Meeting, Gunzburg, 2009. (2) Westling S et al. 10th Psychoimmunology Expert’s Meeting, Gunzburg 2009. (3) Corwin et al. Ann Behav Med 2003;25:41-47.

Suicide, Aggression and Bb infections
18% of post-Lyme patients have suicidal ideation.[1] Aggressiveness has also been associated with Lyme/tick-borne disease. [2,3,4,5,6] Both symptoms may be immune mediated. [6,7,8] [1]Fallon BA. Challenges and Controversy in Lyme Disease and Tick Borne Illness Care Symposium. Unpublished data. Massachusetts General Hospital. November 9, 2013 [2] Fallon BA, Nields JA, Burrascano JJ, Liegner K, DelBene D, Liebowitz MD, “The neuropsychiatric manifestations of Lyme borreliosis” Psychiatric Quarterly 1992; 3(1): [3] Fallon BA, Nields JA, “Lyme disease: A Neuropsychiatric Illness” American Journal of Psychiatry 1994; [4] Fallon BD, Schwartzenberg M, Bransfield R, Zimmerman B, Scotti A, Weber CA, Liebowitz MR, “Late stage neuropsychiatric Lyme borreliosis” Psychosomatics 1995;36(3): [5]Bransfield RC, “Diagnosis, Treatment, and Prevention of Lyme Disease” JAMA, Sept.23/ [6] Bransfield RC. Can infections and immune reactions to them cause violent behavior? Neurology, Psychiatry and Brain Research. 2012;18(2):42. [7] Bransfield RC. The psychoimmunology of lyme/tick-borne diseases and its association with neuropsychiatric symptoms. Open Neurol J. 2012;6:88-93. [8] Coccaro EF, Lee R. Elevated Plasma Inflammatory Markers in Individuals With Intermittent Explosive Disorder and Correlation With Aggression in Humans. JAMA Psychiatry. 2013

Meta-Analysis of Cytokines and Chemokines in Suicidality: Distinguishing Suicidal Versus Nonsuicidal Patients BACKGROUND: Major psychiatric disorders are associated with inflammation. Aberrant cytokine and chemokine levels have been associated with psychiatric disorders and suicidal behavior. RESULTS: 18 studies comprising 583 patients with suicidality, 315 patients without suicidality, and 845 healthy control subjects. We found evidence for aberrant cytokine levels in blood, cerebrospinal fluid, and postmortem brain samples of patients with suicidality. Levels of IL-1β and IL-6 were most robustly associated with suicidality, and these cytokines may help distinguish suicidal from non-suicidal patients. In vitro IL-2 production by peripheral blood mononuclear cells was significantly decreased in patients with suicidality compared with both patients without suicidality and healthy controls (p < .01 for each). Cerebrospinal fluid levels of IL-8 were significantly decreased in patients with suicidality versus control subjects (p < .05). Biol Psychiatry Jul 1;78(1): doi: /j.biopsych Epub 2014 Oct 30. Meta-Analysis of Cytokines and Chemokines in Suicidality: Distinguishing Suicidal Versus Nonsuicidal Patients. Black C(1), Miller BJ(2). Author information: (1)Medical College of Georgia, Georgia Regents University, Augusta, Georgia. (2)Department of Psychiatry and Health Behavior, Georgia Regents University, Augusta, Georgia.. Electronic address: BACKGROUND: Major psychiatric disorders are associated with inflammation. Aberrant cytokine and chemokine levels have been associated with psychiatric disorders and suicidal behavior. We performed a meta-analysis of cytokine and chemokine levels in patients with versus without suicidality and patients with suicidality versus healthy controls. METHODS: We identified articles by searching MEDLINE, PsycINFO, and Thomson Reuters Web of Knowledge databases and the reference lists of identified studies. RESULTS: Study inclusion criteria were met by 18 studies comprising 583 patients with suicidality, 315 patients without suicidality, and 845 healthy control subjects. Levels of interleukin (IL)-1β and IL-6 were significantly increased in blood and postmortem brain samples of patients with suicidality compared with both patients without suicidality and healthy control subjects (p < .05 for each). In vitro IL-2 production by peripheral blood mononuclear cells was significantly decreased in patients with suicidality compared with both patients without suicidality and healthy controls (p < .01 for each). Cerebrospinal fluid levels of IL-8 were significantly decreased in patients with suicidality versus control subjects (p < .05). CONCLUSIONS: We found evidence for aberrant cytokine levels in blood, cerebrospinal fluid, and postmortem brain samples of patients with suicidality. Levels of IL-1β and IL-6 were most robustly associated with suicidality, and these cytokines may help distinguish suicidal from nonsuicidal patients. Rigorously designed longitudinal studies are needed to evaluate these associations further. Black C, Miller BJ. Biol Psychiatry Jul 1;78(1):28-37.

Inflammation in neurodegenerative diseases
Neurodegeneration, the slow and progressive dysfunction and loss of neurons and axons in the central nervous system, is the primary pathological feature of acute and chronic neurodegenerative conditions such as Alzheimer's disease and Parkinson's disease, neurotropic viral infections, stroke, paraneoplastic disorders, traumatic brain injury and multiple sclerosis. Despite different triggering events, a common feature is chronic immune activation, in particular of microglia, the resident macrophages of the central nervous system. Immunology Volume129, Issue2, Inflammation in neurodegenerative diseases Sandra Amor, Fabiola Puentes, David Baker, Paul van der Valk ABSTRACT SummaryNeurodegeneration, the slow and progressive dysfunction and loss of neurons and axons in the central nervous system, is the primary pathological feature of acute and chronic neurodegenerative conditions such as Alzheimer's disease and Parkinson's disease, neurotropic viral infections, stroke, paraneoplastic disorders, traumatic brain injury and multiple sclerosis. Despite different triggering events, a common feature is chronic immune activation, in particular of microglia, the resident macrophages of the central nervous system. Apart from the pathogenic role of immune responses, emerging evidence indicates that immune responses are also critical for neuroregeneration. Here, we review the impact of innate and adaptive immune responses on the central nervous system in autoimmune, viral and other neurodegenerative disorders, and discuss their contribution to either damage or repair. We also discuss potential therapies aimed at the immune responses within the central nervous system. A better understanding of the interaction between the immune and nervous systems will be crucial to either target pathogenic responses, or augment the beneficial effects of immune responses as a strategy to intervene in chronic neurodegenerative diseases. Sandra Amor, Fabiola Puentes, David Baker, Paul van der Valk. Immunology. Vol 129, Issue2,2010.

LATE-STAGE IMMUNE CNS EFFECTS
Mechanisms leading to the injury of neuronal cells include: The secretion of cytotoxic substances by leucocytes and glial cells Direct cytotoxicity Autoimmune-triggered processes via molecular mimicry An interaction between pathogens and the neural cells can cause dysfunction by adherence, invasion, and cytotoxicicity of neural cells. Bransfield RC. Relationship of Inflammation and Autoimmunity to Psychiatric Sequelae in Lyme Disease. Psychiatric Annals. 42(9): September 2012.

Balanced Inflammation
Inflammation could have a protective role and promote regeneration of damaged neurons. We do not yet know how to achieve a "balanced" inflammation. Because some novel anti-inflammatory treatment might have detrimental consequences, carefully monitoring disease progress in patients treated with this category of drugs is indispensable. A variety of neurological diseases the initial triggers differ significantly, while the subsequent pathways involving inflammatory processes and causing brain damage share certain pathological mechanisms. Aktas, O. et al. Arch Neurol 2007;64:

No Adaptive Immunity with Some Infections
Acute infections are usually associated with an early inflammatory reaction followed by adaptive immunity and a resolution of symptoms, but in some chronic infections that evade and suppress the immune system this progression does not always occur. Instead, inflammation can persist without adaptive immunity, autoimmune symptoms may occur, and reinfections are common.

The immune system cannot generate immunological memory during infection with B. burgdorferi
“Our data demonstrate that Bb infection suppresses the development of long-lived antibody production and immunological memory formation and indicates that Bb may achieve this by suppressing the function and/or causing the rapid and global collapse of germinal centers.” “Antibodies disappear rapidly when infection is controlled by antibiotic treatment.” In vertebrates including humans, mice and dogs, the bacteria Borrelia burgdorferi (Bb) causes a chronic, non-resolving infection known as Lyme disease, which requires antibiotic treatment to clear the bacteria. Re-infections are common in endemic regions. Similarly, mice can be re-infected with the same strain of Bb, implying a lack of functional immune responses. The mechanisms underlying this lack of effective short and long-term immunity to Bb are unknown. Using a mouse model of Bb-infection we show that infection with Bb produces strong T-dependent and T-independent serum antibodies, characterized by the unusual continued presence of IgM. Remarkably, both T-dependent and T-independent antibodies disappear rapidly when infection is controlled by antibiotic treatment and Bb-specific memory B cells could not be recovered. Thus, maintenance of Bb-specific humoral responses requires ongoing infections. Histological and flow cytometric examination of germinal centers, birthplaces of long-term humoral immunity, demonstrate their induction within 2 weeks of a primary infection and the presence of germinal center follicular helper T and B cells. However, the apparent normal induction of germinal centers is followed by their rapid and global collapse in multiple lymphoid organs by day 45. To determine whether the lack of memory formation is due to the nature of the Bb-antigens or is a sign of Bb-infection-mediated immune suppression, we vaccinated mice with influenza virus during an ongoing Bb-infection. Remarkably, in Bb infected mice the early antibody response to this unrelated antigen was skewed towards increased IgM production compared to that in non-infected mice, and influenza specific IgG responses were strongly reduced. Together our data demonstrate that Bb infection suppresses the development of long-lived antibody production and immunological memory formation and indicates that Bb may achieve this by suppressing the function and/or causing the rapid and global collapse of germinal centers. Supported by NIH AI and T32 AI R.A. Elsner, S.W. Barthold, N. Baumgarth. Cytokine Vol. 63(3), 2013, P 261

M Embers, MT Philipp et al, Microbes and Infection, 2004 Survival strategies of
Borrelia burgdorferi, the etiologic agent of Lyme disease

TBD Pathophysiology is a Failure to Shift from Inflammation to Adaptive Immunity
Persisting immune activation causes the cytokine storm in chronic TBD. In these patients, the innate immune system is not turned off by a series of specific immune peptides. Specific genetic types are more prone to this phenomenon. Since reinfections are common, adaptive immunity may not occur. [1,2,3] Aberrant immune reactions are most likely the result of persistent infection causing persisting immune provocation.[4] Dr. Karen Newell, lead investigator and immunologist, has found that persisting immune activation is at the root cause of the cytokine storm that typifies active chronic Lyme. Apparently, the innate immune system, which is designed as a rapid attack but non-specific response to infectious invaders, is supposed to turn off when specific immunity develops. In those with persisting Lyme, the innate immune system does not turn off. There are a variety of reasons for this, most of which are host related. The signal from the immune system that is supposed to turn off the innate response is a series of specific immune peptides, which do not turn off the signal in these patients. She has been able to identify and synthesize these peptides, specific to the person and to the infection, thanks to a complex computer program developed with her son, a computer guy. She has already demonstrated efficacy of this approach in Lyme in the rodent model. Now you ask, why, if Lyme is an infection, is it being treated with immune modulation? The answer is both simple and complex. Many know I believe that we probably cannot totally "cure" chronic Lyme, in that some Bb persist despite treatment. It is those people whose immune system can contain these spirochetes without excessive cytokine activity who recover. Those people whose spirochete load is too high for containment, or whose immune system is too weak to contain it do have ongoing active symptoms. A corollary of this is that subset of people who have a defect in the peptide system as studied by Dr. Newell who cannot turn off the innate immune system despite very small or even absent Bb loads that go on to remain chronically ill. The work of Dr. Ritchie Shoemaker and others who clearly have demonstrated that specific genetic types are more prone to chronic disease probably relates to the phenomenon that Dr. Newell has discovered. The computer program I mentioned above takes into account the patient's HL-A type as well as the infecting organism and then designs a peptide that will exactly work to normalize the immune response. An interesting observation is that once the overactive innate immune system is toned down, then the specific immune response works better, and actually helps to better contain the infection. This work has already been done with HIV infection, and there are patients in the series who have HIV, but not AIDS despite no anti-retroviral therapy, as long as they receive peptide treatment. Apparently the work with Lyme is following a similar path. I am so happy that two Lyme groups, Time for Lyme and Turn the Corner Foundation, have been responsible for funding this fabulous work. I look forward to the clinical trials. I hope this info helps explain peptide therapy. Dr. B ! [1] Newell K. [2] Elsner RA, Barthold SW, Baumgarth N. Cytokine Vol. 63(3), 2013, P 261 [3] Elsner RA, Hastey CJ, Olsen KJ, Baumgarth N. Suppression of Long-Lived Humoral Immunity Following Borrelia burgdorferi Infection. PLoS Pathog Jul 2;11(7) [4] Berndtson K. Review of evidence for immune evasion and persistent infection in Lyme disease. Int J Gen Med. (2013) 23;6:

Self Perpetuating Post Infection Immune Process?
Some do not believe in chronic persistent infections and speculate that persistent immune mediated symptoms following an infection are associated with a self-perpetuating immune process that continues after the infection has cleared. However, no self-perpetuating immune process without persistent infection has ever been scientifically proven.

