Robert C Bransfield, MD, DFAPA

Robert C Bransfield, MD, DFAPA
Tick-Borne Infections & Lyme Disease Contributing to Autism Spectrum Disorders Presentation slides Please send your PowerPoint presentation slides or MS-Word outline/narrative by March 15. NAME THE PRESENTATION FILE LIKE THIS: Presenter Name Autism One 2008 (For example: Jeff Bradstreet Autism One 2008) Upload presentations to: We appreciate your help with these items! Sunday May minute power point presentation Terri Arranga Robert C Bransfield, MD, DFAPA Autism One Conference Chicago, Ill May 25, 2008

Disclosure Statement Robert Bransfield, MD, DFAPA, PC
Most of my income is paid directly from patients No insurance, government or other payer contracts that restrict patient care in return for referrals, financial considerations or any other benefit No Lyme disease financial interests. Speakers Bureau: Abbott, Astra Zeneca, Forest, GSK, Jazz, Lilly, Pfizer, Sanofi Aventis, Shire, Takeda, UCB. President Elect International Lyme and Associated Diseases Society

Outline The association between LYD/TBD and ASD Background
Clinical experience Gestational LYD/TBD Laboratory testing of ASD patients for TBD Biochemical similarities Brain imaging similarities Epidemiological findings Pathophysiology Theoretical issues: genes, infections and autism Klüver–Bucy Syndrome, infections and autism Neural networks, neurodevelopment, autism and borreliosis Borreliosis and Borrelia related complex Tick-borne/borreliosis infections and psychiatric illness Immune responses in ASD, Borreliosis and Mycoplasma infections Implications & Response Economic issues Assessment Treatment strategies Further evaluation of the hypothesis Summary

Autism: A Syndrome of Many Different Etiologies & Comorbidities
Comorbidity with any DSM Dx Epilepsy Mental retardation (30% mild to moderate, 40% serious to profound) Hearing & visual impairments Fragile X syndrome & multiple other genetic Tuberous sclerosis Cerebral palsey Phenylketonuria Neurofibromatosis Congenital rubella Rett’s syndrome Rasmussen’s encephalitis Lennox-Gastaut syndrome Post infectious Metabolic Pyruvate d hydrogenase deficiency Impaired purine metabolism (uric acid increased) Brain structural—cyst, etc. PKU phenylalanine Angelman’s syndrome Landau-Kleffner syndrome Prader-Willi Williams Multiple other genetic impairments Associated with older paternal age

What Causes Autism? “Data suggest that autism results from multiple etiologies with both genetic and environmental contributions, which may explain the spectrum of behaviors seen in this disorder.”* *Libbey, et al.

The Neurobiology of Autism
It is becoming clear that the normal trajectory of neurodevelopment is altered in autism, with aberrations in brain growth, neuronal patterning and cortical connectivity. Changes to the structure and function of synapses and dendrites have also been strongly implicated in the pathology of autism by morphological, genetic and animal modeling studies. Environmental factors are likely to interact with the underlying genetic profile, and foster the clinical heterogeneity seen in autism spectrum disorders. In this review we attempt to link the molecular pathways altered in autism to the neurodevelopmental and clinical changes that characterize the disease. We focus on signaling molecules such as neurotrophin, Reelin, PTEN and hepatocyte growth factor, neurotransmitters such as serotonin and glutamate, and synaptic proteins such as neurexin, SHANK and neuroligin. We also discuss evidence implicating oxidative stress, neuroglial activation and neuroimmunity in autism. Pardo CA, EberhartCG. Brain Pathology. Volume 17 Issue 4 Page , October 2007

Personal Experience Primarily clinical practice
35 year work with autistic patients Interest in infectious causes of mental illness for 30+ years. About patients in with infections and other causes of inflammation, especially Lyme/tick-borne disease data points kept on each patient. Many have progressive systemic illnesses with encephalopathy. Moderator of Microbes and Mental Illness Internet discussion group (9 years).

“Whereas Lyme disease and other tick-borne diseases are a serious public health threat;…Findings more common in children include autism, Tourette’s syndrome, attention deficit disorder, dyslexia, lethargy, and a decline in grades, tantrums;…” A Modest Proposal In response to Dr. Virginia Sherr's letter in the July 3 issue about the increase in the number of patients showing an unusual syndrome of neurological soft signs that may be linked to Lyme and other tick-borne diseases, and in the interest of health, public safety, and quality of life, we, as psychiatrists, state the following: Whereas: Lyme disease and other tick-borne diseases are a serious public health threat; These often cryptic diseases are associated with a broad spectrum of mental and other physical disorders, birth defects, and cognitive impairments that increase the risk of accidents, violence, memory loss, disabilities, and suffering; Mental illnesses associated with these frequently unsuspected infections include, but are not limited to, depression, phobias, obsessive-compulsive disorders, panic disorders, aggressiveness, delusions, irritability, suicidality, exhaustion, sexual dysfunction, sleep disorders, eating disorders, and a broad spectrum of cognitive and neurological impairments. Findings more common in children include autism, Tourette syndrome, attention deficit disorder, dyslexia, lethargy, and a decline in grades, tantrums; Since late-stage Lyme disease presents primarily as a neuropsychiatric rather than an arthritic disease, psychiatrists are encouraged to become more active in the diagnosis and treatment of Lyme disease; The diagnosis of Lyme disease should take into consideration epidemiological risk factors for disease and be based upon a thorough history, physical findings (including neuropsychiatric), laboratory testing, and response to antibiotic therapy. Commonly used tests include the Western Blot, neuropsychological testing for the cognitive component, and SPECT scans. Tests that are being used with increasing acceptance include PCR, cultures, Lyme urine antigen test, and PET. Spinal taps are most commonly negative in the late-stage neuropsychiatric syndrome; Research on early Lyme disease has been mistakenly utilized by some insurance companies as the standard that determines diagnostic and treatment guidelines for late-stage Lyme disease. This position results in the inappropriate denial of reimbursement for vital ongoing medical care; We recognize the need for long-term antibiotic treatment in some of these patients. We are concerned that financially motivated, restrictive treatment guidelines of some of the insurance companies are harmful to patients and the overall public welfare; Public awareness, education, prevention, vaccines, early diagnosis, correct psychiatric diagnosis, effective treatment, guidance throughout the treatment, advocacy, and research help to reduce the seriousness of this epidemic; We acknowledge and support the efforts of patients, support groups, clinicians, researchers, drug companies, and advocates who show the commitment, courage, and creativity to meet the challenge of tick-borne diseases; In addition to tick-borne diseases, other infectious diseases and complex interactive infectious diseases are increasingly recognized as being associated with mental illness. We therefore advise that: An APA committee be established to better coordinate information, research, education, policy, and guidelines in this area; The name of the committee shall be the Committee on Tick-Borne and Other Complex Infectious Encephalopathies. Robert C. Bransfield, M.D Red Bank, N.J. Brian Fallon, M.D., M.P.H. New York, N.Y. Bernard Raxlen M.D. Greenwich Conn. Lynn Shepler, M.D., J.D. Falmouth, Mass. Virginia Sherr, M.D. Holland, Pa. Bransfield, Fallon, Raxlen, Shepler, Sherr“A Modest Proposal,” Psychiatric News (Newspaper of the APA), Vol. XXXIII, Number 18, September 18, 1998, p. 16.

A controlled study of cognitive deficits in children with chronic Lyme disease
Twenty children with a history of new-onset cognitive complaints after Lyme disease were compared with 20 matched healthy control subjects. Each child was assessed with measures of cognition and psychopathology. Children with Lyme disease had significantly more cognitive and psychiatric disturbances. Cognitive deficits were still found after controlling for anxiety, depression, and fatigue. Lyme disease in children may be accompanied by long-term neuropsychiatric disturbances, resulting in psychosocial and academic impairments. J Neuropsychiatry Clin Neurosci Fall;13(4):500-7. A controlled study of cognitive deficits in children with chronic Lyme disease. Tager FA, Fallon BA, Keilp J, Rissenberg M, Jones CR, Liebowitz MR. Columbia University Department of Psychiatry, Division of Behavioral Medicine, New York, New York 10032, USA. Although neurologic Lyme disease is known to cause cognitive dysfunction in adults, little is known about its long-term sequelae in children. Twenty children with a history of new-onset cognitive complaints after Lyme disease were compared with 20 matched healthy control subjects. Each child was assessed with measures of cognition and psychopathology. Children with Lyme disease had significantly more cognitive and psychiatric disturbances. Cognitive deficits were still found after controlling for anxiety, depression, and fatigue. Lyme disease in children may be accompanied by long-term neuropsychiatric disturbances, resulting in psychosocial and academic impairments. Areas for further study are discussed. PMID: [PubMed - indexed for MEDLINE] Tager FA et al. J Neuropsychiatry Clin Neurosci Fall;13(4):500-7.

The association between tick-borne infections, Lyme borreliosis and autism spectrum disorders
Tick-borne infections, including Lyme disease contribute to developing autism spectrum disorders (ASD) by direct effects, promoting other infections and immune effects during fetal development and infancy. Combined with other predisposing and contributory factors these infections may provoke immune reactions in susceptible individuals that result in inflammation, molecular mimicry, kynurenine pathway changes, increased quinolinic acid and decreased serotonin, oxidative stress, mitochondrial dysfunction and excitotoxicity that impair the development of the amygdala and other neural structures and neural networks resulting in a partial Klüver–Bucy Syndrome and other deficits resulting in autism spectrum disorders and/or exacerbating ASD from other causes. Supporting data includes multiple cases of mothers with Lyme disease and children with ASD; fetal neurological abnormalities associated with tick-borne diseases; similarities between tick-borne diseases and ASD regarding symptoms, pathophysiology, immune reactivity, temporal lobe pathology, and brain imaging data; positive reactivity in several studies with ASD patients for Lyme disease (22%, 26% and 20–30%) and 58% for mycoplasma; similar geographic distribution and improvement in autistic symptoms from antibiotic treatment. Abstract Tick-borne infections, including Lyme disease contribute to developing autism spectrum disorders (ASD) by direct effects, promoting other infections and immune effects during fetal development and infancy. Combined with other predisposing and contributory factors these infections may provoke immune reactions in susceptible individuals that result in inflammation, molecular mimicry, kynurenine pathway changes, increased quinolinic acid and decreased serotonin, oxidative stress, mitochondrial dysfunction and excitotoxicity that impair the development of the amygdala and other neural structures and neural networks resulting in a partial Klüver–Bucy Syndrome and other deficits resulting in autism spectrum disorders and/or exacerbating ASD from other causes. Supporting data includes multiple cases of mothers with Lyme disease and children with ASD; fetal neurological abnormalities associated with tick-borne diseases; similarities between tick-borne diseases and ASD regarding symptoms, pathophysiology, immune reactivity, temporal lobe pathology, and brain imaging data; positive reactivity in several studies with ASD patients for Lyme disease (22%, 26% and 20–30%) and 58% for mycoplasma; similar geographic Bransfield RC, Wulfman JS, Harvey WT, Usman AI. Medical Hypotheses. 2007

Chronic Bacterial and Viral Infections in Neurodegenerative and Neurobehavioral Diseases
Often patients with neurodegenerative or neurobehavioral diseases have chronic, neuropathic infections that could be important in disease inception, progression or increasing the types/severities of signs/symptoms. Although controversial, the majority of patients with various neurodegenerative or neurobehavioral conditions, such as amyotrophic lateral sclerosis, multiple sclerosis, Alzheimer’s disease, Parkinson’s disease and autistic spectrum disorders, show evidence of central nervous system and/or systemic bacterial and viral infections. For example, using serology or polymerase chain reaction evidence of Chlamydia pneumoniae, Borrelia burgdorferi, Mycoplasma species, human herpesvirus-1 and -6 and other bacterial and viral infections revealed high infection rates that were not found in control subjects. Although chronic infections were not found in some studies and the specific role of chronic infections in neurological disease pathogenesis has not been determined or is inconclusive, the data suggest that chronic bacterial and/or viral infections could be common features of progressive neurodegenerative and neurobehavioral diseases. Nicholson G. Laboratory Medicine In Press

Clinical Experience

Clinical Observations Autism & Lyme/Tick-Borne Disease
A number of clinicians* and myself have noted an association between autism & Lyme/tick-borne disease. This association is seen as: Infected mothers & children with autistic spectrum disorders (ASD) Infected infants & ASD or autistic symptoms Infected children & autistic symptoms Lyme/TBD infections in adults often have some symptoms suggestive of ASD: Sound sensitivity & sensory hyperacusis Emotional detachment Mood instability Decline of speech & language Seizures More severe symptoms are associated with infections at younger age, coinfections (Bartonella, Babesia & other TBD), genetic vulnerability & lengthy misdiagnosis & under-treatment Multi-systemic symptoms is a diagnostic clue Antimicrobial (anti-bacterial & anti-viral) treatment can reverse these symptoms *Schaller, Corson, Levin, Berenbaum

Opinion of Dr Burrascano
“It is my contention that Autism is an inflammatory encephalitis cause by a pathogen such as Bartonella or Mycoplasma. I share the view that Bartonella/BLO is a major infection that may eclipse Bb as the ultimate cause of the morbidity in chronic Lyme. Mycoplasma too is a major concern of mine- in reviewing my cases, those patients who were relentlessly chronic all, at one point or another in their illness, were PCR + for Mycoplasma.”

BI/TBI & ASD: Similar GI Symptoms
Kugathasan S. Pediatric inflammatory bowel disease: clinical and therapeutic aspects. Curr Opin Gastroenterol. 2001;17(4):350-5. Zaidi AS, Singer C. Gastrointestinal and Hepatic Manifestations of Tick-borne Diseases in the United States. Clinical Infect Dis 2002;34: Sherr VT. “Bell’s palsy of the gut” and other GI manifestations of Lyme and associated diseases. Pract Gastroent. 2006:74-91 Fried MD, Abel M, Pietrucha D, Kuo YH, Bal A. The Spectrum of Gastrointestinal Manifestations in Children and Adolescents with Lyme Disease. JSTD 1999;6. Fried M. Gastrointestinal manifestations of Lyme disease. Program and abstracts of the 14th Int Sc Conf Lyme Disease and Other TBD; 2001

BI/TBI & ASD Respond to Similar Treatments
Both BI/TBI and ASD respond to similar treatments of psychiatric and cognitive symptoms with psychotropics (including modafinil, stimulants, memantine, mood stabilizers, atypical agents and serotonin reuptake inhibitors), diets, antimicrobials, mitochondrial enhancers, immune modulators, hyperbaric oxygen, glutathione, chelation and allergen elimination.