Persistent Infection with TBD Disease
Controversy persists over the existence of chronic TBD disease due to persistent infection with B. burgdorferi in patients who are untreated or undertreated for the spirochetal illness (Berndtson, 2013; Stricker and Johnson, 2013). A growing body of clinical and research evidence supports persistent symptomatic infection with the Bb spirochete (Miklossy, 2012; Berndtson,2013; Ljøstad and Mygland, 2013; Stricker and Johnson, 2013).[1,2] A list of 273 peer reviewed articles supporting persistence of infection is available upon request.[3] Persistence of Lyme Disease The following references for persistence of Lyme disease (Lyme borreliosis) are listed alphabetically and chronologically: Aalto A, Sjowall J, Davidsson L, Forsberg P, Smedby O. Brain magnetic resonance imaging does not contribute to the diagnosis of chronic neuroborreliosis. Acta Radiol 2007; 48: [white matter hyperintensities or basal ganglia lesions]. Abele DC and Anders KH. The many faces and phases of borreliosis. J Am Acad Dermotol 1990; 23: [chronic Lyme borreliosis]. Aberer E and Klade H. Cutaneous manifestations of Lyme borreliosis. Infection 1991; 19: [chronic Lyme borreliosis]. Aberer E, Breier F, Stanek G, and Schmidt B. Success and failure in the treatment of acrodermatitis chronica atrophicans skin rash. Infection 1996; 24: Aberer E, Kersten A, Klade H, Poitschek C, Jurecka W. Heterogeneity of Borrelia burgdorferi in the skin. Am J Dermatopathol 1996; 18(6): Akin E, McHugh Gl, Flavell RA, Fikrig E, Steere AC. The immunoglobulin (IgG) antibody response to OspA and OspB correlates with severe and prolonged Lyme arthritis and the IgG response to P35 with mild and brief arthritis. Infect Immun 1999; 67: Albert S, Schulze J, Riegel H, Brade V. Lyme arthritis in a 12-year-old patient after a latency period of 5 years. Infection 1999; 27(4-5): Al-Robaiy S, Dihazi H, Kacza J, et al. Metamorphosis of Borrelia burgdorferi organisms―RNA, lipid and protein composition in context with the spirochete’s shape. J Basic Microbiol 2010, 50 Suppl 1, S5-17. Appel MJG, Allan S, Jacobson RH, Lauderdale TL, Chang YF, Shin SJ, Thomford JW, Todhunter RJ, and Summers BA. Experimental Lyme disease in dogs produces arthritis and persistent infection. J Inf Dis 1993; 167: Åsbrink E, Hovmark A. Successful cultivation of spirochetes from skin lesions of patients with erythema chronicum migrans, Afzelius and acrodermatis chronica atrophicans. Acta Pathol Microbiol Immunol Sect B 1985; 93: Åsbrink E, Hovmark A, and Olsson I. Clinical manifestations of acrodermatitis chronica atrophicans in 50 Swedish patients. Zentralbl Bakteriol Mikrobiol Hyg A 1986; 26: [chronic Lyme borreliosis]. Asch ES, Bujak DI, Weiss M, Peterson MGE, and Weinstein A. Lyme Disease: an infectious and postinfectious syndrome. J Rheumatol 1994; 21 (3): Bankhead T and Chaconas G. The role of VlsE antigenic variation in the Lyme disease spirochete: persistence through a mechanism that differs from other pathogens. Molecular Microbiology 2007; 65: Barthold SW, Persing DH, Armstrong AL, and Peeples RA. Kinetics of Borrelia burgdorferi dissemination and evolution of disease following intradermal inoculation of mice. Am J Pathol 1991; 139: [in mice] Barthold SW, deSouza MS, Janotka JL, Smith AL, and Persing DH. Chronic Lyme borreliosis in laboratory mouse. Am J Pathol 1993; 143: [in mice] Barthold S. Lyme Borreliosis. Chapter 14, In Persistent Bacterial Infections. Edited by J.P. Nataro, M.J. Blaser, and S. Cunningham-Rundles, pp ASM Press, Washington, D.C. Barthold SW, Hodzic E, Imai DM, Feng S, Yang X, and Luft BJ. Ineffectiveness of tigecycline against persistent Borrelia burgdorferi. Antimicrob Agents Chemother 2010; 54(2): [Persistence is listed for many reservoir-competent hosts: mice, rats, Peromyscus leucopus, hamsters, gerbils, rabbits, dogs, nonhuman primates, and humans] Battafarano DF, Combs JA, Enzenauer RJ, Fitzpatrick JE. Chronic septic arthritis caused by Borrelia burgdorferi. Clin Orthop 1993; 297: [Patients with chronic septic Lyme arthritis of the knee for seven years, despite multiple antibiotic trials and synovectomies. Bb documented in synovium and synovial fluid.] Bayer ME, Zhang L, Bayer MH. Borrelia burgdorferi DNA in the urine of treated patients with chronic Lyme disease symptoms. A PCR study of 97 cases. Infection 1996; 24: [97 patients who had been treated with antibiotics for extended periods of time and had symptoms of chronic Lyme were PCR-positive.] Benjamin J and J Luft. Chronic Lyme disease; an evolving syndrome. 9th Annual International Scientific Conference on Lyme Disease & Other Tick-Borne Disorders Berglund J, Stjernberg L, Ornstein K, Tykesson-Joelsson K, Walter H. 5-y follow-up study of patients with neuroborreliosis. Scand. J. Infect. Dis. 2002; 34(6): Bloom BJ, Wyckoff PM, Meissner HC, and Steere AC. Neurocognitive abnormalities in children after classic manifestations of Lyme disease. Pediatric Infect. Dis. J. 1998; 17(3): Bradley JF, Johnson RC, Goodman JL. The persistence of spirochetal nucleic acids in active Lyme arthritis. Ann Intern Med 1994; 120: 487. Bransfield R, Brand S, and Sherr V. Treatment of patients with persistent symptoms and a history of Lyme disease. N Engl Med 2001; 345: Breier F, Khanakah G, Stanek G, Aberer E, Schmidt B, and Tappeiner G. Isolation and polymerase chain reaction typing of Borrelia afzelii from a skin lesion in a seronegative patient with generalized ulcerating bullous lichen sclerosus et atrophicus. Br J Dermatol 2001; 144: [Borrelia afzelii, ulcerating lichen sclerosus et atrophicus]. [Despite treatment with four courses of ceftriaxone, “[s’pirochetes were isolated from skin cultures obtained from enlarging LSA lesion…[S]erology …was repeatedly negative.] Bockenstedt LK, J Mao, E Hodzic, SW Barthold, and D Fish. Detection of attenuated, noninfectious spirochetes in Borrelia burgdorferi-infected mice after antibiotic treatment. J Infect Dis 2002; 186: [in mice] Brorson O and Brorson S-H. Transformation of cystic forms of Borrelia burgdorferi to normal mobile spirochetes. Infection. 1997; 25: [change in physical characteristics; change of spirochetes to other pleomorphic forms, i.e., cell wall deficient forms, namely cysts.] Brorson O and Brorson S. In vitro conversion of Borrelia burgdorferi to cystic forms in spinal fluid, and transformation to mobile spirochetes by incubation in BSK-H medium. Infection. 1998; 26: [change in physical characteristics; change of spirochetes to other pleomorphic forms, i.e., cell wall deficient forms, namely cysts.] Brorson O and Brorson S-H. An in vitro study of the susceptibility of mobile and cystic forms of Borrelia burgdorferi to tinidazole. International Microbiol 2004; 7: Brown JP, Zachary JF, Teuscher C, Weis JJ, and Wooten M. Dual role of interleukin-10 in murine Lyme disease: regulation of arthritis severity and host defense. Infect Immun 1999; 67: [suppression of harmful immune responses: defense stratagem of B. burgdorferi] Burrascano J. Failure of aggressive antibiotic therapy to protect the placenta from invasion by B. burgdorferi in a pregnant patient with Lyme borreliosis. 6th Annual International Science Conference on Lyme Disease and other Tick-borne Diseases.1993. Cabello FC, Godfrey HP, and Newman SA. Hidden in plain sight: Borrelia burgdorferi and the extracellular matrix. Trends in Microbiology 2007; 15: [sequestration] Cadavid D, O’Neill T, Schaefer H, and Pachner AR. Localization of Borrelia burgdorferi in the nervous system and organs in a nonhuman primate model of Lyme disease. Lab Invest 2000; 80: Cadavid D, Y Bai, E Hodzic, K Narayan, SW Barthold, and Pachner AR. Cardiac involvement in non-human primates infected with the Lyme disease spirochete Borrelia burgdorferi. Lab Invest 2004; 84: [in monkeys] Cameron D, Gaito A, Harris N et al. Evidence-based guidelines for the management of Lyme disease. Expert Rev Anti-Infect. Ther 2004; 2 (Suppl. 1), S1-S13. Cameron D. Results from Lyme disease treatment trial. Columbia University/LDA Conference, Lyme & Other Tick-Borne Diseases: Emerging Tick-Borne Diseases. October 28, 2005; Philadelphia, Pennsylvania. Cameron DJ. Generalizability in two clinic trials of Lyme disease. Perspectives and Innovation 2006; 3(12). [ Cameron D. Severity of Lyme disease with persistent symptoms. Insights from a double-blind placebo-controlled clinical trial. Minerva Med 2008; 99: Cameron DJ. Insufficient evidence to deny antibiotic treatment to chronic Lyme disease patients. Med Hypotheses (2009), doi: i/j.mehy Cameron DJ. Proof that Lyme disease exists [ Cameron DJ. Proof that chronic Lyme disease exists. Interdisciplinary Perspect Infect Dis doi: /2010/ Cimmino MA, Azzolini A, Tobia F, Pesce CM. Spirochetes in the spleen of a patient with chronic Lyme disease. Am J Clin Pathol 1989; 91(1): Chary-Valckenaere I, Jaulhac B, Champigneulle J, Piement Y, Mainard D, and Pourel J. Ultrastructural demonstration of intracellular localization of Borrelia burgdorferi in Lyme arthritis. Br J Rheumatol 1998; 37: Chmielewski T, Tylewlska-Wierzhanowska S. Inhibition of fibroblast apoptosis by Borrelia afzelii, Coxiella burnetii and Bartonella henselae. Poll Microbiol 2011; 60(3); Clarke AE, Esdaile JM, Bloch DA, Lacaille D, Danoff, and Fries JF. A Canadian study of the total medical costs for patients with systemic lupus erythema and the predictors of costs. Arthrit. Rheum. 1993; 36(11): Cleveland CP, Dennler PS, Duray PH. Recurrence of Lyme disease presenting as a chest wall mass: Borrelia burgdorferi was present despite five months of IV ceftriaxone 2 g, and three months of oral cefixime 400 mg BID. The presence of Borrelia burgdorferi confirmed by biopsy and culture. Poster presentation at V Lyme Disease Foundation International Scientific Conference. Stamford, CT, April 10-11, 1992. Cleveland CP, and Dennler S. Case history: recurrence of Lyme disease as a chest wall mass. Abstract presented at the 1993 LDF International Conference on Lyme Disease. Coyle P. Lyme Disease. Mosby Year Book, pp. 235, St Louis, Mo. [seclusion into immune privileged sites: defense strategem of B. burgdorferi] Dattwyler RJ, Volkman DJ, Luft BJ, Halperin JJ, Thomas J, and Golightly MG. Seronegative Lyme disease. Dissociation of specific T- and B-lymphocyte response to Borrelia burgdorferi. N Engl J Med 1988; 319(22): Dejmková H, D Hulinska, D Tegzová, K Pavelka, J Gatterová, and P Vavřik. Seronegative Lyme arthritis caused by Borrelia garinii. Clin Rheumatol 2002; 21: DeLong AK, Blossom B, Maloney E, and Phillips SE. Antibiotic retreatment of Lyme disease in patients with persistent symptoms: A biostatistical review of randomized, placebo-controlled, clinical trials. Contemp Clin Trials 2012; epub ahead of print. [refutes Klempers {2001} conjecture that long-term antibiotics don’t work] de Koning J, et al. Demonstration of spirochetes in cardiac biopsies of patients with Lyme disease. J. Infect. Dis. 1989; 160: [intracellar sanctuaries of Bb] Demaershalck I, Messaoud AB, de Kesel M, Hoyois B, Lobet Y, Hoet P, Bigaignon G, Bollen A, and Godfroid E. Simultaneous presence of different Borrelia burgdorferi genospecies in biological fluids of Lyme disease patients. J Clin Microbiol 1995: 33; Diringer MN, Halperin JJ, and Dattwyler RJ. Lyme meningoencephalitis―report of a severe, penicillin resistant case. Arthritis Rheum 1987; 30: Diterich I, Rauter C, Kirschning CJ, and Hartung T. Borrelia burgdorferi-induced tolerance as a model of persistence via immunosuppression. Infect Immun 2003; 71(7): Donta ST. Tetracycline therapy for chronic Lyme disease. Clin Inf Dis 1997; 25 (Suppl 1);S52-56. Donta ST. The existence of chronic Lyme disease. Curr Treat Op Infect Dis 2001; 3: Donta ST. Late and chronic Lyme disease. Med Clin North Am 2002; 86: Donta ST. Macrolide therapy of chronic Lyme disease. Med Sci Monit 2003; 9: Dorward DW, Fischer ER, and Brooks DM. Invasion and cytopathic killing of human lymphocytes by spirochetes causing Lyme disease. Clin. Infect. Dis Suppl 1: S2-8. [intracellular sanctuaries of Bb] Dunham-Ems SM, Caimano MJ, Pal U, et al. Live imaging reveals a biphasic mode of dissemination of Borrelia burgdorferi within ticks. J. Clin Invest. 2009; 119: [biofilms consist of a colony of spirochetes and cysts coated by a gelatinous, protective membrane] Duray PH The surgical pathology of human Lyme disease. An enlarging picture. Am J Surg Pathol S1: [Bb in brain] Duray PH and Steere AC. Clinical pathologic correlations of Lyme disease by stage. Ann N Y Acad Sci 1988; 539: Duray PH, et al. Invasion of human tissue ex vivo by Borrelia burgdorferi. J. Infect. Dis (10): Durovska J, Bazovska S, Ondrisova M, and Pancak J Our experience with examination of antibodies against antigens of Borrelia burgdorferi in patients with suspected Lyme disease. Bratist. Lek. Listy 2010; 111(3): Dvorakova J, and Celer V. [Pharmacological aspects of Lyme borreliosis] Seska Slov Farm. 2004(Jul); 53(4): Ebel GD, Campbell EN, Goethert HK, Spielman A, and Telford SR. Enzootic transmission of deer tick virus in New England and Wisconsin sites. Am. J. Trop. Med. Hyg. 2000; 63(1-2): Ekdahl KN, Henningsson AJ, Sandholm K, Forsberg P, Ernerudh J, Ekerfelt C; Immunity in borreliosis with special emphasis on the role of complement. Adv Exp Med Biol 2007; 598: Embers ME, SW Barthold, JT Borda, L Bowers, L Doyle, E Hodzic, MB Jacobs, NR Hasenkampf, DS Martin, S. Narasimhan, KM Phillippi-Falkenstein, JE Purcell, MS Ratterree, and MT Philipp. Persistence of Borrelia burgdorferi in rhesus macaques following antibiotic treatment of disseminated infection. PLoS ONE 7(1): e doi: /journal.pone (2012) [Bb was cultured from rhesus macques after antibiotic treatment and confirmed by PCR.] Fallon BA, Schwartzberg M, Bransfield R, Zimmerman B, Scotti A, Weber CA, and Liebowitz MR. Late-stage neuropsychiatric Lyme borreliosis. Case reports. Psychosomatics 1995; 36: Fallon BA, Das S, Plutchok JJ, Tager F, Liegner K, Van Heertum R. Functional brain imaging and neuropsychological testing in Lyme disease. Clin Infect Dis 1997; 25 (suppl 1): S57-S63. Fallon BA, et al. Repeated antibiotic treatment in chronic Lyme disease. J Spir Tick Borne Dis. 1999; 6: Fallon BA, Keilp J, Prohovnik I, Heertum RV, Mann JJ. Regional cerebral blood flow and cognitive deficits in chronic Lyme disease. J Neuropsychiatry Clin Neurosci 2003; 15: Fallon BA, Keilp JG, Corbera KM, Petkova K, Britton CB, Dwyer E, et al. A randomized, placebo-controlled trial of repeated IV antibiotic therapy for Lyme encephalopathy. Neurology 2008; 70: Fallon BA, Lipkin RB, Corbera KM, Yu S, Nobler MS, Keilp JG, Petkova E, Lisanby SH, Moeller JR, Slavov I, Van Heertum R, Mensh BD, and Sackeim HA. Regional cerebral blood flow and metabolic rate in persistent Lyme encephalopathy. Arch Gen Psychiatry 2009; 66: Feder Jr., HM and Whitaker DL. Misdiagnosis of erythema migrans. Am. J. Med. 1995; 99: Fein L, and Tilton RC. Bone marrow as a source for Borrelia burgdorferi DNA. J Spir Tick-borne Dis 1997; 4: Ferris J, et al. Lyme borreliosis. [letter] Lancet 1995; 345: Franz JK, O Fritze, M Rittig et al. Insights from a novel three-dimensional in vitro model of Lyme arthritis: standardized analysis of cellular and molecular interactions between Borrelia burgdorferi and synovial explants and fibroblasts. Arthritis Rheum 2001; 44: Fraser DD, Kong LI, and Miller FW. Molecular detection of persistent Borrelia burgdorferi in a man with dermatomyositis. Clinical and Experimental Rheumatology 1992; 10: Frey M, Jaulhac B, Piemont Y, Marcellin L, Boohs PM, Vautravers P, Jesel M, Kuntz JL, Monteil H, and Sibilia J. Detection of Borrelia burgdorferi DNA in muscle of patients with chronic myalgia related to Lyme disease. Am J Med 1988; 104: Fried MD, Duray P. Gastrointestinal disease in children with persistent Lyme disease: spirochetes isolated form the G.I. tract. IX Lyme Disease Foundation International Scientific Conference, Boston, MA, April 19-20, 1996. Garcia-Monco JC, Benach JL. The pathogenesis of Lyme disease. Rheum Dis Clin North Am 1989; 15: Georgilis K, Peacocke M, and Klempner MS. Fibroblasts protect the Lyme disease spirochete, Borrelia burgdorferi, from ceftriaxone in vitro. J Infect Dis 1992; 166: Giambartolomei GH, Dennis VA, and Philipp MT. Borrelia burgdorferi stimulates the production of interleukin-10 in peripheral blood mononuclear cells from uninfected humans and rhesus monkeys. Infect Immun 1998; 66: [suppression of harmful immune responses: defense stratagem of B. burgdorferi] Girschick HJ, Huppertz HI, Rüssmann H, Krenn V, and Karch H. Intracellular persistence of Borrelia burgdorferi in human synovial cells. Rheumatol Int 1996; 16: [intracellar sanctuaries of Bb] Goodman JL, Jurkovich P, Kodner C, and Johnson RC. Persistent cardiac and urinary tract infections with Borrelia burgdorferi in experimentally infected Syrian hamsters. J Clin Microbiol 1991; 29: Grignolo MC, Buffrini L, Monteforte P, and Rovetta G. Reliability of a polymerase chain reaction (PCR) technique in the diagnosis of Lyme borreliosis. Minerva Med 2001; 92(1): [Article in Italian] Gruntar I, et al. Conversion of Borrelia garinii cystic forms to motile spirochetes in vivo. APMIS 2001; 109(5): [Persistence occurs when spirochetes change physical characteristics by converting to dormant cysts, and vis versa.] Halperin JJ,, Luft BJ, Anand AK, Roque CT, Alvarez O, Volkman DJ, Dattwyler RJ. Lyme neuroborreliosis: central nervous system manifestations. Neurology 1989; 39: [hyperintensities persist after treatment] Halperin JJ. Prolonged Lyme disease treatment: enough is enough. Neurology 2008; 70(13): Harvey WT and Salvato P. ‘Lyme disease’: ancient engine of an unrecognized borreliosis pandemic? Med Hypotheses 2003; 60: Hassett AL, Radvanski DC, Buyske S, Savage SV, and Sigal LH. Psychiatric comorbidity and psychological factor in patients with “chronic Lyme disease.” Am. J. Med. 2009; 122(9): Hassler D, Riedel K, Zorn J and Preac-Mursic V. Pulsed high-dose cefotaxime therapy in refractory Lyme borreliosis (letter). Lancet 1991; 338: 193. Häupl T, Hahn G, Rittig M, Krause A, Schoerner C, Schonherr U, Kalden JR, and Burmester GR. Persistence of Borrelia burgdorferi in ligamentous tissue from a patient with chronic Lyme borreliosis. Arthritis Rheum 1993; 36(11): [Repeated antibiotic treatment necessary to stop the progession of disease but did not completely eliminate Bb from all sites of infection. Bb cultured from ligament sample; intracellar sanctuaries for Bb] Henneberg JP, and Neubert U. Borrelia burgdorferi group: in vitro antibiotic sensitivity. Orv Hetil 2002; 143: Hilton E, Tramontano A, DeVoti J, and Sood SK. Temporal study of immunoglobulin M seroreactivity to Borrelia burgdorferi in patients treated for Lyme borreliosis. J Clin Microbiol 1997; 35(3): Hodzic E, Feng S, and Barthold SW. Stability of Borrelia burgdorferi outer surface protein C under immune selection pressure. J Infect Dis 2000; 181: Hodzic E, Feng S, Holden K, Freet KJ, and Barthold SW. Persistence of Borrelia burgdorferi following antibiotic treatment in mice. Antimicrob Agents Chemother 2008; 52: [in mice: following antibiotic treatment; mice remained infected with infectious spirochetes.] Holl-Weiden A, Suerbaum S, and Girschick HJ. Seronegative Lyme arthritis. Rheumatology International 2007; 11: Honegr K, Hulinska D, Dostal V, Gebousky P, Hankova E, Horacek J, Vyslouzil L, and Havlasova J. Persistence of Borrelia burgdorferi sensu lato in patients with Lyme borreliosis. Epidemiol Mikrobiol Immunol. 2001; 50: Horowitz R. Chronic persistent Lyme borreliosis: PCR evidence of chronic infection despite extended antibiotic therapy – a retrospective review. 13th International Scientific Conference on Lyme Disease and Other Tick-Borne Disorders. CT, USA, March 2000. Hudson BJ, Stewart M, Lennox VA, Fukunaga M, Yabuki M, Macorison H, Kitchener-Smith J. Culture-positive Lyme borreliosis. Med J Aust 1998; 168(10): Hulínská D, Krausova M, Janovská D, Rohácová H, Hancil J, Mailer H. Electron microscopy and the polymerase chain reaction of spirochetes from the blood of patients with Lyme disease. Cent Eur J Public Health 1993; 1(2): Hulinska D, Votypka J, and Valesova M. Persistence of Borrelia garinii and Borrelia afzelii in patients with Lyme arthritis. Int J Med Microbiol Virol Parasitol Infecdt Dis 1999; 289(3): Hunfeld KP, Ruzic-Sabljic E, Norris DE, Kraiczy P, and Strle F. In vitro susceptibility testing of Borrelia burgdorferi sensu lato isolates cultured from patients with erythema migrans before and after antimicrobial chemotherapy. Antimicro Agents Chemother 2005; 49: International Lyme and Associated Diseases Society (ILADS). Evaluation of antibiotic treatment in patients with persistent symptoms of Lyme disease. James FM, JB Engiles, and J Beech. Meningitis, cranial neuritis, and radiculoneuritis associated with Borrelia burgdorferi infection in a horse. Journal of American Veterinary Medical Association 2010; 237: [Horse was seropositive for Bb, and PCR assay of CSF for B. burgdorferi DNA was positive; horse was treated with doxycycline, responded well, then relapsed, treated with oxytetracycline and later died; diagnosis consistent with neuroborreliosis.] Johnson L and Stricker JB. Treatment of Lyme disease: a medicolegal assessment. Expert Rev Anti-Infect Ther : Kaiser R. Clinical courses of acute and chronic neuroborreliosis following treatment with ceftriaxone. Nervenarzt. 2004(June); 75(6): Kalish RA, Leong JM, and AC Steere. Association of treatment-resistant chronic Lyme arthritis with HLA-DR4 and antibody reactivity to OspA and OspB of Borrelia burgdorferi. Infect Immun 1993; 61: Karma A, Stenborg T, Summanen P, Immonen I, Mikkila H, and Seppala I. Long-term follow-up of chronic Lyme neuroretinitis. Retina 1996; 16: Keat AC, and Hughes R. Infectious agents in reactive arthritis. Curr Opin Rheumatol 1993; 5: Keller TL, Halperin JJ, and Whitman M. PCR detection of Borrelia burgdorferi DNA in cerebrospinal fluid of Lyme neuroborreliosis patients. Neurology 1992; 43: Kersten A, Poitschek C, Rauch S, and Aberer E. Effects of penicillin, ceftriaxone, and doxycycline on morphology of Borrelia burgdorferi. Antimicrob Agents Chemother 1995; 39: Keszler K, and Tilton RC. Persistent PCR positivity in a patient being treated for Lyme disease. Journal of Spirochetal and Tick-Borne Diseases 1995; 2: Kirsch M,, Ruben FL, Steere AC, Duray PH, Norden CW, Winkelstein A. Fatal adult respiratory distress syndrome in a patient with Lyme disease. JAMA 1988; 259(18) Klempner MS, Noring R, and Rogers RA. Invasion of human skin fibroblasts by the Lyme disease spirochetes, Borrelia burgdorferi. J Inf Dis 1993; 167: Kraiczy P, Hellwage J, Skerka C, Becker H, Kirschfink M,, Simon MM, et al. Complement resistance of Borrelia burgdorferi correlates with the expression of BbCRASP-1, a novel linear plasmid-encoded surface protein that interacts with human factor H and FHL-1 and is unrelated to Erp proteins. J Biol Chem 2004; 279: Krupp LB, Masur D, Schwartz J, Coyle PK, Langenback IJ, and Fernquist SK. Cognitive functioning in late Lyme borreliosis. Arch Neurol 1999; 48: Krupp LB, Hyman LG, Grimson R, Coyle PK, Melville P, Ahnn S, et al. Study and treatment of post Lyme disease (STOP-LD): a randomized double masked clinical trial. Neurology 2003; 60: Krüger H, Helm E, Schuknecht B, and Scholz S. Acute and chronic neuroborreliosis with and without CNS involvement: a clinical, MRI, and HLA study of 27 cases. J Neurol 1991; 238: Kullberg BJ, Berende A, van der Meer JW. The challenge of Lyme disease: tired of the Lyme wars. Neth J Med 2011; 69: [refutes Klempers {2001} conjecture that long-term antibiotics don’t work] Latov N, Wu AT, Chin RL, Sander HW, Alaedini A, and Brannagran TH. Neuropathy and cognitive impairment following vaccination with the OspA protein of Borrelia burgdorferi. J Peripher Nerv Syst 2004; 9: Lavoie PE. Failure of published antibiotic regimens in Lyme borreliosis: observations on prolonged oral therapy. Abstract. Lyme Borreliosis International Conference, Sweden, 1990. Lavoie PE. Protocol from Rakel’s: explains persistence of infection despite “standard” courses of antibiotics. Lyme Times, Lyme Disease Resource Center, 1992; 2: Reprinted from Conn’s Current Therapy, 1991. Lawrence C, Lipton RB, Lowy RD, and Coyle PK. Seronegative chronic relapsing neuroborreliosis. Eur Neurol 1995; 35(2): [Patient’s CSF was positive for complex anti-Bb antibodies, B. burgdorferi nucleic acids and free antigen despite aggressive antibiotic therapy.] Lawrenz MB, Hardham JM, Owens RT, Nowakowski J, Steere AC, Wormser GP, and Norris SJ. Human antibody responses to vlsE antigenic variation protein of Borrelia burgdorferi. J Clin Microbiol 1999; 37: Liang FT, Steere AC, Marques AR, Johnson BJB, Miller JN, and Philipp MT. Sensitive and specific serodiagnosis of Lyme disease by enzyme-linked immunosorbent assay with a peptide based on an immundominant conserved region of Borrelia burgdorferi VlsE. J Clin Microbiol 1999; 37: Liang FT, Jacobs MB, Bowers LC, Philipp MT. An immune evasion mechanism for spirochetal persistence in Lyme borreliosis. J Exp Med 2002; 195: Liegner KB. Lyme disease: the sensible pursuit of answers. J Clin Microbiol 1993; 31: Liegner KB, Shapiro JR, Ramsay D, Halperin AJ, Hogrefe W, and Kong L. Recurrent erythema migrans despite extended antibiotic treatment with minocycline in a patient with persisting Borrelia burgdorferi infection. J Am Acad Dermatol 1993; 28: [Eleven months following treatment, T-cell stimulation test with Bb antigens were strongly positive; a year later, paired serum and CSF samples were strongly positive.] Liegner KB, Duray P, Agricola M, Rosenkilde C, Yannuzzi LA, Ziska M, Tilton RC, Hulinska D, Hubbard J, and Fallon BA. Lyme disease and the clinical spectrum of antibiotic responsive chronic meningoencephalomyelitides. J Spir and Tick-Borne Dis 1997; 4: [live culture of Bb after antibiotic treatment] Livengood JA and Gilmore RD, Jr. Invasion of human neuronal and glial cells by an infectious strain of Borrelia burgdorferi. Microbes and Infection. 2006; 8: [intracellar sanctuaries of Bb] Hodzic E, Feng S Holden K, Freet, KJ, and Barthold SW. Persistence of Borrelia burgdorferi following antibiotic treatment in mice. Antimicrobial Agents and Chemotherapy 2008; 52: [Persistence of Bb in mice] Hudson BJ, Stewart M, Lennox VA, Fukunaga M, Yabuki M, Macorison H, Kitchener-Smith J. Culture-positive Lyme borreliosis. Med J Aust. 1998; 168(10): Lawrence C, Lipton RB, Lowy FD, and Coyle PK. Seronegative chronic relapsing neuroborreliosis. Eur. Neurol. 1995; 35(2): Livengood JA, and Gilmore, RD, Jr. Invasion of human neuronal and glial cells by an infectious strain of Borrelia burgdorferi. Microbes and Infection 2006; 8: Logigian EL, Kaplan RF, and Steere AC. Chronic neurologic manifestations of Lyme disease. N Eng J Med 1990; 323: Logigian EL, Johnson KA, Kijewski MF, Kaplan RF, Becker JA, Jones KJ, Garada BM Holman BL, Steere AC. Reversible cerebral hyoperfusion in Lyme encephalopathy. Neurology 1997; 49: López-Andreu JA, Ferrís J, Canosa CA, Sala-Lizárraga JV. Treatment of late Lyme disease: a challenge to accept. J Clin Microbiol 1994; 32: Luft BJ, Steinman CR, Neimark HC, Muralidhar B, Rush T, Finkel MF, Kundel M, and Dattwyler RJ. Invasion of the CNS by Borrelia burgdorferi in acute disseminated infection. JAMA 1992; 267: Lyme Disease Foundation. The controversies surrounding Lyme disease diagnosis and treatment and why it is not uncommon for patients to experience persistent symptoms despite receiving conventional (short-term) antibiotic therapy for Lyme disease. Ma Y, Sturrock A, and Weis JJ. Intracellular localization of Borrelia burgdorferi within human endothelial cells. Infect Immun 1991; 59: MacDonald AB and Miranda JM. Concurrent neocortical borreliosis and Alzheimer’s disease. Human Pathol 1987; 18: MacDonald AB. Concurrent neocortical borreliosis and Alzheimer’s disease: demonstration of a spirochetal cyst form. Ann NY Acad Sci 1988; 539: MacDonald AB, Berger BW, and Schwan TG. Clinical implications of delayed growth of the Lyme disease spirochete, Borrelia burgdorferi. Acta Trop ; (2): MacDonad AB. In situ DNA hybridization study of granulovacuolar degeneration in human Alzheimer autopsy neurons for flagellin b transcriptomes of Borrelia burgdorferi. Alzheimer’s Dis Dementia 2006; 2 (Suppl. 1): S207. MacDonald AB. Plaques of Alzheimer’s disease originate from cysts of Borrelia burgdorferi. Med Hypotheses 2006; 67: doi: /j.mehy MacDonald AB. Cystic borrelia in Alzheimer’s disease and in non-dementia neuroborreliosis. Alzheimer’s Dementia 2006; 2 (Suppl. 1):S433. MacDonald AB. Transfection “Junk” DNA ― A link to the pathogenesis of Alzheimer’s disease? Med Hypotheses 2006; 66: MacDonald AB. Alzheimer’s neuroborreliosis with trans-synaptic spread of infection and neurofibrillary tangles derived from intraneuronal spirochetes. Med Hypotheses 2007; 68: [7 of 10 cases of Alzheimer’s disease had B. burgdorferi in their brains]. MacDonald AB. Biofilms of Borrelia burgdorferi on chironic cutaneous borrelia. Am J Clin Pathol 2008; 129: MacDonald, AB. Borrelia burgdorferi tissue morphologies and imaging methodologies. Eur J Clin Microbiol Infect Dis DOI /s Mahmoud AAF. The challenge of intracellular pathogens (editorial). N Engl J Med 1992; 326: Malane MS, Grant Kels JM, Feder Hm Jr. et al. Diagnosis of Lyme disease based on dermatologic manifestations. Ann Intern Med 1991; 114: [chronic Lyme borreliosis]. Malawista SE, Barthold SW, and Persing DH. Fate of Borrelia burgdorferi DNA in tissues of infected mice after antibiotic treatment. J Infect Dis 1994; 170: Malawista SE. Resolution of Lyme arthritis, acute or prolonged: a new look. Rheuma 2000 (May 29 issue). Manak MK, González-Villaseñor LI, Crush-Stanton S, and Tilton RC. Use of PCR assays to monitor the clearance of Borrelia burgdorferi DNA from blood following antibiotic therapy. J Spir Tick-Borne Dis 1997; 4: Maraspin V, Ruzic-Sabljic E, Strle F, Cimperman J, Jereb M, Preac-Mursic V. Alpc Adria Microbiol J. Persistence of Borrelia burgdorferi after treatment with antibiotics.1995; 3: Maraspin V, Cimperman J, Lotrič-Furlan S, Ružić-Sabljić E, Jurca T, Picken RN, and Strle F. Solitary borrelial lymphocytoma in adult patients. Wien Klin Wochenschr 2002; 114: Marlovits S, Khanah G, Striessniq G, Vécsei V, and Stanek G. Emergence of Lyme arthritis after autologous chondrocyte transplantation. Arthritis Rheum. 2004; 50: Masters EJ, Lynxwiler P, and Rawlings J. Spirochetemia after continuous high-dose oral amoxicillin therapy. Infect Dis Clin Practice 1995; 3: [Following six months of treatment, patient relapsed and Bb was cultured from blood.] Mattman LH. Cell wall deficient forms: stealth pathogens. 2nd edition. CRC Press, Inc,, Boca Raton, FL [change in physical characteristics; change of spirochetes to other pleomorphic forms, i.e., cell wall deficient forms, namely cysts.] Meier P, Blatz R, Gau M, Spencker FB, Wiedermann P. [Pars plana vitrectomy in Borrelia burgdorferi endophthalmitis][German]. Klin Monatsbl Augenheilkd 1998; 213(6): Miklossy J. Alzheimer’s disease ― a spirochetosis? NeuroReport 1993; 4: Miklossy J, Kasas S, Janzer RC, Ardizzoni F, and Loos H. Further morphological evidence of a spirochetal etiology of Alzheimer’s disease. NeuroReport 1994; 5: Miklossy J, Gern L, Darekar P, Janzer RC, Loos H. Senile plaques, neurofibrillary tangles and neuropil threads contain DNA? J Spirochetal and Tick-borne Dis 1995; 2: 1-5. Miklossy JM, Khalili K, Gern L, Ericson RL, Darekar P, Bolle L, Hurlimann J, and Paster BJ. Borrelia burgdorferi persists in the brain in chronic Lyme neuroborreliosis and may be associated with Alzheimer’s disease. J Alzheimers Dis 2004; 6; Miklossy J, Rosemberg S, and McGeer PL; Beta amyloid deposition in the atrophic form of general paresis. In Alzheimer’s Disease: New advances. Medimond. Proceedings of the 10th International Congress on Alzheimer’s Disease. Edited by: Iqbal K, Winblad B, and Avila J; 2006: Miklossy J, Kris A, Radenovic A, Miller L, Forro L, Martins R, Reiss K, Darbinian N, Darekara P, Mihaly L, and Khalili K. Beta amyloid deposition and Alzheimer’s type changes induced by Borrelia spirochetes. Neurobiol Aging 2006; 27: Miklossy J. Chronic inflammation and amyloidogenesis in Alzheimer’s disease ― role of spirochetes. J Alzheimers Dis 2008; 13: Miklossy, J Biology and neuropathology of dementia in syphilis and Lyme disease. In Handbook of Clinical Neurology, Vol. 89. C. Duyckaerts, I. Litvan (eds.). Elsevier, Amsterdam, Netherlands. p [Persistence of B. burgdorferi is evident in dementia patients.] Miklossy J, Kasas S, Zurn AD, McCall S, Yu S, and McGeer PL. Persisting atypical and cystic forms of Borrelia burgdorferi and local inflammation in Lyme neuroborreliosis. J Neuroinflammation 2008; 5: Miklossy, J Alzheimer’s disease—a neurospirochetosis. Analysis of the evidence following Koch’s and Hill’s criteria. Journal of Neuroinflammation 8:90. [Spirochetes were observed in the brain in more that 90% of Alzheimer’s disease. Persistence occurs when spirochetes change physical characteristics by converting to dormant cysts.] Miklossy, J Alzheimer’s disease – a neurospirochetosis. Analysis of the evidence following Koch’s and Hill’s criteria. 2011; 8: 90 ( [91% of Alzheimer’s patients sampled were positive for spirochetes; 25% of Alzheimer’s patients analyzed had B. burgdorferi spirochetes in their brains] Miller JC, K Narayan, B Stevenson, and AR Pachner. Expression of Borrelia burgdorferi erp genes during infection of non-human primates. Microb Pathol. 2005; 39: [in monkeys] Montgomery RR, Nathanson MH, and Malawista SE. The fate of Borrelia burgdorferi within endothelial cells. Infect Immun 1991; 59: Montgomery RR, MH Nathanson, and SE Malawista. The fate of Borrelia burgdorferi, the agent for Lyme disease, in mouse macrophages. Destruction, survival, recovery. J Immunol 1993; 150: [in mice macrophages] Moriarty TJ, Norman MU, Colarusso P, Bankhead T, Kubes P, and Chaconas G Real-time high resolution 3D imaging of the Lyme disease spirochete adhering to and escaping from the vasculature of a living host. PLoS Pathog 4(6):e doi: /journal.ppat Moses JM, RS Riseberg, and JM Mansbach. Lyme disease presenting with persistent headache. Pediatrics 2003; 112: Mursic VP, Wanner G, Reinhardt S, Wilske B, Busch U, and Marget W. Formation and cultivation of Borrelia burgdorferi spheroplast L-form variants. Infection 1996; 24(4): 335. Nanagara R, Duray PH, and Schumacher HR, Jr. Ultrastructural demonstration of spirochetal antigens in synovial fluid and synovial membrane in chronic Lyme disease: possible factors contributing to persistence of organisms. Hum Pathol 1996; 27(10): [intracellar sanctuaries of Bb] Nocton JJ, Dressler F, Rutledge BJ, Rys PN, Persing DH, and Steere AC. Detection of Borrelia burgdorferi DNA by polymerase chain reaction in synovial fluid from patients with Lyme arthritis. N Eng J Med 1994; 330: [Of 19 Lyme arthritis patients treated with either parenteral antibiotics or long courses of oral antibiotics, PCR confirmed Bb detected in synovial fluid of 37% of patients.] Nocton JJ, Bloom BJ, Rutledge BJ, Persing DJ, Logigian EL, Schmid CH, and Steere AC. Detection of Borrelia burgdorferi DNA by polymerase chain reaction in cerebrospinal fluid in Lyme neuroborreliosis. J. Infect Dis 1996; 174: Norgard MV, Riley BS, Richardson JA, et al Dermal inflammation elicited by synthetic analogs of Treponema pallidum and Borrelia burgdorferi lipoproteins. Infect Immun 63: Oksi J,, Mertsola J, Reunanen M, Marjamaki M, Viljanen MK. Subacute multiple-site osteomyelitis caused by Borrelia burgdorferi. Clin Infect Dis 1994; 19(5): Oksi J, Uksila J, Marjamäki M, Nikoskelainen J, and Viljanen MK. Antibodies against whole sonicated Borrelia burgdorferi spirochetes, 41-kilodalton flagellin, and P39 protein in patients with PCR- or culture-proven late Lyme borreliosis. J Clin Microbiol 1995; 33: Oksi J, Kalimo H, Marttila RJ, Marjamäki M, Sonninen P, Nikoskelainen J, and Viljanen MK. Inflammatory brain changes in Lyme borreliosis. A report on three patients and review of literature. Brain 1996; 119(6): Oksi J, Nikoskelainen J, and Viljanen MK. Comparison of oral cefixime and intravenous ceftriaxone followed by oral amoxicillin in disseminated Lyme borreliosis. Eur J Clin Microbiol Int Dis 1998; 17: Oksi J, Marjamäki M, Nikoskelainen J, and Viljanen MK. Borrelia burgdorferi detected by culture and PCR in clinical relapse of disseminated Lyme borreliosis. Ann Med 1999; 31(3): [40% (13% of 32) patients had clinical relapses that were PCR or culture-fonfirmed.] Pacheco e Silva AC. Espirochetose dos centros nervos Memorias do hospicio de Juguery. 1927, III-IV (3-4): 1-27. Pachner AR, Delaney E, and O’Neill T. Neuroborreliosis in the nonhuman primate: Borrelia burgdorferi persists in the central nervous system. Ann Neurol 1995; 38: [in monkeys]. Pachner AR, J Basta, E Delaney, D Hulinska. Localisation of Borrelia burgdorferi in murine Lyme borreliosis by electron microscopy. Am J Trop Med Hyg 1995; 52: Pachner AR, Cadavid D, Shu G, Dail D, Pachner S, Hodzic E, and Barthold SW. Central and peripheral nervous system infection, immunity, and inflammation in the NHP model of Lyme borreliosis. Ann Neurol 2001; 50: [in monkeys] Pachner AR, D Dail, K Narayan, K Dutta, and D Cadavid. Increased expression of B-lymphocyte chemoattractant, but not pro-inflammatory cytokines, in muscle tissue in rhesus chronic Lyme borreliosis. Cytokine 2002; 19: [in monkeys] Pachner AR, Basta J, Delaney E, and Hulinska D. Localization of Borrelia burgdorferi in murine Lyme borreliosis by electron microscopy. Am J Trop Med Hyg 1995; 52: Pahl A, Kühbrandt U, Brune K, Röllinghoff M, and Gessner A. Quantitative detection of Borrelia burgdorferi by real-time PCR. J Clin Microbiol 1999; 37: Pal GS, Baker JT, and Wright DJM. Penicillin resistant Borrelia encephalitis responding to cefotaxime. Lancet 1988; 338: Reimers CD, de Koing J, Neubert U, Preac Mursic V, Koster JG, Muller Felber W, Pongratz DE, and Duray PH. Borrelia burgdorferi myositis: report of eight patients. J Neurol 1993; 240(5): Petrovic M, Vogelaers D, Van Renterghem L, Carton D, De Reuck J, and Afschrift M. Lyme borreliosis – review of the late stages and treatment of four cases. Acta Clin Belg. 1998; 53: Pfister HW, Preac Mursic V, Wilske B, Schielke E, Sorgel F, Einhaupl KMJ. Randomized comparison of ceftriaxone and cefotaxime in Lyme neuroborreliosis. Infect Dis 1991; 163(2): [In one patient, Bb as isolated from the cerebrospinal fluid 7.5 months after ceftriaxone therapy and, thus, showing that extended therapy is necessary.] Phillips SE, Mattman LH, Hulinska D, and Moayad H. A proposal for the reliable culture of Borrelia burgdorferi from patients with chronic Lyme disease, even from those aggressively treated. Infection 1998; 26: Phillips SE, Harris NS, Horowitz R, Johnson L, Stricker RB. Lyme disease: scratching the surface. Lancet 2005; 366: 1771. Phillips SE, Burrascano JJ, Harris NS, Johnson L, Smith PV, Stricker RB. Chronic infection in ‘post-Lyme borreliosis syndrome.’ Int J Epidemiol 2005; 34: Picken RN, Strle F, Picken MM et al. Identification of three species of Borrelia burgdorferi sensu lato (B. garinii, B. afzelii) among isolates from acrodermatis chronica atrophicans lesions. J Invest Dermatol 1998; 110; [chronic Lyme borreliosis]. Preac-Mursic V, Wilske B, Schierz G, et al. Repeated isolation of spirochetes from the cerebrospinal fluid of a patient with meningoradiculitis Bannwarth syndrome. Eur J Clin Microbiol 1984; 3: Preac-Mursic V, Weber K, Pfister HW, Wilske B, Gross B, Baumann A, and Prokop J. Survival of Borrelia burgdorferi in antibiotically treated patients with Lyme borreliosis. Infection 1989; 17(6): Preac-Mursic V, Patsouris E, Wilske B, Reinhardt S, Gross, and Mehraein P. Persistence of Borrelia burgdorferi and histopathological alterations in experimentally infected animals. A comparison with histopathological findings in human Lyme disease. Infection 1990; 18: Preac-Mursic V, Pfister HW, Spiegel H, Burk K, Wilske B, Reinhardt S, and Boehmer R. First isolation of Borrelia burgdorferi from an iris biopsy. J Clin Neuroophthalmol 1993; 13(3): [Patient with blurred vision treated with two separate month-long cycles of tetracycline had symptoms persist for several years. Bb cultured from iris biopsy.] Preac Mursic V, Wanner G, Reinhardt S, Wilske B, Busch U, Marget W. Formation and cultivation of Borrelia burgdorferi spheroplast-L-form variants. Infection 1996; 24: Preac Mursic V, Marget W, Busch U, Rigler DP, Hagl S. Kill kinetics of Borrelia burgdorferi and bacterial findings in relation to the treatment of Lyme borreliosis. Infection 1996; 24(1): [Bb was isolated by culture in five patients, four of whom had previously tested antibody-negative.] Priem S, Burmester GR, Kamradt T, Wolbart K, Rittig MG, and Krause A. Detection of Borrelia burgdorferi by polymerase chain reaction in synovial membrane, but not in synovial fluid from patients with persisting Lyme arthritis after antibiotic therapy. Ann Rheum Dis 1998; 57(2): [After antibiotic treatment, synovial membrane still demonstrates spirochetes.][Although PCR was negative in synovial fluid and urine, PCR confirmed Bb in synovial membrane of four previously treated patients with Lyme arthritis; intracellar sanctuaries of Bb] Reid MC, Schoen RT, Evans J, Rosenberg JC, and Horwitz RI. The consequences of overdiagnosis and overtreatment of Lyme disease: an observational study. Ann. Intern. Med. 1998; 128(5): Reimers CD, de Koning J, Neubert U, Preac Mursic V, Koster JG, Muller Felberl W, Pongratz DE, and Duray PH. Borrelia burgdorferi myositis: report of eight patients. J Neurol 1993; 240(5): Rittig MG, Häupl T, Krause A, Kressel M, Groscurth P, Burmester GR. Borrelia burgdorferi-induced ultrastructural alterations in human phagocytes: a clue to pathogenicity? J Pathol 1994; 173: Roberts ED, Bohm RP, Jr., Cogswell FB, Lanners HN, Lowrie RC, Jr., Povinelli L, Piesman J, and Philipp MT. Chronic Lyme disease in the rhesus monkey. Lab Invest 1995; 72: Rohácová H, Hancil J, Hulinská D, Mailer H, Havlik J. Ceftriaxone in the treatment of Lyme neuroborreliosis. Infection (Jan-Feb); 24(1): Roelcke U, Barnett W, Wilder-Smith E, Sigmund D, and Hacke W. Untreated neuroborreliosis: Bannwarth syndrome evolving into acute schizophrenia-like psychosis. J Neurol 1992; 239: Ruzic-Sablijic E, Strle F, and Cimperman J. The Ixodes ricinus tick as a vector of Borrelia burgdorferi in Slovenia. Eur J Epidemiol 1993; 9: Sala-Lizarraga JA, Salcede-Vivo J, Ferris J, Lopez-Andreu JA. Lyme borreliosis [Letter] Lancet 1990; 345: Sapi E, and MacDonald A. Biofilms of Borrelia burgdorferi in chronic cutaneous borreliosis. Am. J. Clin. Pathol. 2008; 129: [biofilms consist of a colony of spirochetes and cysts coated by a gelatinous, protective membrane] Sapi E, Kaur N, Anyanwu S, Luecke DF, Datar A, Patel S, Rossi M, Stricker RB. Evaluation of in vitro antibiotic susceptibility of different morphologic form of Borrelia burgdorferi. Drug Resist. 2011; 4: Epub 2011 May 3. [biofilms consist of a colony of spirochetes and cysts coated by a gelatinous, protective membrane] Sapi E, Bastian SL, Mpoy CM, Scott S, Rattelle A, Pabbati N, Poruri A, Buruga D, Theophilus PAS, Pham TV, Datar A, Dhaliwai NK, MacDonald A, Rossi MJ, Sinha SK, and Luecke DF Characterization of biofilm formation by Borrelia burgdorferi in vitro. PLOS One 7(10): e doi: /journal.pone [biofilms consist of a colony of spirochetes and cysts coated by a gelatinous, protective membrane] Schoen RT, Aversa JM, Rahn DW, and Steere AC. Treatment of refractory chronic Lyme arthritis with arthroscopic synvectomy. Arthritis Rheum 1991; 34(8): Schlesinger P, Duray P, Burke B, Steere A, and Stillman A. Maternal-fetal transmission of the Lyme disease spirochete Borrelia burgdorferi. Ann Intern Med 1985; 103: Schmidli J, Hunziker T, Moesli P, and Schaad UB. Cultivation of Borrelia burgdorferi from joint fluid three months after treatment of facial palsy due to Lyme borreliosis. J Inf Dis 1988; 158(4): [Bb was cultured from joint fluid after treatment.] Schwann TG, Piesman J, Golde WT, Dolan MC, Ros PA. Induction of an outer surface protein on Borrelia burgdorferi during tick feeding. Proc Natl. Acad. Sci. USA. 1995; 92: [change in physical characteristics by altering immunogenicity] Seiler KP, and Weis JJ. Immunity to Lyme disease: protection, pathology and persistence. Curr Opin Immunol 1996; 8: Shadick NA, Phillips CB, Logigian EL, Steere AC, Kaplan RF, Berardi VP, et al. The long-term clinical outcomes of Lyme disease. A population-based retrospective cohort study. Ann Int Med 1994; 121: Sherr VT. “Bell’s palsy of the gut” and other GI manifestations of Lyme and associated disease. Practical Gastroenterology. April 2006. Silverman S, Dukes EM, Johnston SS, Brandenburg NA, Sadosky A, and Huse DM. The economic burden of fibromyalgia: comparative analysis rheumatoid arthritis. Current Medical Research and Opinion 2009; 25(4) Singh SK and HJ Girschick. Molecular survival strategies of the Lyme disease spirochete Borrelia burgdorferi. Lancet Infect Dis 2004; 4: [B. burgdorferi survives in brachytophic tissue (ligament, tendon), fibroblasts, synovial cells, endothelial cell {linings of blood and heart vessels, and lymph vessels)}, deep invaginations of cell membranes, myocyctes, joints, eyes, and bones.] Skogman BH, Croner S, Nordwall M, Eknefelt M, Ernerudh J, and Forsberg P. Lyme neuroborreliosis in children: a prospective study of clinical features, prognosis, and outcome. Pediatic Infect. Dis. J. 2008; 27(12): Stanek G, Klein J, Bittner R, and Glogar D. Isolation of Borrelia burgdorferi from the myocardium of a patient with long standing cardiomyopathy. N Engl J Med 1990; 322: Steere AC, Bernardi VP, Weeks KE,, Logigan EL, Ackermann R. Evaluation of the intrathecal antibody response to Borrelia burgdorferi as a diagnostic test for Lyme neuroborreliosis. J. Infect. Dis. 1990(June); 161(6): Steere AC, Taylor E, McHugh GL, and Logigian EL. The overdiagnosis of Lyme disease. J. Med. Ass (14): Steere AC, Levin RE, Molloy PJ, Kalis RA, Abraham JH, Liu NY, and Schmid CH. Treatment of Lyme arthritis. Arthritis Rheum 1994; 37: Stein SL, Solvason HB, Biggart E, and Spiegel D. A 25-year-old woman with hallucinations, hypersexuality, nightmares, and a rash. Am J Psychiatry 1996; 153: Straubinger RK, Straubinger AF, Jacobson RH, Chang Y, Summers BA, Erb HN, and Appel MJG. Two lessons from the canine model of Lyme disease: migration of Borrelia burgdorgferi in tissues and persistence after antibiotic treatment. J Spir Tick-Borne Dis 1997; 4: [In dogs: 30-day treatment diminished but failed to eliminate persistent infection in dogs. Antibody titers fell, but after antibiotic treatment was discontinued antibody levels began to rise again, presumably in response to proliferation of the surviving pool of spirochetes.] Straubinger RK, Summers BA, Chang YF, and Appel MJG. Persistence of Borrelia burgdorferi in experimentally infected dogs after antibiotic treatment. J Clin Microbiol 1997; 35: Straubinger RK. PCR-based quantification of Borrelia burgdorferi organisms in canine tissues over a 500-day postinfection period. J Clin Microbiol 2000; 38: [All 8 infected dogs previously treated with 30-day antibiotics were PCR positive from tissue samples after necrosis; 25 tissue samples per dog were used.] Straubinger RK, Straubinger AF, Summers BA, and Jacobson RH. Status of Borrelia burgdorferi infection after antibiotic treatment and the effects of corticosteroids: an experimental study. J Inf Dis 2000; 181: Straubinger RK. Lyme borreliosis in dogs in recent advances in canine infectious diseases. Edited by L.E. Carmichael. International Veterinary Information Services Stricker RB, Winger EE. Decrease CD57 lymphocyte subset in patients with chronic Lyme disease. Immonology Letters : Stricker RB, Burrascano JJ, and Winger EE. Long-term decrease in the CD57 lymphocyte subset in a patient with chronic Lyme disease. Ann Agric Environ Med 2002; 9: Stricker RB, Lautin A, and Burrascano JJ. Lyme disease: point/counterpoint. Expert Rev Anti-Infect Ther 2005: 3: Stricker RB and Johnson L. Persistent Borrelia burgdorferi infection after treatment with antibiotics and anti-tumor necrosis factor-. J Infect Dis 2008; 197: Stricker RB, Green CL, Savely VR, Chamallas SN, and Johnson L. Benefit of intravenous antibiotic therapy in patients referred for treatment of neurologic Lyme disease. Int J Gen Med 2011; 4: [refutes Klempers {2001} conjecture that long-term antibiotics don’t work] Stricker RB, Johnson L. Lyme disease: the next decade. Infect. Drug Resist. 2011; 4: 1-9. Epub Jan 7. [biofilms consist of a colony of spirochetes and cysts coated by a gelatinous, protective membrane] Strle F, Preac-Mursic V, Cimperman J, Ruzic E, Maraspin V, and Jereb M. Azithromycin versus doxycycline for treatment of eythema migrans: clinical and microbiological findings. Infection 1993; 21(2): Strle F, Cheng Y, Cimperman J, Maraspin V, Lotric-Furlan S, Nelson JA, Picken MM, Ruzic-Sabljic E, and Picken R. Persistence of Borrelia burgdorferi sensu lato in resolved erythema migrans lesions. Clin Inf Dis 1995; 23: Strle F, Maraspin V, Lotric-Furlan, Ruzic-Sabljic E, and Cimperman J. Azithromycin and doxycycline for treatment of Borrelia culture-positive erythema migrans. Infection 1996; 24: [Skin-positive despite repeated antibiotic treatments.] Summers BA, Straubinger AF, Jacobson RH, Chang YF, Appel MJG, and Straubinger RK. Histopathological studies of experimental Lyme disease in the dog. J Comparative Pathol 2005; 133: 1-13. Sung SY, McDowell JV, Carlyon JA, and Marconi RT. Mutation and recombination in the upstream homology box-flanked ospE-related genes of the Lyme disease spirochetes result in the development of new antigenic variants during infection. Infect Immun 2000; 68; Valesová M, et al. Detection of Borrelia in the synovial tissue from a patient with Lyme borreliosis by electron microscopy. J. Rheumatol. 1989;16(11): [intracellar sanctuaries of Bb] Valesová H, Mailer J, Havlik J, Hulínská, D, Hercogová. Long-term results in patients with Lyme arthritis following treatment with ceftriaxone. Infection (Jan-Feb); 24(1): Vartiovaara I. Living with Lyme. Lancet 1995; 345: Vázquez M, Sparrow SS, and Shapiro ED. Long-term neuropsychologic and health outcomes of children with facial nerve palsy attributable to Lyme disease. Pediatrics 2003; 112(2): e93-e97. Walberg P, Granlund H, Nyman D, Panelius J, and Seppälä I. Treatment of late Lyme borreliosis. J Infection 1994; 29: Waniek C, Prohovnik I, Kaufman MA, and Dwork AJ. Rapid progressive frontal-type dementia associated with Lyme disease. J Neuropsychiatry Clin Neurosci 1995; 7: (B. burgdorferi detected at autopsy). Wang P, Gartenhaus R, Sood SK, DeVoti J, Singer C, Dorante G, and Hilton E. Detection of Borrelia DNA in circulating monocytes as evidence of persistent Lyme disease. J Spir and Tick-Borne Dis 2000; 7: Weber K. Treatment failure in erythema migrans: a review. Infection 1996; 24: Weis JJ, Yang L, Seiler KP, and Silver RM. Pathological manifestations in murine Lyme disease: association with tissue invasion and spirochete persistence. Clin Infect Dis 1997 Suppl 1: S18-24. Wienecke R, Zoechling N, Neubert U. Molecular subtyping of Borrelia burgdorferi in erythema migrans and acrodermatitis chronica atrophicans. J Invest Dermatol 1994; 103; [chronic Lyme borreliosis]. Xu Q, Mcshan K, and Liang FT. Modification of Borrelia burgdorferi to overproduce OspA or VlsE alters its infectious behaviour. Microbiology 2008; 154: Yang L, Weis JH, Eichwald E, Kolbert CP, Persing DH, and Weis JJ. Heritable susceptibility to severe Borrelia burgdorferi-induced arthritis is dominant and is associated with persistence of large numbers of spirochetes in tissues. Infect Immun 1994; 62: Young D, Hussell T, and Dougan G. Chronic bacterial infections: living with unwanted guests. Nat Immunol 2002 Nov; 3(11): Yrjänäinen H, Hytönen J, Söderström KO, Oksi J, Hartiala K, Viljanen MK. Persistent joint swelling and borrelia-specific antibodies in Borrelia garinii-infected mice after eradication of vegetative spirochetes with antibiotic treatment. Micr Infect 2006; 8: [persistence if Bb in mice] Yrjänäinen H. Borrelia burgdorferi evades the effects of ceftriaxone treatment in mouse model. Medica Odontologica [thesis] Yrjänäinen H, Hytönen J, Hartiala P, Oksi J, Viljanen MK. APMIS 2010;118(9): [Borrelia burgdorferi DNA in joints and tissue adjacent to the joint is the niche of persisting B. burgdorferi in ceftriaxone-treated mice.] Zhang JR, Hardham JM, Barbour AG, and Norris SJ. Antigenic variation in Lyme disease Borreliae by promiscuous recombination of VMP-like sequence cassettes. Cell 1997; 89: [antigenic variation: a defense stratagem of B. burgdorferi] Ziska MH, Donta ST, and Demarest FC. Physician preferences in the diagnosis and treatment of Lyme disease in the United States. Infection 1996; 24: Compiled by: John D. Scott, Research Division April 2013 Lyme Disease Association of Ontario [1] Stricker RB, Johnson L. Borrelia burgdorferi aggrecanase activity: more evidence for persistent infection in Lyme disease. Front Cell Infect Microbiol ;3:40. [2] Sharma B, Brown AV, Matluck NE, Hu LT, Lewis K. Borrelia burgdorferi, the causative agent of Lyme disease, forms drug-tolerant persister cells. Antimicrob Agents Chemother May 26 [3] Bernt-Dieter Huismans.

Chronic Stress, Insomnia, Sickness Syndrome & Fatigue

Chronic Environmental & Physiological Stress Cause Disease Progression
Chronic environmental stress-> persistent stress response Chronic physiological stress-> inflammatory state Persistent stress response+/or persistent inflammatory state increase allostatic load Chronic allostatic load compromise regeneration, leading to disease progression

Disease Precipitation vs. Disease Perpetuation & Disease Progression
What precipitates a disease process may not be exactly the same as what causes the perpetuation and progression of the disease. Chronic stress and non-restorative sleep contribute to disease perpetuation & are associated with: Decreased regenerative functioning Compromised immunity Decreased resistance to infectious disease Fatigue

Alostatic Load and Inflammation
Environmental Stress &/or Physiological Stress (Sickness Syndrome) Inflammation

Central pathways causing fatigue in neuro-inflammatory and autoimmune illnesses
It is concluded that peripheral inflammation and immune activation, together with the subsequent activation of glial cells and mitochondrial damage, likely account for the severe levels of intractable fatigue and disability seen in many patients with neuroimmune and autoimmune diseases. This would also appear to be the case for many patients afforded a diagnosis of Chronic Fatigue Syndrome. BMC Med Dec;13(1):259. doi: /s Epub 2015 Feb 6. Central pathways causing fatigue in neuro-inflammatory and autoimmune illnesses. Morris G(1), Berk M, Walder K, Maes M. Author information: (1)Tir Na Nog, Bryn Road seaside 87, Llanelli, SA152LW, Wales, UK, BACKGROUND: The genesis of severe fatigue and disability in people following acute pathogen invasion involves the activation of Toll-like receptors followed by the upregulation of proinflammatory cytokines and the activation of microglia and astrocytes. Many patients suffering from neuroinflammatory and autoimmune diseases, such as multiple sclerosis, Parkinson's disease and systemic lupus erythematosus, also commonly suffer from severe disabling fatigue. Such patients also present with chronic peripheral immune activation and systemic inflammation in the guise of elevated proinflammtory cytokines, oxidative stress and activated Toll-like receptors. This is also true of many patients presenting with severe, apparently idiopathic, fatigue accompanied by profound levels of physical and cognitive disability often afforded the non-specific diagnosis of chronic fatigue syndrome. DISCUSSION: Multiple lines of evidence demonstrate a positive association between the degree of peripheral immune activation, inflammation and oxidative stress, gray matter atrophy, glucose hypometabolism and cerebral hypoperfusion in illness, such as multiple sclerosis, Parkinson's disease and chronic fatigue syndrome. Most, if not all, of these abnormalities can be explained by a reduction in the numbers and function of astrocytes secondary to peripheral immune activation and inflammation. This is also true of the widespread mitochondrial dysfunction seen in otherwise normal tissue in neuroinflammatory, neurodegenerative and autoimmune diseases and in many patients with disabling, apparently idiopathic, fatigue. Given the strong association between peripheral immune activation and neuroinflammation with the genesis of fatigue the latter group of patients should be examined using FLAIR magnetic resonance imaging (MRI) and tested for the presence of peripheral immune activation. It is concluded that peripheral inflammation and immune activation, together with the subsequent activation of glial cells and mitochondrial damage, likely account for the severe levels of intractable fatigue and disability seen in many patients with neuroimmune and autoimmune diseases.This would also appear to be the case for many patients afforded a diagnosis of Chronic Fatigue Syndrome. PMCID: PMC PMID: [PubMed - in process] Morris G, Berk M, Walder K, Maes M. BMC Med Dec;13(1):259. BMC Med Dec;13(1):259.

Sleep Drives Metabolite Clearance from the Adult Brain
Sleep is associated with a 60% increase in the interstitial space, resulting in a striking increase in convective exchange of cerebrospinal fluid with interstitial fluid which increases clearance of β-amyloid. The restorative function of sleep may be a consequence of the enhanced removal of potentially neurotoxic waste products that accumulate in the awake central nervous system. Science Oct 18;342(6156): doi: /science Sleep drives metabolite clearance from the adult brain. Xie L(1), Kang H, Xu Q, Chen MJ, Liao Y, Thiyagarajan M, O'Donnell J, Christensen DJ, Nicholson C, Iliff JJ, Takano T, Deane R, Nedergaard M. Author information: (1)Division of Glial Disease and Therapeutics, Center for Translational Neuromedicine, Department of Neurosurgery, University of Rochester Medical Center, Rochester, NY 14642, USA. Comment in Science Oct 18;342(6156):301. Neurosurgery Feb;74(2):N17-8. Mov Disord Jan;29(1):33. Nat Rev Neurosci Dec;14(12): Science Oct 18;342(6156): Nat Rev Neurol Dec;9(12):657. The conservation of sleep across all animal species suggests that sleep serves a vital function. We here report that sleep has a critical function in ensuring metabolic homeostasis. Using real-time assessments of tetramethylammonium diffusion and two-photon imaging in live mice, we show that natural sleep or anesthesia are associated with a 60% increase in the interstitial space, resulting in a striking increase in convective exchange of cerebrospinal fluid with interstitial fluid. In turn, convective fluxes of interstitial fluid increased the rate of β-amyloid clearance during sleep. Thus, the restorative function of sleep may be a consequence of the enhanced removal of potentially neurotoxic waste products that accumulate in the awake central nervous system Xie L(1), Kang H, Xu Q, Chen MJ, Liao Y, Thiyagarajan M, O'Donnell J, Christensen DJ, Nicholson C, Iliff JJ, Takano T, Deane R, Nedergaard M. Science Oct 18;342(6156):373-7.

Diurnal Physiological Variation of Immune Parameters in Humans
Sleep initiates Th1 response in lymph nodes. Early nocturnal sleep promotes T cell & proinflammatory cytokines & naïve T cell dendritic cell interaction. Sleep promotes immunosupportive hormones such as GH & prolactin to suppress anti-inflammatory hormones such as cortisol, norepinephenrine and epinephrine. Lange T et al. Neurology, Psychiatry, and Brain research. 20(2014) 2.

Bidirectional Communication between the Brain and the Immune System: Implications for Physiological Sleep and Disorders with Disrupted Sleep Cytokines produced by cells of the immune and nervous systems regulate sleep. particularly interleukin-1beta and tumor necrosis factor-alpha, signal neuroendocrine, autonomic, limbic and cortical areas of the CNS to affect neural activity and modify behaviors (including sleep), hormone release and autonomic function. Sleep disorders are commonly associated with chronic inflammatory diseases and chronic age- or stress-related disorders. The best studied are rheumatoid arthritis, fibromyalgia and chronic fatigue syndromes. Bidirectional Communication between the Brain and the Immune System: Implications for Physiological Sleep and Disorders with Disrupted Sleep. Neuroimmunomodulation. 2006;13(5-6): Epub 2007 Aug 6. Lorton D, Lubahn CL, Estus C, Millar BA, Carter JL, Wood CA, Bellinger DL. Hoover Arthritis Research Center, Sun Health Research Institute, Sun City, Ariz., USA. PMID: This review describes mechanisms of immune-to-brain and brain-to-immune signaling involved in mediating physiological sleep and altered sleep with disease. The central nervous system (CNS) modulates immune function by signaling target cells of the immune system through autonomic and neuroendocrine pathways. Neurotransmitters and hormones produced and released by these pathways interact with immune cells to alter immune functions, including cytokine production. Cytokines produced by cells of the immune and nervous systems regulate sleep. Cytokines released by immune cells, particularly interleukin-1beta and tumor necrosis factor-alpha, signal neuroendocrine, autonomic, limbic and cortical areas of the CNS to affect neural activity and modify behaviors (including sleep), hormone release and autonomic function. In this manner, immune cells function as a sense organ, informing the CNS of peripheral events related to infection and injury. Equally important, homeostatic mechanisms, involving all levels of the neuroaxis, are needed, not only to turn off the immune response after a pathogen is cleared or tissue repair is completed, but also to restore and regulate natural diurnal fluctuations in cytokine production and sleep. The immune system's ability to affect behavior has important implications for understanding normal and pathological sleep. Sleep disorders are commonly associated with chronic inflammatory diseases and chronic age- or stress-related disorders. The best studied are rheumatoid arthritis, fibromyalgia and chronic fatigue syndromes. This article reviews our current understanding of neuroimmune interactions in normal sleep and sleep deprivation, and the influence of these interactions on selected disorders characterized by pathological sleep. Copyright (c) 2006 S. Karger AG, Basel Lorton D et al. Neuroimmunomodulation. 2006;13(5-6): Epub 2007 Aug 6.

Disease Progression Non-Restorative Sleep Pain Immune Fatigue
Cognitive Impairments Emotional Impairments Pain Sensitivity Immune Dysfunction

Delta Sleep Sleep restriction increases IL-6 and pain-related symptoms in healthy volunteers (1) Impaired Sleep Correlates with Impaired Immune Functioning (2) Growth hormone is dependent upon delta sleep & modulates immune response (3) Increasing delta sleep is therapeutic (1) M. Haack, E. Sanchez, J. Broussard, M. Regan, J. Mullington J Pain; April 2004, Supplement 1 • Volume 5 • Number 3 (2) Modolfsy H. Sleep and the immune system. Int J Immunopharmacol 1995;17: (3) Kelley KW. Ann N Y Acad Sci. 1990;594:

UCLA: Three Distinct Alzheimer’s Types
Inflammatory, in which markers such as C-reactive protein and serum albumin to globulin ratios are increased. Non-inflammatory, in which these markers are not increased but other metabolic abnormalities are present. Cortical, which affects relatively young individuals and appears more widely distributed across the brain than the other subtypes of Alzheimer's. It typically does not seem to cause memory loss at first, but people with this subtype of the disease tend to lose language skills. It is often misdiagnosed, typically affects people who do not have an Alzheimer's-related gene and is associated with a significant zinc deficiency.

Sleep & Alzheimer’s Disease (AD)
Beta amyloid dynamics are regulated by the sleep-wake cycle. Sleep is associated with naturally-occurring flushing/removal of exogenous AB from the brain by cerebrospinal fluid. [Xie] Sleep deprivation exacerbates neuronal injury and tau phosphorylation. Greater amyloid burden was associated with poor sleep efficiency and wakefulness episodes.[Ju] Short sleep duration and poor sleep quality are associated with increased AB burden in PET amyloid imaging.[Spira] Decrease in depth of sleep are associated with 70 to 100% greater odds of having AD 9 years later. [Hahn] Hahn and colleagues found that self reports of decrease in depth of sleep were associated with 70 to 100% greater odds of having AD 9 years later. - See more at: Ju and colleagues reported that greater amyloid burden was associated with poor sleep efficiency and wakefulness episodes - See more at: Spira and colleagues found that self-reported short sleep duration and poor sleep quality were associated with increased AB burden as seen in PET amyloid imaging. - See more at: In 2009, Kang and colleagues reported that beta amyloid dynamics were found to be regulated by the sleep-wake cycle in mice. In 2013, Xie and colleagues reported that in mice sleep was associated with naturally-occurring flushing/removal of exogenous AB from the brain by cerebrospinal fluid. Others have found that deprivation of sleep exacerbates neuronal injury and tau phosphorylation. - See more at: Smita Patel, DO, FAASM, and Anne Marie Fosnacht, MPH, CPT –

Lack Of Sleep Promotes Neurodegenerative Processes
Increases of neuron-specific enolase and S100 calcium binding protein B that typically rise in blood under conditions of brain damage.[1] Increased cerebral β-amyloid 42 levels, which elevates the risk of Alzheimer disease.[2, 3] Mitochondrial stress and degeneration of Locus Ceruleus neurons.[4] The Boston Globe (1/3, Kotz) reports that according to a study published in the current issue of the journal Sleep, “pulling an all-nighter” may “actually injure the brain.” For the 15-participant study, researchers “measured blood levels of certain proteins associated with brain injuries like concussions after the men slept eight hours in a sleep lab and then were kept awake all night playing board games and watching movies.” The Huffington Post(1/3) reported that two “molecules, neuron-specific enolase (NSE) and S100 calcium binding protein B (S-100B), ‘typically rise in blood under conditions of brain damage.’” However, “blood levels of these molecules were higher in the men the morning after the sleep deprivation, compared with the morning after getting a full night’s rest.” The study authors concluded that “a lack of sleep may promote neurodegenerative processes.” Sleep Jan 1;37(1): doi: /sleep Acute sleep deprivation increases serum levels of neuron-specific enolase (NSE) and S100 calcium binding protein B (S-100B) in healthy young men. Benedict C(1), Cedernaes J(1), Giedraitis V(2), Nilsson EK(1), Hogenkamp PS(1), Vågesjö E(3), Massena S(3), Pettersson U(3), Christoffersson G(3), Phillipson M(3), Broman JE(1), Lannfelt L(2), Zetterberg H(4), Schiöth HB(1). Author information: (1)Department of Neuroscience, Uppsala University, Uppsala, Sweden. (2)Molecular Geriatrics, Department of Public Health and Caring Sciences, Uppsala University, Uppsala, Sweden. (3)Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden. (4)Clinical Neurochemistry Laboratory, Institute of Neuroscience and Physiology, Sahlgrenska Academy at University of Gothenburg, Sahlgrenska University Hospital, Mölndal, Sweden ; UCL Institute of Neurology, Queen Square, London, UK. STUDY OBJECTIVES: To investigate whether total sleep deprivation (TSD) affects circulating concentrations of neuron-specific enolase (NSE) and S100 calcium binding protein B (S-100B) in humans. These factors are usually found in the cytoplasm of neurons and glia cells. Increasing concentrations of these factors in blood may be therefore indicative for either neuronal damage, impaired blood brain barrier function, or both. In addition, amyloid β (Aβ) peptides 1-42 and 1-40 were measured in plasma to calculate their ratio. A reduced plasma ratio of Aβ peptides 1-42 to 1-40 is considered an indirect measure of increased deposition of Aβ 1-42 peptide in the brain. DESIGN: Subjects participated in two conditions (including either 8-h of nocturnal sleep [22:30-06:30] or TSD). Fasting blood samples were drawn before and after sleep interventions (19:30 and 07:30, respectively). SETTING: Sleep laboratory. PARTICIPANTS: 15 healthy young men. RESULTS: TSD increased morning serum levels of NSE (P = 0.002) and S-100B (P = 0.02) by approximately 20%, compared with values obtained after a night of sleep. In contrast, the ratio of Aβ peptides 1-42 to 1-40 did not differ between the sleep interventions. CONCLUSIONS: Future studies in which both serum and cerebrospinal fluid are sampled after sleep loss should elucidate whether the increase in serum neuron-specific enolase and S100 calcium binding protein B is primarily caused by neuronal damage, impaired blood brain barrier function, or is just a consequence of increased gene expression in non-neuronal cells, such as leukocytes. JAMA Neurol Jun 2. doi: /jamaneurol [Epub ahead of print] Effect of 1 Night of Total Sleep Deprivation on Cerebrospinal Fluid β-Amyloid 42 in Healthy Middle-Aged Men: A Randomized Clinical Trial. Ooms S(1), Overeem S(2), Besse K(3), Rikkert MO(1), Verbeek M(4), Claassen JA(1). Author information: (1)Donders Institute for Brain, Cognition, and Behaviour, Radboud University Medical Center, Nijmegen, the Netherlands2Radboud Alzheimer Center, Radboud University Medical Center, Nijmegen, the Netherlands3Department of Geriatric Medicine, Radboud University. (2)Donders Institute for Brain, Cognition, and Behaviour, Radboud University Medical Center, Nijmegen, the Netherlands4Department of Neurology, Radboud University Medical Center, Nijmegen, the Netherlands. (3)Department of Anesthesiology, Radboud University Medical Center, Nijmegen, the Netherlands. (4)Donders Institute for Brain, Cognition, and Behaviour, Radboud University Medical Center, Nijmegen, the Netherlands2Radboud Alzheimer Center, Radboud University Medical Center, Nijmegen, the Netherlands4Department of Neurology, Radboud University Medical. IMPORTANCE Increasing evidence suggests a relationship between poor sleep and the risk of developing Alzheimer disease. A previous study found an effect of sleep on β-amyloid (Aβ), which is a key protein in Alzheimer disease pathology. OBJECTIVE To determine the effect of 1 night of total sleep deprivation on cerebrospinal fluid Aβ42 protein levels in healthy middle-aged men. DESIGN, SETTING, AND PARTICIPANTS The Alzheimer, Wakefulness, and Amyloid Kinetics (AWAKE) study at the Radboud Alzheimer Center, a randomized clinical trial that took place between June 1, 2012, and October 1, Participants were cognitively normal middle-aged men (40-60 years of age) with normal sleep (n = 26) recruited from the local population. INTERVENTIONS Participants were randomized to 1 night with unrestricted sleep (n = 13) or 1 night of total sleep deprivation (24 hours of wakefulness) (n = 13). MAIN OUTCOMES AND MEASURES Sleep was monitored using continuous polysomnographic recording from 3 pm until 10 am. Cerebrospinal fluid samples were collected using an intrathecal catheter at defined times to compare cerebral Aβ42 concentrations between evening and morning. RESULTS A night of unrestricted sleep led to a 6% decrease in Aβ42 levels of 25.3 pg/mL (95% CI [0.94, 49.6], P = .04), whereas sleep deprivation counteracted this decrease. When accounting for the individual trajectories of Aβ42 over time, a difference of 75.8 pg/mL of Aβ42 was shown between the unrestricted sleep and sleep deprivation group (95% CI [3.4, 148.4], P = .04). The individual trajectories of evening and morning Aβ42 concentrations differed between the unrestricted sleep and sleep deprivation groups (P = .04) in contrast to stable Aβ40, tau, and total protein levels. CONCLUSIONS AND RELEVANCE Sleep deprivation, or prolonged wakefulness, interferes with a physiological morning decrease in Aβ42. We hypothesize that chronic sleep deprivation increases cerebral Aβ42 levels, which elevates the risk of Alzheimer disease. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT J Neurosci Mar 19;34(12): doi: /JNEUROSCI Extended wakefulness: compromised metabolics in and degeneration of locus ceruleus neurons. Zhang J(1), Zhu Y, Zhan G, Fenik P, Panossian L, Wang MM, Reid S, Lai D, Davis JG, Baur JA, Veasey S. Author information: (1)Department of Respiratory and Critical Care Medicine, Peking University First Hospital, Beijing , China, Center for Sleep and Circadian Neurobiology, Department of Medicine, Institute for Diabetes, Obesity and Metabolism, and Department of Physiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania Modern society enables a shortening of sleep times, yet long-term consequences of extended wakefulness on the brain are largely unknown. Essential for optimal alertness, locus ceruleus neurons (LCns) are metabolically active neurons that fire at increased rates across sustained wakefulness. We hypothesized that wakefulness is a metabolic stressor to LCns and that, with extended wakefulness, adaptive mitochondrial metabolic responses fail and injury ensues. The nicotinamide adenine dinucleotide-dependent deacetylase sirtuin type 3 (SirT3) coordinates mitochondrial energy production and redox homeostasis. We find that brief wakefulness upregulates SirT3 and antioxidants in LCns, protecting metabolic homeostasis. Strikingly, mice lacking SirT3 lose the adaptive antioxidant response and incur oxidative injury in LCns across brief wakefulness. When wakefulness is extended for longer durations in wild-type mice, SirT3 protein declines in LCns, while oxidative stress and acetylation of mitochondrial proteins, including electron transport chain complex I proteins, increase. In parallel with metabolic dyshomeostasis, apoptosis is activated and LCns are lost. This work identifies mitochondrial stress in LCns upon wakefulness, highlights an essential role for SirT3 activation in maintaining metabolic homeostasis in LCns across wakefulness, and demonstrates that extended wakefulness results in reduced SirT3 activity and, ultimately, degeneration of LCns. Poor sleep is linked to cortical amyloid burden Self-reported somnolence, poorer sleep quality, and sleep problems were associated with greater amyloid burden in areas of the brain known to be affected by Alzheimer’s disease. Improved sleep quality might provide protection from Alzheimer’s disease. Sprecher. Annual meeting of the Associated Professional sleep Societies. Minneapolis. 2014 [1] Benedict C et al.Sleep Jan 1;37(1):195-8. [2] Ooms S et al. JAMA Neurol Jun 2. [3] Sprecher. Annual meeting of the Associated Professional sleep Societies. Minneapolis. 2014 [4] Zhang J et al. J Neurosci Mar 19;34(12):

Poor sleep quality is associated with increased cortical atrophy in community-dwelling adults
Poor sleep quality was associated with reduced volume within the right superior frontal cortex in cross-sectional analyses, and an increased rate of atrophy within widespread frontal, temporal, and parietal regions in longitudinal analyses. Cortical atrophy was correlated with sleep quality. Poor sleep quality may be a cause or a consequence of brain atrophy. Neurology Sep 3. pii: /WNL [Epub ahead of print] Poor sleep quality is associated with increased cortical atrophy in community-dwelling adults. Sexton CE(1), Storsve AB(2), Walhovd KB(2), Johansen-Berg H(2), Fjell AM(2). Author information: (1)From the University of Oxford (C.E.S., H.J.-B.), UK; and the University of Oslo (A.B.S., K.B.W., A.M.F.), Norway. (2)From the University of Oxford (C.E.S., H.J.-B.), UK; and the University of Oslo (A.B.S., K.B.W., A.M.F.), Norway. OBJECTIVE: To examine the relationship between sleep quality and cortical and hippocampal volume and atrophy within a community-based sample, explore the influence of age on results, and assess the possible confounding effects of physical activity levels, body mass index (BMI), and blood pressure. METHODS: In 147 community-dwelling adults (92 female; age 53.9 ± 15.5 years), sleep quality was measured using the Pittsburgh Sleep Quality Index and correlated with cross-sectional measures of volume and longitudinal measures of atrophy derived from MRI scans separated by an average of 3.5 years. Exploratory post hoc analysis compared correlations between different age groups and included physical activity, BMI, and blood pressure as additional covariates. RESULTS: Poor sleep quality was associated with reduced volume within the right superior frontal cortex in cross-sectional analyses, and an increased rate of atrophy within widespread frontal, temporal, and parietal regions in longitudinal analyses. Results were largely driven by correlations within adults over the age of 60, and could not be explained by variation in physical activity, BMI, or blood pressure. Sleep quality was not associated with hippocampal volume or atrophy. CONCLUSIONS: We found that longitudinal measures of cortical atrophy were widely correlated with sleep quality. Poor sleep quality may be a cause or a consequence of brain atrophy, and future studies examining the effect of interventions that improve sleep quality on rates of atrophy may hold key insights into the direction of this relationship Sexton CE, Storsve AB, Walhovd KB, Johansen-Berg H, Fjell AM. Neurology

Sleep is related to neuron numbers in the ventrolateral preoptic/intermediate nucleus in older adults with and without Alzheimer's disease The intermediate nucleus is the human homologue of the ventrolateral preoptic nucleus. More intermediate nucleus neurons are associated with better sleep while a paucity of intermediate nucleus neurons is accompanied by sleep fragmentation. Brain Aug 20. pii: awu222. [Epub ahead of print] Sleep is related to neuron numbers in the ventrolateral preoptic/intermediate nucleus in older adults with and without Alzheimer's disease. Lim AS(1), Ellison BA(2), Wang JL(2), Yu L(3), Schneider JA(3), Buchman AS(3), Bennett DA(3), Saper CB(4). Author information: (1)1 Division of Neurology, Department of Medicine, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, ON, Canada 2 Department of Neurology, Beth Israel Deaconess Medical Centre, Boston, MA, USA 3 Department of Neurology, Harvard Medical School, Boston, MA, USA. (2)2 Department of Neurology, Beth Israel Deaconess Medical Centre, Boston, MA, USA 3 Department of Neurology, Harvard Medical School, Boston, MA, USA. (3)4 Rush Alzheimer's Disease Centre, Rush University, Chicago, IL, USA. (4)2 Department of Neurology, Beth Israel Deaconess Medical Centre, Boston, MA, USA 3 Department of Neurology, Harvard Medical School, Boston, MA, USA Fragmented sleep is a common and troubling symptom in ageing and Alzheimer's disease; however, its neurobiological basis in many patients is unknown. In rodents, lesions of the hypothalamic ventrolateral preoptic nucleus cause fragmented sleep. We previously proposed that the intermediate nucleus in the human hypothalamus, which has a similar location and neurotransmitter profile, is the homologue of the ventrolateral preoptic nucleus, but physiological data in humans were lacking. We hypothesized that if the intermediate nucleus is important for human sleep, then intermediate nucleus cell loss may contribute to fragmentation and loss of sleep in ageing and Alzheimer's disease. We studied 45 older adults (mean age at death 89.2 years; 71% female; 12 with Alzheimer's disease) from the Rush Memory and Aging Project, a community-based study of ageing and dementia, who had at least 1 week of wrist actigraphy proximate to death. Upon death a median of 15.5 months later, we used immunohistochemistry and stereology to quantify the number of galanin-immunoreactive intermediate nucleus neurons in each individual, and related this to ante-mortem sleep fragmentation. Individuals with Alzheimer's disease had fewer galaninergic intermediate nucleus neurons than those without (estimate -2872, standard error = 829, P = 0.001). Individuals with more galanin-immunoreactive intermediate nucleus neurons had less fragmented sleep, after adjusting for age and sex, and this association was strongest in those for whom the lag between actigraphy and death was <1 year (estimate , standard error = , P = 0.023). This association did not differ between individuals with and without Alzheimer's disease, and similar associations were not seen for two other cell populations near the intermediate nucleus. These data are consistent with the intermediate nucleus being the human homologue of the ventrolateral preoptic nucleus. Moreover, they demonstrate that a paucity of galanin-immunoreactive intermediate nucleus neurons is accompanied by sleep fragmentation in older adults with and without Alzheimer's disease. © The Author (2014). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please PMID: [PubMed - as supplied by publisher] Lim AS, Ellison BA, Wang JL, Yu L, Schneider JA, Buchman AS, Bennett DA, Saper CB. Brain

Elevated CRP Level Linked to Decline in Executive Function and Frontal Lobe Damage
This study shows a link between elevated levels of high-sensitivity C-reactive protein (hs-CRP), an indicator of low-grade inflammation, and decline in executive function. Authors and Disclosures Susan Jeffrey Elevated CRP Level Linked to Decline in Executive Function and Frontal Lobe Damage Print This this In addition, although white matter hyperintensities and measures of brain atrophy were associated with CRP levels but did not reach statistical significance in this study, the researchers found a significant link between increased hs-CRP levels and diffusion tensor imaging (DTI) indicators of microstructural disintegration of white matter in the frontal lobe — the seat of executive function. April 1, 2010 — A new study shows a link between elevated levels of high-sensitivity C-reactive protein (hs-CRP), an indicator of low-grade inflammation, and decline in executive function but not other cognitive domains. "We thought that this might be a causal pathway, that the CRP may be causing this subtle white matter damage, which then causes executive dysfunction, but it's a still cross-sectional study, so we don't know about causality," lead author Heike Wersching, MD, from the Institute of Epidemiology and Social Medicine at the University of Münster, Germany, told Medscape Neurology. Dr. Wersching and colleagues have already begun a longitudinal study to look at this question further, she added, including some of these participants. An elevated hs-CRP level has been shown to be an independent predictor of myocardial infarction and stroke and has also been linked to Alzheimer's disease and dementia, the study authors write. Previous Findings Inconsistent Their findings are published in the March 30 issue of Neurology. Executive function is the cognitive domain that appears to be most vulnerable to vascular damage, Dr. Wersching noted. Some studies looking at the relationship between CRP and small vessel disease that manifests as white matter intensities and lacunar infarcts have found a link, but others have not replicated these findings. In this study, the researchers used DTI, a developing imaging technique that allows assessment of white matter microstructure, and detection of "even subtle pathologic changes in fiber integrity," the study authors write. "DTI changes correlate with clinical symptoms, histopathologic changes, and neuropsychological deficits in early stages of vascular and degenerative brain damage," they note. In this study, Dr. Wersching and colleagues looked at the association between hs-CRP levels and cognitive function in 447 participants in the Systematic Evaluation and Alteration of Risk Factors for Cognitive Health (SEARCH) Health Study, a population-based sample of community-dwelling elderly individuals without prior stroke. Of these, 321 also underwent high-field magnetic resonance imaging, including fluid-attenuated inversion recovery (FLAIR) sequences evaluating white matter hyperintensities, automated quantification of brain parenchyma volumes, and DTI to assess global and regional white matter integrity, quantified by fractional anisotropy (FA). All subjects also underwent cognitive assessment, including verbal memory, word fluency, and executive functions. They found that higher levels of hs-CRP were associated with worse performance on tests of executive function, even after adjustment for age, sex, education, and cardiovascular risk factors. "It's not like these people are really cognitively impaired," Dr. Wersching emphasized, "but it's just they do worse than people who have a lower CRP." A higher hs-CRP level was also related to reductions in global FA, as well as reduced regional FA in particular areas, including the frontal lobes, corona radiata, and the corpus callosum, particularly the genu, they write. Those areas, Dr. Wersching noted, "are very relevant for executive function." β Measure Table. Relation of High-Sensitivity C-Reactive Protein Level to Executive Function and Imaging Results P Value .02 −.095 Executive function −.237 Global FA < .001 −.246 FA frontal lobes −.222 FA corona radiata −.141 FA corpus callosum −.174 FA genu .016 They also found significant correlation of hs-CRP in motor regions, including the corona radiate and corticospinal tract. However, their assessment did not include a motor task, so "we cannot rule out that motor regions were affected in frontal areas as well, implying a specific effect of hs-CRP on motor fibers," the study authors note. FA = fractional anisotropy .004 Recent results from trials such as Justification for the Use of Statins in Primary Prevention: An Intervention Trial Evaluating Rosuvastatin (JUPITER) have shown that using anti-inflammatory drugs such as statins can lower hs-CRP levels, which is in turn associated with reduced cardiovascular events, they add (Ridker PM, et al. N Engl J Med. 2008;359: ). Lifestyle interventions, such as increased activity and reduced body weight, have also been shown to have beneficial effects on cognitive function and circulating hs-CRP levels. Assay for Brain Microvascular Disease "Whether lowering of CRP can also prevent cognitive decline and/or microstructural white matter alterations needs to be addressed in upcoming clinical trials," they conclude. "By allowing us to visualize both pathways and pathology, DTI provides us with the ability to expand vastly our understanding of the organization and functions of white matter," he notes. "As Wersching and colleagues demonstrated, the associations between C-reactive protein levels and FA contrasted with the failure to find similar associations with white matter lesions in FLAIR images." In an editorial accompanying the publication, Ronald J. Killiany, PhD, director of the Center for Biomedical Imaging at Boston University School of Medicine in Massachusetts, discusses and explains the new imaging techniques used in this study. The findings, Dr. Killiany concludes, "offer the prospect that a combination of measurements of systemic inflammation (C-reactive protein) and sensitive imaging modalities (DTI) might someday provide an assay for brain microvascular disease and provide a means for intervention." The study was supported by the German Research Foundation, the Volkswagen Foundation, the Marie Curie Research and Training Network (funded by the European Commission), the BMBF-Competence Network Mednet Atrial Fibrillation, BMBF-Research Consortium, and the Neuromedical Foundation Münster. Dr. Wersching has disclosed no relevant financial relationships. Disclosures for coauthors are listed in the paper. Dr. Killiany reports that he has a clinical affiliation with Essex Neurological Associates and a research affiliation with the MRI Centers of New England, serves as acting site principal investigator for the Boston University Contributions to the Alzheimer's Disease Neuroimaging Initiative, and receives research support from the National Institutes of Health. Neurology. 2010;74: , Wersching. Neurology. 2010;74: ,

5 TBD Psychoimmunology Articles
Fallon BA, Levin ES, Schweitzer PJ, Hardesty D. Inflammation and Central Nervous System Lyme Disease. Neurobiol Dis. (2010) 37(3): Bransfield RC. Relationship of Inflammation and Autoimmunity to Psychiatric Sequelae in Lyme Disease. Psychiatric Annals. (2012) 42(9): Bransfield RC. The Psychoimmunology of Lyme/Tick-Borne Diseases and its Association with Neuropsychiatric Symptoms. The Open Neurology Journal. ( 2012) 6, (Suppl 1-M3) Bransfield RC. The psychoimmunology of Lyme and associated diseases. Neurology, Psychiatry & Brain Research. (2014) 20(1);8. Ramesh G, Didier PJ, England JD, Santana-Gould L, Doyle-Meyers LA, Martin DS, Jacobs MB, Philipp MT. Inflammation in the pathogenesis of lyme neuroborreliosis. Am J Pathol May;185(5):

Inflammation, Th1 (Innate) Effects
Borrelia burgdorferi infections have been associated with the proinflammatory cytokines and chemokines. Proinflammatory lipoproteins. Other research demonstrates Bb induces an inflammatory response impacting neurons, glial and Schwann cells. Pathophysiological mechanisms include inflammation driving oxidative stress, excitotoxicity, changes in homocysteine metabolism, increases in indoleamine 2,3 dioxygenase causing changes in tryptophan metabolism and increases in quinolinic acid.