BI/TBI & ASD Respond to Similar Treatments: References
Posey DJ, Kem DL, Swiezy NB, Sweeten TL, Wiegand RE, McDougle C. Pilot study of D-cycloserine in subjects with autistic disorder. Am J Psych. 2004;161(11): Sandler RH, Finegold SM, Bolte ER, et al. Short-term benefit from oral vancomycin treatment of regressive-onset autism. J Child Neurol. 2000;15(7): Bransfield, RC. Update on the Neuropsychiatric Management of Lyme and Associated Diseases. ILDS Annual Meeting. 2004 27. Bransfield RC. Treatment of Autism with LYD/TBI. LIA Conference; 2007 28. Erickson CA, Posey DJ, Stingler KA, McDougle CJ. Pharmacotherapy of autism and related disorders. Psychiatric Annals. 37:7

Brain SPECT: Mother with Lyme Disease & 3 ASD Children
SPECT scans of a mother with TD/BI and her three children with ASD which demonstrate many of the points previously described. Brain SPECT: Mother with Lyme Disease & 3 ASD Children Image #1 Mother, 48: There is an extensive hypoperfusion pattern, prominently in the cerebral cortices and much of the frontal lobes, with a lesser degree in the temporal lobes and a small degree hypoperfusion in the cerebellum. The hypoperfusion is moderately extensive and is likely associated with toxic, inflammatory and infectious processes. There is hyperperfusion of the Basal Ganglia, which is associated with anxiety and mood dysregulation. The diagnosis is chronic fatigue syndrome, multiple sclerosis, depression and possible congenital Lyme disease. Lab testing was positive for Borrelia burgdorferi, Babesia WA-1, Bartonella henselae, Mycoplasma fermentans, HHV-6, Epstein Barr virus, high anti-streptolysin o titre and gamma Strep in stool. Image #2 Son, 26: Some motion artifacts, however significant hypoperfusion pattern is both focal as well as generalized. The focal pattern is throughout the cerebral cortex bilaterally and the cerebellar hemispheres (which demonstrate atrophy on MRI) There is mild hyperperfusion of the basal ganglia and a focally intense hypeperfusion area in the deep white matter of the temporal lobe. There is a hyperperfusion pattern involving the temporal lobes and cerebellar hemispheres. The focal decrease is more suggestive of etiologies that would include hypoxic, neuroimmune, traumatic factors, infectious and inflammatory. There is a hyperperfusion pattern of the basal ganglia which may be associated with element of anxiety, whereas the focal intense areas can be associated with present interictal seizure focus and is clinically significant as the present dose of anticonvulsant is not controlling this area. The patient is low functioning with autism spectrum disorder since two years, grand mal seizures, movement disorder, ataxia, hypotonia, megacolon, possible mitochondrial disorder, mild hypergammaglobulenmia and syncope. Lab testing was positive for Borrelia burgdorferi, Babesia WA-1, Bartonella henselae, Mycoplasma fermentans, HHV-6, EBV and high strep titers; stool positive for Citrobacter fundii, Klebsialla p. and gamma Strep. Image #3 Daughter, 23: There is an extensive hyperperfusion pattern in the cerebral cortices, temporal lobes and cerebellum and hypoperufsion of the frontal lobes and is likely associated with toxic, inflammatory and infectious processes. The diagnosis is Asperger’s, obsessive compulsive disorder, generalized anxiety, social anxiety disorder, depression, posttraumatic stress disorder from an auto accident, possible narcolepsy, tremors, cardiac disease, myocardial infarction, osteopenia, arthritis and psuedo rhematoid nodules since 5 years of age. Lab testing was positive for Borrelia burgdorferi, Anaplasma phagocytophilum, Mycoplasma fermentans, Homopholis, HHV-6, EBV, elevated Strep titres; stool was positive for Toxoplasmosis, Cornybacteria and gamma Strep. Image #4 Daughter, 20: there is extensive hypoperfusion in the frontal lobes, temporal lobes and to a lesser degree to the occipital lobes and slightly to the cerebellum. There is hyperperufsion in the right cerebellar hemisphere. The hypoperfusion is likely associated with neuroinflammatory, neuroimmunological, infectious and toxic substance exposure. There is a seizure focus with hyperperfusion in the right cerebellar hemisphere. The diagnosis is autism spectrum disorder since 14 months, petit mal seizure disorder, hypotonia, perceptual impairments, and anxiety. Lab testing was positive for Borrelia burgdorferi, Bartonella henselae, Mycoplasma fermentans, HHV-6; stool positive for Parvo/B-19, Klebsiella, p., Citrobacter f. and gamma Strep.

Mother, 48: There is an extensive hypoperfusion pattern, prominently in the cerebral cortices and much of the frontal lobes, with a lesser degree in the temporal lobes and a small degree hypoperfusion in the cerebellum. The hypoperfusion is moderately extensive and is likely associated with toxic, inflammatory and infectious processes. There is hyperperfusion of the Basal Ganglia, which is associated with anxiety and mood dysregulation. The diagnosis is chronic fatigue syndrome, multiple sclerosis, depression and possible congenital Lyme disease. Lab testing was positive for Borrelia burgdorferi, Babesia WA-1, Bartonella henselae, Mycoplasma fermentans, HHV-6, Epstein Barr virus, high anti-streptolysin o titre and gamma Strep in stool.

Son, 26: Some motion artifacts, however significant hypoperfusion pattern is both focal as well as generalized. The focal pattern is throughout the cerebral cortex bilaterally and the cerebellar hemispheres (which demonstrate atrophy on MRI) There is mild hyperperfusion of the basal ganglia and a focally intense hypeperfusion area in the deep white matter of the temporal lobe. There is a hyperperfusion pattern involving the temporal lobes and cerebellar hemispheres. The focal decrease is more suggestive of etiologies that would include hypoxic, neuroimmune, traumatic factors, infectious and inflammatory. There is a hyperperfusion pattern of the basal ganglia which may be associated with element of anxiety, whereas the focal intense areas can be associated with present interictal seizure focus and is clinically significant as the present dose of anticonvulsant is not controlling this area. The patient is low functioning with autism spectrum disorder since two years, grand mal seizures, movement disorder, ataxia, hypotonia, megacolon, possible mitochondrial disorder, mild hypergammaglobulenmia and syncope. Lab testing was positive for Borrelia burgdorferi, Babesia WA-1, Bartonella henselae, Mycoplasma fermentans, HHV-6, EBV and high strep titers; stool positive for Citrobacter fundii, Klebsialla p. and gamma Strep.

Daughter, 23: There is an extensive hyperperfusion pattern in the cerebral cortices, temporal lobes and cerebellum and hypoperufsion of the frontal lobes and is likely associated with toxic, inflammatory and infectious processes. The diagnosis is Asperger’s, obsessive compulsive disorder, generalized anxiety, social anxiety disorder, depression, posttraumatic stress disorder from an auto accident, possible narcolepsy, tremors, cardiac disease, myocardial infarction, osteopenia, arthritis and psuedo rhematoid nodules since 5 years of age. Lab testing was positive for Borrelia burgdorferi, Anaplasma phagocytophilum, Mycoplasma fermentans, Homopholis, HHV-6, EBV, elevated Strep titres; stool was positive for Toxoplasmosis, Cornybacteria and gamma Strep.

Daughter, 20: there is extensive hypoperfusion in the frontal lobes, temporal lobes and to a lesser degree to the occipital lobes and slightly to the cerebellum. There is hyperperufsion in the right cerebellar hemisphere. The hypoperfusion is likely associated with neuroinflammatory, neuroimmunological, infectious and toxic substance exposure. There is a seizure focus with hyperperfusion in the right cerebellar hemisphere. The diagnosis is autism spectrum disorder since 14 months, petit mal seizure disorder, hypotonia, perceptual impairments, and anxiety. Lab testing was positive for Borrelia burgdorferi, Bartonella henselae, Mycoplasma fermentans, HHV-6; stool positive for Parvo/B-19, Klebsiella, p., Citrobacter f. and gamma Strep.

Gestational Tick-Borne Infections/Borreliosis Infections

Maternal Fetal Issues Antibodies
From mother From fetal immune response to intrauterine infection Pregnancy and the Maternal Immune System Down regulated Teratogenic Issues in the Developing Fetus Rubella infection model for intrauterine infections Mac Donald

Harvey, WT; Salvato, P: ‘Lyme Disease’: Ancient Engine of an Unrecognized Borreliosis Pandemic? Medical Hypotheses (2003) 60(5), ; Elsevier Science Ltd.

Maternal Transmission of LYD
Schlesinger PA, Duray PH, Burke BA, Steere AC, Stillman MT. Maternal-fetal transmission of the LYD spirochete, B. burgdorferi. Ann Intern Med. 1985;103(1):67-8. Lampert F. Infantile multisystem inflammatory disease: another case of a new syndrome. Eur J Pediatr. 1986;144(6):593-6. Lavoie PE, Lattner BP, Duray PH, et al. Culture positive, seronegative, transplacental Lyme borreliosis infant mortality. Arthritis Rheum.1987; 3:S50. MacDonald AB. Gestational Lyme borreliosis. Implications for the fetus. Rheum Dis Clin North Am. 1989;15(4): Markowitz LE, Steere AC, Benach JL, Slade JD, Broome CV. Lyme disease during pregnancy. JAMA. 1986;255(24): Nadal D, Hunziker UA, Bucher HU, Hitzig WH, Duc G. Infants born to mothers with antibodies against Borrelia burgdorferi at delivery. Eur J Pediatr. 1989;148(5):426-7. Hercogova et al. Could borrelia found in the placenta influence the fetus? Study of 19 women with EM during pregnancy. 6th Int Conf Lyme Borreliosis.1994 Gardner T. Lyme disease In Infec Dis Fetus and Newborn Infant. Saunders, 1995 Gardner T. Lyme disease. 66 Pregnancies complicates by Lyme Borreliosis. Infec Dis Fetus and Newborn Infant. Saunders, 2000. Jones CR, Smith H, Gibb E, Johnson L. Gestational Lyme Disease Case studies of 102 Live Births. Lyme Times. 2005;Summer:34-6. Harvey, WT; Salvato, P: ‘Lyme Disease’: Ancient Engine of an Unrecognized Borreliosis Pandemic? Medical Hypotheses (2003) 60(5), Bach G. Sexual Transmission of Lyme Disease. Microbes and Mental Illness Symp; Am Psych Assn Inst Psych Services. 2000 Jones, CR. Lyme Disease and Autism. LIA Conf;2007 Schmidt BL, Aberer E, Stockenhuber C, Klade H, Breier F, Luger A. Detection of Borrelia burgdorferi DNA by polymerase chain reaction in the urine and breast milk of patients with Lyme borreliosis. Diagn Microbiol Infect Dis. 1995;21(3):121-8.

Perinatal Transmission of the Agent of Human Granulocytic Ehrlichiosis
We describe a case of Human Granulocytic Ehrlichiosis that developed in a pregnant woman near term and was transmitted perinatally to her infant. (Hawaii has a high incidence of Ehrlichiosis) P ERINATAL T RANSMISSION OF THE A GENT H UMAN G RANULOCYTIC E HRLICHIOSIS AROLD W. H OROWITZ , M.D., E ITAN K ILCHEVSKY , M.D., S TUART ABER , M.D., M ARIA GUERO -R OSENFELD R AMON RANWINKEL DWARD K. J AMES USAN J. W ONG , P .D., F REDERICK C HU .D., D IONYSIOS L IVERIS AND I RA CHWARTZ .D. From the Department of Medicine, Division of Infectious Diseases (H.W.H.), and Department of Pathology (M.A.-R.), Westchester County Medical Center and New York Medical College, and the Department of Biochemistry and Molecular Biology, New York Medical College (D.L., I.S.) Valhalla, N.Y.; the Department of Pediatrics, Section of Neonatology (E.K., E.K.J.), and the Department of Pathology (R.K.), Danbury Hospital, Danbury, Conn.; the Department of Medicine, United Hospital, Port Chester, N.Y. (S.H.); and the Wadsworth Center, New York State Department of Health, Albany (S.J.W., F.C.). Address reprint requests to Dr. Horowitz at the Westchester County Medical Center, Division of Infectious Diseases, Rm. 209, Macy Pavilion S.E., Valhalla, NY ©1998, Massachusetts Medical Society. UMAN granulocytic ehrlichiosis was first described in the United States, in the northern Midwest, in 1994. 1 Human granulocytic ehrlichiosis is caused by an organism, still referred to as the agent of human granulocytic ehrlichiosis, that is similar to two animal pathogens, Ehrlichia phagocytophila and E. equi. 2-4 Transmission of human granulocytic ehrlichiosis occurs through the bites of ixodes ticks, which are the arthropod vectors for Borrelia burgdorferi Babesia microti. 5,6 Human granulocytic ehrlichiosis is an acute, febrile, nonspecific illness that may be severe enough to cause hospitalization and even death, particularly in the elderly. 1,7,8 We describe a case of human granulocytic ehrlichiosis that developed in a pregnant woman near term and was transmitted perinatally to her infant. Horowitz HW et al. NEJM. Volume 339 Number 6. p 375

Laboratory testing of ASD patients for tick-borne diseases

Testing ASD Patients for TBI
Vojdani tested Autism samples from different clinics in Northern CA, NY, NJ and CT. 22% of (12/54) tested IgG and IgM positive for Bbsl by Immunosciences Lab (Note: in this sample the Western Blot (WB) test used CDC surveillance criteria and did not include the full complement of Bbsl specific bands. A LIAF study tested the blood of 19 children with an ASD diagnoses plus an indication of immune dysfunction and five normal controls. Patients were not screened for BI before study entry. WB and IFA IgG and IgM were performed by IgeneX Laboratory. A result was considered Bbsl positive for exposure if there was reactivity of one or more Bbsl specific bands. 26% of the ASD children were positive compared to 0 controls. Levine tested nine consecutive ASD patients in Connecticut in 2003 and all nine tested positive for Bbsl with WB by IGeneX Laboratory criteria. Nicolson tested 48 ASD patients with forensic PCR and Southern Blot confirmation. 20–30% (depending upon the lab) were positive for Bbsl. 58% were positive for Mycoplasma species while 5% of 45 age matched controls were positive for Mycoplasma (Odds ratio = 13.8) with 35% M. fermentans vs. 0% control, 33% M. pneumoniae vs. 5% control, 10% M. homonis vs. 0% control, 2% M. penetrans vs. 0% control and 25% were M. fermentans and other species. Also 8% were positive for C. pneumoniae vs. 2% of controls (Odds ratio = 5.6) and 29% were positive for Human Herpes Virus-6 (HHV-6) vs. 8% of controls. 6.5% of healthy family members were positive for Mycoplasma and 8% were positive for HHV-6 (P < 0.001) [18]. He also reported WB positive BI patients had a 68% coinfection rate with Mycoplasma (M. Fermentans was 70%), Bartonella, Ehrlichia, and Babesia.

Gestational BI/TBI & Austism
Jones et al. performed a comprehensive case history review on the charts of 102 gestational BI/TBI cases. 9% had been diagnosed with autism and 56% with attention deficit disorder. Psychiatric symptoms included irritability or mood swings (54%), anger or rage (23%), anxiety (21%), depression (13%), emotional (13%), OCD (11%) and suicidal thoughts (7%). Neurological symptoms included headache (50%), vertigo (30%), developmental delays (18%), tic disorders (14%), seizure disorders (11%), involuntary athetoid movements (9%) and hypotonia (7%). Sensory sensitivity symptoms included photophobia (43%), hyperacuity (36%), motion sickness (9%) and other (tactile, taste or smell) (23%). Cognitive symptoms included poor memory (39%), cognitive impairments (27%), speech delays (21%), reading/writing (19%), articulation (17%), auditory/visual processing (13%), word selectivity (12%), and dyslexia (18%). GI symptoms were common and included GERD (27%), abdominal pain (29%), diarrhea or constipation (32%), and nausea (23%). As a control, 66 mothers with Lyme disease who were treated with antibiotics prior to conception and during the entire pregnancy; all gave birth to normal healthy infants. Jones CR, Smith H, Gibb E, Johnson L. Gestational Lyme Disease Case studies of 102 Live Births. Lyme Times 2005:34–6. Summer.

Biochemical Similarities

Biochemical Similarities
Testing patients with autism and BI/TBI also reveals biochemical similarities. Disorders of an oxidoreductive system in CSF and serum, increases of superoxide dismutase, increased glutathione peroxidase activity, increased concentration of serum malondialdehyde and decreased glutathione have been detected in neuroborreliosis and BI. In autism, several studies have suggested alterations in the activities of antioxidant enzymes such as superoxide dismutase and glutathione peroxidase, altered glutathione levels and homocysteine/methionine metabolism, increased malondialdehyde levels and reduced glutathione. Impaired methylation & sulfation in both ASD & BI/TBI

Biochemical Similarities: References
Pancewicz SA, Skrzydlewska E, Hermanowska-Szpakowicz T, Stankiewicz A, Kondrusik M. Evaluation of oxidoreductive potential of patients with neuroborreliosis. Przegl Epidemiol. 2002;56(3): Pancewicz SA, Skrzydlewska E, Hermanowska-Szpakowicz T, Zajkowska JM, Kondrusik M. Role of reactive oxygen species (ROS) in patients with erythema migrans, an early manifestation of Lyme borreliosis. Med Sci Monit. 2001;7(6): Chauhan A, Chauhan V. Oxidative stress in autism. Pathophysiol. 2006;13(3): Chauhan A, Chauhan V, Brown WT, Cohen I. Oxidative stress in autism: increased lipid peroxidation and reduced serum levels of ceruloplasmin and transferrin--the antioxidant proteins. Life Sci. 2004;75(21): James SJ, Cutler P, Melnyk S, Jernigan S, Janak L, Gaylor DW, Neubrander JA. Metabolic biomarkers of increased oxidative stress and impaired methylation capacity in children with autism. Am J Clin Nutr. 2004;80(6):

Brain Imaging Tick-Borne Diseases/Borreliosis and Autism

Brain Imaging Similarities
Both BI/TBI and ASD patients demonstrate significant temporal lobe dysfunction. In autism the cerebral cortex, hippocampus, and amygdala showed trends toward being disproportionately smaller in the developing autistic brain. In addition smaller amygdala volume correlates with impairments in nonverbal social impairment in autistic patients. Infectious encephalopathies associated with autistic symptoms have demonstrated lesions of the temporal lobes. PET scanning of neuroborreliosis patients demonstrates the most striking finding was hypometabolism, which correlates with decreased activity, in the temporal lobes in 74% patients. Both BI/TBI and ASD demonstrate predominately white matter encephalopathy. Regional cerebral blood flow suggests that Lyme encephalopathy may primarily affect cerebral white matter. Disruption of white matter tracts between regions implicated in social functioning may contribute to impaired social cognition in autism. Both ASD and BI/TBI patients demonstrate sensory hyperacusis and this clinical observation is supported by brain imaging of patients with BI that demonstrates increased thalamus activity and increased activity in auditory and visual areas of cortex.

Maternal infection and white matter toxicity
Studies examining maternal infection as a risk factor for neurological disorders in the offspring have suggested that altered maternal immune status during pregnancy can be considered as an adverse event in prenatal development. Infection occurring in the mother during the gestational period has been implicated in multiple neurological effects. The current manuscript will consider the issue of immune/inflammatory conditions during prenatal development where adverse outcomes have been linked to maternal systemic infection. The discussions will focus primary on white matter and oligodendrocytes as they have been identified as target processes. This white matter damage occurs in very early preterm infants and in various other human diseases currently being examined for a linkage to maternal or early developmental immune status. The intent is to draw attention to the impact of altered immune status during pregnancy on the offspring for the consideration of such contributing factors to the general assessment of developmental neurotoxicology. Maternal infection and white matter toxicity G. Jean Harrya, , , Cindy Lawlerb and Susan H. Brunssena, c aNeurotoxicology Group, Laboratory of Neurobiology, National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, NC 27709, USA bDivision of Extramural Research and Training, National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, NC 27709, USA cSchool of Nursing and Neurodevelopmental Disorders Research Center, University of North Carolina, Chapel Hill, NC, USA Received 16 February 2006; accepted 10 May 2006. Available online 17 May 2006. Abstract Studies examining maternal infection as a risk factor for neurological disorders in the offspring have suggested that altered maternal immune status during pregnancy can be considered as an adverse event in prenatal development. Infection occurring in the mother during the gestational period has been implicated in multiple neurological effects. The current manuscript will consider the issue of immune/inflammatory conditions during prenatal development where adverse outcomes have been linked to maternal systemic infection. The discussions will focus primary on white matter and oligodendrocytes as they have been identified as target processes. This white matter damage occurs in very early preterm infants and in various other human diseases currently being examined for a linkage to maternal or early developmental immune status. The intent is to draw attention to the impact of altered immune status during pregnancy on the offspring for the consideration of such contributing factors to the general assessment of developmental neurotoxicology. Keywords: Microglia; White matter damage; Inflammation; Oligodendrocyte Corresponding author. Tel.: ; fax: Harry GJ, Cindy L, Brunssen SH. Neurotoxicology Sep;27(5):

Brain Imaging Similarities References
Herbert MR, Ziegler DA, Deutsch CK, et al. Dissociations of cerebral cortex, subcort and cerebral white matter volumes in autistic boys. Brain. 2003;126(5): Nacewicz BM, Dalton KM, Johnstone T, et al. Amygdala volume and nonverbal social impairment in adolescent and adult males with autism. Arch Gen Psych. 2006;63(12): DeLong GR, Bean SC, Brown FR 3rd. Acquired reversible autistic syndrome in acute encephalopathic illness in children. Arch Neurol. 1981;38(3):191-4. Newberg A, Hassan A, Alavi A. Cerebral metabolic changes associated with Lyme disease. Nucl Med Commun. 2002;23(8):773-7. 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(3): Morgen K, Martin R, Stone RD, et al. A. FLAIR and magnetization transfer imaging of patients with post-treatment Lyme disease syndrome. Neurol. 2001;57(11): Steinbach JP, Melms A, Skalej M, Dichgans J. Delayed resolution of white matter changes following therapy of B burgdorferi encephalitis. Neurol. 2005;64(4):758-9. Belman AL, Coyle PK, Roque C, Cantos E. MRI findings in children infected by Borrelia burgdorferi. Pediatr Neurol. 1992;8(6): Fernandez RE, Rothberg M, Ferencz G, Wujack D. Lyme disease of the CNS: MR imaging findings in 14 cases. AJNR Am J Neuroradiol. 1990;11(3): Logigian EL, Johnson KA, Kijewski MF, et al. Reversible cerebral hypoperfusion in Lyme encephalopathy. Neurol. 1997;49(6): Barnea-Goraly N, Kwon H, Menon V, Eliez S, Lotspeich L, Reiss AL. White matter structure in autism: preliminary evidence from diffusion tensor imaging. Biol Psych. 2004;55(3):323-6. Chung MK, Dalton KM, Alexander AL, Davidson RJ. Less white matter concentration in autism: 2D voxel-based morphometry. Neuroimage. 2004;23(1): Moeller, JR. Functional Neuroimaging findings in Chronic LYD; Research as a Tool to Solve Medical Controversies. Lyme and TBD Research Cen Columbia Univ. 2007

Epidemiological Findings: Lyme Disease/Tick-Borne Disease and Autism

Number of Lyme disease cases according to the CDC
The Lyme-Autism Connection 5/21/2007 Number of Lyme disease cases according to the CDC Tami Duncan -

BI/TBI Epidemiology Acute BI/TBI is more endemic in humid temperate locations with ecosystems that support populations of ticks and other hosts that carry the infectious agents. These locations are more commonly the Northeast; coastal regions; areas near the Mississippi River, the Mississippi tributaries, the Great Lakes region and the lake region of the upper Mid West. These endemic regions also coincide with the Atlantic, Mississippi and Pacific migratory bird flyways and migratory birds have been found to disseminate infected ticks. Veterinary data is helpful in this analysis (

A Rapidly Changing Global Environment Encourages the Proliferation of Parasites, Including Ticks and Tick-Borne Diseases

Is there as association between migratory bird flyways (Atlantic, Pacific & Mississippi), TBD and ASD? Appl Environ Microbiol Feb 1; [Epub ahead of print] The role of migratory birds in introduction and range expansion of Ixodes scapularis ticks, and Borrelia burgdorferi and Anaplasma phagocytophilum in Canada. Ogden NH, Lindsay RL, Hanincova K, Barker IK, Bigras-Poulin M, Charron DF, Heagy A, Francis CM, O'Callaghan CJ, Schwartz I, Thompson RA. Foodborne, Waterborne and Zoonotic Infections Division, Public Health Agency of Canada, Ottawa, Canada; Groupe de recherche en epidemiologie des zoonoses et sante publique, Faculte de medecine veterinaire, Universite de Montreal, Quebec, Canada; Special Pathogens Division, Public Health Agency of Canada, National Microbiology Laboratory, Winnipeg, Canada; Department of Microbiology and Immunology, New York Medical College, Valhalla, NY, USA; Canadian Cooperative Wildlife Health Centre, Dept Pathobiology, University of Guelph, Guelph, Ontario, Canada; International Development Research Centre, Ottawa, Canada; Bird Studies Canada, Port Rowan, Ontario, Canada; Migratory Bird Populations Division, Canadian Wildlife Service, Environment Canada, Ottawa, Canada; Department of Community Health and Epidemiology, Queen's University, Kingston, Ontario, Canada. During spring of 2005 and 2006, northward migrating landbirds were captured at 12 bird observatories in eastern Canada to investigate the role of migratory birds in northward range expansion of Lyme borreliosis, Human Granulocytic Anaplasmosis and their tick vector Ixodes scapularis. The prevalence of birds carrying I. scapularis ticks (mostly nymphs) was 0.35% (95% confidence interval [CI] = ), but a nested study by experienced observers suggested a more realistic infestation prevalence of 2.2% (95% CI = ). Mean infestation intensity was 1.66 per bird. Overall, 15.4% of I. scapularis nymphs (95% CI = ) were PCR-positive for Borrelia burgdorferi, but only 8% (95% CI = ) were positive when excluding nymphs collected at Long Point, Ontario where B. burgdorferi is endemic. A wide range of ospC and rrs-rrl intergenic spacer alleles of B. burgdorferi were identified in infected ticks, including those associated with disseminated Lyme disease, and alleles that are rare in northeastern USA. Overall, 0.4% (95% CI = ) of I. scapularis nymphs were PCR-positive for Anaplasma phagocytophilum. We estimate that migratory birds disperse million I. scapularis across Canada each spring, implicating migratory birds as possibly significant in I. scapularis range expansion in Canada. However, the low infection prevalence in ticks carried by the birds raises questions as to how B. burgdorferi and A. phagocytophilum become endemic in any tick populations established by bird-transported ticks. PMID: [PubMed - as supplied by publisher]

CDC: Lyme Disease --- United States, 2005

Top 15 States for Autism & Lyme Disease vs. Obesity (Control)
1, Minnesota 2, Oregon 3, Indiana 4, Maine 5, Massachusetts 6, Michigan 7, California 8, Maryland 9, Connecticut 10, Wisconsin 11, Rhode Island 12, New Jersey 13, Pennsylvania 14, Hawaii 15, Virginia Lyme 1, Delaware 2, Connecticut 3, New Jersey 4, Massachusetts 5, Pennsylvania 6, New York 7, Wisconsin 8, Maryland 9, New Hampshire 10, Maine 11, Minnesota 12, Vermont 13, Rhode Island 14, Virginia 15, West Virginia Obesity 1. Mississippi 2. Alabama 3. West Virginia 4. Louisiana 5. Kentucky 6. Tennessee 7. Arkansas 8. Indiana (tie for 8th) 8. South Carolina 10. Texas 11. Michigan 12. Georgia 13. Oklahoma 14. Missouri 15. Alaska CDC & IDEA

Informal Poll An informal poll by a show of hands was conducted at the LIAF Conference. It has been calculated 6.7/ y/o children have ASD (CDC). In addition, it has been calculated 11/100, y/o children have LYD/year (CDC). According to the Infectious Disease Society of America (IDSA) LYD is easily diagnosed & treated & not chronic, therefore incidence equals prevalence. The statistical probability of comorbid ASD + LYD is 6.7/1000 x 11/100,000 = 7/10,000,000, or approximately 1 in one million. If LYD + ASD are comorbid more than 1/1,000,000 and CDC & IDSA are correct, there is a causal association. As a control group, 18,000 have hemophilia in the US: this number is similar to the approximately 20,000 yearly prevalence of LYD in the US. At the LIA conference the author asked the 200 in attendance how many have seen ASD associated with hemophilia. One attendee raised her hand. The attendees were then asked how many have seen ASD associated with LYD. Half raised their hands. In addition a significant number have seen ASD associated with LYD in 10 or more cases, 6 have seen ASD associated with LYD in 100 or more cases and one physician has seen ASD associated with LYD in 500 or more cases.

Theoretical Issues: Genes, Infections and Autism

Physics, Math & Astrophysics: Newton to Einstein
Newton-Universal gravitation and the three laws of motion Einstein-Theory of relativity, mass-energy equivalence, (E=mc²), nonuniform motion & a new theory of gravitation

Complex Human Diseases Beyond Koch and Mendel
Mendel-Human traits are determined by individual genes which function independently of other genes and of environmental influences Koch-Many human diseases are caused by microbes which exert their effect independently of other microbes, environmental factors and genes Yolken

Gene-Environmental Interactions Beyond Koch’s Postulates
Most common human diseases are caused by the interaction of environmental insults and susceptibility genes. Many of the susceptibility genes are diverse determinants of human response to environmental factors to infection. Informative laboratory methods for complex disorders have to address both genetic and environmental factors. Prevention or treatment of the infections may result in the effective treatment of complex disorders: Helicobacter-Peptic Ulcer HPV-Genital Cancer Chlamydia-Cardiac Disease? Yolken

Emerging Infectious Determinants of Chronic Diseases
Evidence now confirms that 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 globeâ€”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. Vol. 12, No. 7

Associations between Chlamydophila infections, schizophrenia and risk of HLA-A10
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. 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= , odds ratio (OR)=9.43), especially with Chlamydophila psittaci (P= , OR=24.39). Schizophrenic carriers of the HLA-A10 genotype were clearly most often infected with Chlamydophila, especially C. psittaci (P= , 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. Read first Original Article Molecular Psychiatry (2007) 12, 264–272. doi: /sj.mp ; published online 14 November 2006 Associations between Chlamydophila infections, schizophrenia and risk of HLA-A10 B Fellerhoff1, B Laumbacher1, N Mueller2, S Gu1 and R Wank1,3 1Institute of Immunology, Ludwig-Maximilans University of Munich, Munich, Germany 2Psychiatric Hospital, University of Munich, Munich, Germany 3Immunotherapy Research Center GIS e.V., Munich, Germany Correspondence: Dr B Fellerhoff, Institute of Immunology, Ludwig-Maximilans University of Munich, Goethestrasse 31, D Munich, Germany. Received 16 July 2006; Revised 24 September 2006; Accepted 25 September 2006; Published online 14 November 2006. Top of page Abstract 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= , odds ratio (OR)=9.43), especially with Chlamydophila psittaci (P= , OR=24.39). Schizophrenic carriers of the HLA-A10 genotype were clearly most often infected with Chlamydophila, especially C. psittaci (P= , 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 et al. Molecular Psychiatry (2007) 12, 264–272. doi: /sj.mp