TBD and Increased Proinflammatory Cytokines
Increased levels of the proinflammatory cytokines IL-6, IL-8, IL-12, IL-17, IL-18 and interferon γ and of the chemokines CXCL12 and CXCL13 have been reported in the CSF of patients with neurologic Bb infections (Weller et al., 1991; Grusell et al., 2002; Widhe et al., 2002, 2005). The magnitude of IL-6 in human serum and CSF has been shown to correlate with disease activity in neurologic Bb infections (Weller et al., 1991). Elevated levels of IL-6 can cause symptoms of fatigue and malaise in Lyme disease as well as many other infectious conditions (Pachner et al., 1997). [1.2] PLoS Pathog Oct 14;6(10):e Early production of IL-22 but not IL-17 by peripheral blood mononuclear cells exposed to live Borrelia burgdorferi: the role of monocytes and interleukin-1. Bachmann M, Horn K, Rudloff I, Goren I, Holdener M, Christen U, Darsow N, Hunfeld KP, Koehl U, Kind P, Pfeilschifter J, Kraiczy P, Mühl H. pharmazentrum frankfurt/ZAFES, University Hospital Goethe University Frankfurt, Frankfurt, Germany. Abstract If insufficiently treated, Lyme borreliosis can evolve into an inflammatory disorder affecting skin, joints, and the CNS. Early innate immunity may determine host responses targeting infection. Thus, we sought to characterize the immediate cytokine storm associated with exposure of PBMC to moderate levels of live Borrelia burgdorferi. Since Th17 cytokines are connected to host defense against extracellular bacteria, we focused on interleukin (IL)-17 and IL-22. Here, we report that, despite induction of inflammatory cytokines including IL-23, IL-17 remained barely detectable in response to B. burgdorferi. In contrast, T cell-dependent expression of IL-22 became evident within 10 h of exposure to the spirochetes. This dichotomy was unrelated to interferon-γ but to a large part dependent on caspase-1 and IL-1 bioactivity derived from monocytes. In fact, IL-1β as a single stimulus induced IL-22 but not IL-17. Neutrophils display antibacterial activity against B. burgdorferi, particularly when opsonized by antibodies. Since neutrophilic inflammation, indicative of IL-17 bioactivity, is scarcely observed in Erythema migrans, a manifestation of skin inflammation after infection, protective and antibacterial properties of IL-22 may close this gap and serve essential functions in the initial phase of spirochete infection. [1] OostingM et al. Eur. J. Immunol : 172–181. [2] Fallon BA, Levin ES, Schweitzer PJ, Hardesty D. Neurobiol Dis

Bb Induces IL-10 Mediated Immunosupression
Bb enhances IL-10 production by macrophages and dendritic cells which impedes bacterial clearance, diminishes Bb uptake and trafficking by macrophages, suppresses ROS production, decreases production of proinflammatory mediators and co-stimulatory molecules, and suppress phagocytosis-associated events that are important for mediating both innate and adaptive immune responses. Chung Y, Zhang N, Wooten RM. Borrelia burgdorferi Elicited-IL-10 Suppresses the Production of Inflammatory Mediators, Phagocytosis, and Expression of Co-Stimulatory Receptors by Murine Macrophages and/or Dendritic Cells. PLoS One. (2013)8(12):e84980

Bb Proinflammatory Lipoproteins
Bb. spirochetes express lipoproteins on the outermembrane of the borrelial cell wall that are known to be pro-inflammatory. (Fraser et al., 1997; Casjens et al., 2000; Garcia-Monco & Benach 1997) These lipoproteins attract neutrophils (Szczepanski and Benach, 1991) and have been shown to be 50- to 500-fold more active inducers of cytokines and mitogens of B cells than lipoproteins of other organisms, such as Escherichia coli (Weis et al., 1994). B.b. spirochetes express lipoproteins on the outermembrane of the 284 borrelial cell wall that are known to be pro-inflammatory. More than 285 8% of the coding sequence of strain B31 is devoted to presumed 286 lipoprotein sequences (Fraser et al., 1997; Casjens et al., 2000) Fallon BA, Levin ES, Schweitzer PJ, Hardesty D. Neurobiol Dis Nov 26.

Bacterial & Borrelia Lipoproteins can Disseminate from the Periphery to Inflame the Brain
We conclude that some bacterial lipoproteins can disseminate from the periphery to inflame the brain. [1] Borrelia lipoproteins, including the VlsE lipoprotein, can disseminate from the periphery to inflame the brain. [2,3] Am J Pathol Apr 29; [Epub ahead of print] Bacterial Lipoproteins Can Disseminate from the Periphery to Inflame the Brain. Londono D, Cadavid D. The current view is that bacteria need to enter the brain to cause inflammation. However, in mice infected with the spirochete Borrelia turicatae, we observed widespread cerebral inflammation despite a paucity of spirochetes in the brain parenchyma at times of high bacteremia. Here we studied the possibility that bacterial lipoproteins may be capable of disseminating from the periphery across the blood-brain barrier to inflame the brain. For this we injected normal and infected mice intraperitoneally with lanthanide-labeled variable outer membrane lipoproteins of B. turicatae and measured their localization in blood, various peripheral organs, and whole and capillary-depleted brain protein extracts at various times. Lanthanide-labeled nonlipidated lipoproteins of B. turicatae and mouse albumin were used as controls. Brain inflammation was measured by TaqMan RT-PCR amplification of genes known to be up-regulated in response to borrelial infection. The results showed that the two lipoproteins we studied, LVsp1 and LVsp2, were capable of inflaming the brain after intraperitoneal injection to different degrees: LVsp1 was better than LVsp2 and Bt1 spirochetes at moving from blood to brain. The dissemination of LVsp1 from the periphery to the brain occurred under normal conditions and significantly increased with infection. In contrast, LVsp2 disseminated better to peripheral organs. We conclude that some bacterial lipoproteins can disseminate from the periphery to inflame the brain. Diego Cadavid, MD Borrelia Lipoproteins Can Disseminate from the Periphery to Inflame the Brain; Massachusetts General Hospital, Consultant in Immunology and Inflammatory Diseases; Biogen Idec, Associate Director of Experimental Neurology 11th Lyme & Tick Borne Diseases Conference 10-2 (1) Londono D, Cadavid D. Bacterial Lipoproteins Can Disseminate from the Periphery to Inflame the Brain. Am J Pathol Apr 29; [Epub ahead of print] (2) Cadavid D. Borrelia Lipoproteins Can Disseminate from the Periphery to Inflame the Brain. 11th Lyme & Tick Borne Diseases Conference. Oct 2, 2010. [3] Bransfield RC. Relationship of Inflammation and Autoimmunity to Psychiatric Sequelae in Lyme Disease. Psychiatric Annals. 42(9): September 2012.

Borrelia burgdorferi induces inflammation and apoptosis in cells from dorsal root ganglia
Bb neuroborreliosis affects both the peripheral and the central nervous systems. Radiculitis or nerve root inflammation, which can cause pain, sensory loss, and weakness, is the most common manifestation of peripheral LNB in humans. B. burgdorferi induced an inflammatory response and neuronal apoptosis of dorsal root ganglia. These pathophysiological processes could contribute to peripheral neuropathy in Lyme neuroborreliosis. J Neuroinflammation Jul 18;10:88. doi: / The Lyme disease spirochete Borrelia burgdorferi induces inflammation and apoptosis in cells from dorsal root ganglia. Ramesh G, Santana-Gould L, Inglis FM, England JD, Philipp MT. Source Division of Bacteriology and Parasitology, Tulane National Primate Research Center, Covington, LA, USA. Abstract BACKGROUND: Lyme neuroborreliosis (LNB), caused by the spirochete Borrelia burgdorferi, affects both the peripheral and the central nervous systems. Radiculitis or nerve root inflammation, which can cause pain, sensory loss, and weakness, is the most common manifestation of peripheral LNB in humans. We previously reported that rhesus monkeys infected with B. burgdorferi develop radiculitis as well as inflammation in the dorsal root ganglia (DRG), with elevated levels of neuronal and satellite glial cell apoptosis in the DRG. We hypothesized that B. burgdorferi induces inflammatory mediators in glial and neuronal cells and that this inflammatory milieu precipitates glial and neuronal apoptosis. METHODS: To model peripheral neuropathy in LNB we incubated normal rhesus DRG tissue explants with live B. burgdorferi ex vivo and identified immune mediators, producer cells, and verified the presence of B. burgdorferi in tissue sections by immunofluorescence staining and confocal microscopy. We also set up primary cultures of DRG cells from normal adult rhesus macaques and ihttp:// the cultures with live B. burgdorferi. Culture supernatants were subjected to multiplex ELISA to detect immune mediators, while the cells were evaluated for apoptosis by the in situ TUNEL assay. A role for inflammation in mediating apoptosis was assessed by evaluating the above phenomena in the presence and absence of various concentrations of the anti-inflammatory drug dexamethasone. As Schwann cells ensheath the dorsal roots of the DRG, we evaluated the potential of live B. burgdorferi to induce inflammatory mediators in human Schwann cell (HSC) cultures. RESULTS: Rhesus DRG tissue explants exposed to live B. burgdorferi showed localization of CCL2 and IL-6 in sensory neurons, satellite glial cells and Schwann cells while IL-8 was seen in satellite glial cells and Schwann cells. Live B. burgdorferi induced elevated levels of IL-6, IL-8 and CCL2 in HSC and DRG cultures and apoptosis of sensory neurons. Dexamethasone reduced the levels of immune mediators and neuronal apoptosis in a dose dependent manner. CONCLUSION: In this model, B. burgdorferi induced an inflammatory response and neuronal apoptosis of DRG. These pathophysiological processes could contribute to peripheral neuropathy in LNB. PMID: [PubMed - in process] PMCID: PMC Ramesh G, Santana-Gould L, Inglis FM, England JD, Philipp MT. J Neuroinflammation Jul 18;10:88.

Other Immune Effects In addition, B. burgdorferi outer surface protein A induces apoptosis and astrogliosis. B. burgdorferi spirochetes interacting with Schwann and glial cells also appear to produce nitric oxide, and the spirochetes can induce cytokines such as IL-6 or TNF-alpha in glial cells, both of which are neurotoxic and might provoke autoimmune reactions. Garcia-Monco JC, Benach JL. Mechanisms of injury in Lyme neuroborreliosis. Semin Neurol Mar;17(1):57-62 Bransfield R. The Psychoimmunology of Lyme/tick-borne diseases and its association with neuropsychiatric symptoms. Open Neurol J. 2012;6, (Suppl 1-M3) 88-93

Pathophysiology: Autoimmunity

Pediatric Autoimmune Diseases Associated with Strep (PANDAS)
Strep infections in a genetically susceptible individual at a young age can result in OCD, tics and sometimes attention span difficulties Often comorbid with Lyme/tick-borne disease PITAND (Pediatric Infection-triggered Autoimmune Neuropsychiatric Disorders) Symptom flares follow a strep infection and correlate with increased antibody production ASO & anti-DNA titers may be elevated Antibiotics are effective in treating and preventing these symptoms IVIG & plasmapheresis can also be effective.

Antibodies to surface dopamine-2 receptor in autoimmune movement and psychiatric disorders
Recent reports of autoantibodies that bind to neuronal surface receptors or synaptic proteins have defined treatable forms of autoimmune encephalitis. We conclude that assessment of dopamine-2 receptor antibodies can help define autoimmune movement and psychiatric disorders. Brain Nov;135(Pt 11): doi: /brain/aws256. Epub 2012 Oct 11. Antibodies to surface dopamine-2 receptor in autoimmune movement and psychiatric disorders. Dale RC, Merheb V, Pillai S, Wang D, Cantrill L, Murphy TK, Ben-Pazi H, Varadkar S, Aumann TD, Horne MK, Church AJ, Fath T, Brilot F. Neuroimmunology group, Institute for Neuroscience and Muscle Research, The Kids Research Institute at the Children’s Hospital at Westmead, University of Sydney, Westmead NSW 2145, Australia. Comment in Brain Nov;135(Pt 11): J Neurol Apr;260(4): Mov Disord Jun;28(6):733. Recent reports of autoantibodies that bind to neuronal surface receptors or synaptic proteins have defined treatable forms of autoimmune encephalitis. Despite these developments, many cases of encephalitis remain unexplained. We have previously described a basal ganglia encephalitis with dominant movement and psychiatric disease, and proposed an autoimmune aetiology. Given the role of dopamine and dopamine receptors in the control of movement and behaviour, we hypothesized that patients with basal ganglia encephalitis and other putative autoimmune basal ganglia disorders harboured serum autoantibodies against important dopamine surface proteins. Basal ganglia encephalitis sera immunolabelled live surface cultured neurons that have high expression of dopamine surface proteins. To detect autoantibodies, we performed flow cytometry cell-based assays using human embryonic kidney cells to express surface antigens. Twelve of 17 children (aged years, nine males) with basal ganglia encephalitis had elevated immunoglobulin G to extracellular dopamine-2 receptor, compared with 0/67 controls. Immunofluorescence on wild-type mouse brain showed that basal ganglia encephalitis sera immunolabelled microtubule-associated protein 2-positive neurons in striatum and also in cultured striatal neurons, whereas the immunolabelling was significantly decreased in dopamine-2 receptor knock-out brains. Immunocytochemistry confirmed that immunoreactivity localized to the surface of dopamine-2 receptor-transfected cells. Immunoabsorption of basal ganglia encephalitis sera on dopamine-2 receptor-transfected human embryonic kidney cells decreased immunolabelling of dopamine-2 receptor-transfected human embryonic kidney cells, neurons and wild-type mouse brain. Using a similar flow cytometry cell-based assay, we found no elevated immunoglobulin G binding to dopamine 1, 3 or 5 receptor, dopamine transporter or N-methyl-d-aspartate receptor. The 12 dopamine-2 receptor antibody-positive patients with encephalitis had movement disorders characterized by parkinsonism, dystonia and chorea. In addition, the patients had psychiatric disturbance with emotional lability, attention deficit and psychosis. Brain magnetic resonance imaging showed lesions localized to the basal ganglia in 50% of the patients. Elevated dopamine-2 receptor immunoglobulin G was also found in 10/30 patients with Sydenham's chorea, 0/22 patients with paediatric autoimmune neuropsychiatric disorders associated with streptococcal infection and 4/44 patients with Tourette's syndrome. No dopamine-1 receptor immunoglobulin G was detected in any disease or control groups. We conclude that assessment of dopamine-2 receptor antibodies can help define autoimmune movement and psychiatric disorders. PMID: [PubMed - indexed for MEDLINE] Dale RC et al. Brain Nov;135(Pt 11):

Autoimmune Encephalopathies
Paraneoplastic limbic encephalopathy autoantibodies directed against intracellular neuronal antigens Nonparaneoplastic limbic encephalitis voltage-gated potassium channel limbic encephalitis Hashimoto’s encephalopathy Anti-NMDA & other glutamate receptor encephalitis Encephalitis associated with GABAergic signaling Kayser, Josep Dalmau j; Psychiatric Times. Psychiatric Presentations of Autoimmune Encephalopathies Vol 27(3)

Autism: Brain Inflammation & Anti-Neural Antibodies
The blood–brain barrier is permeable during fetal development and can be compromised by infections and environmental exposures throughout life. The absence of a complete barrier allows immune components access to the brain. Individuals with autism show increased pro-inflammatory cytokines in the brain, as well as activation of resident immune cells known as microglia. Additionally, antibodies that target brain tissues have been described in both children with autism and their mothers. These immunological phenomena may interfere with normal brain development and function, potentially contributing to the development and/or symptoms of autism spectrum disorders During postnatal life, an intact blood–brain barrier limits the entry of immune species into the brain. Lymphocytes, macrophages, various cytokines, and antibodies are generally maintained in the periphery. However, the blood–brain barrier is permeable during fetal development and can be compromised by infections and environmental exposures throughout life. The absence of a complete barrier allows immune components access to the brain. Individuals with autism show increased pro-inflammatory cytokines in the brain, as well as activation of resident immune cells known as microglia. Additionally, antibodies that target brain tissues have been described in both children with autism and their mothers. These immunological phenomena may interfere with normal brain development and function, potentially contributing to the development and/or symptoms of autism spectrum disorders Goines & Van de Water

Autoimmune diseases and severe infections as risk factors for mood disorders: a nationwide study
Autoimmune diseases and infections are risk factors for subsequent mood disorder diagnosis. These associations seem compatible with an immunologic hypothesis for the development of mood disorders in subgroups of patients. JAMA Psychiatry Aug 1;70(8): doi: /jamapsychiatry Autoimmune diseases and severe infections as risk factors for mood disorders: a nationwide study. Benros ME, Waltoft BL, Nordentoft M, Ostergaard SD, Eaton WW, Krogh J, Mortensen PB. National Centre for Register-Based Research, Aarhus University, Aarhus, Denmark2Mental Health Centre Copenhagen, University of Copenhagen, Faculty of Health Sciences, Copenhagen, Denmark. IMPORTANCE Mood disorders frequently co-occur with medical diseases that involve inflammatory pathophysiologic mechanisms. Immune responses can affect the brain and might increase the risk of mood disorders, but longitudinal studies of comorbidity are lacking. OBJECTIVE To estimate the effect of autoimmune diseases and infections on the risk of developing mood disorders. DESIGN Nationwide, population-based, prospective cohort study with 78 million person-years of follow-up. Data were analyzed with survival analysis techniques and adjusted for calendar year, age, and sex. SETTING Individual data drawn from Danish longitudinal registers. PARTICIPANTS A total of 3.56 million people born between 1945 and 1996 were followed up from January 1, 1977, through December 31, 2010, with 91 637 people having hospital contacts for mood disorders. MAIN OUTCOMES AND MEASURES The risk of a first lifetime diagnosis of mood disorder assigned by a psychiatrist in a hospital, outpatient clinic, or emergency department setting. Incidence rate ratios (IRRs) and accompanying 95% CIs are used as measures of relative risk. RESULTS A prior hospital contact because of autoimmune disease increased the risk of a subsequent mood disorder diagnosis by 45% (IRR, 1.45; 95% CI, ). Any history of hospitalization for infection increased the risk of later mood disorders by 62% (IRR, 1.62; 95% CI, ). The 2 risk factors interacted in synergy and increased the risk of subsequent mood disorders even further (IRR, 2.35; 95% CI, ). The number of infections and autoimmune diseases increased the risk of mood disorders in a dose-response relationship. Approximately one-third (32%) of the participants diagnosed as having a mood disorder had a previous hospital contact because of an infection, whereas 5% had a previous hospital contact because of an autoimmune disease. CONCLUSIONS AND RELEVANCE Autoimmune diseases and infections are risk factors for subsequent mood disorder diagnosis. These associations seem compatible with an immunologic hypothesis for the development of mood disorders in subgroups of patients. PMID: [PubMed - in process] Benros ME, Waltoft BL, Nordentoft M, Ostergaard SD, Eaton WW, Krogh J, Mortensen PB. JAMA Psychiatry Aug 1;70(8):

Th2 Autoimmune Effects Microbial sequences are incorporated into human DNA & contribute to autoimmune risk. Bb surface glycolipids and flagella antibodies appear to elicit anti-neuronal antibodies. Anti-neuronal antibodies in late stage Bb infections and lipid exchange between Bb and host cells may provoke autoimmune processes. Autoimmune mechanisms provoked by Bb are implicated in the pathogenesis of psychotic & neurologic symptoms of the central and peripheral nervous systems.[1,2] [1] Carter CJ. Schizophrenia: a pathogenetic autoimmune disease caused by viruses and pathogens and dependent on genes. J Pathog. 2011; doi: /2011/ [2] Schluesener et al. Autoimmunity in Lyme disease: molecular cloning of antigens recognized by antibodies in the cerebrospinal fluid. Autoimmunity. 1989;2(4):

Bb. Surface Antigens Cause Molecular Mimicry
Bb. spirochetes surface glycolipids may elicit cross-reactive antibodies (Garcia-Monco and Benach 1997). [1] IgM Bb. flagella antibodies cross-reacted with neuronal antigens (Sigal and Tatum, 1988; Sigal, 1993; Sigal and Williams, 1997). [1] These processes can evoke autoimmune symptoms in the brain, including intrusive symptoms, obsessiveness, movement disorders, paranoia, and other symptoms. [2,3] [1] Fallon BA, Levin ES, Schweitzer PJ, Hardesty D. Neurobiol Dis Nov 26. [2] Alaedini A, Latov N. J Neuroimmunol. 2005;159: [3] Bransfield R. Neurol Psychiatry Brain Res. 2012;18(3):42.

Anti-Neural Antibody Reactivity and Persistent Lyme Symptoms
Anti-neural antibody reactivity is significantly higher in Bb infected patients vs control group. (p<0.01) [1] Immunohistochemical analysis of serum antibody activity demonstrated binding to cells in the central and peripheral nervous systems. [1] These immunologic abnormalities can be caused by an ongoing infectious process & persistent infection is required for the production of autoantibodies such as the anti-neural antibodies. [2] [1] Chandra A, et al. Brain Behav Immun Aug;24(6): [2] Stricker R, Johnson L. Brain, Behavior, and Immunity Aug;24(6):1025.

Lipid Exchange between Borrelia burgdorferi and Host Cells
"Furthermore, exchange of lipids between spirochetes and host cells could be important for cholesterol acquisition by the spirochetes, acting as an important nutritional source. Additionally, acquisition of spirochetal antigens by the cells could result in presentation of these antigens in a manner that would be recognized by the immune response leading to a potential mechanism for cellular damage." Abstract Borrelia burgdorferi, the agent of Lyme disease, has cholesterol and cholesterol-glycolipids that are essential for bacterial fitness, are antigenic, and could be important in mediating interactions with cells of the eukaryotic host. We show that the spirochetes can acquire cholesterol from plasma membranes of epithelial cells. In addition, through fluorescent and confocal microscopy combined with biochemical approaches, we demonstrated that B. burgdorferi labeled with the fluorescent cholesterol analog BODIPY-cholesterol or 3H-labeled cholesterol transfer both cholesterol and cholesterol-glycolipids to HeLa cells. The transfer occurs through two different mechanisms, by direct contact between the bacteria and eukaryotic cell and/or through release of outer membrane vesicles. Thus, two-way lipid exchange between spirochetes and host cells can occur. This lipid exchange could be an important process that contributes to the pathogenesis of Lyme disease. Crowley JT et al. PLOS Pathogens. 2013;9(1): e

Pathophysiology: Biochemistry

Immune Provoked Pathophysiology
Pathophysiologic changes are associated with oxidative stress, excitotoxicity, changes in homocysteine metabolism, mitochondrial dysfunction and altered tryptophan pathways.

Franklin TC, Wohleb ES, Duman RS. Psychiatric Annals. 2015;45(5)235.

Oxidative Stress “Oxygen free radicals or activated oxygen has been implicated in diverse environmental stresses in plants and animals and appears to be a common participation in most, if not all, degenerative conditions in eukaryotic cells. The peroxidation of lipids, the cross-linking and inactivation of proteins and mutations in DNA are typical consequences of free radicals” Bryan D. McKersie Dept of Crop Science, University of Guelph

Excitotoxicity Homocysteine excites NMDA receptors and is at least as neurotoxic as glutamate. Glutamate excites NMDA receptors. Homocysteine enhances this excitatory effect on NMDA receptors. Once glutamate and homocysteine bind to the receptor, calcium ions flow into the cell, increasing the electrical charge inside the neuron. The increased intracellular charge triggers changes in the neuron that may ultimately result in neuronal death the neuron’s cell membrane and essential proteins begin to degrade. Reactive oxygen species are generated Cell death eventually results from the combination of oxidative stress, DNA-damage, and apoptosis triggered by increased calcium levels. Thus, increased concentrations of homocysteine in the CNS may trigger the cascade of events that follow hyper-activation of the NMDA receptor ultimately leading to nerve cell death. Bleich S et al. Prog Neuropsychopharmacol Biol Psychiatry. 2004;28:

Homocysteine Metabolism in the Brain
Remethylation Transulfuration Homocysteine metabolism in the brain is less efficient than in the serum. In the serum, Hcy is metabolized through two pathways, methylation and transulfuration. In the brain, the transulfuration enzyme cystathionine betasynthase, is minimally expressed resulting in Hcy having to be metabolized through the methylation pathway. Inadequate remethylation leads to increased Hcy levels which are excitotoxic.

Homocysteine, depression and cognitive function in older adults
Depression and high total plasma homocysteine are independently associated with cognitive impairment in older adults. Elevated total plasma homocysteine was associated with weaker performance in tests of immediate and delayed memory and global cognitive performance when compared to those with normal total plasma homocysteine independent of the presence of major depression or the severity of depressive symptoms. J Affect Disord Aug 5. pii: S (13)00565-X. doi: /j.jad [Epub ahead of print] Homocysteine, depression and cognitive function in older adults. Ford AH, Flicker L, Singh U, Hirani V, Almeida OP. Western Australian Centre for Health & Ageing (M573), Centre for Medical Research, University of Western Australia, 35 Stirling Highway, Crawley, Perth, WA 6009, Australia; School of Psychiatry and Clinical Neurosciences, University of Western Australia, 35 Stirling Highway, Crawley, Perth, WA 6009, Australia; Department of Psychiatry, Royal Perth Hospital, 50 Murray Street, Perth, WA 6000, Australia. Electronic address: BACKGROUND: Depression and high total plasma homocysteine (tHcy) are independently associated with cognitive impairment in older adults. We designed this study to determine if high tHcy is a mediator of cognitive performance in older adults with major depression. METHODS: We recruited 358 community-dwelling older adults experiencing depressive symptoms, 236 (65.9%) of who met DSM-IV-TR criteria for major depression. Assessment included the Montgomery Asberg Depression Rating Scale (MADRS), fasting tHcy and the Consortium to Establish a Registry for Alzheimer's Disease neuropsychological battery. RESULTS: Individuals with major depression and high tHcy had significantly worse immediate verbal and delayed visual recall. Non-depressed participants with high tHcy had lower MMSE, immediate and delayed recall scores than those with normal tHcy. The odds of cognitive inefficiency for those with high tHcy was nearly doubled for the MMSE (OR 1.9, 95%CI ), immediate (OR 1.9, 95%CI ) and delayed (OR 1.9, 95%CI ) word recall after adjusting for age, gender, IHD and MADRS score. LIMITATIONS: The presence of sub-syndromal depressive symptoms in our non-depressed group and exclusion of participants with established cognitive impairment may limit the generalizability of this study. CONCLUSIONS: Elevated tHcy was associated with weaker performance in tests of immediate and delayed memory and global cognitive performance when compared to those with normal tHcy independent of the presence of major depression or the severity of depressive symptoms. Homocysteine lowering B-vitamin supplementation may offer a potential therapeutic target to try and mitigate the often-disabling impact of cognitive deficits found in this population. Copyright © 2013 Elsevier B.V. All rights reserved. PMID: [PubMed - as supplied by publisher] Ford AH, Flicker L, Singh U, Hirani V, Almeida OP. J Affect Disord Aug 5. pii: S (13)00565-X.

IDO shifts tryptophan metabolism from serotonin to quinolinic acid
In Lyme/coinfections, chronic activation of TNF-alpha stimulates IFN-gamma, which overactivates indoleamine 2,3 dioxygenase (IDO), the rate-limiting enzyme for catabolism of tryptophan in the brain. Overactivated IDO causes neurotoxicity, and immune suppression (of cytotoxic T cells). Underactivation of IDO is known to cause autoimmune reactions. But it has recently been discovered that overactivated IDO causes autoimmune B cell antibody production. I assume this is the reason for supposed autoimmunity in Lyme/coinfections. The damage from autoimmune reactions can be temporarily repaired with stem cells. This is the explanation that makes the most sense to me. Anthony Murawski Attorney at Law th Avenue SW Seattle, WA 98126 (206)

IDO and interferon--induced depressive symptoms: a shift in hypothesis from tryptophan depletion to neurotoxicity The enzyme indoleamine 2,3-dioxygenase (IDO), which converts tryptophan (TRP) into kynurenine (KYN) and which is stimulated by proinflammatory cytokines, may be implicated in the development of IFN--induced depressive symptoms, first by decreasing the TRP availability to the brain and second by the induction of the KYN pathway resulting in the production of neurotoxic metabolites. This study does support a role for IDO activity in the pathophysiology of IFN--induced depressive symptoms, through its induction of neurotoxic KYN metabolites. IDO and interferon--induced depressive symptoms: a shift in hypothesis from tryptophan depletion to neurotoxicity M C Wichers1, G H Koek2, G Robaeys3, R Verkerk4, S Scharpé4 and M Maes1 1Department of Psychiatry and Neuropsychology, Maastricht University, Maastricht, The Netherlands 2Department of Internal Medicine, Academic Hospital Maastricht (AZM), Maastricht, The Netherlands 3Department of Internal Medicine, Ziekenhuis Oost Limburg (ZOL), Genk, Belgium 4Department of Medical Biochemistry, University of Antwerp, Edegem, Belgium Correspondence: MC Wichers, Department of Psychiatry and Neuropsychology, South Limburg Mental Health Research and Teaching Network, EURON, Maastricht University, PO BOX 616, Parallwlweg 45-47, Maastricht 6200 MD, The Netherlands. Received 18 May 2004; Revised 13 August 2004; Accepted 6 September 2004; Published online 19 October Studies show that administration of interferon (IFN)- causes a significant increase in depressive symptoms. The enzyme indoleamine 2,3-dioxygenase (IDO), which converts tryptophan (TRP) into kynurenine (KYN) and which is stimulated by proinflammatory cytokines, may be implicated in the development of IFN--induced depressive symptoms, first by decreasing the TRP availability to the brain and second by the induction of the KYN pathway resulting in the production of neurotoxic metabolites. Sixteen patients with chronic hepatitis C, free of psychiatric disorders and eligible for IFN- treatment, were recruited. Depressive symptoms were measured using the Montgomery Asberg Depression Rating Scale (MADRS). Measurements of TRP, amino acids competing with TRP for entrance through the blood–brain barrier, KYN and kynurenic acid (KA), a neuroprotective metabolite, were performed using high-performance liquid chromatography. All assessments were carried out at baseline and 1, 2, 4, 8, 12 and 24 weeks after treatment was initiated. The MADRS score significantly increased during IFN- treatment as did the KYN/TRP ratio, reflecting IDO activity, and the KYN/KA ratio, reflecting the neurotoxic challenge. The TRP/CAA (competing amino acids) ratio, reflecting TRP availability to the brain, did not significantly change during treatment. Total MADRS score was significantly associated over time with the KYN/KA ratio, but not with the TRP/CAA ratio. Although no support was found that IDO decreases TRP availability to the brain, this study does support a role for IDO activity in the pathophysiology of IFN--induced depressive symptoms, through its induction of neurotoxic KYN metabolites. Keywords: interferon-, depressive symptoms, kynurenine pathway, neurotoxicity, quinolinic acid, kynurenic acid M C Wichers, G H Koek, G Robaeys, R Verkerk, S Scharpé, M Maes. Molecular Psychiatry (2005) 10, 538–544. doi: /sj.mp Published online 19 October 2004

Bb and Quinolinic Acid CSF quinolinic acid is significantly elevated in Bb infection-- dramatically in patients with CNS inflammation, less in encephalopathy and correlates with the severity of CNS symptoms, including depression. The presence of this known agonist of NMDA synaptic function--a receptor involved in learning, memory, and synaptic plasticity--may contribute to the neurologic and cognitive deficits seen in many Lyme disease patients. Halperin JJ, Heyes MP. Neuroactive kynurenines in Lyme borreliosis. Neurology. 1992;42(1):43-50. Wichers MC, Koek GH, Robaeys G, et al.: IDO and interferon-induced depressive symptoms: a shift in hypothesis from tryptophan depletion to neurotoxicity. Mol Psychiatry. 2005;10:538–544. Bransfield Psychiatric Annals. 42(9): September 2012

Clinical Presentations

Infections Throughout the Lifespan
Infections and immune reactions to them have different effects throughout the lifespan and are mostly more severe in the young and old. Immune provoked brain impairment can cause: Autism, schizophrenia, etc. in the fetus. Impaired cognitive and emotional developmental in children and adolescents. Hyperarousal, apathy, anxiety, depression in adults. Dementia in the less resilient geriatric population.

Autism

Infections Associated with Autism Spectrum Disorders
Babesia Bartonella Blastocystis Borna (animal model) Borrelia burgdorferi and other tick-borne diseases Chlamydia pneunomiae Cytomegalovirus Ehrlichia Herpes simplex Human Herpesvirus-6 Herpes virus family Mycoplasma fermentans Mycoplasma genitalium Mycoplasma hominis Mycoplasma pneumoniae Plasmodium (malaria) Rubella Rubeola Shigella Taenia solium (Neurocysticercosis) Toxoplasma gondii (Toxoplasmosis) Treponema pallidum pallidum (Syphilis) Varicella Unknown viral and other infectious Bransfield RC. Preventable cases of autism: relationship between chronic infectious diseases and neurological outcome Pediatric Health. 3(2): (2009)

Chronic Infections Associated with Autism Spectrum Disorder
Babesia Bartonella Blastocystis Borrelia burgdorferi Chlamydia pneumoniae Cytomegalovirus Ehrlichia Herpes simplex Herpes virus family Human heprevirus-6 Mycoplasma fermentans Mycoplasma genetalium Mycoplasma hominis Mycoplasma pneumoniae Plasmodium Taenia solium Toxoplasma gondaii Treponema pallidum pallidum Bransfield RC. Preventable cases of autism: relationship between chronic infectious diseases and neurological outcome Pediatric Health. 3(2): (2009)

Preventable cases of autism: relationship between chronic infectious diseases and neurological outcome There is evidence that chronic infections and the immune reactions associated with them may contribute to causing autism spectrum disorders. These infections include Babesia, Bartonella, Borrelia burgdorferi, Ehrlichia, Human herpesvirus-6, Chlamydia pneumoniae and Mycoplasma (in particular Mycoplasma fermentans). Maternal immune reactions to infections appear to adversely affect fetal brain development and possible pathophysiological mechanisms include both inflammatory cytokines. The timing of the infection and immune response is critical in determining the pathophysiology. It is advisable to evaluate women who are pregnant or planning on becoming pregnant for chronic infections, especially if they demonstrate symptoms of an infection or a systemic illness with persistent inflammatory symptoms. Bransfield R. Pediatric Health. 3(2): (2009)

Autism Spectrum Disorders
There is evidence some cases of Autism Spectrum Disorder are associated with tick-borne diseses. [see references] Regressive autism associated with Bb may improve in response to antibiotic treatment [1] and reactivity of the 34 and 31 bands on the Bb Western blot are particularly significant. [1] Kuhn M, Grave S, Bransfield R, Harris S. Med Hypotheses. 78(5): (2012) [2] Kuhn M, Bransfield R. Divergent opinions of Lyme disease diagnosis and implications for children co-morbid with Autism Spectrum Disorder. Med Hypotheses

Articles on Tick-Borne Disease and Autism Spectrum Disorders I
Bransfield RC, Fallon BA, Raxlen B, Shepler L, Sherr VT. A Modest Proposal, Psychiatric News, 31(18):16 (1998) Nicolson GL, Gan R, Nicolson NL, Haier J. Evidence for Mycoplasma, Chlamydia pneunomiae and HHV-6 Co-infections in the blood of patients with Autism Spectrum Disorders. J Neuroscience Res. 2007;85: Bransfield RC, Wulfman JS, Harvey WT, Usman AI. The association between tick-borne infections, Lyme borreliosis and autism spectrum disorders Medical Hypotheses. 70(5): (2008) Nicholson G. Chronic Bacterial and Viral Infections in Neurodegenerative and Neurobehavioral Diseases Laboratory Medicine. 39(5)291-9 (2008) Vojdani A. Antibodies as predictors of complex autoimmune diseases and cancer. Int J Immunopathol Pharmacol. 21(3): (2008) Erratum in: Int J Imunopathol Pharmacol. 21(4):following 1051 (2008) Bransfield RC. Preventable cases of autism: relationship between chronic infectious diseases and neurological outcome Pediatric Health. 3(2): (2009) Bransfield R. Chronic Infections Contributing to Autism Spectrum Disorders. Neurology Psychiatry & Brain Research. Universitatsverlag. Heidelberg. 16, Suppl 1 (2009)

Articles on Tick-Borne Disease and Autism Spectrum Disorders II
Kuhn M, Grave S, Bransfield R, Harris S. Long term antibiotic therapy may be an effective treatment for children co-morbid with Lyme disease and autism spectrum disorder. Med Hypotheses. 78(5): (2012) Bransfield R. Relationship of Inflammation and Autoimmunity to Psychiatric Sequelae in Lyme Disease. Psychiatric Annals. 42(9): September 2012. Bransfield R.The Psychoimmunology of Lyme/Tick-Borne Diseases and its Association with Neuropsychiatric Symptoms. The Open Neurology Journal , 6, (Suppl 1-M3) 88-93 Bransfield R. Kuhn M. Autism and Lyme Disease. JAMA. 310(8). (2013) Burbelo PD, Swedo SE, Thurm A, Bayat A, Levin AE, Marques A, Iadarola MJ. Lack of serum antibodies against Borrelia burgdorferi in children with autism. Clin Vaccine Immunol Jul;20(7):1092-3 Planche P, Botbol M. Lyme disease, Autism Spectrum Disorder and antibiotic therapy: A case report. Annales Médico-psychologiques, revue psychiatrique 171(10):711–715. (2013) Kuhn M, Bransfield R. Divergent opinions of Lyme disease diagnosis and implications for children co-morbid with Autism Spectrum Disorder. Med Hypotheses

Intrusive Symptoms “Frightening, stabbing, horrific images -usually of death, dying or pain and suffering. Often gory and unreal as in a horror story. Faces mostly with blood or terror exaggerated awful expressions. Visions of stabbing or killing often of those close to you or familiar. Episodic, not continuous. Fleeting faces most usually of the worse possible situation Helpless stumped bodies perhaps close to death. These images don’t seem to necessarily be associated with a particular occasion, place or time, but come and invade the privacy of my mind.”