Selected Infectious Agents and Risk of Schizophrenia Among U. S
Selected Infectious Agents and Risk of Schizophrenia Among U.S. Military Personnel The authors found significant associations between increased levels of scaled T. gondii IgG antibodies and schizophrenia for antibodies measured both prior to and after diagnosis. Selected Infectious Agents and Risk of Schizophrenia Among U.S. Military Personnel David W. Niebuhr, M.D., M.P.H., M.Sc., Amy M. Millikan, M.D., M.P.H., David N. Cowan, Ph.D., M.P.H., Robert Yolken, M.D., Yuanzhang Li, Ph.D., and Natalya S. Weber, M.D., M.P.H. Am J Psychiatry 2008; 165: (published online December 17, 2007; doi: /appi.ajp ) OBJECTIVE: A number of studies have reported associations between Toxoplasma gondii (T. gondii) infection and the risk of schizophrenia. Most existing studies have used small populations and postdiagnosis specimens. As part of a larger research program, the authors conducted a hypothesis-generating case control study of T. gondii antibodies among individuals discharged from the U.S. military with a diagnosis of schizophrenia and serum specimens available from both before and after diagnosis. METHOD: The patients (N=180) were military members who had been hospitalized and discharged from military service with a diagnosis of schizophrenia. Healthy comparison subjects (3:1 matched on several factors) were members of the military who were not discharged. The U.S. military routinely collects and stores serum specimens of military service members. The authors used microplate-enzyme immunoassay to measure immunoglobulin G (IgG) antibody levels to T. gondii, six herpes viruses, and influenza A and B viruses and immunoglobulin M (IgM) antibody levels to T. gondii in pre- and postdiagnosis serum specimens. RESULTS: A significant positive association between the T. gondii IgG antibody and schizophrenia was found; the overall hazard ratio was The association between IgG and schizophrenia varied by the time between the serum specimen collection and onset of illness. CONCLUSION: The authors found significant associations between increased levels of scaled T. gondii IgG antibodies and schizophrenia for antibodies measured both prior to and after diagnosis. Niebuhr DW, et al. Am J Psychiatry 2008; 165:99-106

Maternal Exposure to Herpes Simplex Virus and Risk of Psychosis Among Adult Offspring
Background: Viral exposure during gestation is thought to be a risk factor for schizophrenia. Previous studies have indicated that prenatal exposure to herpes simplex virus type 2 (HSV-2) may be a risk for the subsequent development of schizophrenia in some populations. In this investigation, we tested a large and diverse population to assess the risk of psychoses among offspring of mothers with serological evidence of HSV-2 infection. Results: Offspring of mothers with serologic evidence of HSV-2 infection were at significantly increased risk for the development of psychoses (odds ratio [OR] = 1.6; 95% confidence interval [CI] = 1.1–2.3). This risk was particularly elevated among women with high rates of sexual activity during pregnancy (OR = 2.6; 95% CI = 1.4–4.6). Conclusions: Maternal exposure to herpes simplex virus type 2 is associated with an increased risk for psychoses among adult offspring. These results are consistent with a general model of risk resulting from enhanced maternal immune activation during pregnancy. Maternal Exposure to Herpes Simplex Virus and Risk of Psychosis Among Adult Offspring Stephen L. Bukaa, b, , , Tyrone D. Cannonc, E. Fuller Torreyd, Robert H. Yolkene and Collaborative Study Group on the Perinatal Origins of Severe Psychiatric Disorders aBrown University Department of Community Health, Providence, Rhode Island bHarvard School of Public Health, Boston, Massachusetts cDepartments of Psychology, Psychiatry and Biobehavioral Sciences, and Brain Research Institute, University of California (UCLA), Los Angeles, California dStanley Medical Research Institute, Chevy Chase, Maryland eStanley Division of Developmental Neurovirology, Johns Hopkins School of Medicine, Baltimore, Maryland. Received 25 May 2007; revised 29 August 2007; accepted 12 September 2007. Available online 5 November 2007. Background Viral exposure during gestation is thought to be a risk factor for schizophrenia. Previous studies have indicated that prenatal exposure to herpes simplex virus type 2 (HSV-2) may be a risk for the subsequent development of schizophrenia in some populations. In this investigation, we tested a large and diverse population to assess the risk of psychoses among offspring of mothers with serological evidence of HSV-2 infection. Methods We conducted a nested case-control study of 200 adults with psychoses and 554 matched control subjects (matched for city and date of birth, race/ethnicity, gender, and parent history of treatment for mental disorder) from three cohorts of the Collaborative Perinatal Project (Boston, Providence, and Philadelphia). We analyzed stored serum samples that had been obtained from these mothers at the end of pregnancy for antibodies directed at HSV-2, using type-specific solid-phase enzyme immunoassay techniques. Results Offspring of mothers with serologic evidence of HSV-2 infection were at significantly increased risk for the development of psychoses (odds ratio [OR] = 1.6; 95% confidence interval [CI] = 1.1–2.3). This risk was particularly elevated among women with high rates of sexual activity during pregnancy (OR = 2.6; 95% CI = 1.4–4.6). Conclusions Maternal exposure to herpes simplex virus type 2 is associated with an increased risk for psychoses among adult offspring. These results are consistent with a general model of risk resulting from enhanced maternal immune activation during pregnancy. Key Words: Herpes simplex virus; pregnancy complications; psychoses; schizophrenia; viral exposure Stephen L. Buka, Tyrone D. Cannonc, E. Fuller Torrey, Robert H. Yolken. Biological Psychiatry. Volume 63, Issue 8, 15 April 2008, Pages

Disease Contributors Change with Time
Predisposing Factors Precipitating Factors Perpetuating Factors Symptom “Intensity” Threshold The mechanism of the perpetuation of insomnia proposed by Spielman and colleagues breaks insomnia into preclinical, onset, short-term, and chronic phases, not all of which may be present in a given patient.1 Factors that predispose one to insomnia may be present long before symptoms occur and may set the stage for its occurrence by lowering the threshold for triggering insomnia.2 Precipitating factors then increase the “intensity” or propensity for insomnia over the threshold, causing the initial onset of insomnia. Over time, the influence of the precipitating factors wanes, but perpetuating factors may contribute to the overall intensity of the insomnia. If the perpetuating factors persist, their influence may be sufficient to sustain chronic symptoms of insomnia after the precipitating incidents have long subsided.1-3 1. Spielman AJ, Caruso LS, Glovinsky PB. A behavioral perspective on insomnia treatment. Psychiatr Clin North Am. 1987;10: 2. Spielman AJ. Assessment of insomnia. Clin Psychol Rev. 1986;6:11-25. 3. Jiva TM. Factors that affect insomnia. Sleep Rev. 2003;4. Available at: leepreviewmag.com/Articles.ASP?articleid=S0307F04. Accessed January 10, 2005. Preclinical Onset Short-Term Chronic Course Adapted from Spielman AJ et al. Psychiatr Clin North Am. Course of Insomnia; 1987;10:

Schema of Etiologic and Pathogenetic Factors That Have Been Implicated in Cell Death in Parkinson Disease and Possible Neuroprotective Approaches Schapira, A. H. V. et al. JAMA 2004;291: Copyright restrictions may apply.

Heavy Metal Toxicity INSIGHT Magazine CDC Study Raises Level of Suspicion Posted Dec. 8, By Kelly Patricia O Meara Canned tuna or canned poison? That was the teaser for a CBS 2 News "HealthWatch" Report of Nov. 22 that focused on high levels of mercury found in tuna and the possible health risks associated with them. CBS 2 News reporter Paul Moniz quoted a number of physicians, who observed of the toxic substance that, "Once it gets into our bodies, a substantial part of it will end up in our nervous system, in our brains, and it's there that it causes a variety of symptoms." A pediatrician is quoted as saying, "We know that high levels of mercury can impair the cognitive development as well as the growth and development of a young child." What the report appears to be revealing is that while overweight Americans may flee to fish to lose unwanted pounds, too much of that tasty tuna could reduce the IQ more than the waistline. What the critics of mercury in vaccines find provocative about this report is the acknowledgement by physicians that the high levels of mercury ingested from canned tuna can cause severe health risks. One such critic, the mother of an autistic child, wonders "why everyone gets up in arms over ingesting small amounts of mercury from fish or from breaking a thermometer but finds it acceptable to inject an even more toxic form of mercury directly into the bloodstream of infants. The evidence is overwhelming that hundreds of thousands of children were damaged by gross overexposure to mercury through vaccines [containing thimerosal] and millions more were and continue to be put at risk, yet network news has not addressed this in any significant way. The public needs and deserves to know the truth - not only about the biggest medical bungling in our history, but also about the extraordinary efforts of both the pharmaceutical industry and government agencies to cover it up." A pharmaceutical and government cover-up? It is a familiar enough accusation, and this time the fuse was lit by yet another study from the federal Centers for Disease Control and Prevention (CDC), this one titled Safety of Thimerosal-Containing Vaccines: A Two-Phased Study of Computerized Health Maintenance Organization Databases. The report concluded that "no consistent significant associations were found between TCVs [thimerosal-containing vaccines] and neurodevelopment outcomes." Critics scoff at such a conclusion. "Sure," laughs one, "they say you can't eat tuna because the level of mercury you ingest isn't good for you, but there's no health risk associated with injecting high levels of mercury directly into a newborn baby?" The CDC study, released in the November 2003 issue of Pediatrics, seemed to puzzle news media, with most who took note of it making at least a mention of the fact that the lead author, Thomas Verstraeten, was an employee of GlaxoSmithKline, the pharmaceutical giant and vaccine manufacturer, when he submitted the study for publication. The first part of the two-phase study to determine whether there is a connection between thimerosal-containing vaccines and neurodevelopment disorders began in 1999 and involved the review of data from Seattle's Group Health Cooperative and Northern California Kaiser, both large health-maintenance organizations (HMOs). The data used in this first phase actually revealed a significant association between TCVs administered to infants and later developmental abnormalities such as speech and language delays and neurodevelopment problems in general, such as tics and the alleged hyperactivity symptoms of attention-deficit disorder and attention-deficit/hyperactivity disorder. However, this conclusion was not included in the final draft; it was only made public afterward when Verstraeten's notes were revealed in another forum, according to specialists. The notes, not published with the CDC study, showed that the "relative risk" for autism was 2.48 times higher for children who received 62.5 micrograms or more of mercury from TCVs by 3 months of age. The second phase of the study in June 2000, however, involved the Harvard Pilgrim HMO in Massachusetts - an unlikely choice, critics say. Among the problems with using Harvard Pilgrim's database was that the HMO was in bankruptcy and had been taken over by the commonwealth of Massachusetts. The medical records not only were incomplete, but the data were stored with a diagnostic coding system completely unlike that used in the first phase of the study using data from the two West Coast HMOs. Furthermore, the Harvard Pilgrim data, say the expert analysts, had incomplete data on autism and did not even address the issue. Thus medical reviewers of the CDC study charge that it is rife with data manipulation. Since it relied on incompatible diagnostic coding to validate whether there were adverse effects from exposure to TCVs, the effect was to sabotage the result. So, they say, it was not surprising that the CDC study's analysis of the Harvard Pilgrim data found no consistent association between vaccines containing thimerosal and the mercury-related neurological disorders found previously in the first phase based on the two West Coast HMOs. One of the few physicians in Congress, Rep. Dave Weldon (R-Fla.), immediately saw the problems associated with the CDC study and notified CDC Director Julie Gerberding. Weldon wrote, "I have serious reservations about the four-year evolution and conclusions of this study. A review of these documents leaves me very concerned that rather than seeking to understand whether or not some children were exposed to harmful levels of mercury in childhood vaccines in the 1990s, there may have been a selective use of the data to make the associations in the earliest study disappear." Weldon's letter to Gerberding goes on to observe that "the first version of the study, produced in February 2000, found a significant association between exposure to thimerosal-containing vaccines and autism and neurological developmental delays. A June 2000 version of the study applied various data manipulations to reduce the autism association to 1.69, and the authors went outside the VSD [Vaccine Safety Datalink] database to secure data from a Massachusetts HMO [Harvard Pilgrim] in order to counter the association found between TCVs and speech delays." Clear enough. The Florida lawmaker, who is a staunch supporter of immunization, tells Insight, "I don't know what's going on. It's a pretty lame study to begin with. The way they've done it is they got some findings and started adding more numbers to the denominator - it's kind of a strange protocol they followed. Then there are all these quotes from the researchers from other documents about how you can add numbers and stratify things and get any outcome you want. Then you consider that the lead author is working for a drug company, didn't disclose this fact and also that it is one of the drug companies being sued over this mercury issue. I'm just very concerned that we're not going to get answers as long as there are careers at stake. You know there are people at the CDC who have been involved in the vaccine program who didn't recognize the amount of mercury they were giving kids, and now they're in the process of investigating themselves. Meanwhile a lot of these investigators bounce to and from the drug companies. I think it all is very, very murky and very suspicious." Weldon summarizes: "The CDC produced an article by Dr. Verstraeten, published on Nov. 3 in Pediatrics. Dr. Verstraeten is a former CDC employee. Since 2001 he has worked for GlaxoSmithKline - a vaccine manufacturer. While working for the CDC in 2000, the first version of Dr. Verstraeten's unpublished study found an association between higher thimerosal exposures and neurodevelopment disorders, including autism. Between 2000 and 2003, Dr. Verstraeten and coauthors manipulated and stratified the data so much that each of these associations magically disappeared. I don't know if it was deliberate, but that is nonetheless what happened. This study has done nothing in my mind to put these concerns to rest, but only serves to raise suspicions." This veteran member of Congress puts it plainly: "We're not going to get answers to these questions until Congress or some outside group starts poring through this information. But it's very coincidental that they added the hepatitis vaccine, the HiB vaccine and the chicken-pox vaccine - they added all these additional childhood vaccines around the time when the autism rate started to skyrocket. Then when you actually sit down and do the calculations, according to the Environmental Protection Agency [EPA], they were giving these kids very toxic levels of mercury. I mean as a 150- to 200-pound adult the EPA says you're not supposed to take in more than one microgram per day. They were taking little seven- and 10-pound babies and pumping 50 and 75 micrograms of mercury into them in one shot. That's like giving an adult 1,000 micrograms. And, on top of that, the World Health Organization says mercury is 10 times more toxic in children than it is in adults. It's horrifying." While Weldon and others cite huge and undeniable flaws, a spokesman for the CDC, Von Roebuck, tells Insight that "the CDC stands by the study." As he explains it, "We pretty much looked into that [manipulation of data] in the sense of how the information was presented, and we do stand behind it. The CDC knew that Dr. Verstraeten worked for GlaxoSmithKline, and the one thing that we would want to happen differently is that would have been known before, but the work that Dr. Verstraeten did was for the CDC at the time the work was produced - the work that he did for the study was done when he worked for the CDC." Mark Geier, M.D., Ph.D., is president of the Genetic Centers of America. He and his son, David Geier, president of Medcon Inc., are consultants on vaccine cases. David Geier tells Insight, "What happened here is Dr. Verstraeten goes to the Institute of Medicine [IOM] and says that he looked at it in one California HMO and it was statistical and he saw the effect, and then he did it in another California HMO and it was statistical and he saw the effect, then he went to Harvard Pilgrim HMO and he didn't see the effect. The IOM said it's biologically plausible, but the epidemiology is mixed and therefore we're not sure." "In my opinion," explains Mark Geier, "if they had seen clear epidemiology they would have recommended the immediate removal of thimerosal and hundreds of children would have been saved. But Verstraeten went to the one state in the country where the percentage of autism was the lowest. According to the U.S. Department of Education the average increase in autism was 400 percent, and every state in the union had at least a 100 percent increase. But Harvard Pilgrim had just a 10 percent increase." "We went to Atlanta," he continues, "to the CDC, and looked at the VSD data. There is thimerosal-containing DTaP [diphtheria, tetanus and pertussis vaccine] and thimerosal-free DTaP, so we asked a question: Among children that got a minimum of either three consecutive thimerosal-containing DTaPs or three consecutive thimerosal-free DTaPs, was there a difference in the number of autism cases in the two groups? We found mega differences. More than 20 times higher. The rate of autism in the children that got more than three doses of thimerosal-containing DTaP vaccines was much, much higher. Almost all the children that have autism in that group were the ones that got the thimerosal-containing DTaP vaccine. The more thimerosal the greater the cases of autism." Mark Geier says, "Believe us, there is no scientific issue here. This is fraud. The CDC and the FDA [Food and Drug Administration] know what is happening. They just can't admit it because it is one of the worst things ever to have happened to this United States. If a terrorist had done this, we wouldn't attack them, we'd nuke them. We're talking about one in eight children in the U.S. that currently are in special education, and that number is going to change to about one in five. What percentage of our young population can we destroy before we realize how serious this is?" Lyn Redwood, a registered nurse, mother of an autistic child and president and cofounder of (Sensible Action for Ending Mercury-Induced Neurological Disorders), a nonprofit organization dedicated to ending devastation caused by the needless use of mercury in medicines, tells Insight that "there are so many problems with the study, but over time you can see how all the manipulations of the data slowly bring down the signals for neurological disorders. I think they were trying to get lower numbers. It must be very hard to admit that a program that was designed to eradicate infectious disease has resulted in an epidemic of a whole new kind of disease. But to think that we weren't given a choice when the regulators and manufacturers knew these products contained mercury is inconceivable." Redwood says with a sigh, "On a scale of one to 10, I give the CDC study a big fat zero. I think it started out good, but when they saw the early numbers it scared the hell out of them. I don't have any faith in the CDC doing a decent study of this matter. It's like having the tobacco industry monitor cigarettes for safety. From a parent's perspective and from a health-care professional's perspective it's maddening that we can't get products that are safe, and yet we're forced by law to use them. They need to just get the thimerosal out. It's barbaric." Kelly Patricia O'Meara is an investigative reporter for Insight. the author 59