Lyme/TBD & Intrusive Symptoms
131 cases with a history of complex interactive infections, mostly Borrelia, Babesia, Bartonella, Anaplasma, Ehrlichia and other known and unknown pathogens whose eradication could not be confirmed by current technology, demonstrates 45 (34%) acquired intrusive symptoms (89% aggressive, 18% sexual and altered sexual imagery, 40% other--bizarre, horrific, etc.). Within these 45 cases other symptoms included cognitive 100%, neurological 98%, musculoskeletal 89%, obsessiveness 89%, depersonalization 87%, depression 80%, low frustration tolerance 80%, fatigue 76%, explosive anger 73%, suicidal 69%, social isolation 67%, anhedonia 62%, disinhibition 62%, paranoia 49%, hallucinations 42%, homicidal 31%, OCD 29%, PTSD 13%. [Bransfield RC, in review] LSTBD causes an increase of chronic inflammatory markers (TNF-alpha, IL-1β, IL-6, CRP) that also correlate with intrusive symptoms, severity of symptom, volumetric brain changes (hippocampal shrinkage) and activation of the basolateral amygdala and ventral hippocampus [Bransfield RC Copeland Bob P Gill J Heath NM Zimmerman G Eraly SA Ritov. G 2014]. Bransfield R. Neurology Psychiatry & Brain Research. Vol 22(2016).

Schizophrenia

PRENATAL INFECTION, MATERNAL IMMUNE ACTIVATION, AND RISK FOR SCHIZOPHRENIA
A body of epidemiological literature has suggested an association between prenatal infection, subsequent maternal immune activation (MIA), and later risk of schizophrenia. The findings from these preclinical studies indicate that severe infection and immune activation during pregnancy can negatively impact offspring brain development and impair adult behavior. This review aims to summarize the major epidemiological and preclinical findings addressing the connection between prenatal infection and immune activation and later risk of developing schizophrenia, as well as the more limited literature addressing the mechanisms by which this gestational insult might affect offspring neurodevelopment. Canetta SE, Brown AS. Transl Neurosci Dec 1;3(4):

Is childhood cat ownership a risk factor for schizophrenia later in life?
Two previous studies suggested that childhood cat ownership is a possible risk factor for later developing schizophrenia or other serious mental illness. We therefore used an earlier, large NAMI questionnaire to try and replicate this finding. The results were the same, suggesting that cat ownership in childhood is significantly more common in families in which the child later becomes seriously mentally ill. If true, an explanatory mechanism may be Toxoplasma gondii. We urge our colleagues to try and replicate these findings to clarify whether childhood cat ownership is truly a risk factor for later schizophrenia. Fuller Torrey E, Simmons W, Yolken RH. Schizophr Res Jun;165(1):1-2.

Geographical correlation of schizophrenia to Ixodes ticks and Lyme disease in the USA
The epidemiological correlation between Ixodes ticks and schizophrenia originally published by Brown has been adjusted according to the more recent epidemiological data on the risk of Lyme disease including zooprophylaxis.

Associations between Chlamydophila infections, schizophrenia and risk of HLA-A10
We have previously observed increased frequencies of chlamydial infections and of human lymphocyte antigen (HLA)-A10 in independent studies of schizophrenia. We found chlamydial infection in 40.3% of the schizophrenic patients compared to 6.7% in the controls. The association of schizophrenia with Chlamydiaceae infections was highly significant (P=1.39 x 10(-10), odds ratio (OR)=9.43), especially with Chlamydophila psittaci (P=2.81 x 10(-7), OR=24.39). Schizophrenic carriers of the HLA-A10 genotype were clearly most often infected with Chlamydophila, especially C. psittaci (P=8.03 x 10(-5), OR=50.00). Chlamydophila infections represent the highest risk factor yet found to be associated with schizophrenia. This risk is even further enhanced in carriers of the HLA-A10 genotype. Mol Psychiatry Mar;12(3): Epub 2006 Nov 14. Associations between Chlamydophila infections, schizophrenia and risk of HLA-A10. Fellerhoff B(1), Laumbacher B, Mueller N, Gu S, Wank R. Author information: (1)Institute of Immunology, Ludwig-Maximilans University of Munich, Munich, Germany. Several microbes have been suspected as pathogenetic factors in schizophrenia. We have previously observed increased frequencies of chlamydial infections and of human lymphocyte antigen (HLA)-A10 in independent studies of schizophrenia. Our aim here was to analyze frequencies of three types of Chlamydiaceae in schizophrenic patients (n=72), random controls (n=225) and hospital-patient controls (n=36), together with HLA-A genotypes. Patients were diagnosed with schizophrenia according to Diagnostic and Statistical Manual of Mental Disorders-IV. Blood samples were collected at the beginning of hospitalization and analyzed with Chlamydiaceae species-specific polymerase chain reaction (PCR). Control panels consisted of randomly selected volunteers and hospitalized, non-schizophrenic patients. We found chlamydial infection in 40.3% of the schizophrenic patients compared to 6.7% in the controls. The association of schizophrenia with Chlamydiaceae infections was highly significant (P=1.39 x 10(-10), odds ratio (OR)=9.43), especially with Chlamydophila psittaci (P=2.81 x 10(-7), OR=24.39). Schizophrenic carriers of the HLA-A10 genotype were clearly most often infected with Chlamydophila, especially C. psittaci (P=8.03 x 10(-5), OR=50.00). Chlamydophila infections represent the highest risk factor yet found to be associated with schizophrenia. This risk is even further enhanced in carriers of the HLA-A10 genotype. Fellerhoff B, Laumbacher B, Mueller N, Gu S, Wank R. Mol Psychiatry Mar;12(3):

Association of Lyme Disease and Schizoaffective Disorder, Bipolar Type: Is it Inflammation Mediated?
Borrelia burgdorferi (Bb) can present with symptoms similar to schizophrenia and bipolar disorder. It has been suggested that inflammation incurred during the Bb infection leads to neurodegenerative changes that result in schizophrenia-like presentations. We report a case of a 41-year-old male with a past history of Bb infection who presents with psychosis. Later in the course of his hospitalization, he developed mood symptoms and was diagnosed with schizoaffective disorder, bipolar type. This case highlights the diagnosis and treatment of a patient with the unique presentation of schizoaffective disorder, bipolar type in the setting of previous Bb infection. Indian J Psychol Med Apr-Jun;37(2): doi: / Association of Lyme Disease and Schizoaffective Disorder, Bipolar Type: Is it Inflammation Mediated? Mattingley DW(1), Koola MM(2). Author information: (1)Doctor of Medicine Program, Saba University School of Medicine, Saba, Dutch Caribbean, Netherlands and Department of Anesthesiology, University of Toledo College of Medicine, Toledo, OH, United States. (2)Clinical Research Program, Sheppard Pratt Health System and Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD, United States. Lyme disease has been reported to be associated with various psychiatric presentations. Borreliaburgdorferi (Bb) can present with symptoms similar to schizophrenia and bipolar disorder. It has been suggested that inflammation incurred during the Bb infection leads to neurodegenerative changes that result in schizophrenia-like presentations. We report a case of a 41-year-old male with a past history of Bb infection who presents with psychosis. Later in the course of his hospitalization, he developed mood symptoms and was diagnosed with schizoaffective disorder, bipolar type. This case highlights the diagnosis and treatment of a patient with the unique presentation of schizoaffective disorder, bipolar type in the setting of previous Bb infection. Mattingley DW, Koola MM. Association of Lyme Disease and Schizoaffective Disorder, Bipolar Type: Is it Inflammation Mediated? Indian J Psychol Med Apr-Jun;37(2):243-6.

The role of inflammation in epilepsy
Here, we focus on the rapidly growing body of evidence that supports the involvement of inflammatory mediators—released by brain cells and peripheral immune cells—in both the origin of individual seizures and the epileptogenic process. We explore the evidence from clinical and experimental studies for a relationship between inflammation and epilepsy. Subsequently, we discuss how seizures cause inflammation, and whether such inflammation, in turn, influences the occurrence and severity of seizures, and seizure-related neuronal death. Vezzani A, French J, Bartfai T, Baram TZ. Nature Reviews Neurology 7, (January 2011)

Dementia

Dementia Because CNS B. burgdorferi infections are associated with CNS inflammation and systemic TBD are also associated with low-grade inflammatory processes, it supports clinical observations that rapidly progressive dementia can be associated with CNS infection and that slowly progressive dementia can be associated with systemic infection. Miklossy J. Alzheimer’s disease — a neurospirochetosis analysis of the evidence following Koch’s and Hill’s criteria. J Neuroinflam. 2011;8:90. Bransfield RC. Relationship of Inflammation and Autoimmunity to Psychiatric Sequelae in Lyme Disease. Psychiatric Annals. 42(9): September 2012.

Rapidly progressive frontal-type dementia associated with Lyme disease
The authors report a case of fatal neuropsychiatric Lyme disease (LD) that was expressed clinically by progressive frontal lobe dementia and pathologically by severe subcortical degeneration. Antibiotic treatment resulted in transient improvement, but the patient relapsed after the antibiotics were discontinued. LD must be considered even in cases with purely psychiatric presentation, and prolonged antibiotic therapy may be necessary. J Neuropsychiatry Clin Neurosci Summer;7(3): Rapidly progressive frontal-type dementia associated with Lyme disease. Waniek C(1), Prohovnik I, Kaufman MA, Dwork AJ. Author information: (1)New York State Psychiatric Institute, NY 10032, USA. The authors report a case of fatal neuropsychiatric Lyme disease (LD) that was expressed clinically by progressive frontal lobe dementia and pathologically by severe subcortical degeneration. Antibiotic treatment resulted in transient improvement, but the patient relapsed after the antibiotics were discontinued. LD must be considered even in cases with purely psychiatric presentation, and prolonged antibiotic therapy may be necessary. Waniek C, Prohovnik I, Kaufman MA, Dwork AJ. J Neuropsychiatry Clin Neurosci. 1995;7(3):345-7

ATCV-1 and Cognitive Decline
Yolken found a microbe that seems to sap intelligence, not sanity. In the October issue of Proceedings of the National Academy of Sciences, he described a study that included mental tests followed by physical screenings. a previously unsuspected virus, Acanthocystis turfacea chlorella virus 1, or ATCV-1, lurking in the throats of two of every five of their Baltimore research subjects. ATCV-1 is a chlorovirus, which infects algae, and viruses that transcend species usually do so in modest increments within their kingdom. Yet this pathogen scaled the evolutionary ladder in a single bound as it jumped from algae to humans.

The association between infectious burden and Parkinson's disease: A case-control study
METHODS: Antibody titers to common infectious pathogens including cytomegalovirus (CMV), Epstein Barr virus (EBV)，herpes simplex virus type-1 (HSV-1), Borrelia burgdorferi (B. burgdorferi), Chlamydophila pneumoniae (C. pneumoniae) and Helicobacter pylori (H. pylori) were measured by ELISA. RESULTS: Seropositivities toward zero-two, three-four and five-six of these pathogens were found in 11%, 74% and 15% of normal controls while in 4%, 61% and 35% of PD patients, respectively. IB, bacterial burden and viral burden were independently associated with PD. Schwab and England (S&E) scores were negatively correlated with IB in patients with PD. Serum α-synuclein protein levels and inflammatory cytokines (interleukin-1β and interleukin-6) in individuals with higher IB were also significantly higher. CONCLUSIONS: IB consisting of CMV, EBV, HSV-1, B. burgdorferi, C. pneumoniae and H. pylori is associated with PD. This study supports the role of infection in the etiology of PD. Parkinsonism Relat Disord May 30. pii: S (15) doi: /j.parkreldis [Epub ahead of print] The association between infectious burden and Parkinson's disease: A case-control study. Bu XL(1), Wang X(1), Xiang Y(1), Shen LL(1), Wang QH(1), Liu YH(1), Jiao SS(1), Wang YR(1), Cao HY(1), Yi X(1), Liu CH(1), Deng B(1), Yao XQ(1), Xu ZQ(1), Zhou HD(1), Wang YJ(2). Author information: (1)Department of Neurology and Center for Clinical Neuroscience, Daping Hospital, Third Military Medical University, 10 Changjiang Branch Road, Yuzhong District, Chongqing , China. (2)Department of Neurology and Center for Clinical Neuroscience, Daping Hospital, Third Military Medical University, 10 Changjiang Branch Road, Yuzhong District, Chongqing , China. Electronic address: INTRODUCTION: The etiology of Parkinson's disease (PD) remains unclear. The aim of this study was to examine the association between common pathogenic infections and PD. METHODS: Antibody titers to common infectious pathogens including cytomegalovirus (CMV), Epstein Barr virus (EBV)，herpes simplex virus type-1 (HSV-1), Borrelia burgdorferi (B. burgdorferi), Chlamydophila pneumoniae (C. pneumoniae) and Helicobacter pylori (H. pylori) were measured by ELISA in serum of 131 PD patients and 141 normal controls. Infectious burden (IB) was defined as a composite serologic measure of exposure to these common pathogens. RESULTS: Seropositivities toward zero-two, three-four and five-six of these pathogens were found in 11%, 74% and 15% of normal controls while in 4%, 61% and 35% of PD patients, respectively. IB, bacterial burden and viral burden were independently associated with PD. Schwab and England (S&E) scores were negatively correlated with IB in patients with PD. Serum α-synuclein protein levels and inflammatory cytokines (interleukin-1β and interleukin-6) in individuals with higher IB were also significantly higher. CONCLUSIONS: IB consisting of CMV, EBV, HSV-1, B. burgdorferi, C. pneumoniae and H. pylori is associated with PD. This study supports the role of infection in the etiology of PD. Bu XL et al. Parkinsonism Relat Disord May 30.

Violence

Contributors vs. Deterrents of Violence

Contributors and Deterrents of Violence
Community Social and economic connections Relationships Access to care Ethical and religious beliefs Coping skills Cognitive abilities Empathy Mood Obsessive Frustration tolerance Sexual issues Level of fear Power issues Narcissism Nurturing vs. abusive development Developmental impairments Exposure to violence Exposure to trauma Triggering events Grounded in reality vs. psychotic Outlets for frustration Neurological functioning Substance abuse Toxic exposure Nutritional status General medical status Parasites Genes

Brain Physiology There is a hierarchy of functioning within the CNS, developed through evolution. Going from the most advanced to the most primitive areas of the brain, the hierarchy consists of the prefrontal cortex, other cortical regions, para-limbic associative areas, the limbic system, and the brain stem and hypothalamus. These centers function together with many feed forward and feed back pathways that are both stimulatory and inhibitory. Injury to a higher center can result in a dysfunction or a loss of a function. Injury to an inhibiting pathway will cause a decline or an inability to inhibit that function. As a result, brain injury leads to a decline of adaptive abilities.

Plato: Human Functioning
“In the case of the human soul, first of all it is a pair of horses that the charioteer dominates; one of them is noble and handsome and of good breeding, while the other is the very opposite, so that our charioteer necessarily has a difficult and troublesome task.” Healthy mental functioning helps achieve this balance. Theories to explain human mental functioning have existed for millennia and knowledge of human anatomy has existed for centuries. However, knowledge of brain physiology has mostly evolved during recent decades years ago Plato described a model of human functioning that is surprisingly accurate. It has similarities to both Freudian theory and our current view of brain physiology. He recognizes both the concept of hierarchy as well as the constant struggle to reconcile simultaneous opposing forces within us: “In the case of the human soul, first of all it is a pair of horses that the charioteer dominates; one of them is noble and handsome and of good breeding, while the other is the very opposite, so that our charioteer necessarily has a difficult and troublesome task.” Michelangelo demonstrates a remarkable insight into the anatomy of the human brain in The Creation of Adam

Brain Scan Normal and Murderer
Brain scan (PET) of a normal control (left) and a murderer (right), illustrating the lack of activation in the prefrontal cortex in the murderer. The figures are a transverse (horizontal) slice through the brain, so you are looking down on the brain. The prefrontal region is at the top of the figure, and the occipital cortex (the back part of the brain controlling vision) is at the bottom. Warm colors (e.g., red and yellow) indicate areas of high brain activation; cold colors (e.g. blue and green) indicate low activation. Brain scan (PET) of a normal control (left) and a murderer (right), illustrating the lack of activation in the prefrontal cortex in the murderer. The figures are a transverse (horizontal) slice through the brain, so you are looking down on the brain. The prefrontal region is at the top of the figure, and the occipital cortex (the back part of the brain controlling vision) is at the bottom. (Flickr.com)

Infections, Immune reactions & Violence
Violent behavior is the result of a complex interaction of many contributors and deterrents. Infections may cause impairments that contribute to violence through multiple mechanisms and some appear immune mediated by proinflammatory and autoimmune mechanisms. The resulting impairments include cognitive impairments; sensory hyperacusis; decreased frustration tolerance; decreased impulse control; intrusive symptoms of an aggressive and or sexually aggressive nature; homicidal preoccupations; mood instability; depersonalization; dissociative states; paranoia; psychosis; social anxiety contributing to social isolation; altered sexual behavior; decreased bonding capacity, empathy, facial recognition and emotional insight; and decreased tolerance to the effects of drugs and alcohol.

Parasite Prevalence and the Worldwide Distribution of Cognitive Ability
In this study, we hypothesize that the worldwide distribution of cognitive ability is determined in part by variation in the intensity of infectious diseases. From an energetics standpoint, a developing human will have difficulty building a brain and fighting off infectious diseases at the same time, as both are very metabolically costly tasks. Using three measures of average national intelligence quotient (IQ), we found that the zero-order correlation between average IQ and parasite stress ranges from r ¼ to r ¼ (p , ). These correlations are robust worldwide, as well as within five of six world regions. Infectious disease remains the most powerful predictor of average national IQ when temperature, distance from Africa, gross domestic product per capita and several measures of education are controlled for. These findings suggest that the Flynn effect may be caused in part by the decrease in the intensity of infectious diseases as nations develop. Eppig C, Fincher CL, Thornhill R. Proceedings of the Royal Society 2010.

Question Did the many infections associated with World War I (Spanish Flu, Typhus, tick-borne diseases) cause encephalopathy in many which contributed to causing World War II? Did infectious encephalopathies in populations and leaders contribute to wars and crimes throughout history? Can endemic violence be partially explained by infectious diseases causing encephalopathy? Are there infectious encephalopathies contributing to population violence in the Middle East and Africa today?

Afghanistan Vector-borne Diseases
Crimean-Congo Hemorrhagic Fever Malaria Sand Fly Fever Dengue Fever Yellow Fever Japanese Encephalitis African Trypanosomiasis Cutaneous Leishmaniasis Plague Rift Valley fever Chikungunya Schistosomiasi aerosolized dust or soil contact disease Lassa fever Filariasis Trench Fever Five-Day Fever Wolhynia Fever Boutonneuse (Mediterranean) FeverCutaneous Leishmaniasis (zoonotic) Cutaneous Leishmaniasis(anthroponic) Visceral Leishmaniasis Q Fever Rocky Mountain Spotted Fever West Nile Fever Sindbis Fever Siberian Tick Typhus Mite-borne Typhus (Tsutsugamushi Fever) Louse-borne Typhus Epidemic Typhus Murine Typhus Endemic Typhus Fever Epidemic Relapsing Fever Tick-borne Relapsing Fever Leptospirosis Leptospira icterohaemo-rrhagiae, L. hebdomadis L. tarassovi, L. grippotyphosa, L. pomona, L. javanica, L. canicola, L. ballum, L. bataviae Afghanistan Infectious diseases in Afghanistan: Report by the Global Disaster Information Network (GDIN) Global Disaster Information Network — Report The following report is an analysis of the infectious diseases in Afghanistan, designed for use by humanitarian relief workers. The author is the GDIN Infectious Disease Working Group. Questions and suggestions for improvement of the data is encouraged. Send to Other information on GDIN, the Global Disaster Information Network (GDIN) and its Infectious Disease Working Group can be found at GDIN's Infectious Disease Working Group functions independently but in concert with official infectious disease reporting and verification systems. Its objective is to serve as a resource multiplier and a facilitator of efficient, rapid, cost-effective infectious disease management by the international community and individual governments through improved communication and information support. Food-borne and water-borne diseases Bacterial and protozoal diarrhea: In general, bacterial agents such as enterotoxigenic Escherishia coli, Campylobacter, Shigella, and Salmonella are the most common causes of acute bacterial diarrhea. Resistance to the standard therapeutic agent sulfamethoxazole/trimethoprim (SMZ/TMP) has been reported. Endemic protozoa such as Cryptosporidium spp., Giardia lamblia, and Entamoeba histolytica often are associated with more chronic infections, but can cause acute diarrhea. Amoebiasis infection rates up to 3 percent have been estimated for the general Afghan population. Giardiasis has been found in up to 11 percent of surveyed children. Sanitation is extremely poor throughout the country. Local food and water sources (including ice) are heavily contaminated with pathogenic bacteria, parasites, and viruses. Risk is year-round and countrywide, including in major urban areas. Hepatitis A and E: Most Afghans contract hepatitis A virus (HAV) infection during childhood, indicating active transmission of the virus both person-toperson and through contact with contaminated water. Hepatitis E virus (HEV) infection has been reported, but levels are unclear. Cholera: as of March 2000, the World Health Organization considered the following provinces cholera endemic: Badakhshan, Baghlan, Balkh, Bamian, Helmand, Herat, Kabol, Kandahar, Kapisa, Kondoz, Lowgar, Nangarhar, and Zabol. Vector-borne diseasesDuring the warmer months of May to November, the climate and ecological habitat support large populations of arthropod vectors, including mosquitoes, ticks, and sand flies. Significant disease transmission is sustained countrywide, including in urban areas. Malaria is the major vector-borne risk in Afghanistan. In addition, many other serious diseases may not be recognized or reported due to the lack of surveillance and diagnostic capability. Typhoid and paratyphoid fever: outbreaks have been reported in rural and urban areas. Cutaneous-mucosal Leishmaniasis: Seasonal (Apr to Oct) associated with the period of greatest sand fly activity. Risk is limited to focal areas in rural and periurban areas in the northern plains of Baghlan, Balkh, Faryab, Jowzjan, Kondoz, Samangan, and Takhar Provinces, and in the southwestern lowlands. Foci of L. tropica have been reported from most towns and cities of Badakhshtan, Ghazni, Herat, Kabol, Kandahar, Kapisa, and Parvan Provinces. Crimean-Congo hemorrhagic fever: Tick-borne (Amblyomma variegatum and Hyalomma marginatum). Infection also may be transmitted through contact with blood and body fluids of infected patients, and during slaughter of infected animals. Risk is year-round (peak transmission in warmer months) and primarily in rural areas. Relapsing fever: Tick-borne (Ornithodoros papillipes). Identified in Alpine regions of central Afghanistan. Malaria: Seasonal (May to Nov), transmission generally is limited to the warmer months with seasonal variations dependent on elevation. Risk exits countrywide (including urban areas) below 2,000 meters elevation. Plasmodium vivax predominates countrywide, but P. falciparumz also occurs. Cholorquine resistance has been reported. Typhus (mite-borne): foci likely exist countrywide up to 3,200 meters elevation in areas of scrub brush and secondary growth vegetation favorable for vector mite populations. Typhus (louse-borne): Risk is year-round and countrywide (Up to 13 percent of surveyed adults have been seropositive). Sand fly fever: Seasonal (Apr to Oct) associated with periods of greatest sand fly activity. Focally endemic, based on regional occurrence and on virus isolation (Sicilian and Naples viruses) in Paravan Province in central-eastern Afghanistan. Respiratory-borne Diseases:Overcrowding associated with cold conditions and use of temporary shelter is highly conducive to the transmission of measles, diphtheria, meningitis, influenza, tuberculosis, and acute respiratory infections. The biggest concern is high mortality among the 5 and under age group, with some relief organizations estimating mortality of 5.9 per 10,000. High mortality is almost inevitable when vaccination rates are low; measles vaccination rates are estimated to be as low as 35 percent of the population. Complicating low measles vaccination rates is the fact that children are undernourished and vitamin A deficient. In addition, displacement of the Afghan people is disrupting ongoing tuberculosis treatment, contributing to further spread of infections. Although the immediate impact of disrupted tuberculosis control is minimal, this will eventually influence longer-term health status. Tuberculosis: Afghanistan is one of the highest burden countries for tuberculosis in the world; nearly 35 percent of the population reportedly is infected. The World Health Organization estimated that in 1999 there were 325 new tuberculosis cases per 100,000 population. Meningococcal meningitis: Transmitted by direct contact, including exposure to respiratory droplets from nose and throat of infected people. Disease may occur countrywide and year-round (peak transmission period Nov to Feb); risk may be elevated during cooler months. Measles: Outbreaks have been reported, with Measles vaccine has been a priority of ongoing relief efforts, but many children likely remain susceptible. Other diseases:Poliomyelitis: Transmitted via the fecal-oral route, polio is a serious health threat to Afghan children. Polio control has been an ongoing relief priority, at times prompting cease-fires to conduct vaccination campaigns. Leptospirosis: Lakes, rivers, streams or other surface water in the northern and eastern plains may be contaminated with leptospirosis. Anthrax: Cutaneous anthrax (transmitted through direct contact with infected animals or carcasses, including hides) and gastrointestinal anthrax (contracted through eating infected meat) occur year-round, primarily in rural areas. (see appendix on Anthrax) Major infectious diseases: degree of risk: high food or waterborne diseases: bacterial and protozoal diarrhea, hepatitis A, and typhoid fever vectorborne disease: malaria animal contact disease: rabies note: highly pathogenic H5N1 avian influenza has been identified in this country; it poses a negligible risk with extremely rare cases possible among US citizens who have close contact with birds (2009) Rabies: human and animal cases occur annually Definition: This entry lists major infectious diseases likely to be encountered in countries where the risk of such diseases is assessed to be very high as compared to the United States. These infectious diseases represent risks to US government personnel traveling to the specified country for a period of less than three years. The degree of risk is assessed by considering the foreign nature of these infectious diseases, their severity, and the probability of being affected by the diseases present. The diseases listed do not necessarily represent the total disease burden experienced by the local population. The risk to an individual traveler varies considerably by the specific location, visit duration, type of activities, type of accommodations, time of year, and other factors. Consultation with a travel medicine physician is needed to evaluate individual risk and recommend appropriate preventive measures such as vaccines. Diseases are organized into the following six exposure categories shown in italics and listed in typical descending order of risk. Note: The sequence of exposure categories listed in individual country entries may vary according to local conditions. food or waterborne diseases acquired through eating or drinking on the local economy: Hepatitis A - viral disease that interferes with the functioning of the liver; spread through consumption of food or water contaminated with fecal matter, principally in areas of poor sanitation; victims exhibit fever, jaundice, and diarrhea; 15% of victims will experience prolonged symptoms over 6-9 months; vaccine available. Hepatitis E - water-borne viral disease that interferes with the functioning of the liver; most commonly spread through fecal contamination of drinking water; victims exhibit jaundice, fatigue, abdominal pain, and dark colored urine. Typhoid fever - bacterial disease spread through contact with food or water contaminated by fecal matter or sewage; victims exhibit sustained high fevers; left untreated, mortality rates can reach 20%. vectorborne diseases acquired through the bite of an infected arthropod: Malaria - caused by single-cell parasitic protozoa Plasmodium; transmitted to humans via the bite of the female Anopheles mosquito; parasites multiply in the liver attacking red blood cells resulting in cycles of fever, chills, and sweats accompanied by anemia; death due to damage to vital organs and interruption of blood supply to the brain; endemic in 100, mostly tropical, countries with 90% of cases and the majority of million estimated annual deaths occurring in sub-Saharan Africa. Dengue fever - mosquito-borne (Aedes aegypti) viral disease associated with urban environments; manifests as sudden onset of fever and severe headache; occasionally produces shock and hemorrhage leading to death in 5% of cases. Yellow fever - mosquito-borne viral disease; severity ranges from influenza-like symptoms to severe hepatitis and hemorrhagic fever; occurs only in tropical South America and sub-Saharan Africa, where most cases are reported; fatality rate is less than 20%. Japanese Encephalitis - mosquito-borne (Culex tritaeniorhynchus) viral disease associated with rural areas in Asia; acute encephalitis can progress to paralysis, coma, and death; fatality rates 30%. African Trypanosomiasis - caused by the parasitic protozoa Trypanosoma; transmitted to humans via the bite of bloodsucking Tsetse flies; infection leads to malaise and irregular fevers and, in advanced cases when the parasites invade the central nervous system, coma and death; endemic in 36 countries of sub-Saharan Africa; cattle and wild animals act as reservoir hosts for the parasites. Cutaneous Leishmaniasis - caused by the parasitic protozoa leishmania; transmitted to humans via the bite of sandflies; results in skin lesions that may become chronic; endemic in 88 countries; 90% of cases occur in Iran, Afghanistan, Syria, Saudi Arabia, Brazil, and Peru; wild and domesticated animals as well as humans can act as reservoirs of infection. Plague - bacterial disease transmitted by fleas normally associated with rats; person-to-person airborne transmission also possible; recent plague epidemics occurred in areas of Asia, Africa, and South America associated with rural areas or small towns and villages; manifests as fever, headache, and painfully swollen lymph nodes; disease progresses rapidly and without antibiotic treatment leads to pneumonic form with a death rate in excess of 50%. Crimean-Congo hemorrhagic fever - tick-borne viral disease; infection may also result from exposure to infected animal blood or tissue; geographic distribution includes Africa, Asia, the Middle East, and Eastern Europe; sudden onset of fever, headache, and muscle aches followed by hemorrhaging in the bowels, urine, nose, and gums; mortality rate is approximately 30%. Rift Valley fever - viral disease affecting domesticated animals and humans; transmission is by mosquito and other biting insects; infection may also occur through handling of infected meat or contact with blood; geographic distribution includes eastern and southern Africa where cattle and sheep are raised; symptoms are generally mild with fever and some liver abnormalities, but the disease may progress to hemorrhagic fever, encephalitis, or ocular disease; fatality rates are low at about 1% of cases. Chikungunya - mosquito-borne (Aedes aegypti) viral disease associated with urban environments, similar to Dengue Fever; characterized by sudden onset of fever, rash, and severe joint pain usually lasting 3-7 days, some cases result in persistent arthritis. water contact diseases acquired through swimming or wading in freshwater lakes, streams, and rivers: Leptospirosis - bacterial disease that affects animals and humans; infection occurs through contact with water, food, or soil contaminated by animal urine; symptoms include high fever, severe headache, vomiting, jaundice, and diarrhea; untreated, the disease can result in kidney damage, liver failure, meningitis, or respiratory distress; fatality rates are low but left untreated recovery can take months. Schistosomiasis - caused by parasitic trematode flatworm Schistosoma; fresh water snails act as intermediate host and release larval form of parasite that penetrates the skin of people exposed to contaminated water; worms mature and reproduce in the blood vessels, liver, kidneys, and intestines releasing eggs, which become trapped in tissues triggering an immune response; may manifest as either urinary or intestinal disease resulting in decreased work or learning capacity; mortality, while generally low, may occur in advanced cases usually due to bladder cancer; endemic in 74 developing countries with 80% of infected people living in sub-Saharan Africa; humans act as the reservoir for this parasite. aerosolized dust or soil contact disease acquired through inhalation of aerosols contaminated with rodent urine: Lassa fever - viral disease carried by rats of the genus Mastomys; endemic in portions of West Africa; infection occurs through direct contact with or consumption of food contaminated by rodent urine or fecal matter containing virus particles; fatality rate can reach 50% in epidemic outbreaks. respiratory disease acquired through close contact with an infectious person: Meningococcal meningitis - bacterial disease causing an inflammation of the lining of the brain and spinal cord; one of the most important bacterial pathogens is Neisseria meningitidis because of its potential to cause epidemics; symptoms include stiff neck, high fever, headaches, and vomiting; bacteria are transmitted from person to person by respiratory droplets and facilitated by close and prolonged contact resulting from crowded living conditions, often with a seasonal distribution; death occurs in 5-15% of cases, typically within hours of onset of symptoms; highest burden of meningococcal disease occurs in the hyperendemic region of sub-Saharan Africa known as the "Meningitis Belt" which stretches from Senegal east to Ethiopia. animal contact disease acquired through direct contact with local animals: Rabies - viral disease of mammals usually transmitted through the bite of an infected animal, most commonly dogs; virus affects the central nervous system causing brain alteration and death; symptoms initially are non-specific fever and headache progressing to neurological symptoms; death occurs within days of the onset of symptoms. Vector-borne Infectious Diseases in Afghanistan Source: CIA World Factbook - Unless otherwise noted, information in this page is accurate as of July 12, 2011 Laborgruppe Medizinische Zoologie Regierungsdirektor, Zentrales Institut des Sanitätsdienstes der Bundeswehr Dr. Michael K. Faulde Translated by TRS Translation Services, Washington, DC 56065 Koblenz, GERMANY Postfach 7340 Edited by Dr. Richard G. Robbins and Major Sharon L. Spradling, AFPMB, Washington, DC CIA World Factbook, Global Disaster Information Network, Faulde