Summarizing the Theories
Most commonly human diseases are caused by the interaction of environmental insults and susceptibility genes. Many of the susceptibility genes respond to environmental factors and infection. Environmental insults contributing to ASD may include a complex interaction with infections, heavy metals, biotoxins, allergens, nutritional excesses/deficits and possibly vaccines resulting in a pathogenic interaction that includes inflammation, oxidative stress, mitochondrial dysfunction and excitotoxicity resulting in neuronal dysfunction.

Klüver–Bucy Syndrome, Infections and Autism

Limbic System The limbic system is the mammalian brain
The creation & evolution of the limbic system parallels the creation & evolution of the family

The Amygdala Theory of Autism
There is a network of neural regions that comprise the "social brain", which includes the amygdala Since the childhood psychiatric condition of autism involves deficits in "social intelligence", it is plausible that autism may be caused by an amygdala abnormality This includes reference to the Klüver-Bucy syndrome 1: Neurosci Biobehav Rev May;24(3): Cited in PMC, LinkOut The amygdala theory of autism. Baron-Cohen S, Ring HA, Bullmore ET, Wheelwright S, Ashwin C, Williams SC. Departments of Experimental Psychology and Psychiatry, University of Cambridge, Downing Street, Cambridge, UK. Brothers (Brothers L\. Concepts in Neuroscience 1990;1:27-51) proposed a network of neural regions that comprise the "social brain", which includes the amygdala\. Since the childhood psychiatric condition of autism involves deficits in "social intelligence", it is plausible that autism may be caused by an amygdala abnormality\. In this paper we review the evidence for a social function of the amygdala\. This includes reference to the Kluver-Bucy syndrome (which Hetzler and Griffin suggested may serve as an animal model of autism)\. We then review evidence for an amygdala deficit in people with autism, who are well known to have deficits in social behaviour\. This includes a detailed summary of our recent functional magnetic resonance imaging (fMRI) study involving judging from the expressions of another person's eyes what that other person might be thinking or feeling\. In this study, patients with autism or AS did not activate the amygdala when making mentalistic inferences from the eyes, whilst people without autism did show amygdala activity\. The amygdala is therefore proposed to be one of several neural regions that are abnormal in autism\. We conclude that the amygdala theory of autism contains promise and suggest some new lines of research. PMID: [PubMed - indexed for MEDLINE] Baron-Cohen S, et. Al. Neurosci Biobehav Rev May;24(3):

Klüver-Bucy Syndrome The syndrome is named for Heinrich Klüver and Paul Bucy, who removed the temporal lobe bilaterally in rhesus monkeys in an attempt to determine its function. This caused the monkeys to develop visual agnosia, emotional changes, altered sexual behavior, hypermetamorphosis and oral tendencies. Though the monkeys could see, they were unable to recognize even previously familiar objects, or their use. They would examine their world with their mouths instead of their eyes ("oral tendencies") and developed a desire to explore everything ("hypermetamorphosis"). Their overt sexual behavior increased dramatically ("hypersexualism"), and the monkeys indulged in indiscriminate sexual behavior including masturbation, heterosexual acts and homosexual acts. Emotionally, the monkeys became dulled, and their facial expressions and vocalizations became far less expressive. They were also less fearful of things that would have instinctively panicked them in their natural state, such as humans or snakes. Even after being attacked by a snake, they would willingly approach it again. This aspect of change was termed "placidity". People with bilateral lesions in their temporal lobes show similar behaviors. They may display oral or tactile exploratory behavior (socially inappropriate licking or touching); hypersexuality; bulimia; memory disorders; flattened emotions (placidity); and an inability to recognize objects or faces. Wikipedia

Infantile Autism and the Temporal Lobes of the Brain
Studies are reviewed that support the hypothesis that infantile autism results from a neuropathology of the temporal lobes of the brain. First, there are parallels between symptoms noted in autism and those found in the Kluver-Bucy and amnesic syndromes. Second, there is a similarity between developmental dysphasia and autism. Third, the formation of cross-modal associations may be deficient in autistic children, a symptom resembling aspects of Geschwind's disconnection syndromes. Finally, a large number of organic factors have been associated with the development of autism, some of these having specific implications for temporal lobe involvement. It is concluded that the main autistic symptoms are most consistent with a neurological model involving bilateral dysfunction of the temporal lobes. Individual differences in the extent of bilateral involvement and/or other coexistent neuropathologies could contribute to the heterogeneity of the autistic population. Infantile autism and the temporal lobe of the brain. Hetzler BE, Griffin JL. Studies are reviewed that support the hypothesis that infantile autism results from a neuropathology of the temporal lobes of the brain. First, there are parallels between symptoms noted in autism and those found in the Kluver-Bucy and amnesic syndromes. Second, there is a similarity between developmental dysphasia and autism. Third, the formation of cross-modal associations may be deficient in autistic children, a symptom resembling aspects of Geschwind's disconnection syndromes. Finally, a large number of organic factors have been associated with the development of autism, some of these having specific implications for temporal lobe involvement. It is concluded that the main autistic symptoms are most consistent with a neurological model involving bilateral dysfunction of the temporal lobes. Individual differences in the extent of bilateral involvement and/or other coexistent neuropathologies could contribute to the heterogeneity of the autistic population. PMID: [PubMed - indexed for MEDLINE] Hetzler BE, Griffin JL. J Autism Dev Disord Sep;11(3):

Autism, the superior temporal sulcus and social perception
Based on recent brain-imaging results, our hypothesis is that abnormalities in the superior temporal sulcus (STS) are highly implicated in ASD. STS abnormalities are characterized by decreased gray matter concentration, rest hypoperfusion and abnormal activation during social tasks. STS anatomical and functional anomalies occurring during early brain development could constitute the first step in the cascade of neural dysfunction underlying ASD. We will focus this review on the STS, which has been highly implicated in social cognition. We will review recent data on the contribution of the STS to normal social cognition and review brain-imaging data implicating this area in ASD. Trends Neurosci Jul;29(7): Epub 2006 Jun 27. Links Autism, the superior temporal sulcus and social perception. Zilbovicius M, Meresse I, Chabane N, Brunelle F, Samson Y, Boddaert N. URM 0205 Brain Imaging in Psychiatry, INSERM-CEA, Service Hospitalier Frédéric Joliot, CEA, 4 Place du General Leclerc, Orsay 91406, France. The most common clinical sign of autism spectrum disorders (ASD) is social interaction impairment, which is associated with communication deficits and stereotyped behaviors. Based on recent brain-imaging results, our hypothesis is that abnormalities in the superior temporal sulcus (STS) are highly implicated in ASD. STS abnormalities are characterized by decreased gray matter concentration, rest hypoperfusion and abnormal activation during social tasks. STS anatomical and functional anomalies occurring during early brain development could constitute the first step in the cascade of neural dysfunction underlying ASD. We will focus this review on the STS, which has been highly implicated in social cognition. We will review recent data on the contribution of the STS to normal social cognition and review brain-imaging data implicating this area in ASD. This review is part of the INMED/TINS special issue "Nature and nurture in brain development and neurological disorders", based on presentations at the annual INMED/TINS symposium ( PMID: [PubMed - indexed for MEDLINE Zibovicius M et al. Trends Neurosci Jul;29(7): Epub 2006 Jun 27.

Amygdala volume and nonverbal social impairment in adolescent and adult males with autism
In study 1, individuals with autism who had small amygdalae were slowest to distinguish emotional from neutral expressions (P=.02) and showed least fixation of eye regions (P=.04). These same individuals were most socially impaired in early childhood, as reported on the Autism Diagnostic Interview-Revised (P<.04). Study 2 showed smaller amygdalae in individuals with autism than in control subjects (P=.03) and group differences in the relation between amygdala volume and age. Study 2 also replicated findings of more gaze avoidance and childhood impairment in participants with autism with the smallest amygdalae. Across the combined sample, severity of social deficits interacted with age to predict different patterns of amygdala development in autism (P=.047). CONCLUSIONS: These findings best support a model of amygdala hyperactivity that could explain most volumetric findings in autism. Further psychophysiological and histopathological studies are indicated to confirm these findings Amygdala volume and nonverbal social impairment in adolescent and adult males with autism. Nacewicz BM, Dalton KM, Johnstone T, Long MT, McAuliff EM, Oakes TR, Alexander AL, Davidson RJ. Waisman Laboratory for Brain Imaging and Behavior, University of Wisconsin-Madison, Waisman Center, 1500 Highland Avenue, Madison, WI 53705, USA. BACKGROUND: Autism is a syndrome of unknown cause, marked by abnormal development of social behavior. Attempts to link pathological features of the amygdala, which plays a key role in emotional processing, to autism have shown little consensus. OBJECTIVE: To evaluate amygdala volume in individuals with autism spectrum disorders and its relationship to laboratory measures of social behavior to examine whether variations in amygdala structure relate to symptom severity. DESIGN: We conducted 2 cross-sectional studies of amygdala volume, measured blind to diagnosis on high-resolution, anatomical magnetic resonance images. Participants were 54 males aged 8 to 25 years, including 23 with autism and 5 with Asperger syndrome or pervasive developmental disorder not otherwise specified, recruited and evaluated at an academic center for developmental disabilities and 26 age- and sex-matched community volunteers. The Autism Diagnostic Interview-Revised was used to confirm diagnoses and to validate relationships with laboratory measures of social function. MAIN OUTCOME MEASURES: Amygdala volume, judgment of facial expressions, and eye tracking. RESULTS: In study 1, individuals with autism who had small amygdalae were slowest to distinguish emotional from neutral expressions (P=.02) and showed least fixation of eye regions (P=.04). These same individuals were most socially impaired in early childhood, as reported on the Autism Diagnostic Interview-Revised (P<.04). Study 2 showed smaller amygdalae in individuals with autism than in control subjects (P=.03) and group differences in the relation between amygdala volume and age. Study 2 also replicated findings of more gaze avoidance and childhood impairment in participants with autism with the smallest amygdalae. Across the combined sample, severity of social deficits interacted with age to predict different patterns of amygdala development in autism (P=.047). CONCLUSIONS: These findings best support a model of amygdala hyperactivity that could explain most volumetric findings in autism. Further psychophysiological and histopathological studies are indicated to confirm these findings. PMID: [PubMed - indexed for MEDLINE] Nacewicz, et. al. Arch Gen Psychiatry Dec;63(12):

Medline Cited Infectious Causes of Autism
Rubella, Herpes simplex Mycoplasma pneumoniae Shigella Neurocysticercosis Unknown Various viral infection Borna HHV-6 Chlamydia Herpes virus family Malaria Blastocystis Cytomegalovirus Syphilis Varicella Toxoplasmosis Yet unrecognized infectious Tick-Borne/Lyme

Microbes that Can Cause Mental Symptoms
Syphilis Malaria Toxoplasmosis Candidiasis Other spirochetes 1. Borrelia burgdorferi sensu stricto(USA,UK,Europe) 2. Borrelia garinii (UK, Europe) 3. Borrelia afzelii (UK, Europe) "CHRONIC LYME DISEASE" or "NEW LYME DISEASE" is a combination of LYME DISEASE and one or more of the following Co-infections: Relapsing Fever caused by the spirochetes: - Borrelia hermsii - Borrelia turicatae Mycoplasmas: - Mycoplasma fermentans - Mycoplasma pneumoniae Babesiosis: - Babesia microti - Babesia WA and other Babesia species - Chlamydia pneumoniae Rickettsial Diseases: - Rocky Mountain Spotted Fever - Coxiella burnetti (Q-Fever and "Post-Q Fever Fatigue Syndrome") - Colorado Tick Fever - Eastern tick-borne Rickettsiosis - Rickettsialpox - Tularemia (rabbit fever) - Ehrlichiosis (caused by Ehrlichia, and rickettsia-like bacteria) - Anaplasmas (related to the genera Rickettsia and Ehrlichia) - Hepatitis-C Bartonellosis: - Bartonella henselae (cat scratch fever), Bartonella rochalimae - Bartonella quintana (trench fever) - Viral Meningitis Candida dubliniensis Asfarviridae, Reoviridae, Rhabdoviridae, Orthomyxoviridae, Bunyaviridae, Flaviviridae & Arenaviridae family viruses (38+ species Streptococcus Japanese B encephalitis HHV-1 HHV-2 Borna virus Epstein-Barr virus Pandemic Influenza of 1918 Hong Kong flu Coxackie virus Pneumococcus Haemophilus Meningococcus Leptospira Mycobacterium tuberculosis Cytomegalovirus Enterovirus HIV Pandemic Influenza of 1918 Influenza virus Measles Papovirus Poliovirus Rabies Toga virus Toxoplasmosis Cryptococcus Coccidiomycosis Histoplasmosis Cysticercosis Rubella, Herpes simplex Mycoplasma pneumoniae Shigella Neurocysticercosis Unknown Various viral infection Borna Herpes virus family Malaria Blastocystis Cytomegalovirus Syphilis Varicella Yet unrecognized infectious

Infections, Klüver-Bucy & Autism I
Baron-Cohen S, Ring HA, Bullmore ET, Wheelwright S, Ashwin C, Williams SC. The amygdala theory of autism. Neurosci Biobehav Rev. 2000;24(3): Hetzler BE, Griffin JL. Infantile autism and the temporal lobe of the brain. J Autism Dev Disord. 1981;11(3): Libbey JE, Sweeten TL, McMahon WM, Fujinami RS. Autistic disorder and viral infections. J Neurovirol. 2005;11(1):1-10 Stubbs EG, Crawford ML. Depressed lymphocyte responsiveness in autistic children. J Autism Child Schizophr. 1977;7(1):49-55. De Tiege X, De Laet C, Mazoin N, et. al. Postinfectious immune-mediated encephalitis after pediatric herpes simplex encephalitis. Brain Dev. 2005;27(4):304-7. DeLong GR, Bean SC, Brown FR 3rd. Acquired reversible autistic syndrome in acute encephalopathic illness in children. Arch Neurol. 1981;38(3):191-4. Lancaster K, Dietz DM, Moran TH, Pletnikov MV.Abnormal social behaviors in young and adult rats neonatally infected with Borna disease virus. Behav Brain Res. 2007;176(1):141-8. Stubbs EG, Crawford ML. Depressed lymphocyte responsiveness in autistic children. J Autism Child Schizophr. 1977;7(1):49-55.

Infections, Klüver-Bucy & Autism II
Markowitz PI. Autism in a Child with Congenital Cytomegalovirus Infection. J Autism Dev Disord. 1983;13(3) Stubbs EG, Ash E, Williams CPS. Autism and Congenital Cytomegalovirus. J Autism Dev Disord. 1984;14(2). Auvichayapat N, Auvichayapat P, Watanatorn J, Thamaroj J, Jitpimolmard S. Kluver-Bucy syndrome after mycoplasmal bronchitis. Epilepsy Behav. 2005;8(1):320-2. Guedalia JS, Zlotogorski Z, Goren A, Steinberg A. A reversible case of Klüver-Bucy syndrome in association with shigellosis. J Child Neurol. 1993;8(4):313-5. Stubbs EG, Crawford ML. Depressed lymphocyte responsiveness in autistic children. J Autism Child Schizophr. 1977;7(1):49-55. Patel R, Jha S, Yadav RK. Pleomorphism of the clinical manifestations of neurocysticercosis. Trans R Soc Trop Med Hyg. 2006;100(2): Mankoski RE, Collins M, Ndosi NK, Mgalla EH, Sarwatt VV, Folstein SE. Etiologies of autism in a case-series from Tanzania. J Autism Dev Disord. 2006;36(8): Thong YH. Reptilian behavioural patterns in childhood autism. Med Hypotheses. 1984;13(4): Boorom KF. Is this recently characterized gastrointestinal pathogen responsible for rising rates of inflammatory bowel disease (IBD) and IBD associated autism in Europe and the United States in the 1990s? Med Hypotheses. 2007;69(3):652-9.

Infections, Klüver-Bucy & Autism III
Singh VK and Jensen RL. Elevated levels of measles antibodies in children with autism. Pediatric Neurol. 2003;28: Singh VK. Autism, vaccines, and immune reactions. Accessed Halsey NA, Hyman SL. Measles-mumps-rubella vaccine and ASD: report from the New Challenges in Childhood Immunizations Conf. Pediatrics. 2001;107(5):E84 Bransfield RC, Wulfman JS, Harvey WT, Usman AI. The association between tick-borne infections, Lyme borreliosis and autism spectrum disorders Medical Hypotheses. 2007 Nicolson GL, Gan R, Nicolson NL, et al. Evidence for Mycoplasma, Chlamydia pneunomiae and HHV-6 Co-infections in the blood of patients with Autism Spectrum Disorders. J Neuroscience Res. 2007;85: Takahashi H, Arai S, Tanaka-Taya K, et al. Autism and infection/immunization episodes in Japan. Jpn J Infect Dis. 2001;54:78-79. Yamashita Y, Fujimoto C, Nakajima E, et al. Possible association between congenital cytomegalovirus infection and autistic disorder. J Autism Dev Disord. 2003;33: Rosen NJ, Yoshida CK, Croen LA. Infection in the first 2 years of life and autism spectrum disorders. Pediatrics. 2007;119:61-9. Nicolson GL, Berns P, Gan R, et al. Chronic mycoplasmal infections in Gulf War veterans’ children and autism patients. Med Veritas. 2005;2: Nicolson GL. Chronic Bacterial and Viral Infections in Neurodegenerative and Neurobehavioral Diseases. Laboratory Medicine In Press

Neural Networks, Neurodevelopment, Autism and Borreliosis

The neurodevelopmental impact of prenatal infections at different times of pregnancy: the earlier the worse? Infection associated immunological events in early fetal life can have adverse effects on cell proliferation and differentiation; predispose the developing nervous system to undergo additional failures in subsequent cell migration, target selection, and synapse maturation, eventually leading to multiple brain and behavioral abnormalities apparent later in life. Meyer U, Yee BK, Feldon J. Neuroscientist 2007;13(3):241–56.

Critical periods of vulnerability for the developing nervous system: evidence from humans and animal models Brain developmental processes (i.e. cell proliferation, migration, differentiation, synaptogenesis, myelination, and apoptosis) occur at vulnerable periods during the development of the nervous system and are sensitive to environmental insults that can contribute to autism. Rice D, Barone S. Environ Health Perspect 2000;108(3):511–33.

Immune Reactions to LYD Disrupt Nerve Fibers
Younger has demonstrated on biopsies that small nerve fiber disruption can occur in Lyme vaccine recipients and BI/TBI patients who subsequently may heal in response to anti-infective treatment Younger D. Small nerve fiber disruption in OspA vaccine recipients. Am Acad Neurol. Meeting 2007.

Oxidative Stress “Chronic intracellular infections (Mycoplasma, Borrelia, Chlamydia, etc.) cause increased oxidative stress by their release of ROS and stimulation of ROS in mitochondria. This causes increased oxidation of mitochondrial lipid membranes and proteins and loss of mitochondrial function. We see the same thing in CFS patients who also have these infections, although in fully developed brains we do not, of course, see the autism and other developmental disorders.” Prof. Garth Nicolson

Evidence of toxicity, oxidative stress, and neuronal insult in autism
This article discusses the evidence for the case that some children with autism may become autistic from neuronal cell death or brain damage sometime after birth as result of insult; and addresses the hypotheses that toxicity and oxidative stress may be a cause of neuronal insult in autism. The article first describes the Purkinje cell loss found in autism, Purkinje cell physiology and vulnerability, and the evidence for postnatal cell loss. Second, the article describes the increased brain volume in autism and how it may be related to the Purkinje cell loss. Third, the evidence for toxicity and oxidative stress is covered and the possible involvement of glutathione is discussed. Finally, the article discusses what may be happening over the course of development and the multiple factors that may interplay and make these children more vulnerable to toxicity, oxidative stress, and neuronal insult. According to the Autism Society of America, autism is now considered to be an epidemic. The increase in the rate of autism revealed by epidemiological studies and government reports implicates the importance of external or environmental factors that may be changing. This article discusses the evidence for the case that some children with autism may become autistic from neuronal cell death or brain damage sometime after birth as result of insult; and addresses the hypotheses that toxicity and oxidative stress may be a cause of neuronal insult in autism. The article first describes the Purkinje cell loss found in autism, Purkinje cell physiology and vulnerability, and the evidence for postnatal cell loss. Second, the article describes the increased brain volume in autism and how it may be related to the Purkinje cell loss. Third, the evidence for toxicity and oxidative stress is covered and the possible involvement of glutathione is discussed. Finally, the article discusses what may be happening over the course of development and the multiple factors that may interplay and make these children more vulnerable to toxicity, oxidative stress, and neuronal insult. Copyright © 2003 Published by Elsevier Science B.V. Review article Purkinje cell vulnerability and autism: a possible etiological connection Janet Kinnear Kern , Department of Psychiatry, University of Texas Southwestern Medical Center at Dallas, St. Paul Professional Building I, 5959 Harry Hines Boulevard, Suite 520, Dallas, TX , USA Received 9 September 2002; revised 7 February 2003; accepted 8 February 2003. ; Available online 11 June 2003. Abstract Autism is a neurological disorder of unknown etiology. The onset of the abnormal growth and development within the brain is also not known. Current thought by experts in autism is that the time of onset is prenatal, occurring prior to 30 weeks gestation. However, autism comprises a heterogeneous population in that parents report either that their child was abnormal from birth, or that their child was developmentally normal until sometime after birth, at which time the child began to regress or deteriorate. Anecdotal reports suggest that some children with autism have significant illness or clinical events prior to the development of autistic symptoms. Conceivably, these children may become autistic from neuronal cell death or brain damage sometime after birth as result of insult. To support this theory is that marked Purkinje cell loss, the most consistent finding in the autistic disorder, can result from insult. Evidence suggests that the Purkinje cell is selectively vulnerable. This article discusses a theory that the selective vulnerability of the Purkinje cell may play a role in the etiology of autism, and suggests that a future direction in autism research may be to investigate the possibility of neuronal cell loss from insult as a cause of autism. Results of a small pilot survey are also discussed. Kern & Jones. J Toxicol Environ Health B Crit Rev Nov-Dec;9(6):485-99

Oxidative stress, nitric oxide, and the mechanisms of cell death in Lurcher Purkinje cells
Oxidative stress is postulated to play a role in cell death in many neurodegenerative diseases. As a model of neonatal neuronal cell death, we have examined the role of oxidative stress in Purkinje cell death in the heterozygous Lurcher mutant (+/Lc). Lurcher is a gain of function mutation in the delta2 glutamate receptor (GluRdelta2) that turns the receptor into a leaky membrane channel, resulting in chronic depolarization of +/Lc Purkinje cells starting around the first week of postnatal development. Virtually, all +/Lc Purkinje cells die by the end of the first postnatal month. To investigate the role of oxidative stress in +/Lc Purkinje cell death, we have examined nitric oxide synthase (NOS) activity and the expression of two markers for oxidative stress, nitrotyrosine and manganese super oxide dismutase (MnSOD), in wild type and +/Lc Purkinje cells at P10, P15, and P25. The results show that NOS activity and immunolabeling for nitrotyrosine and MnSOD are increased in +/Lc Purkinje cells. To determine whether peroxynitrite formation is a prerequisite for +/Lc Purkinje cell death, +/Lc mutants were crossed with an alpha-nNOS knockout mutant (nNOSalpha(-/-)) to reduce the production of NO. Analysis of the double mutants showed that blocking alpha-nNOS expression does not rescue +/Lc Purkinje cells. However, we present evidence for sustained NOS activity and nitrotyrosine formation in the GluRdelta2(+/Lc):nNOS(-/-) double mutant Purkinje cells, which suggests that the failure to rescue GluRdelta2(+/Lc):nNOS(-/-) Purkinje cells may be explained by the induction of alternative nNOS isoforms. Dev Neurobiol Jul;67(8): Links Oxidative stress, nitric oxide, and the mechanisms of cell death in Lurcher Purkinje cells. McFarland R, Blokhin A, Sydnor J, Mariani J, Vogel MW. Department of Biology, University of Maryland Baltimore County, Baltimore, Maryland 21250, USA. Oxidative stress is postulated to play a role in cell death in many neurodegenerative diseases. As a model of neonatal neuronal cell death, we have examined the role of oxidative stress in Purkinje cell death in the heterozygous Lurcher mutant (+/Lc). Lurcher is a gain of function mutation in the delta2 glutamate receptor (GluRdelta2) that turns the receptor into a leaky membrane channel, resulting in chronic depolarization of +/Lc Purkinje cells starting around the first week of postnatal development. Virtually, all +/Lc Purkinje cells die by the end of the first postnatal month. To investigate the role of oxidative stress in +/Lc Purkinje cell death, we have examined nitric oxide synthase (NOS) activity and the expression of two markers for oxidative stress, nitrotyrosine and manganese super oxide dismutase (MnSOD), in wild type and +/Lc Purkinje cells at P10, P15, and P25. The results show that NOS activity and immunolabeling for nitrotyrosine and MnSOD are increased in +/Lc Purkinje cells. To determine whether peroxynitrite formation is a prerequisite for +/Lc Purkinje cell death, +/Lc mutants were crossed with an alpha-nNOS knockout mutant (nNOSalpha(-/-)) to reduce the production of NO. Analysis of the double mutants showed that blocking alpha-nNOS expression does not rescue +/Lc Purkinje cells. However, we present evidence for sustained NOS activity and nitrotyrosine formation in the GluRdelta2(+/Lc):nNOS(-/-) double mutant Purkinje cells, which suggests that the failure to rescue GluRdelta2(+/Lc):nNOS(-/-) Purkinje cells may be explained by the induction of alternative nNOS isoforms. Copyright (c) 2007 Wiley Periodicals, Inc. McFarland R et al. Dev Neurobiol Jul;67(8):