Other Infectious Diseases in Afghanistan
Measles Diphtheria Meningitis Influenza Tuberculosis acute respiratory infections Meningococcal meningitis Poliomyelitis Anthrax Leptospirosis Rabies Enterotoxigenic Escherishia coli Campylobacter Shigella Salmonella Cryptosporidium spp. Giardia lamblia Entamoeba histolytica Amoebiasis Hepatitis A and E Typhoid Paratyphoid Fever Afghanistan Infectious diseases in Afghanistan: Report by the Global Disaster Information Network (GDIN) Global Disaster Information Network — Report The following report is an analysis of the infectious diseases in Afghanistan, designed for use by humanitarian relief workers. The author is the GDIN Infectious Disease Working Group. Questions and suggestions for improvement of the data is encouraged. Send to Other information on GDIN, the Global Disaster Information Network (GDIN) and its Infectious Disease Working Group can be found at GDIN's Infectious Disease Working Group functions independently but in concert with official infectious disease reporting and verification systems. Its objective is to serve as a resource multiplier and a facilitator of efficient, rapid, cost-effective infectious disease management by the international community and individual governments through improved communication and information support. Sanitation is extremely poor throughout the country. Local food and water sources (including ice) are heavily contaminated with pathogenic bacteria, parasites, and viruses. Risk is year-round and countrywide, including in major urban areas. Food-borne and water-borne diseases Bacterial and protozoal diarrhea: In general, bacterial agents such as enterotoxigenic Escherishia coli, Campylobacter, Shigella, and Salmonella are the most common causes of acute bacterial diarrhea. Resistance to the standard therapeutic agent sulfamethoxazole/trimethoprim (SMZ/TMP) has been reported. Endemic protozoa such as Cryptosporidium spp., Giardia lamblia, and Entamoeba histolytica often are associated with more chronic infections, but can cause acute diarrhea. Amoebiasis infection rates up to 3 percent have been estimated for the general Afghan population. Giardiasis has been found in up to 11 percent of surveyed children. Typhoid and paratyphoid fever: outbreaks have been reported in rural and urban areas. Hepatitis A and E: Most Afghans contract hepatitis A virus (HAV) infection during childhood, indicating active transmission of the virus both person-toperson and through contact with contaminated water. Hepatitis E virus (HEV) infection has been reported, but levels are unclear. Cholera: as of March 2000, the World Health Organization considered the following provinces cholera endemic: Badakhshan, Baghlan, Balkh, Bamian, Helmand, Herat, Kabol, Kandahar, Kapisa, Kondoz, Lowgar, Nangarhar, and Zabol. Vector-borne diseasesDuring the warmer months of May to November, the climate and ecological habitat support large populations of arthropod vectors, including mosquitoes, ticks, and sand flies. Significant disease transmission is sustained countrywide, including in urban areas. Malaria is the major vector-borne risk in Afghanistan. In addition, many other serious diseases may not be recognized or reported due to the lack of surveillance and diagnostic capability. Cutaneous-mucosal Leishmaniasis: Seasonal (Apr to Oct) associated with the period of greatest sand fly activity. Risk is limited to focal areas in rural and periurban areas in the northern plains of Baghlan, Balkh, Faryab, Jowzjan, Kondoz, Samangan, and Takhar Provinces, and in the southwestern lowlands. Foci of L. tropica have been reported from most towns and cities of Badakhshtan, Ghazni, Herat, Kabol, Kandahar, Kapisa, and Parvan Provinces. Crimean-Congo hemorrhagic fever: Tick-borne (Amblyomma variegatum and Hyalomma marginatum). Infection also may be transmitted through contact with blood and body fluids of infected patients, and during slaughter of infected animals. Risk is year-round (peak transmission in warmer months) and primarily in rural areas. Malaria: Seasonal (May to Nov), transmission generally is limited to the warmer months with seasonal variations dependent on elevation. Risk exits countrywide (including urban areas) below 2,000 meters elevation. Plasmodium vivax predominates countrywide, but P. falciparumz also occurs. Cholorquine resistance has been reported. Relapsing fever: Tick-borne (Ornithodoros papillipes). Identified in Alpine regions of central Afghanistan. Typhus (mite-borne): foci likely exist countrywide up to 3,200 meters elevation in areas of scrub brush and secondary growth vegetation favorable for vector mite populations. Typhus (louse-borne): Risk is year-round and countrywide (Up to 13 percent of surveyed adults have been seropositive). Sand fly fever: Seasonal (Apr to Oct) associated with periods of greatest sand fly activity. Focally endemic, based on regional occurrence and on virus isolation (Sicilian and Naples viruses) in Paravan Province in central-eastern Afghanistan. Respiratory-borne Diseases:Overcrowding associated with cold conditions and use of temporary shelter is highly conducive to the transmission of measles, diphtheria, meningitis, influenza, tuberculosis, and acute respiratory infections. The biggest concern is high mortality among the 5 and under age group, with some relief organizations estimating mortality of 5.9 per 10,000. High mortality is almost inevitable when vaccination rates are low; measles vaccination rates are estimated to be as low as 35 percent of the population. Complicating low measles vaccination rates is the fact that children are undernourished and vitamin A deficient. In addition, displacement of the Afghan people is disrupting ongoing tuberculosis treatment, contributing to further spread of infections. Although the immediate impact of disrupted tuberculosis control is minimal, this will eventually influence longer-term health status. Meningococcal meningitis: Transmitted by direct contact, including exposure to respiratory droplets from nose and throat of infected people. Disease may occur countrywide and year-round (peak transmission period Nov to Feb); risk may be elevated during cooler months. Measles: Outbreaks have been reported, with Measles vaccine has been a priority of ongoing relief efforts, but many children likely remain susceptible. Tuberculosis: Afghanistan is one of the highest burden countries for tuberculosis in the world; nearly 35 percent of the population reportedly is infected. The World Health Organization estimated that in 1999 there were 325 new tuberculosis cases per 100,000 population. Other diseases:Poliomyelitis: Transmitted via the fecal-oral route, polio is a serious health threat to Afghan children. Polio control has been an ongoing relief priority, at times prompting cease-fires to conduct vaccination campaigns. Leptospirosis: Lakes, rivers, streams or other surface water in the northern and eastern plains may be contaminated with leptospirosis. Anthrax: Cutaneous anthrax (transmitted through direct contact with infected animals or carcasses, including hides) and gastrointestinal anthrax (contracted through eating infected meat) occur year-round, primarily in rural areas. (see appendix on Anthrax) Rabies: human and animal cases occur annually Global Disaster Information Network

Treatment

Symptomatic Treatment
Regardless of the debate treating psychiatric symptoms with psychotropics can prevent and sometimes reverse progression of illness. Symptomatic treatment improves: Functioning Immune functioning Resistance to infection

Symptom Priority A complex, chronic, TBD patient may have over 100 different symptoms. Consider the multi-system combined effects of both the contributors and deterrents to disease. After completing an assessment, prioritize which symptoms are most sever and contribute the most towards perpetuating chronic illness. Treat the high priority symptoms first and proceed down the list.

What Symptoms Perpetuate TBD Disease?
Sleep Disorders Fatigue Cognitive Impairments Depression Anxiety Pain and Headaches Other Symptoms

Treatment Options to Reduce Glutamate Mediated Excitotoxicity
Ceftriaxone [1] Memantine [2] Acetylcarnitine [3] Dextromethorphan hydrobromide & quinidine sulfate [4, 5] N-acetyl cysteine [6] [1] Knackstedt LA et al. [2] Anathia M. et al. [3] Famularo G. et al. [4] Werling LL et al. [5] Rosen H. [6] Dean OM.

Antibiotics or Psychotropics or Other Treatments?
When a patient has been treated with just antibiotics and has not adequately responded, consider psychotropics. When a patient has been treated with just psychotropics and has not adequately responded, consider antibiotics. When a patient is treatment resistant consider both &/or other treatments.

Old rat brains rejuvenated and new neurons grown by asthma drug
An asthma drug, montelukast (Singulair), rejuvenated rat brains, making old rats perform as well as young rats in tests of memory and cognition, encouraged the birth of new brain cells, reduces brain inflammation and can cross the blood-brain barrier, unlike other anti-inflammatories. By the end of their six-week drug regime, old animals performed as well as their younger companions. “We’ve restored learning and memory 100 per cent, to a level comparable with youth.” old rats on montelukast had 80 per cent less inflammation. They also had an enhanced level of new neuron growth compared with untreated old rats – about 50 per cent of that seen in young rats. The blood-brain barrier – which weakens in old age – was stronger in treated old rats. “Structurally, the brain had rejuvenated.” The drug had no effect on young animals, probably because it targets inflammation associated with age and disease. “We’ve identified a target that affects many different systems of the aged and degenerated brain,” he says. “I think the drug reverses the damage associated with ageing. It’s as good as new. An asthma drug has rejuvenated rat brains, making old rats perform as well as young rats in tests of memory and cognition. The drug also encouraged the birth of new brain cells. As we get older, most of us will experience some kind of brain degeneration. Typically, we lose the ability to make new neurons. Another problem is chronic, low-grade inflammation in the brain, which is implicated in many age-related brain disorders. To tackle both problems in one go, Ludwig Aigner at Paracelsus Medical University Salzburg in Austria and his colleagues targeted a set of receptors in the brain that, when activated, trigger inflammation. High numbers of these receptors are found in areas of the brain where neurons are born, suggesting they might also be involved in this process, too. A drug called montelukast (Singulair), regularly prescribed for asthma and allergic rhinitis, blocks these receptors, so Aigner and his colleagues tried it on young and old rats. The team used oral doses equivalent to those taken by people with asthma. The older animals were 20 months old – roughly equivalent to between 65 and 75 in human years. The younger rats were 4 months old – about 17 in human years. The animals were fed the drug daily for six weeks, while another set of young and old rats were left untreated. There were 20 young and 14 old rats in total. Escape plan The rats took part in a range of learning and memory tests. One of these, for example, involved the rats being placed in a pool of water with a hidden escape platform. At the start of the study, untreated young rats learned to recognise landmarks and quickly find their way to the platform, while the untreated older animals struggled at the task. By the end of their six-week drug regime, though, old animals performed as well as their younger companions. “We’ve restored learning and memory 100 per cent, to a level comparable with youth,” says Aigner. He presented his findings last week at the Society for Neuroscience meeting in Chicago. When the team studied the brains of the animals, they found that old rats that had been given montelukast had 80 per cent less inflammation. They also had an enhanced level of new neuron growth compared with untreated old rats – about 50 per cent of that seen in young rats, says Aigner. The team also found that the blood-brain barrier – which stops infectious agents reaching the brain and which weakens in old age – was stronger in treated old rats. “Structurally, the brain had rejuvenated,” says Aigner. No effect on the young The drug had no effect on young animals, probably because it targets inflammation associated with age and disease, says Aigner. “We’ve identified a target that affects many different systems of the aged and degenerated brain,” he says. “I think the drug reverses the damage associated with ageing.” Because montelukast is widely used, it should be relatively quick and easy to look for similar effects in clinical trials in people, says James Nicoll, a neuropathologist at the University of Southampton, UK. Aigner says the results from the rat study are significant enough to warrant a clinical trial. He will start by testing the drug in people with Parkinson’s disease, he says. “It’s a very promising approach,” says Arthur Roach, director of research and development at charity Parkinson’s UK. “They’ve reversed certain aspects of the aged brain.” Real ageing Although the results are in rats, they are exciting because the team used animals that had aged naturally, rather than young rodents with genetic mutations that make them age prematurely, or rodents bred to have age-related disease. “You don’t often see studies in old rats because they’re so expensive,” says Roach. It is also a promising sign that montelukast can access the brain. “There are a lot of anti-inflammatory drugs out there, but they don’t tend to cross the blood-brain barrier,” says Gary Wenk at Ohio State University in Columbus. Wenk isn’t surprised that a drug that targets inflammation in the brain should have such “restorative” effects. “It is now becoming accepted that inflammation does lead to neurodegeneration,” he says. Inflammation has also been linked to Alzheimer’s disease and Huntington’s disease, among other conditions. Bryce Vissel at the Garvan Institute of Medical Research in Sydney, Australia, is cautious. “Millions of people are affected by Alzheimer’s and Parkinson’s worldwide… and hope that science will deliver a cure,” he says. “But so far no promising therapy in an animal model has translated to a therapy in people in neurodegenerative disease.” Image information: The blood-brain barrier, credit: C. J. Guerin/MRC Toxicology Unit/SPL By Jessica Hamzelou Jessica Hamzelou Quoting Aigner. Society for Neuroscience meeting in Chicago. Nov 2015.

Structural and functional rejuvenation of the aged brain by an approved anti-asthmatic drug
Targeting histopathological processes that correlate with age-related cognitive declines, such as neuroinflammation, low levels of neurogenesis, disrupted blood-brain barrier and altered neuronal activity, might lead to structural and functional rejuvenation of the aged brain. Here we show that a 6-week treatment of young (4 months) and old (20 months) rats with montelukast, a marketed anti-asthmatic drug antagonizing leukotriene receptors, reduces neuroinflammation, elevates hippocampal neurogenesis and improves learning and memory in old animals. We demonstrate that the effect is mediated through inhibition of the GPR17 receptor. This work illustrates that inhibition of leukotriene receptor signaling might represent a safe target to restore cognitive functions in old individuals and paves the way for future clinical translation of leukotriene receptor inhibition for the treatment of dementias. Nat Commun Oct 27;6:8466. doi: /ncomms9466. Structural and functional rejuvenation of the aged brain by an approved anti-asthmatic drug. Marschallinger J(1,)(2), Schäffner I(3), Klein B(1,)(2), Gelfert R(1,)(2), Rivera FJ(1,)(2), Illes S(1,)(2), Grassner L(1,)(2,)(4), Janssen M(1,)(2), Rotheneichner P(1,)(2,)(5), Schmuckermair C(6), Coras R(7), Boccazzi M(8), Chishty M(9), Lagler FB(10), Renic M(11), Bauer HC(2,)(12), Singewald N(6), Blümcke I(7), Bogdahn U(13), Couillard-Despres S(2,)(5), Lie DC(3), Abbracchio MP(8), Aigner L(1,)(2). Author information: (1)Institute of Molecular Regenerative Medicine, Paracelsus Medical University, 5020 Salzburg, Austria. (2)Spinal Cord Injury and Tissue Regeneration Center Salzburg (SCI-TReCS), Paracelsus Medical University, 5020 Salzburg, Austria. (3)Institute of Biochemistry, Emil Fischer Center, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany. (4)Center for Spinal Cord Injuries, BG Trauma Center Murnau, Murnau am Staffelsee, Germany. (5)Institute of Experimental Neuroregeneration, Paracelsus Medical University, 5020 Salzburg, Austria. (6)Department of Pharmacology and Toxicology, Institute of Pharmacy and CMBI, Leopold-Franzens-University of Innsbruck, 6020 Innsbruck, Austria. (7)Department of Neuropathology, University Hospital Erlangen, Erlangen, Germany. (8)Department of Pharmacological and Biomolecular Sciences, University of Milan, Milan, Italy. (9)Pharmidex, London W1S 1RR, UK. (10)Department for Paediatrics, Institute for Inborn Errors of Metabolism, Paracelsus Medical University, 5020 Salzburg, Austria. (11)Croatian Institute for Brain Research, University of Zagreb School of Medicine, Zagreb, Croatia. (12)Institute of Tendon and Bone Regeneration, Paracelsus Medical University, 5020 Salzburg, Austria. (13)Department of Neurology, University Hospital Regensburg, Regensburg, Germany. As human life expectancy has improved rapidly in industrialized societies, age-related cognitive impairment presents an increasing challenge. Targeting histopathological processes that correlate with age-related cognitive declines, such as neuroinflammation, low levels of neurogenesis, disrupted blood-brain barrier and altered neuronal activity, might lead to structural and functional rejuvenation of the aged brain. Here we show that a 6-week treatment of young (4 months) and old (20 months) rats with montelukast, a marketed anti-asthmatic drug antagonizing leukotriene receptors, reduces neuroinflammation, elevates hippocampal neurogenesis and improves learning and memory in old animals. By using gene knockdown and knockout approaches, we demonstrate that the effect is mediated through inhibition of the GPR17 receptor. This work illustrates that inhibition of leukotriene receptor signalling might represent a safe and druggable target to restore cognitive functions in old individuals and paves the way for future clinical translation of leukotriene receptor inhibition for the treatment of dementias. Klein B, Gelfert R, Aigner L et al. Nat Commun Oct 27;6:8466

How Much Treatment is Enough?
Successful psychiatric management can sometimes result in reduction of infection. Successful reduction of infection can sometimes result in reducing psychotropics. Our current technological limitations prevents us from being sure all tick-borne infections have been eradicated. After stabilization constant vigilance is needed to prevent relapse.

Conclusion Infections, Tick-borne infections and and persistent complex interactive infections with immune evasion and suppression provoke persistent inflammatory and autoimmune immune reactions that result in disease progression of psychiatric symptoms. Chronic inflammation in the body can result in chronic inflammation in the brain. This, combined with other inflammatory and autoimmune effects result in an increasing deleterious effect upon brain functioning that contribute to causing mental illness including anxiety, apathy, cognitive impairments, depression, autism, schizophrenia, dementia and violence. Prevention, diagnosis & effective treatment can help prevent mental illness and violence.

Thanks for your attention and your commitment to our patients

Backup Slides

Personal Experience Primarily clinical practice
Interest in infectious causes of mental illness for 45 years. At least 5000 patients with infections and associated mental illness. Moderator of Microbes and Mental Illness Internet discussion group (16 years).

Syndromes vs. Cause of Mental Illness
DSM-5 categorizes mental dysfunction into different syndromes with associated symptoms. It does not address the cause of these syndromes. A better understanding of all the causes of mental syndromes and symptoms provides greater opportunities for prevention and treatment.

What Causes Mental Illness?
Mental illness is always caused by something. Most illnesses are developmental impairments afflicting the young or degenerative diseases afflicting the aged. But most mental illnesses however afflict patients throughout the lifespan, suggesting different pathophysiology.

Can Infections and Immune Reactions Contribute to…
Mental illness? Cognitive decline? Degenerative neurological disease? Autism and other developmental disabilities? Personality change? Violent & criminal behavior? Obesity?

Revising Prior Beliefs
All scientific hypotheses and theories need revision when conflicting data challenges their credibility. Narrow , rigid and restrictive disease definitions and guidelines give a foundation but restrict progress. Randomized controlled clinical trials, are only useful when few variables are present.

Pathophysiology: Time & Space
Evolutionary concepts The patient: disease progression over years and decades Space A systems approach that considers multi-systemic contributors and deterrents to disease

What Causes Chronic Illness (Time)?
From an evolutionary perspective: Genetic vulnerabilities from the unique path of evolution Design compromises Competing organisms (always consider parasites) From the perspective of the organism: Interaction of vulnerabilities & environment Trauma causing adaptive mechanisms to go awry

13th Psychoimmunology Expert Meeting

Brain/Body Interaction
Voluntary Nervous System Autonomic Nervous System Circulatory System Endocrine System Immune System Soma

Could Depression Be Caused By An Infection?
About 1907, psychiatrist Henry Cotton began removing decaying teeth, tonsils, testicles, ovaries and, in some cases, colons from his patients in hopes of curing their mental disorders at the the New Jersey State Hospital for the Insane. Steka B. NPR. Oct 25,

Microglial Activity in People at Ultra High Risk of Psychosis and in Schizophrenia: An [(11)C]PBR28 PET Brain Imaging Study Microglial activity is elevated in patients with schizophrenia and in persons with subclinical symptoms who are at ultra high risk of psychosis and is related to at-risk symptom severity. These findings suggest that neuroinflammation is linked to the risk of psychosis and related disorders, as well as the expression of subclinical symptoms. Am J Psychiatry Oct 16:appiajp [Epub ahead of print] Microglial Activity in People at Ultra High Risk of Psychosis and in Schizophrenia: An [(11)C]PBR28 PET Brain Imaging Study. Bloomfield PS(1), Selvaraj S(1), Veronese M(1), Rizzo G(1), Bertoldo A(1), Owen DR(1), Bloomfield MA(1), Bonoldi I(1), Kalk N(1), Turkheimer F(1), McGuire P(1), de Paola V(1), Howes OD(1). Author information: (1)From the Institute of Clinical Science, Imperial College London; the Department of Psychiatric Imaging, Imperial College London; Centre for Neuroimaging Sciences, King's College London; University of Padova, Padova, Italy; King's College London; the Department of Neuroplasticity and Disease, Imperial College London; and the University of Texas Health Science Center, Houston. OBJECTIVE: The purpose of this study was to determine whether microglial activity, measured using translocator-protein positron emission tomography (PET) imaging, is increased in unmedicated persons presenting with subclinical symptoms indicating that they are at ultra high risk of psychosis and to determine whether microglial activity is elevated in schizophrenia after controlling for a translocator-specific genetic polymorphism. METHOD: The authors used the second-generation radioligand [(11)C]PBR28 and PET to image microglial activity in the brains of participants at ultra high risk for psychosis. Participants were recruited from early intervention centers. The authors also imaged a cohort of patients with schizophrenia and matched healthy subjects for comparison. In total, 56 individuals completed the study. At screening, participants were genotyped to account for the rs6971 polymorphism in the gene encoding the 18Kd translocator protein. The main outcome measure was total gray matter [(11)C]PBR28 binding ratio, representing microglial activity. RESULTS: [(11)C]PBR28 binding ratio in gray matter was elevated in ultra-high-risk participants compared with matched comparison subjects (Cohen's d >1.2) and was positively correlated with symptom severity (r=0.730). Patients with schizophrenia also demonstrated elevated microglial activity relative to matched comparison subjects (Cohen's d >1.7). CONCLUSIONS: Microglial activity is elevated in patients with schizophrenia and in persons with subclinical symptoms who are at ultra high risk of psychosis and is related to at-risk symptom severity. These findings suggest that neuroinflammation is linked to the risk of psychosis and related disorders, as well as the expression of subclinical symptoms. Bloomfield MA et al. Am J Psychiatry Oct 16

Inflammation Definition
A protective tissue response to injury or destruction of tissues, which serves to destroy, dilute, or wall off both the injurious agent and the injured tissues. The classical signs of acute inflammation are pain (dolor), heat (calor), redness (rubor), swelling (tumor), and loss of function (functio laesa).inflam´matory

Pathophysiology: Inflammation
Is Inflammation: A friend? A foe? Both? What provokes and perpetuates it? What are the treatments?

Progressive Inflammation is Associated with Increasing Encephalopathy & Increasing Mental Symptoms
Mild Moderate Severe Executive dysfunction Increasing cognitive deficits Dementia Reduced frustration tolerance, irritability, dysthymia Anxiety disorders, major depression, impulsivity, personality disorders Major psychiatric disorders, psychosis, suicide, homicide Insomnia, decreased appetite & libido Moderately impaired sleep, eating & sexual functioning Severely impaired sleep, eating & sexual functioning Increasing Neurological, Multisystemic Symptoms & Fatigue

The evolution of the danger theory
The dominant model of immunity does not explain a wealth of accumulated data and has recently suggested an alternative, the danger model, which suggests that the immune system is far less concerned with things that are foreign than with those that do damage. Expert Rev Clin Immunol May;8(4): doi: /eci The evolution of the danger theory. Interview by Lauren Constable, Commissioning Editor. Matzinger P(1). Author information: (1)Ghost Laboratory, Laboratory of Cellular & Molecular Immunology, National Institute of Allergy & Infectious Diseases/NIH, Bethesda, MD 20894, USA. Comment in Clin Immunol May;147(2): Polly Matzinger, now Chief of the Ghost Laboratory and the section on T-cell Tolerance and Memory at the NIH, has previously worked as a bartender, carpenter, jazz musician, Playboy bunny and dog trainer. She completed her PhD at the University of California, San Diego (USA) and was a postdoctoral fellow at the University of Cambridge (UK). She has worried for years that the dominant model of immunity does not explain a wealth of accumulated data and has recently suggested an alternative, the danger model, which suggests that the immune system is far less concerned with things that are foreign than with those that do damage. This model, whose two major tenets Matzinger admits were thought up in a bath and on a field while herding sheep, has very few assumptions and yet "explains most of what the immune system seems to do right, as well as most of what it appears to do wrong", covering such areas as transplantation, autoimmunity and the immunobiology of tumors. The model has been the subject of a BBC Horizon film and has featured in two other films about immunity and countless articles in both the scientific and the lay press. In her spare time, Matzinger trains border collies for competitive shepherding trials and, in her own words, "composes songs that are not really worth listening to, and worries about the next major question in the immune system", namely "once it decides to respond, how does the immune system know what kind of response to make?" Matzinger P. Expert Rev Clin Immunol May;8(4):311-7.

Immune System & Nervous System
They communicate with each other. Both respond to danger. Both have early, innate, as well as long term learned adaptive mechanisms. Pathology occurs with failure to adapt or excessive reactivity to danger or adaptive mechanisms gone awry, or chronic trauma from chronic reactivity to chronic stressors.

Structural and functional features of central nervous system lymphatic vessels
We discovered functional lymphatic vessels lining the dural sinuses. These structures are able to carry both fluid and immune cells from the cerebrospinal fluid, and are connected to the deep cervical lymph nodes. The discovery of the central nervous system lymphatic system may call for a reassessment of basic assumptions in neuroimmunology and sheds new light on the aetiology of neuroinflammatory and neurodegenerative diseases associated with immune system dysfunction. Nature Jun 1. doi: /nature [Epub ahead of print] Structural and functional features of central nervous system lymphatic vessels. Louveau A(1), Smirnov I(1), Keyes TJ(1), Eccles JD(2), Rouhani SJ(3), Peske JD(3), Derecki NC(1), Castle D(4), Mandell JW(5), Lee KS(6), Harris TH(1), Kipnis J(7). Author information: (1)1] Center for Brain Immunology and Glia, School of Medicine, University of Virginia, Charlottesville, Virginia 22908, USA [2] Department of Neuroscience, School of Medicine, University of Virginia, Charlottesville, Virginia 22908, USA. (2)1] Medical Scientist Training Program, School of Medicine, University of Virginia, Charlottesville, Virginia 22908, USA [2] Beirne B. Carter Center for Immunology Research, School of Medicine, University of Virginia, Charlottesville, Virginia 22908, USA [3] Department of Medicine (Division of Allergy), School of Medicine, University of Virginia, Charlottesville, Virginia 22908, USA. (3)1] Medical Scientist Training Program, School of Medicine, University of Virginia, Charlottesville, Virginia 22908, USA [2] Beirne B. Carter Center for Immunology Research, School of Medicine, University of Virginia, Charlottesville, Virginia 22908, USA [3] Department of Microbiology, Immunology, and Cancer Biology, School of Medicine, University of Virginia, Charlottesville, Virginia 22908, USA. (4)Department of Cell Biology, School of Medicine, University of Virginia, Charlottesville, Virginia 22908, USA. (5)Department of Pathology (Neuropathology), School of Medicine, University of Virginia, Charlottesville, Virginia 22908, USA. (6)1] Center for Brain Immunology and Glia, School of Medicine, University of Virginia, Charlottesville, Virginia 22908, USA [2] Department of Neuroscience, School of Medicine, University of Virginia, Charlottesville, Virginia 22908, USA [3] Department of Neurosurgery, School of Medicine, University of Virginia, Charlottesville, Virginia 22908, USA. (7)1] Center for Brain Immunology and Glia, School of Medicine, University of Virginia, Charlottesville, Virginia 22908, USA [2] Department of Neuroscience, School of Medicine, University of Virginia, Charlottesville, Virginia 22908, USA [3] Medical Scientist Training Program, School of Medicine, University of Virginia, Charlottesville, Virginia 22908, USA. One of the characteristics of the central nervous system is the lack of a classical lymphatic drainage system. Although it is now accepted that the central nervous system undergoes constant immune surveillance that takes place within the meningeal compartment, the mechanisms governing the entrance and exit of immune cells from the central nervous system remain poorly understood. In searching for T-cell gateways into and out of the meninges, we discovered functional lymphatic vessels lining the dural sinuses. These structures express all of the molecular hallmarks of lymphatic endothelial cells, are able to carry both fluid and immune cells from the cerebrospinal fluid, and are connected to the deep cervical lymph nodes. The unique location of these vessels may have impeded their discovery to date, thereby contributing to the long-held concept of the absence of lymphatic vasculature in the central nervous system. The discovery of the central nervous system lymphatic system may call for a reassessment of basic assumptions in neuroimmunology and sheds new light on the aetiology of neuroinflammatory and neurodegenerative diseases associated with immune system dysfunction. Louveau A, et al. Nature Jun 1.

Louveau A, et al. Nature. 2015 Jun 1.
the brain is directly connected to the immune system by vessels previously thought not to exist. - See more at: Because the brain is like every other tissue connected to the peripheral immune system through meningeal lymphatic vessels," said Jonathan Kipnis, PhD, professor in the UVA Department of Neuroscience and director of UVA's Center for Brain Immunology and Glia (BIG). "It changes entirely the way we perceive the neuro-immune interaction. - See more at: they follow a major blood vessel down into the sinuses, - See more at: Louveau A, et al. Nature Jun 1.

Meta-Analysis: Bipolar, Schizophrenia, Major Depression
A meta-analysis of 36 studies found elevations in blood cytokine levels of interleukin-6 in chronically ill patients with major depressive disorder, chronic schizophrenia, and euthymic bipolar disorder. For MDD and schizophrenia, the soluble IL-2 receptor and IL-1 beta were also elevated. ASCP: Variable pattern of inflammation markers found in serious mental illness By: KARI OAKES, Clinical Psychiatry News Digital Network | July 9, 2015 AT THE ASCP ANNUAL MEETING Vitals Key clinical point: A meta-analysis found elevations in the cytokine receptor interleukin-6 (IL-6) in outpatients with three serious mental illnesses. Major finding: The cytokine receptor IL-6 was significantly elevated in major depressive disorder, chronic schizophrenia, and euthymic bipolar disorder (P < .01); variable patterns of inflammation were seen in the individual disorders. Data source: Meta-analysis of 36 studies of blood cytokine levels in chronically ill patients with bipolar disorder, schizophrenia, and major depression. This week's quiz: Treating child and adolescent depression: Part 1 More » MIAMI BEACH – Elevated levels of the same cytokine receptor were seen in three serious mental illnesses, but each illness had separate and distinct patterns of inflammatory markers, according to a study of immune function and mental illness. Dr. David R. Goldsmith and colleagues conducted a meta-analysis that pooled results of three dozen studies of outpatients with bipolar disorder, schizophrenia, and major depression, to search for commonalities and differences in immune system activation. The results were presented in a poster session at a meeting of the American Society of Clinical Psychopharmacology, formerly known as the New Clinical Drug Evaluation Unit meeting. Dr. David R. Goldsmith looked at 36 studies examining individuals with major depressive disorder (MDD) (12 studies), euthymic bipolar disorder (14 studies), and chronic schizophrenia (10 studies). It is the first meta-analysis to pool results from studies of blood cytokine levels in outpatients with three serious mental illnesses, he said. Serious mental illness is associated with immune activation, and previous studies have found activation of various cytokines in many mental illnesses. In the acute phase of mental illness, elevations have been found in both interleukin-6 (IL-6) and the cytokine receptor SIL-2R; for MDD and schizophrenia, cytokine levels are acutely increased, tend to decrease with treatment, and eventually rise again, he said. However, Dr. Goldsmith and his collaborators found that only the cytokine receptor IL-6 was significantly elevated, compared with healthy controls, for all three illnesses included in the meta-analysis (P < .01 for all). IL-6 is associated with acute and chronic inflammation. For MDD and schizophrenia, two other cytokines were significantly elevated in the meta-analysis: the soluble IL-2 receptor (SIL–2R), a cytokine receptor associated with T-cell activation; and IL-1 beta, a cytokine produced by activated macrophages (P < .01 for all interactions, except P = .01 for IL-1 beta in bipolar disorder.) For all three disorders, several inflammatory cytokines were significantly elevated, compared with healthy subjects. Goldsmith DR. ASCP Meeting. Miami. FL. July 9, 2015.

A Meta-Analysis of Cytokines in Major Depression
This meta-analysis (24 studies) reports significantly higher concentrations of the proinflammatory cytokines TNF-α and IL-6 in depressed subjects compared with control subjects. While both positive and negative results have been reported in individual studies, this meta-analytic result strengthens evidence that depression is accompanied by activation of the inflammatory response system. Biological Psychiatry Archival Report A Meta-Analysis of Cytokines in Major Depression Yekta Dowlat, Nathan Herrmann, Walter Swardfager, Helena Liu, Lauren Sham, Elyse K. Reim and Krista L. Lanctô Background Major depression occurs in 4.4% to 20% of the general population. Studies suggest that major depression is accompanied by immune dysregulation and activation of the inflammatory response system (IRS). Our objective was to quantitatively summarize the data on concentrations of specific cytokines in patients diagnosed with a major depressive episode and controls. Methods We performed a meta-analysis of studies measuring cytokine concentration in patients with major depression, with a database search of the English literature (to August 2009) and a manual search of references. Results Twenty-four studies involving unstimulated measurements of cytokines in patients meeting DSM criteria for major depression were included in the meta-analysis; 13 for tumor necrosis factor (TNF)-α, 9 for interleukin (IL)-1β, 16 for IL-6, 5 for IL-4, 5 for IL-2, 4 for IL-8, 6 for IL-10, and 4 for interferon (IFN)-γ. There were significantly higher concentrations of TNF-α (p < ), weighted mean difference (WMD) (95% confidence interval) 3.97 pg/mL (2.24 to 5.71), in depressed subjects compared with control subjects (438 depressed/350 nondepressed). Also, IL-6 concentrations were significantly higher (p < ) in depressed subjects compared with control subjects (492 depressed/400 nondepressed) with an overall WMD of 1.78 pg/mL (1.23 to 2.33). There were no significant differences among depressed and nondepressed subjects for the other cytokines studied. Conclusions This meta-analysis reports significantly higher concentrations of the proinflammatory cytokines TNF-α and IL-6 in depressed subjects compared with control subjects. While both positive and negative results have been reported in individual studies, this meta-analytic result strengthens evidence that depression is accompanied by activation of the IRS. Dowlat Y et al. Biological Psychiatry.

Inflammatory Proteins in Plasma and the Risk of Dementia: The Rotterdam Study
Conclusion Plasma levels of inflammatory proteins are increased before clinical onset of dementia, Alzheimer disease, and vascular dementia. Inflammatory Proteins in Plasma and the Risk of Dementia The Rotterdam Study Marianne J. Engelhart, MD, PhD; Mirjam I. Geerlings, PhD; John Meijer, MSc; Amanda Kiliaan, PhD; Annemieke Ruitenberg, MD, PhD; John C. van Swieten, MD, PhD; Theo Stijnen, PhD; Albert Hofman, MD, PhD; Jacqueline C. M. Witteman, PhD; Monique M. B. Breteler, MD, PhD Arch Neurol. 2004;61: Background Increased levels of inflammatory proteins have been found in the brains and plasma samples of patients with dementia. Whether the levels of inflammatory proteins in plasma samples are elevated before clinical onset of dementia is unclear. Objective To determine whether high levels of inflammatory proteins in plasma samples are associated with an increased risk of dementia. Design and Setting A case-cohort study within the Rotterdam Study, a population-based prospective cohort study in the Netherlands. Participants The source population comprises 6713 subjects who, at baseline ( ), were free of dementia and underwent venipuncture. From these, we selected both a random subcohort of 727 subjects and 188 cases who had developed dementia at follow-up. Main Outcome Measures The associations between plasma levels of 1-antichymotrypsin, C-reactive protein, interleukin 6, the soluble forms of intercellular adhesion molecule-1, and vascular cell adhesion molecule-1 and the risk of dementia were examined using the Cox proportional hazards regression models. Results High levels of 1-antichymotrypsin, interleukin 6, and, to a lesser extent, C-reactive protein were associated with an increased risk of dementia; rate ratios per standard deviation increase were 1.49 (95% confidence interval, ), 1.28 (95% confidence interval, ), and 1.12 (95% confidence interval, ), respectively. Similar associations were observed for Alzheimer disease, whereas rate ratios of vascular dementia were higher for 1-antichymotrypsin and C-reactive protein. Soluble forms of intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 were not associated with dementia. Conclusion Plasma levels of inflammatory proteins are increased before clinical onset of dementia, Alzheimer disease, and vascular dementia. From the Departments of Epidemiology and Biostatistics (Drs Engelhart, Geerlings, Ruitenberg, Stijnen, Hofman, Witteman, and Breteler) and Neurology (Drs Ruitenberg and van Swieten), Erasmus Medical Center, Rotterdam, the Julius Center for Health Sciences and Primary Care, University Medical Center, Utrecht (Dr Geerlings), Numico Research, Wageningen (Dr Kiliaan and Mr Meijer), and the Department of Anatomy, University Medical Center, Nijmegen (Dr Kiliaan), the Netherlands. RELATED ARTICLES IN ARCHIVES OF NEUROLOGY This Month in Archives of Neurology Arch Neurol. 2004;61: FULL TEXT Arch Neurol. 2004;61: 173

Cytokines, Stress, and Depression
Immune activation, and particularly increased activity of several cytokines, notably interleukin-1, interleukin-2, interleukin-6, tumor necrosis factor- as well as their soluble receptors is characteristic of depression. Affective changes may stem from the neuroendocrine and central neurochemical changes elicited by cytokines, as these are reminiscent of those associated thought to sub serve depression. doi: /S (02) Copyright © 2002 Elsevier Science (USA). All rights reserved. Cytokines, stress, and depressive illness H. Anisman , , a, b and Z. Meralib, c a Institute of Neuroscience, Carleton University, Ottawa, Ont., Canada K1S 5B6 b Department of Psychiatry, Royal Ottawa Hospital, Canada c Department of Cellular and Molecular Medicine, School of Psychology, University of Ottawa, Ottawa, Ont., Canada Received 29 January 2001. Available online 1 October 2002. Abstract It has been suggested that immune activation, and particularly increased activity of several cytokines, notably interleukin-1, interleukin-2, interleukin-6, tumor necrosis factor- as well as their soluble receptors is characteristic of depression. Normalization of cytokine activity does not necessarily occur following successful antidepressant, suggesting that cytokines may be trait markers of depression, or simply represent bystander effects of the illness. The relationship between cytokines and depression is complicated as a variety factors could directly or indirectly influence cytokine activity. While cytokine elevations are most pronounced in severe (melancholic) depression, their activity may also be related to chronicity of illness, neurovegetative features of depression (altered sleep patterns, food intake, weight changes, fatigue or general activity), or the high stress perception characteristic of depression. Although, studies assessing cytokines in depressive populations are basically correlational in nature, patients receiving cytokine immunotherapy frequently show depressive symptoms, which may be attenuated by antidepressant medication, supporting a causal role for cytokines in depressive disorders. The processes underlying such outcomes remain to be established, but the affective changes may stem from the neuroendocrine and central neurochemical changes elicited by cytokines, as these are reminiscent of those associated thought to subserve depression. Author Keywords: Depression; Anxiety; Stress; Neuroendocrine; Cytokine; Interleukin-1; Interleukin-2 H. Anisman, Z. Merali 174

Stress and inflammation in MDD
Raison et al, Arch Gen Psychiatry. 2010;67(12):

Blunted Ventral Striatum Development in Adolescence Reflects Emotional Neglect and Predicts Depressive Symptoms Our results provide an important demonstration that blunted development of reward-related ventral striatum activity as a function of emotional neglect predicts the emergence of depressive symptoms in adolescents. Further, our results are consistent with emerging evidence for the importance of reward-related ventral striatum dysfunction in the etiology and pathophysiology of depression. These results are a first step toward developing the ability to predict, prevent, and treat stress-related psychopathology through the targeting of specific neural phenotypes. Biol Psychiatry Nov 1;78(9): doi: /j.biopsych Epub 2015 May 27. Blunted Ventral Striatum Development in Adolescence Reflects Emotional Neglect and Predicts Depressive Symptoms. Hanson JL(1), Hariri AR(2), Williamson DE(3). Author information: (1)Department of Psychology and Neuroscience, Durham, North Carolina. Electronic address: (2)Department of Psychology and Neuroscience, Durham, North Carolina. (3)Department of Psychiatry, University of Texas Health Sciences Center at San Antonio, San Antonio, Texas; South Texas Veterans Health Care System, San Antonio, Texas. BACKGROUND: Emotional neglect is associated with multiple negative outcomes, particularly increased risk for depression. Motivated by increasing evidence of reward-related ventral striatum (VS) dysfunction in depression, we investigated the role of developmental changes in VS activity on the emergence of depressive symptomatology as a function of emotional neglect. METHODS: We examined relationships between longitudinal neuroimaging of reward-related VS activity, assessments of mood, and measures of emotional neglect in 106 participants first scanned between ages 11 to 15 and then 2 years later. RESULTS: We found that greater levels of emotional neglect were associated with blunted development of reward-related VS activity between the first and second assessments (as indexed by lower residualized change scores). Additionally, we found that decreases in this reward-related VS activity were related to greater depressive symptomatology and partially mediated the association between emotional neglect and subsequent depressive symptomatology. CONCLUSIONS: Our results provide an important demonstration that blunted development of reward-related VS activity as a function of emotional neglect predicts the emergence of depressive symptoms in adolescents. Further, our results are consistent with emerging evidence for the importance of reward-related VS dysfunction in the etiology and pathophysiology of depression. These results are a first step toward developing the ability to predict, prevent, and treat stress-related psychopathology through the targeting of specific neural phenotypes. Hanson JL, Hariri AR, Williamson DE. Biol Psychiatry Nov 1;78(9):

Cerebral inflammation is an underlying mechanism of early death in Alzheimer's disease: a 13-year cause-specific multivariate mortality study Our results suggest that inflammation, and not amyloid or tau pathology, is an independent underlying mechanism in the malignancy of AD. Alzheimers Res Ther Jul 7;6(4):41. doi: /alzrt271. eCollection Cerebral inflammation is an underlying mechanism of early death in Alzheimer's disease: a 13-year cause-specific multivariate mortality study. Nägga K(1), Wattmo C(1), Zhang Y(2), Wahlund LO(2), Palmqvist S(3). Author information: (1)Clinical Memory Research Unit, Department of Clinical Sciences Malmö, Lund University, Malmö, Sweden. (2)Department of Neuroradiology, Karolinska University Hospital, Stockholm, Sweden ; Department of Neurobiology, Care Sciences and Society, Section of Clinical Geriatrics, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden. (3)Clinical Memory Research Unit, Department of Clinical Sciences Malmö, Lund University, Malmö, Sweden ; Department of Neurology, Skåne University Hospital, Lund SE , Sweden. INTRODUCTION: Although Alzheimer's disease (AD) is associated with early death, its life expectancy differs greatly between patients. A better understanding of this heterogeneity may reveal important disease mechanisms underlying the malignancy of AD. The aim of this study was to examine the relation between AD pathologies and early death in AD caused by dementia. METHODS: At a memory clinic, 247 referred consecutive patients with AD were monitored during 12.6 ± 1.6 years. Multivariate Cox regression analyses were performed with baseline measures of amyloid beta (Aβ) pathology (APOE genotype, cerebrospinal fluid (CSF) Aβ42) tau pathology (CSF phosphorylated tau and total tau), cerebrovascular pathology (white-matter lesions and CSF/serum albumin ratio), neuroinflammatory pathology (CSF soluble vascular cell adhesion molecule-1, sVCAM-1), frontal, temporal, and central brain atrophies, global cognition, sex, and age. Comorbidities and medications also were analyzed. All continuous variables were transformed to z scores to compare hazard ratios (HRs) and 95% confidence intervals (CIs). RESULTS: At follow-up, 89% of the patients had died. The mean survival time was 6.4 ± 3.0 years. The AD pathology that independently predicted an early death caused by dementia was cerebral inflammation (sVCAM-1; HR, 1.32; 95% CI, ). Other independent predictors were lower global cognition (HR, 0.51; 95% CI, ), frontal atrophy (HR, 1.38; 95% CI, ), and medial temporal atrophy (HR, 1.23; 95% CI, ). When examining death caused by dementia and related causes (vascular diseases and infections), age (HR, 1.23; 95% CI, ) and cerebrovascular pathology (white-matter lesions: HR, 1.17; 95% CI, ; and CSF/serum albumin ratio: HR, 1.16; 95% CI, ) were also significant risk factors in addition to the previous variables. No comorbidity or medication was significant in the specific-cause models. CONCLUSIONS: This is the first study to link neuroinflammation independently to early death in AD and, hence, a rapidly progressing disease. Frontal and medial temporal atrophies and low cognition were also significant predictors. These are probably downstream biomarkers that reflect neuronal degeneration and late-stage disease. Our results suggest that inflammation, and not amyloid or tau pathology, is an independent underlying mechanism in the malignancy of AD. Nägga K, Wattmo C, Zhang Y, Wahlund LO, Palmqvist S. Alzheimers Res Ther ;6(4):41.

A Meta-Analysis of Cytokines in Alzheimer’s Disease
A review of 86 studies strengthen the clinical evidence that AD is accompanied by an inflammatory response, particularly higher peripheral concentrations of IL-6, TNF-, IL-1, TGF-, IL-12 and IL-18 and higher CSF concentrations of transforming growth factor. A Meta-Analysis of Cytokines in Alzheimer’s Disease Walter Swardfager, Krista Lanctôt, Lana Rothenburg, Amy Wong, Jaclyn Cappell, and Nathan Herrmann Background: Studies suggest that inflammation is involved in the neurodegenerative cascade leading to Alzheimer’s disease (AD) pathology and symptoms. This study sought to quantitatively summarize the clinical cytokine data. Methods: Original English language peer-reviewed studies measuring cytokine concentrations in AD and healthy control subjects were included. Mean (standard deviation) cytokine concentrations for AD and control subjects were extracted. Results: Forty studies measuring peripheral blood cytokine concentrations and 14 measuring cerebrospinal fluid (CSF) cytokine concentrations were included. In peripheral blood, there were significantly higher concentrations (weighted mean difference [95% confidence interval]) of interleukin (IL)-6 (2.86 [1.68, 4.04] pg/mL, p , N[AD/control subjects] 985/680, 14 studies), tumor necrosis factor (TNF)- (3.25 [.76, 5.74] pg/mL, p .01, N 680/447, 14 studies), IL-1 (.55 [.32, .78] pg/mL, p , N 574/370, 10 studies), transforming growth factor (TGF)- (67.23 [28.62, ] pg/mL, p , N 190/158, 5 studies), IL-12 (7.60 [5.58, 9.62] pg/mL, p .00001, N148/106, 5 studies), and IL-18 (15.82 [1.98, 29.66] pg/mL, p.03, N131/94, 4 studies) but not of IL-4, IL-8, IL-10, interferon-, or C-reactive protein in AD subjects compared with control subjects. There were significantly higher concentrations of TGF- (7.81 [2.27, 13.35] pg/mL, p .006, N 113/114, 5 studies) but not IL-6, TNF-, and IL-1 in the CSF of AD subjects compared with control subjects. Conclusions: These results strengthen the clinical evidence that AD is accompanied by an inflammatory response, particularly higher peripheral concentrations of IL-6, TNF-, IL-1, TGF-, IL-12 and IL-18 and higher CSF concentrations of TGF-. Swardfager W, Krista Lanctôt K, Rothenburg L, Wong A, Cappell J, Herrmann N. BIOL PSYCHIATRY 2010

Depression as a risk factor for Alzheimer disease: the MIRAGE Study
Depression symptoms before the onset of AD are associated with the development of AD, even in families where first depression symptoms occurred more than 25 years before the onset of AD. These data suggest that depression symptoms are a risk factor for later development of AD. Arch Neurol May;60(5): Depression as a risk factor for Alzheimer disease: the MIRAGE Study. Green RC(1), Cupples LA, Kurz A, Auerbach S, Go R, Sadovnick D, Duara R, Kukull WA, Chui H, Edeki T, Griffith PA, Friedland RP, Bachman D, Farrer L. Author information: (1)Department of Neurology, Genetics Program, Boston University School of Medicine, MA 02118, USA. BACKGROUND: Depression symptoms may be associated with the development of Alzheimer disease (AD). OBJECTIVES: To evaluate the association between depression symptoms and risk of AD, and to explore the temporal aspects of this association. SETTING: Academic institutions with specialized memory clinics. DESIGN: Cross-sectional, family-based, case-control study with standardized self- and proxy questionnaires to collect information on depression symptoms and other risk factors. PARTICIPANTS: A total of 1953 subjects with AD and 2093 of their unaffected relatives enrolled in the Multi-institutional Research in Alzheimer's Genetic Epidemiology Study. MAIN OUTCOME MEASURES: Odds ratios (ORs) of AD were estimated with and without depression symptoms, adjusted for age, sex, education, history of head trauma, and apolipoprotein E status. RESULTS: There was a significant association between depression symptoms and AD (adjusted OR, 2.13; 95% confidence interval [CI], ). In families where depression symptoms first occurred within 1 year before the onset of AD, the association was higher (OR, 4.57; 95% CI, ), while in the families where the depression symptoms first occurred more than 1 year before the onset of AD, the association was lower (OR, 1.38; 95% CI, ). In families where depression symptoms first occurred more than 25 years before the onset of AD, there was still a modest association (OR, 1.71; 95% CI, ). CONCLUSIONS: Depression symptoms before the onset of AD are associated with the development of AD, even in families where first depression symptoms occurred more than 25 years before the onset of AD. These data suggest that depression symptoms are a risk factor for later development of AD. Green RC et al. Arch Neurol 2003 May;60(5):753-9.

Anxiety & Depression Increase Risk of Parkinson’s Disease
Gustafsson H, Nordström A, Nordström P. Depression and subsequent risk of Parkinson disease: A nationwide cohort study. Neurology May 20. Lin CH, Lin JW, Liu YC, Chang CH, Wu RM. Risk of Parkinson's disease following anxiety disorders: a nationwide population-based cohort study. Eur J Neurol May 29.

Inflammation and the phenomenology, pathophysiology, comorbidity, and treatment of bipolar disorder: a systematic review of the literature Available evidence indicates that bipolar disorder and inflammation are linked through shared genetic polymorphisms and gene expression as well as altered cytokine levels during symptomatic (i.e., mania and depression) and asymptomatic intervals. However, results are inconsistent. Several conventional mood stabilizers have anti-inflammatory properties. Inflammation is closely linked with behavioral parameters such as exercise, sleep, alcohol abuse, and smoking, as well as with medical comorbidities including coronary artery disease, obesity and insulin resistance, osteoporosis, and pain. CONCLUSION: Inflammation appears relevant to bipolar disorder across several important domains. J Clin Psychiatry Jun 2. [Epub ahead of print] Inflammation and the phenomenology, pathophysiology, comorbidity, and treatment of bipolar disorder: a systematic review of the literature. Goldstein BI, Kemp DE, Soczynska JK, McIntyre RS. Western Psychiatric Institute and Clinic, University of Pittsburgh School of Medicine, 3811 O'Hara Street, Pittsburgh, PA 16213, USA. OBJECTIVE: To review extant literature implicating inflammation in the pathophysiology of bipolar disorder. Furthermore, we review evidence regarding the anti-inflammatory actions of mood-stabilizing medication, the putative reciprocal association of inflammation with behavioral parameters and medical burden in bipolar disorder, and the potential role of anti-inflammatory agents in the treatment of bipolar disorder. DATA SOURCES: MEDLINE and PubMed searches were conducted of English-language articles published from 1950 to April 2008 using the search terms bipolar disorder, manic, or mania, cross-referenced with inflammation, inflammatory, interleukin, cytokine, C-reactive protein, or tumor necrosis factor. The search, which was conducted most recently on August 20, 2008, was supplemented by manually reviewing reference lists from the identified publications. STUDY SELECTION: Articles selected for review were based on adequacy of sample size, the use of standardized experimental procedures, validated assessment measures, and overall manuscript quality. DATA EXTRACTION: Studies were reviewed for statistical comparisons of cytokines among persons with and without bipolar disorder, during symptomatic and non-symptomatic intervals and before and after pharmacologic treatment. Significant and nonsignificant findings were tabulated. DATA SYNTHESIS: Available evidence indicates that bipolar disorder and inflammation are linked through shared genetic polymorphisms and gene expression as well as altered cytokine levels during symptomatic (i.e., mania and depression) and asymptomatic intervals. However, results are inconsistent. Several conventional mood stabilizers have anti-inflammatory properties. The cyclooxygenase-2-selective anti-inflammatory celecoxib may offer antidepressant effects. Inflammation is closely linked with behavioral parameters such as exercise, sleep, alcohol abuse, and smoking, as well as with medical comorbidities including coronary artery disease, obesity and insulin resistance, osteoporosis, and pain. Methodological limitations precluding definitive conclusions are heterogeneity in sample composition, cytokine assessment procedures, and treatment regimens. The inclusion of multiple ethnic groups introduces another source of variability but also increases the generalizability of study findings. CONCLUSION: Inflammation appears relevant to bipolar disorder across several important domains. Further research is warranted to parse the reciprocal associations between inflammation and symptoms, comorbidities, and treatments in bipolar disorder. Studies of this topic among youth are needed and may best serve this purpose. © Copyright 2009 Physicians Postgraduate Press, Inc. Goldstein BI, Kemp DE, Soczynska JK, McIntyre RS. J Clin Psychiatry Jun 2. [Epub]

Inflammation, Psychosis, and the Brain
Hundreds of studies of schizophrenic illness in adults have documented immunological abnormalities in these patients First-episode psychosis in children is associated with evidence of increased inflammation Increasing evidence now suggests that the glia, cerebral vasculature, and the BBB may be involved. Our results support the inflammatory theory of schizophrenia that was formulated over a 100 years ago and perhaps offer hope that prevention of chronicity can occur if the first episode of psychosis is rapidly and effectively controlled. Inflammation, Psychosis, and the Brain Dr Falcone is associate professor of psychiatry in the department of psychiatry and neurology at the Cleveland Clinic Neurological Institute. Erin Carlton is a medical student at the University of Toledo. Dr Franco is a consultation liaison psychiatrist at the Cleveland Clinic and associate dean of admissions and student affairs, and professor of medicine and psychiatry at the Cleveland Clinic Lerner College of Medicine of Case Western Reserve University. Dr Janigro is the director of cerebrovascular research at Cleveland Clinic and professor of molecular medicine at the Cleve-land Clinic Lerner College of Medicine. Tatiana Falcone, MD, Erin Carlton, MS, Kathleen Franco, MD, and Damir Janigro, PhD July 10, Psychiatric Times. Vol. 26 No. 7 New Research When the solution to a clinical or scientific puzzle eludes us for more than a century, as with schizophrenia, we need new methods to examine the pathology. If we want to make an impact on the disease we must shift research paradigms and focus on the early detection, early intervention, and new avenues of treatment that address different symptoms of schizophrenia. Immunological and blood-brain barrier (BBB) abnormalities in patients with psychosis have been repeatedly noted. Hundreds of studies of schizophrenic illness in adults have documented immunological abnormalities in these patients, and an increasing number of studies have shown a link between S100b, a marker of BBB function, and schizophrenic illness (Table).1-3 In looking at the possible causes of schizophrenia, earlier studies focused on neurons. Increasing evidence now suggests that the glia, cerebral vasculature, and the BBB may be involved. Two postmortem studies reported activated glial cells in a subgroup of patients with schizophrenia.4,5 Using the marker PK11195 to label glial cells in patients with psychosis, Hirsch6 found activation throughout the cortex using positron emission tomographic accentuation in the frontal lobes. Here we present evidence linking inflammation, immunological abnormalities, BBB disruption, and neurological disorders. BBB in health and disease The BBB is a physical and metabolic barrier that regulates and protects the brain. This barrier is composed of tight junctions between endothelial cells in CNS vessels that restrict the passage of solutes. Several lines of evidence have pointed to a link between CNS problems—such as psychiatric disorders and inflammation—that occur in response to pathogens. Impairment of the BBB may be the consequence of immunopathogenic mechanisms.7 Little is known about the microvascular endothelial cells that form the BBB. Technical difficulties and lack of specific markers for BBB endothelial cells have made this research difficult. However, with recent advances in methodological techniques, it is becoming possible to identify important characteristics of BBB endothelial cells. Integrity of the BBB reduces entry of immunocompetent cells and antibodies and is necessary for the immune system to attack infectious agents. A highly specialized tight endothelium isolates the brain from immune surveillance and allows only a few mononuclear cells, activated T cells, and macrophages to migrate into the CNS.8 During inflammation, extensive leukocyte migration occurs at the BBB.9 Both endothelial cells and astrocytes act as antigen-presenting cells to facilitate entry of T lymphocytes and antibodies. The BBB itself plays an active role in mediating the neuro-immune response. Cytokines, or cellular hormones, include neurotrophins, neuropoietic factors, interleukin (IL)-1 and IL-6, interferons (IFNs), colony-stimulating factors, growth factors, and thymic hormones that are released following stress. Perivascular macrophages, microglial cells, astrocytes, and cerebral endothelial cells can produce cyto-kines on activation.10 Cytokines influence the transport of compounds into the brain by altering the permeability of the BBB. In vitro studies reveal that the administration of IL-1, IL-6, tumor necrosis factor (TNF)-a, and IFN-g increases endothelial permeability TNF-a can induce the production of matrix metalloproteinases—in particular gelatinase B—that attack the basal lamina macromolecule-like type 4 collagen that surrounds the brain microvessels. Modulation of adhesion molecules may promote leukocyte adhesion to the cerebral endothelium and permit the migration of lymphocytes across the BBB via a transcellular route (Figure 1). Serum and cerebrospinal fluid S100b protein, inflammation, and schizophrenia There is increasing interest in the brain-specific protein S100b and its physiological roles and behavior in various neuropathological conditions. Levels of S100b, a small astrocytic calcium-binding protein, are increased in some neurological conditions, such as brain trauma, ischemia, epilepsy, and brain tumors. Increased serum levels of S100b help rule out BBB disruption as reliably as contrast-enhanced MRI and can be identified in seconds to minutes after BBB disruption. Elevated serum levels of S100b also predict the presence of neoplasms in the CNS. S100b thus serves as a noninvasive measurement of BBB function in patients and healthy persons. S100b levels are elevated in first-episode psychosis, chronic schizophrenia, and acute psychosis (Table). In 14 studies that evaluated 399 adults with schizophrenia and 389 controls, S100b concentrations were above normal: average levels were ng/mL in patients who have schizophrenia and 0.02 ng/mL in healthy controls. In a larger sample, Rothermundt and colleagues3 demonstrated the association of negative symptoms of schizophrenia with continuously elevated S100b for 24 weeks after an acute episode. Findings indicate that patients with initially elevated S100b concentrations show significantly slower improvement. Monocytosis in patients with schizophrenia Monocytosis has been reported in 5 studies. In their original observations of catatonia, Bruce and Peebles15 reported 12 cases of adolescents with psychosis and leukocytosis—particularly monocytosis. Zorrilla and colleagues16 reported monocytosis in symptomatic schizophrenic patients. Nikkila and associates17 compared cerebrospinal fluid samples obtained from schizophrenic patients and controls. The proportion of mononuclear/macrophages was significantly higher in samples taken from patients who had schizophrenia. Wilke and coworkers18 detected a statistically significant increase in leukocyte numbers, particularly monocytes (P < .05), in patients compared with controls. Kowalski and colleagues19 demonstrated activation of monocytes in 20 patients with paranoid schizophrenia and an increased serum concentration of IL-1b and TNF-a that normalized with antipsychotic treatment. Infections with different pathogens, viruses, retroviruses, and bacteria are increased across the life span of schizophrenic patients with a specific genotype. Fellerhoff and colleagues9 reported that Chlamydia stimulated the transmigration of monocytes through the BBB in 40.3% of 72 schizophrenic patients. This is a possible mechanism for monocyte activation and the inflammatory cascade.20 For example, the presence of this infection activates the inflammatory response and increases production of cytokines associated with schizophrenia. It is perhaps genotype HLA-A10 in addition to the infection that may be associated with psychotic symptoms in some schizophrenic patients. In our pilot study to analyze white blood cell abnormalities in children with psychosis, conducted from 2003 through 2006, we enrolled 102 inpatients admitted to the Cleveland Clinic Child and Adolescent Psychiatry unit. Sixteen patients who were taking anti-biotics or lithium, who had a fever on admission, or who had bipolar disorder were excluded from the sample. A total of 86 patients with a median age of 14 years participated in the study. In those patients, 2 child psychiatrists diagnosed psychosis using DSM-IV-TR criteria for psychosis not otherwise specified (NOS), schizophreniform disorder, schizoaffective disorder, or new-onset schizophrenia. Active psychosis included hallucinations, delusions, or peculiar fantasies. A group of 86 nonpsychotic patients, recruited from the same inpatient unit, served as controls. When comparing hematological results of these patients with those of controls, monocytosis was the most common and statistically significant finding (P < .01) (Figure 2). In the psychotic group, most patients had monocyte counts that were well above what is considered normal for children. The percentage of monocytes was particularly high. These findings did not correlate with drug use before admission or with therapeutic and pharmacological interventions. Prospective study of inflammatory markers in children with psychosis To further assess the role of inflammation in the pathogenesis of psychosis, we studied the relationship between S100b serum concentrations and acute psychosis in children and adolescents. Participants had been admitted to the child and adolescent inpatient psychiatry unit with a diagnosis of acute psychosis. (Psychosis NOS, schizophreniform disorder, or schizophrenia had been diagnosed in the past 6 months.) Parent(s) or guardian(s) gave consent for us to obtain blood samples. Our hypothesis was that proinflammatory changes were responsible for observed differences in the monocyte counts of the psychotic patients and that a downstream effect of monocytosis was damaging to the endothelial cells constituting the BBB. Serum samples of 10 psychotic children were compared with those of 9 healthy children. In the healthy control group, a preliminary interview had ruled out psychosis, any neurodegenerative disorder, fever, current infection, or current use of antibiotics. S100b levels were significantly higher in children with psychosis than in controls (P < .05) (Figure 3). Most psychotic children had S100b levels above normal. Nonetheless, S100b is a nonspecific measure of BBB permeability. Elevated S100b does not give insight into the mechanism of BBB disruption, and it does not prove a causal link to psychotic symptoms. Psychosis may precede elevations of S100b and BBB dysfunction. From this standpoint, S100b can still serve as a biomarker of BBB disruption. Conclusion First-episode psychosis in children is associated with evidence of increased inflammation (eg, monocytosis) and elevated serum concentrations of S100b. Several cytokines—TNF-a, IL-1b, and IL-6, among others—have been reported to be elevated in patients with schizophrenia. These inflammatory mediators are often associated with BBB leakage, which is consis-tent with animal models of schizophrenia Curiously, some antipsychotic medications have immunomodulatory effects.25 Future research may determine whether serum factors are causally related or only associated with transendothelial leakage of S100b. Our results support the inflammatory theory of schizophrenia that was formulated over a 100 years ago and perhaps offer hope that prevention of chronicity can occur if the first episode of psychosis is rapidly and effectively controlled.26 Although there are mixed results in 6 studies using anti-inflammatory medications in schizophrenic patients, Müller and colleagues27,28 believe that these agents are more likely to be effective in first-episode patients than in those with chronic schizophrenia. The missing images can be viewed on the website: Tatiana Falcone T, Carlton E, Franco K, Janigro D. Psychiatric Times. Vol. 26 No. 7

Increased levels of IL-6 in the cerebrospinal fluid of patients with chronic schizophrenia--significance for activation of the kynurenine pathway We have shown that IL-6, kynurenine (KYN) and KYNA are elevated in patients with chronic schizophrenia, strengthening the idea of brain immune activation in patients with this disease. Our concurrent cell culture and clinical findings suggest that IL-6 induces the KYN pathway, leading to increased production of the N-methyl-D-aspartate receptor antagonist KYNA in patients with schizophrenia. Interleukin-1beta can upset the dopamine system in rats in a similar way to schizophrenia in humans. J Psychiatry Neurosci Mar;40(2): Increased levels of IL-6 in the cerebrospinal fluid of patients with chronic schizophrenia--significance for activation of the kynurenine pathway. Schwieler L(1), Larsson MK(1), Skogh E(2), Kegel ME(1), Orhan F(1), Abdelmoaty S(1), Finn A(1), Bhat M(3), Samuelsson M(2), Lundberg K(2), Dahl ML(4), Sellgren C(5), Schuppe-Koistinen I(3), Svensson C(1), Erhardt S(1), Engberg G(1). Author information: (1)Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden. (2)Department of Clinical and Experimental Medicine, Section of Psychiatry, Faculty of Health Sciences, Linköping University, Linköping, Sweden. (3)AstraZeneca, Research & Development, Innovative Medicines, Personalised Healthcare & Biomarkers, Science for Life Laboratory, Solna, Sweden, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden. (4)Department of Laboratory Medicine, Division of Clinical Pharmacology, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden. (5)Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden. BACKGROUND: Accumulating evidence indicates that schizophrenia is associated with brain immune activation. While a number of reports suggest increased cytokine levels in patients with schizophrenia, many of these studies have been limited by their focus on peripheral cytokines or confounded by various antipsychotic treatments. Here, well-characterized patients with schizophrenia, all receiving olanzapine treatment, and healthy volunteers were analyzed with regard to cerebrospinal fluid (CSF) levels of cytokines. We correlated the CSF cytokine levels to previously analyzed metabolites of the kynurenine (KYN) pathway. METHODS: We analyzed the CSF from patients and controls using electrochemiluminescence detection with regard to cytokines. Cell culture media from human cortical astrocytes were analyzed for KYN and kynurenic acid (KYNA) using high-pressure liquid chromatography or liquid chromatography/mass spectrometry. RESULTS: We included 23 patients and 37 controls in our study. Patients with schizophrenia had increased CSF levels of interleukin (IL)-6 compared with healthy volunteers. In patients, we also observed a positive correlation between IL-6 and the tryptophan:KYNA ratio, indicating that IL-6 activates the KYN pathway. In line with this, application of IL-6 to cultured human astrocytes increased cell medium concentration of KYNA. LIMITATIONS: The CSF samples had been frozen and thawed twice before analysis of cytokines. Median age differed between patients and controls. When appropriate, all present analyses were adjusted for age. CONCLUSION: We have shown that IL-6, KYN and KYNA are elevated in patients with chronic schizophrenia, strengthening the idea of brain immune activation in patients with this disease. Our concurrent cell culture and clinical findings suggest that IL-6 induces the KYN pathway, leading to increased production of the N-methyl-D-aspartate receptor antagonist KYNA in patients with schizophrenia. Schwieler L, et al. J Psychiatry Neurosci Mar;40(2):

The Putative Role of Viruses, Bacteria, and Chronic Fungal Biotoxin Exposure in the Genesis of Intractable Fatigue Accompanied by Cognitive and Physical Disability More sophisticated investigations often reveal the presence of a range of pathogens capable of establishing life-long infections with sophisticated immune evasion strategies, including Parvoviruses, HHV6, variants of Epstein-Barr, Cytomegalovirus, Mycoplasma, and Borrelia burgdorferi. Other patients have a history of chronic fungal or other biotoxin exposure. The presence of active, reactivated, or even latent Herpes virus could be a potential source of intractable fatigue accompanied by profound physical and or cognitive disability in some patients, and the same may be true of persistent Parvovirus B12 and mycoplasma infection. A history of chronic mold exposure is a feasible explanation for such symptoms, as is the presence of B. burgdorferi. The complex tropism, life cycles, genetic variability, and low titer of many of these pathogens makes their detection in blood a challenge. Mol Neurobiol Jun 17. [Epub ahead of print] The Putative Role of Viruses, Bacteria, and Chronic Fungal Biotoxin Exposure in the Genesis of Intractable Fatigue Accompanied by Cognitive and Physical Disability. Morris G(1), Berk M, Walder K, Maes M. Author information: (1)Tir Na Nog, Bryn Road seaside 87, Llanelli, SA15 2LW, Wales, UK. Patients who present with severe intractable apparently idiopathic fatigue accompanied by profound physical and or cognitive disability present a significant therapeutic challenge. The effect of psychological counseling is limited, with significant but very slight improvements in psychometric measures of fatigue and disability but no improvement on scientific measures of physical impairment compared to controls. Similarly, exercise regimes either produce significant, but practically unimportant, benefit or provoke symptom exacerbation. Many such patients are afforded the exclusionary, non-specific diagnosis of chronic fatigue syndrome if rudimentary testing fails to discover the cause of their symptoms. More sophisticated investigations often reveal the presence of a range of pathogens capable of establishing life-long infections with sophisticated immune evasion strategies, including Parvoviruses, HHV6, variants of Epstein-Barr, Cytomegalovirus, Mycoplasma, and Borrelia burgdorferi. Other patients have a history of chronic fungal or other biotoxin exposure. Herein, we explain the epigenetic factors that may render such individuals susceptible to the chronic pathology induced by such agents, how such agents induce pathology, and, indeed, how such pathology can persist and even amplify even when infections have cleared or when biotoxin exposure has ceased. The presence of active, reactivated, or even latent Herpes virus could be a potential source of intractable fatigue accompanied by profound physical and or cognitive disability in some patients, and the same may be true of persistent Parvovirus B12 and mycoplasma infection. A history of chronic mold exposure is a feasible explanation for such symptoms, as is the presence of B. burgdorferi. The complex tropism, life cycles, genetic variability, and low titer of many of these pathogens makes their detection in blood a challenge. Examination of lymphoid tissue or CSF in such circumstances may be warranted. Morris G, Berk M, Walder K, Maes M. Mol Neurobiol Jun 17.

OspA, OspB Reactivity & Autism
Reactivity to protein bands OspA and/or OspB were found in 92% (44/48) of patients with autism associated with Lyme disease and reactivity to OspB correlates with symptom severity (OspA is 31 and OspB is 34 kDa band on Western blot testing).[1] Bb OspA antibodies cross-react with neural tissue.[2] These two bands were targeted for use in vaccine trials, unfortunately removed from the US CDC interpretation of the Western blot and reactivity of these bands are not reported by many commercial labs.[1] This finding raises Lyme vaccine safety concerns! Two particularly significant antigens associated with autistic symptoms include Borrelia burgdorferi Outer Surface Protein A (band 31) and Outer Surface Protein B (band 34) on the Western blot. [5] Since these two bands are so specific to Borrelia burgdorferi they were targeted for use in vaccine trials, unfortunately removed from the United States Center for Disease Control interpretation of the Western blot and reactivity of these bands are not reported by many commercial labs. [1] Kuhn M, Bransfield R. Divergent Opinions of Proper Lyme Disease Diagnosis and Implications For Children CoMorbid with Autism Spectrum Disorder. [2] Alaedini A, Latov N. Antibodies against OspA epitopes of Borrelia burgdorferi cross- react with neural tissue. J Neuroimmunol Feb;159(1-2):192-5.