Major Histocompatibility Complex
An infection during pregnancy or early development in a genetically predisposed individual may evoke an immune response that that disrupts fetal brain development by altering major histocompatibility complex molecules that impact glia and microgila cells, glutamate functioning and synaptic development and plasticity and contribute to the pathophysiology of autism. IMMUNE SYSTEM RESEARCH PROMISES TO HELP TREAT AILMENTS RANGING FROM ALZHEIMER’S AND STROKE TO MENTAL DISORDERS SAN DIEGO, November 4, Recent discoveries in the field of neuroimmunology, which studies the interaction between the immune and nervous systems, are offering promising new leads for the treatment of many devastating neurological disorders, from Alzheimer's disease to stroke.New research suggests that reducing the expression of an immune system protein in the brain may help repair neurons damaged by spinal cord injury and other trauma. Other research has uncovered the important role that immune molecules perform in the prenatal development of such diseases as autism and schizophrenia. Additional findings reveal that an innovative type of immunotherapy assists with the recovery of memory after stroke."The discovery that immune molecules play a crucial role in shaping neuronal connections and are even expressed on nerve cells important in learning and memory is opening up a whole range of potential new treatment targets for diseases in which these connections have gone awry, such as Alzheimer's and other dementias, autism, amyotrophic lateral sclerosis (ALS), Parkinson's disease, schizophrenia, and in nerve injury," says Esther Sternberg, MD, of the National Institutes of Health. "Understanding these neural immune connections at a molecular and cellular level will shed light on the reasons these diseases develop and will help provide new ways to prevent or treat them."Several years ago, researchers at Harvard Medical School made the unexpected discovery that neurons have major histocompatibility complex (MHC) class I molecules on their cell surface. MHC class I molecules play a central role in a healthy, functioning immune system by helping the body recognize and destroy disease-infected cells."We were amazed by this finding," says Carla Shatz, PhD, now at Stanford University. "Previously it had been thought that neurons were the only cells in the body that didn't express these molecules."When Shatz and her colleagues studied mouse models that lack MHC class I, they found another surprise: greater-than-normal strengthening of the synapses between neurons. This observation suggests that MHC class I acts as a kind of "molecular brake" on synaptic plasticity, the ability of brain cells to rewire themselves. Such plasticity is essential to learning and memory.In mice, the "brake" for the gene encoding MHC class I appears to be released twice: during early development and again in old age. Interestingly, late in life, the gene's neural expression occurs primarily in the hippocampus and other areas of the brain involved in learning and memory."MHC class I neurons may also play a role in age-related neurodegenerative diseases, such as Alzheimer's and Parkinson's," says Shatz. "It may mistakenly signal the immune system to attack brain cells, just as it triggers a similar attack on the joints in cases of rheumatoid arthritis."More recently, Shatz and her team have reported that neurons also express an immune system protein called paired-immunoglobulin-like receptor-B (PirB), which, over time, gradually inhibits brain plasticity. Mice that lack PirB exhibit greater synaptic plasticity as they age -- a finding that suggests that reducing PirB might help reestablish the connections among neurons damaged by spinal cord injury, stroke, or other trauma.Together, these studies indicate that immune molecules perform important functions in the brain, including how much or how quickly our brain changes in response to new experiences.Researchers at the Karolinska Institute in Stockholm, Sweden, have found that removal of synapses from damaged neurons after a motor nerve injury, a process known as "synaptic stripping," is much stronger in mice who lack functioning MHC class I molecules. They also found that such mice are less likely to experience a regeneration of their motor neurons and that their glial cells react differently to the damaged neurons than do those of mice with functioning MHC class I molecules."These results provide a surprising link between neuroscience and immunology," says Staffan Cullheim, MD, PhD. They also mark the first time a family of molecules has been linked directly to how the cell body of a neuron reacts after its axon -- the long projection that conducts electrical signals away from the cell's body -- has been injured.In earlier studies, Cullheim and other scientists had reported that MHC class I molecules can be found in particularly high levels among motor neurons in the brain stem and the spinal cord, especially after the neurons have been damaged. In his most recent study, Cullheim found that the presence of MHC class I helps retain certain inhibitory synapses on the surface of injured motor neurons, thus reducing the likelihood that the neurons will fire a nerve impulse, or action potential, to neighboring cells.MHC class I also has an effect on the action of glial cells, which in turn may influence neurons in various ways. Although microglia, the "immune cells" of the central nervous system, responded more weakly in the absence of MHC class I molecules, other glial cells, known as astrocytes, responded more vigorously. If -- and how -- these different responses are linked with synaptic stripping is not yet known."The consequences of the effects of MHC class I is still not clear," says Cullheim, "but it may be linked with the the ability of motor neurons to produce new axons. Mice with peripheral nerve lesions in their hind limbs exhibit less axonal bridging on those lesions when their MCH class I function is impaired."High levels of MHC class I, on the other hand, may pose a danger to neurons in the same way as is seen for other cell types -- during viral infection, for example. These high levels may even be involved in the development of neurodegenerative diseases. Research has shown that motor neurons involved in ALS and dopaminergic neurons involved in Parkinson's disease express among the largest amounts of MHC class I molecules in the nervous system.At the University of California, San Diego, Lisa Boulanger, PhD, and her colleagues have found that changes in the levels of specific immune molecules, members of the MHC class I family, are sufficient to cause cellular and behavioral symptoms of autism and schizophrenia in mice.One set of preliminary studies from Boulanger's laboratory suggests that normal levels of MHC class I are needed for proper neuronal signaling by the neurotransmitter glutamate. The disruption of the glutamate signaling system is a hallmark of schizophrenia. It's also been recently characterized in patients with autism.In a second line of research, Boulanger has found that changes in MHC class I levels cause a striking disruption of the ability to "tune out" irrelevant sensory information, as measured by a neurological phenomenon known as prepulse inhibition, or PPI. Scientists have long known that PPI is impaired in people with schizophrenia, and recent studies suggest that it's also impaired in people with autism."We found in our current study that mice with altered levels of MHC class I share both abnormal glutamate signaling and this deficit in PPI," Boulanger says. "These results are exciting because they may provide clues to understanding the puzzle of why immune abnormalities are frequent among patients with autism and schizophrenia and their close relatives."Boulanger and her colleagues are currently investigating whether MHC class I molecules are altered in people with autism and schizophrenia. They are also using animal models to determine how immune signaling may affect the earliest events in fetal brain development."Human data show that in genetically predisposed individuals, a maternal viral infection during pregnancy increases the chance of the child developing either autism or schizophrenia later in life," says Boulanger. "Recent research in animal models suggests that it's not the infection itself, but rather an unknown, shared feature of the immune response to a variety of infectious agents that disrupts fetal brain development and leads to impairments in PPI."A leading candidate for this mysterious immune trigger is the release of cellular signals called cytokines, which are produced during infection and injury. Cytokine levels are altered in the fetal brain following a maternal infection -- and in the brains of people with autism. Cytokines can increase the levels of MHC class I molecules in many types of cells, including neurons."We're now trying to determine if changes in MHC class I molecules are the necessary link between maternal infections and abnormal fetal brain development," says Boulanger.An experimental treatment called anti-NOGO-A immunotherapy has been found to improve performance on a test of cognitive ability after stroke in aged rats, according to a new study from a team of researchers led by Gwendolyn Kartje, MD, PhD, at Loyola University and the Edward Hines VA Hospital in Chicago. This finding may one day lead to more effective treatments for the millions of people worldwide who survive a stroke each year and for the millions of others suffering from Alzheimer's disease and other memory disorders.Anti-NOGO-A immunotherapy blocks the NOGO-A protein, a molecule found in the brain. The precise role of this protein is unknown, but it appears to inhibit aberrant growth. When the brain becomes damaged, however, this inhibitory function turns harmful, preventing injured cells from regenerating and repairing themselves. It also prevents uninjured cells from changing to help with the recovery.In earlier studies, Kartje and her colleagues showed that anti-NOGO-A immunotherapy led to the recovery of forepaw and arm movement after induced stroke in aged rats. The new study found that the therapy also improved cognitive recovery when testing performance on a spatial memory task."This suggests that the NOGO-A protein limits the recovery of memory after stroke and that by blocking the protein, more recovery may occur," Kartje says. Her laboratory next plans to look for structural changes in the brain that underlie the recovery process.

Cerebellar atrophy in temporal lobe epilepsy
The goal of this work was to determine the presence and degree of cerebellar atrophy in chronic temporal lobe epilepsy CONCLUSIONS: The presence of cerebellar atrophy is a reflection of the extra-temporal abnormalities that can be observed in localization-related temporal lobe epilepsy, which may be due, at least in part, to factors associated with epilepsy chronicity. Epilepsy Behav Sep;7(2): Links Cerebellar atrophy in temporal lobe epilepsy. Hermann BP, Bayless K, Hansen R, Parrish J, Seidenberg M. Department of Neurology, University of Wisconsin, Madison, WI 53792, USA. PURPOSE: The goal of this work was to determine the presence and degree of cerebellar atrophy in chronic temporal lobe epilepsy, its clinical seizure correlates, and its association with general cortical atrophy. METHODS: Study participants were 78 persons with temporal lobe epilepsy and 63 age- and gender-matched healthy controls. All subjects underwent high-resolution MRI with manual tracing of the cerebellum. Clinical seizure features and history were obtained by structured interview and review of medical records. RESULTS: The epilepsy group exhibited significant abnormality in cerebellar volume, with mean reductions ranging from 4 to 6.6% depending on adjustments. Significantly more individual subjects with epilepsy exhibited cerebellar atrophy compared with controls across all operational definitions or thresholds of abnormality including z < or = -2.0 (13% TLE, 3.4% controls) and z < or = 1.5 (22% TLE, 3.4% controls). Clinical seizure features reflecting both neurodevelopmental (history of initial precipitating injuries) and severity of course (longer duration, increased number of lifetime generalized tonic-clonic seizures) factors were associated with cerebellar atrophy. Atrophy of the cerebellum could be observed independent of more general (cerebral) atrophic processes. CONCLUSIONS: The presence of cerebellar atrophy is a reflection of the extratemporal abnormalities that can be observed in localization-related temporal lobe epilepsy, which may be due, at least in part, to factors associated with epilepsy chronicity. Hermann BP et al. Epilepsy Behav Sep;7(2):

Borreliosis and Borrelia Related Complex

Tick-Borne Pathogens Humans have 400 different species of bacteria in their mouth. What pathogens, known and unknown, can be transmitted from a tick that lives in filth and sucks on the blood of rodents?

POLYMICROBIAL INFECTIONS IN ANIMALS AND HUMANS
Polymicrobial diseases represent the clinical and pathological manifestations induced by the presence of multiple microorganisms. These are serious diseases whose etiologic agents are sometimes difficult to diagnose and difficult to treat. They are often called complex infections, complicated infections, dual infections, mixed infections, secondary infections, co-infections, synergistic infections, concurrent infections, or polymicrobial infections. These diseases in animals and humans are induced by multiple viral infections, multiple bacterial infections, viral and bacterial infections, multiple mycotic and parasitic infections, and opportunistic infections secondary to microbe-induced immunosuppression. There are five common underlying mechanisms of disease pathogenesis. First, physical, physiologic, or metabolic abnormalities and stress predispose the host to polymicrobial disease. Second, one microorganism induces changes in the mucosa that favors the colonization of other microorganisms. Third, microorganisms or their products can trigger proinflammatory cytokines that increase the severity of disease, reactivate latent infections, or favor the colonization of other microorganisms. Fourth, microorganisms share determinants among each other allowing them the collective ability to damage tissue. Finally, one microorganism alters the immune system, which allows the colonization of the host by other microorganisms. Many areas of study in polymicrobial diseases are at their infancy and it is our hope that this Conference will stimulate interest and work in this evolving area. POLYMICROBIAL INFECTIONS IN ANIMALS AND HUMANS Author Brogden, Kim Submitted to: Meeting Abstract Publication Type: Abstract Publication Acceptance Date: October 20, Publication Date: October 20, 2003 Citation: BROGDEN, K.A. POLYMICROBIAL INFECTIONS IN ANIMALS AND HUMANS. CONFERENCE ON POLYMICROBIAL DISEASES ABSTRACT. P. 11. Technical Abstract: Polymicrobial diseases represent the clinical and pathological manifestations induced by the presence of multiple microorganisms. These are serious diseases whose etiologic agents are sometimes difficult to diagnose and difficult to treat. They are often called complex infections, complicated infections, dual infections, mixed infections, secondary infections, co-infections, synergistic infections, concurrent infections, or polymicrobial infections. These diseases in animals and humans are induced by multiple viral infections, multiple bacterial infections, viral and bacterial infections, multiple mycotic and parasitic infections, and opportunistic infections secondary to microbe-induced immunosuppression. There are five common underlying mechanisms of disease pathogenesis. First, physical, physiologic, or metabolic abnormalities and stress predispose the host to polymicrobial disease. Second, one microorganism induces changes in the mucosa that favors the colonization of other microorganisms. Third, microorganisms or their products can trigger proinflammatory cytokines that increase the severity of disease, reactivate latent infections, or favor the colonization of other microorganisms. Fourth, microorganisms share determinants among each other allowing them the collective ability to damage tissue. Finally, one microorganism alters the immune system, which allows the colonization of the host by other microorganisms. Many areas of study in polymicrobial diseases are at their infancy and it is our hope that this Conference will stimulate interest and work in this evolving area. Brogden K. CONFERENCE ON POLYMICROBIAL DISEASES ABSTRACT. P. 11.

What is Chronic LYD/TBD?
LYME DISEASE caused by three types of Spirochete Borrelia bacteria (300 strains): 1. Borrelia burgdorferi sensu stricto(USA,UK,Europe) 2. Borrelia garinii (UK, Europe) 3. Borrelia afzelii (UK, Europe) "CHRONIC LYME DISEASE" or "NEW LYME DISEASE" is a combination of LYME DISEASE and one or more of the following Co-infections: Relapsing Fever caused by the spirochetes: - Borrelia hermsii - Borrelia turicatae Mycoplasmas: - Mycoplasma fermentans - Mycoplasma pneumoniae Babesiosis: - Babesia microti - Babesia WA and other Babesia species - Chlamydia pneumoniae Rickettsial Diseases: - Rocky Mountain Spotted Fever - Coxiella burnetti (Q-Fever and "Post-Q Fever Fatigue Syndrome") - Colorado Tick Fever - Eastern tick-borne Rickettsiosis - Rickettsialpox - Tularemia (rabbit fever) - Ehrlichiosis (caused by Ehrlichia, a rickettsia-like bacteria) - Anaplasmas (related to the genera Rickettsia and Ehrlichia) - Hepatitis-C Bartonellosis: - Bartonella henselae (cat scratch fever) - Bartonella quintana (trench fever) - Viral Meningitis Candida dubliniensis Asfarviridae, Reoviridae, Rhabdoviridae, Orthomyxoviridae, Bunyaviridae, Flaviviridae & Arenaviridae family viruses (38+ species) Below is an excerpt from an article written by Sean & Leslee Dudlee who are the founders of the Micoplasma Registry (a Yahoo Group). It may not square with the assessment that many of us may have regarding the relationship between variations of Lyme and Micoplasmas, but they could be a helpful source. John Coughlan * * * * * * * * * * * * * * * * * * * * * * * * *Systemic Mycoplasma Infections are found in patients with: Gulf War Syndrome, Chronic Fatigue Syndrome, Myalgic Encephalomyelitis, Fibromyalgia, Lyme Disease, Rheumatoid Arthritis, Systemic Lupus Erythematosus, Scleroderma, Sjogren's Syndrome, Amyotrophic Lateral Sclerosis, Multiple Sclerosis, Cystic Fibrosis, Asthma, Respiratory Distress Syndrome, Pneumonia, Bronchitis, Inflammatory Bowel Disease, Sarcoidosis, Wegener's Disease, Kikuchi's Disease, Leukemia, Alzheimer's Disease, Autism, Infertility, Stevens- Johnson Syndrome, and Acquired Immune Deficiency Syndrome, Hypercoagulation, Heart Disease, Stroke and Cancer. • LYME DISEASE • "CHRONIC LYME DISEASE" or "NEW LYME DISEASE" • "MONTANA LYME DISEASE" If bitten by ticks or fleas carrying Borrelia burgdorferi you can develop traditional Lyme Disease, which is self-limiting and carried by a deer tick. Our experience with patients suggests that if the tick or flea also carries co-infections, such as Babesiosis or especially Mycoplasmas, you may develop "Chronic Lyme Disease" also known as "New Lyme Disease" as well as Chronic Fatigue Syndrome, Fibromyalgia and Autoimmune Diseases. "MONTANA LYME DISEASE" symptoms are similar to Lyme Disease. However, it is caused by a Lyme disease-like agent that has adapted to the Rocky Mountain wood ticks found in Montana and the Western United States. LYME DISEASE caused by three types of Spirochete Borrelia bacteria: 1. Borrelia burgdorferi sensu stricto(USA,UK,Europe) 2. Borrelia garinii (UK, Europe) 3. Borrelia afzelii (UK, Europe) "CHRONIC LYME DISEASE" or "NEW LYME DISEASE" is a combination of LYME DISEASE and one or more of the following Co-infections: Relapsing Fever caused by the spirochetes: - Borrelia hermsii - Borrelia turicatae Mycoplasmas: - Mycoplasma fermentans - Mycoplasma pneumoniae Babesiosis: - Babesia microti - Babesia WA - Chlamydia pneumoniae Rickettsial Diseases: - Rocky Mountain Spotted Fever - Coxiella burnetti (Q-Fever and "Post-Q Fever Fatigue Syndrome") - Colorado Tick Fever - Eastern tick-borne Rickettsiosis - Rickettsialpox - Tularemia (rabbit fever) - Ehrlichiosis (caused by Ehrlichia, a rickettsia-like bacteria) - Anaplasmas (related to the genera Rickettsia and Ehrlichia) - Hepatitis-C Bartonellosis: - Bartonella henselae (cat scratch fever) - Bartonella quintana (trench fever) - Viral Meningitis Tick-borne viruses. Labuda M, Nuttall PA. Institute of Zoology, Slovak Academy of Sciences, Dubravska cesta 9, Bratislava, Slovakia. At least 38 viral species are transmitted by ticks. Virus-tick-vertebrate host relationships are highly specific and less than 10% of all tick species (Argasidae and Ixodidae) are known to play a role as vectors of arboviruses. However, a few tick species transmit several (e.g. Ixodes ricinus, Amblyomma variegatum) or many (I. uriae) tick-borne viruses. Tick-borne viruses are found in six different virus families (Asfarviridae, Reoviridae, Rhabdoviridae, Orthomyxoviridae, Bunyaviridae, Flaviviridae) and at least 9 genera. Some as yet unassigned tick-borne viruses may belong to a seventh family, the Arenaviridae. With only one exception (African swine fever virus, family Asfarviridae) all tick-borne viruses (as well as all other arboviruses) are RNA viruses. Tick-borne viruses are found in all the RNA virus families in which insect-borne members are found, with the exception of the family Togaviridae. Some tick-borne viruses pose a significant threat to the health of humans (Tick-borne encephalitis virus, Crimean-Congo haemorrhagic fever virus) or livestock (African swine fever virus, Nairobi sheep disease virus). Key challenges are to determine the molecular adaptations that allow tick-borne viruses to infect and replicate in both tick and vertebrate cells, and to identify the principal ecological determinants of tick-borne virus survival. Publication Types: Review PMID: [PubMed - indexed for MEDLINE] Emerg Infect Dis May;13(5): Environmental Source of Candida dubliniensis. Nunn MA. National Environment Research Council Centre for Ecology and Hydrology, Oxford, United Kingdom. We isolated Candida dubliniensis from a nonhuman source, namely, tick samples from an Irish seabird colony. The species was unambiguously identified by phenotypic and genotypic means. Analysis of the 5.8S rRNA gene showed that the environmental isolates belong to C. dubliniensis genotype 1. PMID: [PubMed - in process] Sean and Leslee Dudley & Labuda and Nuttall & Nunn 87