The scores in black indicated a positive result for OSP B
The scores in black indicated a positive result for OSP B. The scores in white had other positive bands on their Western Blot but not OspB. Kuhn M, Bransfield RC

Intrusive Post Traumatic Symptoms
Intrusive Posttraumatic Stress (PTSD) symptoms are associated with activation of the basolateral amygdala and the ventral hippocampus. [1] Individuals who experience clinical levels of PTSD exhibited higher CRP levels. [2, 3] PTSD symptoms are associated with increased TNF-alpha and IL-6. [4,5] Interleukin-1β is associated with increases with symptoms severity and volumetric brain changes in PTSD patients. [6] 1. Front Behav Neurosci Jan 29;8:18. doi: /fnbeh eCollection 2014. exposure to a reminder of underwater trauma. Differential activation of amygdala, dorsal and ventral hippocampus following an Ritov G(1), Ardi Z(1), Richter-Levin G(2). Institute for the Study of Affective Neuroscience (ISAN), University of Haifa (1)Sagol Department of Neurobiology, University of Haifa Haifa, Israel ; The Author information: (2)Sagol Department of Neurobiology, University of Haifa Haifa, Israel ; The Haifa, Israel. Haifa, Israel ; Psychology Department, University of Haifa Haifa, Israel. ventral hippocampus (VH) in traumatic stress processing and emotional memory amygdala and the hippocampus. Recent hypothesis suggests a pivotal role for the Recollection of emotional memories is attributed in part to the activation of the recollections are often triggered by reminders associated with the trauma. We symptoms in acute and posttraumatic stress disorders (ASD; PTSD). Such intrusive retrieval. Persistent re-experiencing and intrusive recollections are core examined the impact of exposure to a trauma reminder (under water trauma (UWT)) Phosphorylation of the extracellular signal-regulated kinase (ERK) was used as a exposed to UWT and 24 h later were re-exposed to the context of the trauma. on the activation of the basolateral amygdala (BLA), dorsal and VH. Rats were marker for level of activation of these regions. Significant increase in ERK reminder. Additionally, the dissociative pattern of activation of the VH in animals exposed only to the trauma or in animals exposed only to the trauma activation was found in the VH and BLA. Such pattern of activation was not found sub-regions positively correlated with the activation of the BLA. Our findings to the traumatic experience, the current findings relate to relatively early reminder, with a unique contribution of the VH. Measured 24 h after the exposure suggest a specific pattern of neural activation during recollection of a trauma underlying these initial stages may contribute to developing intervention stages of traumatic memory consolidation. Understanding the neural mechanisms strategies that could reduce the risk of eventually developing PTSD. 20. 2. Cytokine Aug;63(2): doi: /j.cyto Epub 2013 May higher C-reactive protein levels. Interpersonal violence, PTSD, and inflammation: potential psychogenic pathways to SE. Heath NM, Chesney SA, Gerhart JI, Goldsmith RE, Luborsky JL, Stevens NR, Hobfoll Department of Behavioral Sciences, Rush University Medical Center, 1645 W. Jackson, Suite 400, Chicago, IL 60612, United States. alterations of immune and inflammation processes. There is a need to identify the sequelae including depression, posttraumatic stress disorder (PTSD), and possible Interpersonal violence (IPV) is major public health concern with wide-ranging psycho-biological pathways through which IPV may translate to altered disease. This study investigated the relationships between IPV, psychological serious physical health conditions such as obesity, diabetes, and cardiovascular inflammatory processes since both PTSD and inflammation are associated with 139 urban women who have a high likelihood for having experienced IPV. distress, and the inflammatory marker C-reactive protein (CRP), in a sample of well as to have their blood sampled using a finger stick. Results indicated that self-report measures about their IPV histories and psychological symptoms, as Participants were recruited from an outpatient gynecology clinic to complete exposure to IPV predicted the presence of probable depression and PTSD diagnoses. analyses suggested that reexperiencing symptoms may explain the link between PTSD and this relationship held after adjusting for comorbid depression. Correlational Individuals who experience clinical levels of PTSD exhibited higher CRP levels, fit to the overall data, and indicated that the relationship between probable diagnosis and higher levels of CRP. Follow-up path analytic models provided good and diminished health. for increased attention to the role of PTSD in explaining links between trauma PTSD status and CRP is not explained by higher BMI. Overall, these findings call 3. J Affect Disord Jan;120(1-3): doi: /j.jad Depression, traumatic stress and interleukin-6. Benakova H, Zima T. Bob P, Raboch J, Maes M, Susta M, Pavlat J, Jasova D, Vevera J, Uhrova J, Department of Psychiatry, 1st Faculty of Medicine, Charles University, Prague, Czech Republic. nervous and immune system are important in pathogenesis of depression. These BACKGROUND: Recent evidence indicates that various types of interactions between findings show that a significant role in developing depression play pro-inflammatory cytokines that may mediate its psychological, and process related to depression may be influenced by psychological stress as well plays interleukin-6 (IL-6). There is growing evidence that this inflammatory neurobiological manifestations. Great importance among these cytokine molecules as organic inflammatory conditions. These findings suggest that specific METHODS: In the present study we have performed psychometric measurement of relationship to increased level of cytokine IL-6. influences related to traumatic stress and dissociation could be found in close depression (BDI-II), traumatic stress symptoms (TSC-40) and dissociation (DES, RESULTS: The results show that IL-6 is significantly correlated to BDI-II depression (mean age 42.3+/-6.8). SDQ-20), and immunochemical measure of serum IL-6 in 40 inpatients with unipolar R=0.34, p<0.05) but not to DES (Spearman R=0.25, p=0.11). (Spearman R=0.47, p<0.01), TSC-40 (Spearman R=0.32, p<0.05), SDQ-20 (Spearman somatoform dissociation. IL-6 in depression could be directly related to symptoms of traumatic stress and CONCLUSION: The findings of the present study indicate that increased level of 4. J Trauma Stress Dec;21(6): doi: /jts women with PTSD. Low cortisol, high DHEA, and high levels of stimulated TNF-alpha, and IL-6 in Gill J, Vythilingam M, Page GG. MD , USA. National Institute of Nursing Research, National Institutes of Health, Bethesda, hypothalamic-pituitary-adrenal (HPA) axis and immune function alterations; Posttraumatic stress disorder (PTSD) has been associated with however, few studies have simultaneously investigated these systems in participants with PTSD. In this study, HPA axis and immune function in 26 women disorder was associated with low cortisol and higher levels of DHEA and greater traumatized controls and to 21 nontraumatized controls. Posttraumatic stress with PTSD with and without major depressive disorder was compared to 24 production of tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) (DHEA) than those with PTSD, but without depression. These findings suggest exhibited greater production of IL-6 and higher levels of dehydroepiandrosterone compared to traumatized and healthy controls. Women with PTSD and depression depression may contribute to these abnormalities. dysregulated HPA axis and immune function in women with PTSD, and that comorbid Transl Psychiatry Feb 21;2:e78. doi: /tp to evade the pro-inflammatory NFκB pathway. Post-traumatic anxiety associates with failure of the innate immune receptor TLR9 H, Berliner SA, Shelef I, Shoham S, Friedman A, Cohen H, Soreq H. Zimmerman G, Shaltiel G, Barbash S, Cohen J, Gasho CJ, Shenhar-Tsarfaty S, Shalev Sciences, The Hebrew University of Jerusalem, Jerusalem, Israel. The Edmond and Lily Safra Center for Brain Sciences, The Institute of Life innate immune system Toll-like receptor 9 (TLR9) to limit inflammation is functional significance are yet unclear. Here, we report that failure of the Post-traumatic anxiety notably involves inflammation, but its causes and administration of specific oligonucleotide activators of TLR9 may prevent causally involved with anxiety-associated inflammation and that peripheral phenotype, we found association of serum interleukin-1β increases with symptoms NFκB-mediated enhancement of inflammatory reactions in the post-traumatic post-traumatic consequences in stressed mice. Suggesting involvement of severity and volumetric brain changes in post-traumatic stress disorder patients. oligonucleotide ODN1826, induced anxiolytic effects. In stressed mice, mEN101 and its human ortholog BL-7040, but not the canonic NFκB activator In predator scent-stressed mice, the moderate NFκB-activating oligonucleotides peripherally administered mEN101 prevented delayed stress-inducible serum activation. Attesting to the TLR9 specificity of this response, BL-7040 transcript modifications and the anxiety-induced EGR1-mediated neuronal interleukin-1β increases while limiting stress-characteristic hippocampal suppressed NFκB-mediated luciferase in transfected cells co-expressing TLR9, but transcripts. Our findings demonstrate functional relevance of TLR9 in protecting presented unprovoked anxiety-like behavior and anxiety-characteristic hippocampal not other TLRs. Furthermore, TLR9-/- mice were mEN101 and BL-7040 resistant and oligonucleotide-mediated peripheral TLR9 activation to potentiate the innate stressed mammals from overreacting to traumatic experiences and suggest using immune system and prevent post-traumatic inflammation and anxiety. [1] Ritov G, et al. Front Behav Neurosci Jan 29;8:18. [2] Heath NM, et al. Cytokine Aug;63(2):172-8. [3] Eraly SA et al. JAMA Psychiatry [4] Bob P, et al. J Affect Disord Jan;120(1-3):231-4. [5] Gill J, et al. J Trauma Stress Dec;21(6):530-9. [6] Zimmerman G, et al. Transl Psychiatry Feb 21;2:e78.

Gene networks specific for innate immunity define post-traumatic stress disorder
We identified discrete groups of co-regulated genes (i.e., co-expression modules) and tested them for association to PTSD. We identified one module at both pre- and post-deployment containing putative causal signatures for PTSD development displaying an over-expression of genes enriched for functions of innate-immune response and interferon signaling (Type-I and Type-II). Importantly, these results were replicated in a second non-overlapping independent dataset of U.S. Marines (N=96), further outlining the role of innate immune and interferon signaling genes within co-expression modules to explain at least part of the causal pathophysiology for PTSD development. Mol Psychiatry Mar 10. doi: /mp [Epub ahead of print] Gene networks specific for innate immunity define post-traumatic stress disorder. Breen MS(1), Maihofer AX(2), Glatt SJ(3), Tylee DS(3), Chandler SD(2), Tsuang MT(4), Risbrough VB(5), Baker DG(5), O'Connor DT(6), Nievergelt CM(5), Woelk CH(1). Author information: (1)Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, UK. (2)Department of Psychiatry, University of California San Diego, California, USA. (3)Psychiatric Genetic Epidemiology and Neurobiology Laboratory (PsychGENe Lab), Departments of Psychiatry and Behavioral Sciences and Neuroscience and Physiology, Medical Genetics Research Center, SUNY Upstate Medical University, Syracuse, New York, USA. (4)1] Department of Psychiatry, University of California San Diego, California, USA [2] Veterans Affairs Center of Excellence for Stress and Mental Health, San Diego, California, USA [3] Veterans Affairs San Diego Healthcare System, San Diego, California, USA [4] Institute of Genomic Medicine, University of California, San Diego, La Jolla, California, USA [5] Center for Behavioral Genomics, Department of Psychiatry, University of California San Diego, California, USA. (5)1] Department of Psychiatry, University of California San Diego, California, USA [2] Veterans Affairs Center of Excellence for Stress and Mental Health, San Diego, California, USA. (6)1] Institute of Genomic Medicine, University of California, San Diego, La Jolla, California, USA [2] Departments of Medicine and Pharmacology, University of California San Diego, California, USA. The molecular factors involved in the development of Post-Traumatic Stress Disorder (PTSD) remain poorly understood. Previous transcriptomic studies investigating the mechanisms of PTSD apply targeted approaches to identify individual genes under a cross-sectional framework lack a holistic view of the behaviours and properties of these genes at the system-level. Here we sought to apply an unsupervised gene-network based approach to a prospective experimental design using whole-transcriptome RNA-Seq gene expression from peripheral blood leukocytes of U.S. Marines (N=188), obtained both pre- and post-deployment to conflict zones. We identified discrete groups of co-regulated genes (i.e., co-expression modules) and tested them for association to PTSD. We identified one module at both pre- and post-deployment containing putative causal signatures for PTSD development displaying an over-expression of genes enriched for functions of innate-immune response and interferon signalling (Type-I and Type-II). Importantly, these results were replicated in a second non-overlapping independent dataset of U.S. Marines (N=96), further outlining the role of innate immune and interferon signalling genes within co-expression modules to explain at least part of the causal pathophysiology for PTSD development. A second module, consequential of trauma exposure, contained PTSD resiliency signatures and an over-expression of genes involved in hemostasis and wound responsiveness suggesting that chronic levels of stress impair proper wound healing during/after exposure to the battlefield while highlighting the role of the hemostatic system as a clinical indicator of chronic-based stress. These findings provide novel insights for early preventative measures and advanced PTSD detection, which may lead to interventions that delay or perhaps abrogate the development of PTSD.Molecular Psychiatry advance online publication, 10 March 2015; doi: /mp PMID: [PubMed - as supplied by publisher] Breen MS, Maihofer AX, Glatt SJ, Tylee DS, Chandler SD, Tsuang MT, Risbrough VB, Baker DG, O'Connor DT, Nievergelt CM, Woelk CH. Mol Psychiatry Mar 10.

The Association between Infections and General Cognitive Ability in Young Men - A Nationwide Study
Infections and activated immune responses can affect the brain through several pathways that might also affect cognition. Significant associations between infections and cognitive ability were observed. Infections or related immune responses might directly affect the cognitive ability; however, associated heritable and environmental factors might also account for the lowered cognitive ability. PLoS One May 13;10(5):e doi: /journal.pone eCollection The Association between Infections and General Cognitive Ability in Young Men - A Nationwide Study. Benros ME(1), Sørensen HJ(2), Nielsen PR(3), Nordentoft M(2), Mortensen PB(4), Petersen L(3). Author information: (1)Mental Health Centre Copenhagen, University of Copenhagen, Faculty of Health Sciences, Bispebjerg Bakke 23, 2400 Copenhagen NV, Denmark; National Centre for Register-based Research, Aarhus University, Fuglesangs allé 4, 8210 Aarhus V, Denmark. (2)Mental Health Centre Copenhagen, University of Copenhagen, Faculty of Health Sciences, Bispebjerg Bakke 23, 2400 Copenhagen NV, Denmark; The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Aarhus, Denmark. (3)National Centre for Register-based Research, Aarhus University, Fuglesangs allé 4, 8210 Aarhus V, Denmark. (4)National Centre for Register-based Research, Aarhus University, Fuglesangs allé 4, 8210 Aarhus V, Denmark; The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Aarhus, Denmark. BACKGROUND: Infections and activated immune responses can affect the brain through several pathways that might also affect cognition. However, no large-scale study has previously investigated the effect of infections on the general cognitive ability in the general population. METHODS: Danish nationwide registers were linked to establish a cohort of all 161,696 male conscripts during the years who were tested for cognitive ability, which was based on logical, verbal, numerical and spatial reasoning at a mean age of 19.4 years. Test scores were converted to a mean of and with a standard deviation (SD) of 15. Data were analyzed as a cohort study with severe infections requiring hospitalization as exposure using linear regression. RESULTS: Adjusted effect sizes were calculated with non-exposure to severe infections as reference, ranging from 0.12 SD to 0.63 SD on general cognitive ability. A prior infection was associated with significantly lower cognitive ability by a mean of 1.76 (95%CI: to -1.61; corresponding to 0.12 SD). The cognitive ability was affected the most by the temporal proximity of the last infection (P<0.001) and by the severity of infection measured by days of admission (P<0.001). The number of infections were associated with decreased cognitive ability in a dose-response relationship, and highest mean differences were found for ≥10 hospital contacts for infections (Mean: -5.54; 95%CI: to -3.89; corresponding to 0.37 SD), and for ≥5 different types of infections (Mean: -9.44; 95%CI: to -5.69; corresponding to 0.63 SD). Hospital contacts with infections had occurred in 35% of the individuals prior to conscription. CONCLUSIONS: Independent of a wide range of possible confounders, significant associations between infections and cognitive ability were observed. Infections or related immune responses might directly affect the cognitive ability; however, associated heritable and environmental factors might also account for the lowered cognitive ability. Benros ME, Sørensen HJ, Nielsen PR, Nordentoft M, Mortensen PB, Petersen L. PLoS One May 13;10(5).

Systemic infections and inflammation affect chronic neurodegeneration
In chronic neurodegenerative diseases such as Alzheimer's disease, with an ongoing innate immune response in the brain, systemic infections and inflammation can cause acute exacerbations of symptoms and drive the progression of neurodegeneration. Perspective Nature Reviews Immunology 7, (February 2007) | doi: /nri2015 Opinion: Systemic infections and inflammation affect chronic neurodegeneration V. Hugh Perry1, Colm Cunningham1 and Clive Holmes1 Abstract It is well known that systemic infections cause flare-ups of disease in individuals with asthma and rheumatoid arthritis, and that relapses in multiple sclerosis can often be associated with upper respiratory-tract infections. Here we review evidence to support our hypothesis that in chronic neurodegenerative diseases such as Alzheimer's disease, with an ongoing innate immune response in the brain, systemic infections and inflammation can cause acute exacerbations of symptoms and drive the progression of neurodegeneration. Author affiliations 1. V. Hugh Perry, Colm Cunningham and Clive Holmes are at the Southampton Neuroscience Group, School of Biological Sciences and School of Medicine, University of Southampton, Southampton SO16 7PX, UK. Correspondence to: V. Hugh Perry1 Perry et. Al. Nature Reviews Immunology 7, (February 2007) 191

Tick-Borne Diseases and Dementia I
MacDonald AB, Miranda JM. Hum Pathol Jul;18(7): Concurrent neocortical borreliosis and Alzheimer's disease. Miklossy J. Neuroreport Jul;4(7): Alzheimer's disease--a spirochetosis? Miklossy J, Kasas S, Janzer RC, Ardizzoni F, Van der Loos H. Further ultrastructural evidence that spirochaetes may play a role in the aetiology of Alzheimer's disease. Neuroreport Jun 2;5(10): Waniek C, Prohovnik I, Kaufman MA, Dwork AJ. Rapidly progressive frontal-type dementia associated with Lyme disease. J Neuropsychiatry Clin Neurosci. 1995;7(3):345-7. Miklossy J, Kis A, Radenovic A, Miller L, Forro L, Martins R, Reiss K, Darbinian N, Darekar P, Mihaly L, Khalili K. Beta-amyloid deposition and Alzheimer's type changes induced by Borrelia spirochetes. Neurobiol Aging. May 12, Osvaldo P. Almeida and Nicola T. Lautenschlager. Dementia associated with infectious diseases. International Psychogeriatrics (2005), 17:Supp., S65–S77 C _ 2005. MacDonald AB. Plaques of Alzheimer's disease originate from cysts of Borrelia burgdorferi, the Lyme disease spirochete. Med Hypotheses. 2006;67(3):

Tick-Borne Diseases and Dementia II
Macdonald AB. Transfection ‘‘Junk’’ DNA – A link to the pathogenesis of Alzheimer’s disease? Medical Hypothesis January. MacDonald AB (2006) Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association, 2 (3), Supplement, S207, S275, S433. Meer-Scherrer L, Chang Loa C, Adelson ME, Mordechai E, Lobrinus JA, Fallon BA, Tilton RC. Lyme Disease Associated with Alzheimer's Disease. Curr Microbiol Mar 9. Miklossy J. Biology and neuropathology of dementia in syphilis and Lyme disease. Handb Clin Neurol. 2008;89: Miklossy J. Chronic inflammation and amyloidogenesis in Alzheimer's disease -- role of Spirochetes. J Alzheimers Dis May;13(4): Aboul-Enein F, Kristoferitsch W. Normal pressure hydrocephalus or neuroborreliosis? Wien Med Wochenschr. 2009;159(1-2):58-61. Miklossy J. Alzheimer's disease - a neurospirochetosis. Analysis of the evidence following Koch's and Hill's criteria. J Neuroinflammation Aug 4;8(1):90.

Lyme and Dementia III Bannwarth, A. (1944) Zur Klinik und Pathogenese der chronischen lymphocytären Meningitis. Arch. Psychiatr.Nervenkr. 117, MacDonald, A. B. (1986) Borrelia in the brains of patients dying with dementia. J. Am. Med. Assoc. 256, MacDonald AB (1988) Concurrent Neocortical Borreliosis and Alzheimer’s Disease: Demonstration of a Spirochetal Cyst Form . Annals of the New York Academy of Sciences, Lyme Disease and Related Disorders. 539, 468–470. Pappolla MA, Omar R, Saran B, et al. (1989) Concurrent neuroborreliosis and Alzheimer's disease: analysis of the evidence. Hum Pathol 20(8), Miklossy J, Kuntzer T, Bogousslavsky J, Regli F, Janzer RC. (1990) Meningovascular form of neuroborreliosis: Similarities between neuropathological findings in a case of Lyme disease and those occurring in tertiary neurosyphilis. Acta Neuropathol Miklossy J, Van der Loos H. (1991) The long distance effects of brain lesions: A study of myelinated pathways in the human brain using polarizing and fluorescence microscopy. J Neuropathol Exp Neurol 50, 1-15.

Tick-Borne Diseases and Dementia IV
Mirra SS, Heyman A, McKeel D et al (1991) The Consortium to Establish a Registry for Alzheimer's Disease (CERAD). II. Standardization of the neuropathologic assessment of Alzheimer's disease. Neurology 41, Miklossy J, Taddei K, Martins R et al. (1999) Alzheimer disease: curly fibers and tangles in organs other than brain. J Neuropathol Exp Neurol. 58, Bransfield RC. Hosp Pract (1995) Aug 15;31(8):35, 40. The diagnosis of Lyme disease. McLaughlin R, Kin NM, Chen MF, et al. (1999) Alzheimer's disease may not be a spirochetosis. Neuroreport 10(7), Lue LF, Kuo YM, Roher AE, Brachova L, Shen Y, Sue L, Beach T, Kurth JH, Rydel RE, Rogers J (1999) Soluble amyloid beta peptide concentration as a predictor of synaptic change in Alzheimer's disease. Am J Pathol 155, Zajkowska JM, Hermanowska-Szpakowicz T (2002) New aspects of the pathogenesis of lyme disease. Przegl Epidemiol Suter O-C, Sunthorn T, Kraftsik R, Straubel J, Darekar P, Khalili K, Miklossy J (2002) Cerebral Hypoperfusion Generates Cortical Watershed Microinfarcts in Alzheimer Disease. Stroke 33,

Tick-Borne Diseases and Dementia V
Lue LF, Kuo YM, Roher AE, Brachova L, Shen Y, Sue L, Beach T, Kurth JH, Rydel RE, Rogers J (1999) Soluble amyloid beta peptide concentration as a predictor of synaptic change in Alzheimer's disease. Am J Pathol 155, Zajkowska JM, Hermanowska-Szpakowicz T (2002) New aspects of the pathogenesis of lyme disease. Przegl Epidemiol Suter O-C, Sunthorn T, Kraftsik R, Straubel J, Darekar P, Khalili K, Miklossy J (2002) Cerebral Hypoperfusion Generates Cortical Watershed Microinfarcts in Alzheimer Disease. Stroke 33, Hardy J, Selkoe DJ (2002) The amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeutics. Science 297, 353-6 Miklossy J, Khalili K, Gern L, Ericson RL, Darekar P, Bolle L, Hurlimann J, Paster BJ. (2004) Borrelia burgdorferi persists in the brain in chronic Lyme neuroborreliosis and may be associated with Alzheimer disease. J Alzheimer’s Dissease 6 (6), 1-11.

Tick-Borne Diseases and Dementia VI
Miklossy J, Khalili K, Gern L, et al. (2004) Borrelia burgdorferi persists in the brain in chronic lyme neuroborreliosis and may be associated with Alzheimer disease. J Alzheimers Dis. 6(6), ; discussion Ruitenberg A, den Heijer T, Bakker SL, van Swieten JC, Koudstaal PJ, Hofman A, Breteler MM (2005) Cerebral hypoperfusion and clinical onset of dementia: the Rotterdam study. Ann Neurol 57, Guo JP, Arai T, Miklossy J, McGeer PL (2006) Aβ and tau form soluble complexes that may promote self aggregation of both into the insoluble forms observed in Alzheimer’s disease. PNAS 103(6) MacDonald AB (2006) Alzheimer's neuroborreliosis with trans-synaptic spread of infection and neurofibrillary tangles derived from intraneuronal spirochetes. Med Hypotheses 68(4), MacDonald AB (2006) Cystic borrelia in Alzheimer’s disease and in non-dementia neuroborreliosis. Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association, 2(3), Supplement, Page S207, S275, S433

Tick-Borne Diseases and Dementia VII
Riek R (2006) Cell biology: Infectious Alzheimer’s disease? Nature 444, MacDonald AB (2007) Alzheimer’s disease Braak Stage progressions: reexamined and redefined as Borrelia infection transmission through neural circuits. Med Hypotheses. 68(5), MacDonald AB (2007) Alzheimer’s neuroborreliosis with trans-synaptic spread of infection and neurofibrillary tangles derived from intraneuronal spirochetes. Med Hypotheses. 68(4), MacDonald AB (2007) Alzheimer's disease Braak Stage progressions: reexamined and redefined as Borrelia infection transmission through neural circuits. Med Hypotheses 68(5), Haass C, Selkoe DJ (2007) Soluble protein oligomers in neurodegeneration: lessons from the Alzheimer's amyloid beta-peptide. Nat Rev Mol Cell Biol 8, MacDonald, A. B. (2008) (on-line manuscript). Plaques of Alzheimers disease originate from cysts of Borrelia burgdorferi, the Lyme disease spirochete. Manuscript no. YMEHYD R1. Elsevier Editorial System™ for Medical Hypotheses. 5 pp.

Tick-Borne Diseases and Dementia VIII
Miklossy J, Kasas S, Zurn AD, McCall S, Yu S, McGeer PL. (2008) Persisting atypical and cystic forms of Borrelia burgdorferi and local inflammation in Lyme neuroborreliosis. J. Neuroinflammation. 5, 40 Doi: / Galbussera A, Tremolizzo L, Isella V, et al. (2008) Lack of evidence for Borrelia burgdorferi seropositivity in Alzheimer disease. Alzheimer Dis Assoc Disord 22(3), 308. Holmes C, Cotterell D (2009) Role of infection in the pathogenesis of Alzheimer's disease: implications for treatment. CNS Drugs 23(12), Duyckaerts C, Delatour B, Potier MC (2009) Classification and basic pathology of Alzheimer disease. Acta Neuropathol 118, 5-36 Sorensen AA (2009) Alzheimer’s Disease Research: Scientific Productivity and Impact of the Top 100 Investigators in the Field. Journal of Alzheimer’s Disease, 16, 451–465 Jack CR Jr, Knopman DS, Jagust WJ, Shaw LM, Aisen PS, Weiner MW, Petersen RC, Trojanowski JQ (2010) Hypothetical model of dynamic biomarkers of the Alzheimer's pathological cascade. Lancet Neurol 9,

Tick-Borne Diseases and Dementia IX
Miklossy J (2011) Emerging roles of pathogens in Alzheimer disease. Expert Rev Mol Med e30. Miklossy J (2011) Alzheimer's disease - a neurospirochetosis. Analysis of the evidence following Koch's and Hill's criteria. J Neuroinflammation 90. Zlokovic BV (2011) Neurovascular pathways to neurodegeneration in Alzheimer's disease and other disorders. Nat Rev Neurosci 12, Selkoe DJ (2012) Preventing Alzheimer's disease. Science 337, Miklossy J, Donta SE, Mueller K, Nolte O, Perry G (2012) Editorial: Chronic or Late Lyme Neuroborreliosis: Present and Future. The Open Neurology Journal, 2012, 6, (Suppl 1-M1) Miklossy J. (2012) Chronic or late lyme neuroborreliosis: analysis of evidence compared to chronic or late neurosyphilis. Open Neurol J. 6,

Tick-Borne Diseases and Dementia X
Nilsson P et al. (2013) Aβ secretion and plaque formation depend on autophagy. Cell Reports 5(1), 61-69 Williams WM, Torres S, Siedlak SL, Castellani RJ, Perry G, Smith MA, Zhu X. (2013). Antimicrobial peptide beta-defensin-1 expression is upregulated in Alzheimer's brain. J Neuroinflammation. 10(1), 127. Usman A Khan, Li Liu, Frank A Provenzano, Diego E Berman, Caterina P Profaci, Richard Sloan, Richard Mayeux, Karen E Duff, Scott A Small. (2013) Molecular drivers and cortical spread of lateral entorhinal cortex dysfunction in preclinical Alzheimer's disease. Nature Neuroscience, DOI: /nn.3606 Blanc F, Philippi N, Cretin B, Kleitz C, Berly L, Jung B, Kremer S, Namer IJ, Sellal F, Jaulhac B, de Seze J. Lyme Neuroborreliosis and Dementia. J Alzheimers Dis. 2014, 41(4): Miklossy J. The lack of correlation between the incidence of Lyme disease and deaths due to Alzheimer’s disease cannot reflect the lack of involvement of Borrelia burgdorferi in Alzheimer’s dementia. The Journal of Alzheimer’s Disease. Aug Miklossy J. Historic evidence to support a causal relationship between spirochetal infections and Alzheimer's disease. Frontiers in Aging Neuroscience Apr 16;7:46. Bernt - Dieter Huismans, Letzte Revision März

Determining the presence of periodontopathic virulence factors in short-term postmortem Alzheimer's disease brain tissue Establishes a link between periodontal disease and Alzheimer's disease with the major periodontal disease bacteria (Treponema denticola, Tannerella forsythia, and Porphyromonas gingivalis). Vascular involvement can also contribute to dementia. Poole S, Singhrao SK, Kesavalu L, Curtis MA, Crean S. J Alzheimers Dis. 2013;36(4):

MS Deaths vs. Lyme Deaths
Blewett, M.

Vagotomy and subsequent risk of Parkinson's disease
Parkinson's disease (PD) may be caused by an enteric neurotropic pathogen entering the brain through the vagal nerve, a process that may take over 20 years. Full truncal vagotomy is associated with a decreased risk for subsequent PD, suggesting that the vagal nerve may be critically involved in the pathogenesis of PD. Ann Neurol May 29. doi: /ana [Epub ahead of print] Vagotomy and subsequent risk of Parkinson's disease. Svensson E(1), Horváth-Puhó E(1), Thomsen RW(1), Djurhuus JC(2), Pedersen L(1), Borghammer P(2,)(3), Sørensen HT(1). Author information: (1)Department of Clinical Epidemiology, Institute of Clinical Medicine, Aarhus University Hospital, Denmark. (2)Institute of Clinical Medicine, Aarhus University, Denmark. (3)Department of Nuclear Medicine & PET Centre, Aarhus University Hospital, Denmark. OBJECTIVES: Parkinson's disease (PD) may be caused by an enteric neurotropic pathogen entering the brain through the vagal nerve, a process that may take over 20 years. We investigated the risk of PD in patients who underwent vagotomy, and hypothesized that truncal vagotomy is associated with a protective effect, while super-selective vagotomy has a minor effect. METHODS: We constructed cohorts of all patients in Denmark who underwent vagotomy during and a matched general population cohort, by linking Danish registries. We used Cox regression to compute hazard ratios (HRs) for PD and corresponding 95% confidence intervals [CIs], adjusting for potential confounders. RESULTS: Risk of PD was decreased in patients who underwent truncal [HR = 0.85, 95% CI= ; follow-up of >20 years: HR = 0.58, 95% CI: ] compared to super-selective vagotomy. Risk of PD was also decreased following truncal vagotomy when compared to the general population cohort [overall adjusted HR = 0.85, 95% CI ; follow-up >20 years, adjusted HR = 0.53 [95% CI: ]. In patients who underwent super-selective vagotomy, risk of PD was similar to the general population [HR = 1.09, 95% CI: ; follow-up of >20 years: HR = 1.16, 95% CI: ]. The statistical precision of the risk estimates was limited. Results were consistent after external adjustment for unmeasured confounding by smoking. INTERPRETATION: Full truncal vagotomy is associated with a decreased risk for subsequent PD, suggesting that the vagal nerve may be critically involved in the pathogenesis of PD. Svensson E, Horváth-Puhó E, Thomsen RW, Djurhuus JC, Pedersen L, Borghammer P, Sørensen HT. Ann Neurol May 29.

Evidence-Based Practice
Evidence-based practice (EBP) is defined by the Institute of Medicine as - the integration of best-researched evidence and clinical expertise with patient values. Institute of Medicine Committee on Quality of Health Care in America (2001). Crossing the Quality Chasm: A New Health System for the 21st Century. Washington, DC: National Academies Press.

Osler: History, Examination & Judgment
"There is no more difficult art to acquire than the art of observation." "The good observer is not limited to the large hospital.“ "If you listen long enough, the patient will give you the diagnosis." "Medicine is learned by the bedside and not in the class room. Let not your conception of manifestations of disease come from work heard in the lecture room or read from the book: see and then research, compare and control. But see first.“ Although Sir William Osler recognized the value of evidence, he also recognized the significance of clinical observation and experience: "To treat patients without reading the literature is like sailing without maps; medicine without treating patients is like never going to see at all." I doubt he would have endorsed an imbalanced and excessive weight given to "evidence" rather than clinical judgment since he gave great emphasis to the clinical exam, clinical experience and the art of medicine: "If you listen long enough, the patient will give you the diagnosis." "Medicine is learned by the bedside and not in the class room." "There is no more difficult art to acquire than the art of observation." "The good observer is not limited to the large hospital." "The practice of medicine is an art, not a trade, a calling, not a business; a calling in which your heart will be exercised equally with your head." "The practice of medicine is an art, based upon science." "There is no more difficult art to acquire than the art of observation, and for some men it is quite as difficult to record an observation in brief and plain language." "Observations are made with accuracy and care, no pains are spared, nothing is thought a trouble in the investigation of a problem. The facts are looked at in connection with similar ones, their relation to others is studied, and the experiences of the recorder are compared with that of others who have worked upon the question." "One finger in the throat and one in the rectum makes a good diagnostician." "Looking at a woman's legs has often saved her life." "Never ask a new patient a question without a notebook and a pencil in hand." "In taking histories, follow each line of thought; ask no leading questions; never suggest. Give the patient's own words in the complaint." "Learn to see, learn to hear, learn to feel, learn to smell and know that by practice alone can you become experts." "Medicine is learned by the bedside and not in the class room. Let not your conception of manifestations of disease come from work heard in the lecture room or read from the book: see and then research, compare and control. But see first." "Don't touch the patient--state first what you see, cultivate your powers of observation." "Our profession is to honor and patient to serve above all." Sir William Osler Founder, Johns Hopkins University School of Medicine

The most common definition of EBP is taken from Dr
The most common definition of EBP is taken from Dr. David Sackett, a pioneer in evidence-based practice. EBP is the integration of clinical expertise, patient values, and the best research evidence into the decision making process for patient care. Clinical expertise refers to the clinician's cumulated experience, education and clinical skills. The patient brings to the encounter his or her own personal and unique concerns, expectations, and values. The best evidence is usually found in clinically relevant research that has been conducted using sound methodology. (Sackett D, 2002) The most common definition of EBP is taken from Dr. David Sackett, a pioneer in evidence-based practice. EBP is "the conscientious, explicit and judicious use of current best evidence in making decisions about the care of the individual patient. It means integrating individual clinical expertise with the best available external clinical evidence from systematic research." (Sackett D, 1996) EBP is the integration of clinical expertise, patient values, and the best research evidence into the decision making process for patient care. Clinical expertise refers to the clinician's cumulated experience, education and clinical skills. The patient brings to the encounter his or her own personal and unique concerns, expectations, and values. The best evidence is usually found in clinically relevant research that has been conducted using sound methodology. (Sackett D, 2002)

In 1992, the Institute of Medicine estimated that only 4% of medicine was supported by strong evidence. A more recent estimate pegs the number at 20% of medicine being supported by rigorous clinical trials, and yet another authority suggests that between 10-40% of medicine is evidence based. This creates an enormous evidence gap—roughly 80%-- if you set the evidence bar at controlled studies. The IOM and other commentators have noted that the lack of strong evidence creates the potential for inappropriate treatment vacuums if the evidence levels are set too high. To the extent that insurers can take advantage of this gap, they increase profits by denying care. Eddy notes that “in a field filled with uncertainty and doubt, the difference between “when in doubt, do it” and “when in doubt, stop” could easily swing $100 billion in revenue. Clearly, the incentive for insurers to set inappropriately high evidence hurdles exists, however, this increased cash flow comes at the expense of patients who remain seriously ill To the extent that unequivocal evidence exists, it should be followed—the question is what we do where, it doesn’t, as is more often the case. Institute of Medicine

Quality of Medical Evidence

Discussion

Discussion Albert, did you ask any interesting questions today?
Pauline Einstein (Albert Einstein’s mother)

Discussion

Robert C Bransfield, MD, DLFAPA

Similar presentations

Presentation on theme: "Robert C Bransfield, MD, DLFAPA"— Presentation transcript:

Similar presentations

About project

Feedback

Log in

Auth with social network:

Robert C Bransfield, MD, DLFAPA

Similar presentations

Presentation on theme: "Robert C Bransfield, MD, DLFAPA"— Presentation transcript:

Similar presentations

About project

Feedback