Borrelia Pathophysiology
Invade, penetrate, injure or kill host cells Indirect injury at a distance (coagulation cascade of proteins, activation of coagulation system, blebs, microthrombi, septic emboli) Biological amplification-cascade of injury Reservoir inside of host Leeching-”saps nutrients” Toxins Incorporate gene sequences into host genome Immune effects—inflammation, immunosupression, molecular mimicry Herxheimer pathophysiology Adapted from Mac Donald

Fighting Back: How B burgdorferi Persists
That spirochetes tend to persist in the human body has been demonstrated in both syphilis, caused by Treponema pallidum, and Lyme disease, caused by Borrelia burgdorferi. What accounts for this ability to evade or suppress an effective immune response? According to Charles Pavia, PhD,[1] of the New York College of Osteopathic Medicine, New York Institute of Technology, Old Westbury, New York, there are at least 6 potential explanations: antigenic variation (this is seen with the Borrelia species that cause tick-borne relapsing fever) or differential expression of antigens (especially the outer surface proteins; with B burgdorferi, only OspC is expressed during mammalian infection) production of an outer protective coat (eg, capsule, as seen with T pallidum) atypical forms (eg, cyst-like variants) incomplete immune response (eg, insufficient antibody , T-cell , or phagocytic response) deranged host immune response (eg, host-, tick-, or spirochete-derived immunosuppressive factors) other evasive factors (eg, motility) Immune Suppression Is there evidence that any of these mechanisms allow B burgdorferi to persist in the human body? As of now, not much. However, there have been a few suggestive studies in animals that support immune suppression as a possible explanation. For instance, a study by Chiao and colleagues[2] showed that B burgdorferi is capable of suppressing the immune response. When sonicated Borrelia were added to lymphocytes, the ability of the lymphocytes to proliferate -- a measure of the immune system's ability to respond to an infectious challenge -- was inhibited. A similar study by Giambartolomei and coworkers[3] showed that Borrelia can stimulate interleukin-10 (IL-10) production, a downregulator of the immune system. In this series of experiments, heat-killed B burgdorferi caused peripheral blood mononuclear cells of humans and rhesus monkeys to produce this cytokine. Another study, by Keane-Myers and Nickell,[4] found that B burgdorferi could suppress T-cell responses in mice, specifically T-helper cells. Even the tick itself may play a role in immunosuppression. Urioste and colleagues[5] showed that the saliva of Ixodes dammini ticks contains an uncharacterized substance that can suppress the immune response, specifically suppressing lymphocyte proliferation and other markers of immune system activity. Looking at the issue of immune suppression from the other side -- that is, by boosting the immune response with the use of cytokines -- Zeidner and colleagues[6] showed that tumor necrosis factor alpha (TNF-alpha), IL-2, and interferon-gamma could suppress B burgdorferi infection in mice. By contrast, it appears that infection with B burgdorferi can also overstimulate the immune system, and this may explain many of the symptoms of both acute and chronic Lyme disease. For instance, Lim and colleagues[7] showed that CD4+ T cells play a role in the arthritis seen in the hamster model of Lyme disease. Fighting Back: How B burgdorferi Persists CME Disclosures Harry Goldhagen, MS Julie Rawlings, MPH Persistence Is a Virtue That spirochetes tend to persist in the human body has been demonstrated in both syphilis, caused by Treponema pallidum, and Lyme disease, caused by Borrelia burgdorferi. What accounts for this ability to evade or suppress an effective immune response? According to Charles Pavia, PhD,[1] of the New York College of Osteopathic Medicine, New York Institute of Technology, Old Westbury, New York, there are at least 6 potential explanations: antigenic variation (this is seen with the Borrelia species that cause tick-borne relapsing fever) or differential expression of antigens (especially the outer surface proteins; with B burgdorferi, only OspC is expressed during mammalian infection) production of an outer protective coat (eg, capsule, as seen with T pallidum) atypical forms (eg, cyst-like variants) incomplete immune response (eg, insufficient antibody , T-cell , or phagocytic response) deranged host immune response (eg, host-, tick-, or spirochete-derived immunosuppressive factors) other evasive factors (eg, motility) Immune Suppression Is there evidence that any of these mechanisms allow B burgdorferi to persist in the human body? As of now, not much. However, there have been a few suggestive studies in animals that support immune suppression as a possible explanation. For instance, a study by Chiao and colleagues[2] showed that B burgdorferi is capable of suppressing the immune response. When sonicated Borrelia were added to lymphocytes, the ability of the lymphocytes to proliferate -- a measure of the immune system's ability to respond to an infectious challenge -- was inhibited. A similar study by Giambartolomei and coworkers[3] showed that Borrelia can stimulate interleukin-10 (IL-10) production, a downregulator of the immune system. In this series of experiments, heat-killed B burgdorferi caused peripheral blood mononuclear cells of humans and rhesus monkeys to produce this cytokine. Another study, by Keane-Myers and Nickell,[4] found that B burgdorferi could suppress T-cell responses in mice, specifically T-helper cells. Even the tick itself may play a role in immunosuppression. Urioste and colleagues[5] showed that the saliva of Ixodes dammini ticks contains an uncharacterized substance that can suppress the immune response, specifically suppressing lymphocyte proliferation and other markers of immune system activity. Looking at the issue of immune suppression from the other side -- that is, by boosting the immune response with the use of cytokines -- Zeidner and colleagues[6] showed that tumor necrosis factor alpha (TNF-alpha), IL-2, and interferon-gamma could suppress B burgdorferi infection in mice. By contrast, it appears that infection with B burgdorferi can also overstimulate the immune system, and this may explain many of the symptoms of both acute and chronic Lyme disease. For instance, Lim and colleagues[7] showed that CD4+ T cells play a role in the arthritis seen in the hamster model of Lyme disease. Remainder of the article at: [Note: I am posting this article along with another that associates babesia with immune suppression. But since the effects seem to be more complicated, maybe immune derangement or some such phrase would be more accurate and should be adopted. That would cover the apparent autoimmunity associated in some people with their lyme infections, while not giving the impression that lyme behaves likes AIDS.] Harry Goldhagen, MS Julie Rawlings, MPH.

TBD: Borrelia Burgdorferi, Babesia Cause Immunosupression
Borrelia burgdorferi-induced tolerance as a model of persistence via immunosuppression. (Diterich et. al. Infect Immun Jul;71(7): ) Immunodepression in Babesia microti infections. (Purvis AC. Parasitology Oct;75(2): ) Other tick-borne pathogens may also be immunosupressant

Tick Saliva Causes Immunospression
Kyckova & Kopecky. Effect of tick saliva on mechanisms of innate immune response against Borrelia afzelii. J Med Entomol Nov;43(6): Holden K, Hodzic E, Feng S, Freet KJ, Lefebvre RB, Barthold SW. Coinfection with Anaplasma phagocytophilum alters Borrelia burgdorferi population distribution in C3H/HeN mice. Infect Immun Jun;73(6): Hannier S, Liversidge J, Sternberg JM, Bowman AS. Characterization of the B-cell inhibitory protein factor in Ixodes ricinus tick saliva: a potential role in enhanced Borrelia burgdoferi transmission.Immunology Nov;113(3):401-8. Wikel SK. Tick modulation of host immunity: an important factor in pathogen transmission. Int J Parasitol Jun;29(6):851-9.

Propensity to excessive proinflammatory response in chronic Lyme borreliosis
All the clinical manifestations, acute or chronic, are characterized by strong inflammation. Borrelia burgdorferi can induce the production of several proinflammatory and anti-inflammatory cytokines We conclude that chronic forms of Lyme borreliosis can evolve due to an aberrant innate proinflammatory response. < APMIS, Volume 115 Issue 2 Page February 2007 Propensity to excessive proinflammatory response in chronic Lyme borreliosis KAI E. KISAND,1epartment of Immunology, Institute of General and Molecular Pathology, Centre of Molecular and Clinical Medicine, TIINA PRÜKK,2Department of Infectious Diseases, University of Tartu, KALLE V. KISAND,1Department of Immunology, Institute of General and Molecular Pathology, Centre of Molecular and Clinical Medicine, SIIRI-MERIKE LÜÜS,3Neurology Clinic of Tartu University Hospital, Tartu, Estonia IRJA KALBE3Neurology Clinic of Tartu University Hospital, Tartu, Estonia and RAIVO UIBO1Department of Immunology, Institute of General and Molecular Pathology, Centre of Molecular and Clinical Medicine, Kai Kisand, Department of Immunology, Institute of General and Molecular Pathology, University of Tartu, Ravila Str. 19, Tartu 50411, Estonia. Kisand KE, Prükk T, Kisand KV, Lüüs SM, Kalbe I, Uibo R. Propensity to excessive proinflammatory response in chronic Lyme borreliosis. APMIS 2007;115:134–41. The clinical course of Lyme borreliosis is extremely variable. However, all the clinical manifestations, acute or chronic, are characterized by strong inflammation. Borrelia burgdorferi can induce the production of several proinflammatory and anti-inflammatory cytokines. The aim of our study was to find out whether the balance between inflammatory and regulatory mechanisms is important in determining the course of Lyme borreliosis. 13 patients with early Lyme borreliosis, 8 patients with chronic Lyme disease with neurological or joint manifestations, and 15 age- and sex-matched healthy controls were studied. Chronic forms of Lyme borreliosis were characterized by stronger TNF-? response by monocytes to lipopolysaccharide as well as to borrelia antigen compared to early Lyme borreliosis and the healthy state. The percentage of IL-10-secreting monocytes in response to borrelia lysate was lower in the Lyme borreliosis patients than in healthy controls. The percentage of CD4 + CTLA-4+ regulatory T cells showed the highest values in early Lyme borreliosis. We conclude that chronic forms of Lyme borreliosis can evolve due to an aberrant innate proinflammatory response. Kisand et. al. APMIS, Volume 115 Issue 2 Page February 2007 92

93 I hope that every one of you believes in the
reality of Cystic forms of Bb. This image from 1987 is the basis for my personal belief in cystic borrelia burgdorferi. Antibody id= H9724 murine (gift from Dr. Alan Barbour) If anyone does not yet believe in the Cystic form of Bb, please do a Google search for Dr Nelson's paper on "stress altered forms" ..(an editorial "euphemism") and Drs. Brorson and Brorson's many papers of Cystic Bb with many models published over the years. and then there's always the classic Delammater series in the JEM from the 50's which is available on line in the JEM archives. Best to you all Alan 93

Invasion of human neuronal and glial cells by an infectious strain of Borrelia burgdorferi
Human infection by Borrelia burgdorferi, the etiological agent for Lyme disease, can result in serious acute and late-term disorders including neuroborreliosis, a degenerative condition of the peripheral and central nervous systems. To examine the mechanisms involved in the cellular pathogenesis of neuroborreliosis, we investigated the ability of B. burgdorferi to attach to and/or invade a panel of human neuroglial and cortical neuronal cells. In all neural cells tested, we observed B. burgdorferi in association with the cell by confocal microscopy. Further analysis by differential immunofluorescent staining of external and internal organisms, and a gentamicin protection assay demonstrated an intracellular localization of B. burgdorferi. A non-infectious strain of B. burgdorferi was attenuated in its ability to associate with these neural cells, suggesting that a specific borrelial factor related to cellular infectivity was responsible for the association. Cytopathic effects were not observed following infection of these cell lines with B. burgdorferi, and internalized spirochetes were found to be viable. Invasion of neural cells by B. burgdorferi provides a putative mechanism for the organism to avoid the host's immune response while potentially causing functional damage to neural cells during infection of the CNS. Invasion of human neuronal and glial cells by an infectious strain of Borrelia burgdorferi. Livengood JA, Gilmore RD Jr. Centers for Disease Control and Prevention, Division of Vector-borne Infectious Diseases, 3150 Rampart Road, CSU Foothills Campus, Fort Collins, CO 80522, USA. Human infection by Borrelia burgdorferi, the etiological agent for Lyme disease, can result in serious acute and late-term disorders including neuroborreliosis, a degenerative condition of the peripheral and central nervous systems. To examine the mechanisms involved in the cellular pathogenesis of neuroborreliosis, we investigated the ability of B. burgdorferi to attach to and/or invade a panel of human neuroglial and cortical neuronal cells. In all neural cells tested, we observed B. burgdorferi in association with the cell by confocal microscopy. Further analysis by differential immunofluorescent staining of external and internal organisms, and a gentamicin protection assay demonstrated an intracellular localization of B. burgdorferi. A non-infectious strain of B. burgdorferi was attenuated in its ability to associate with these neural cells, suggesting that a specific borrelial factor related to cellular infectivity was responsible for the association. Cytopathic effects were not observed following infection of these cell lines with B. burgdorferi, and internalized spirochetes were found to be viable. Invasion of neural cells by B. burgdorferi provides a putative mechanism for the organism to avoid the host's immune response while potentially causing functional damage to neural cells during infection of the CNS. PMID: [PubMed - in process] Livengood & Gilmore. Microbes Infect Nov-Dec;8(14-15): Epub 2006 Sep 22.

Lyme Disease: The Quest for Magic Bullets
Borrelia burgdorferi is one of the most complex bacteria known to man. Two major clinical hurdles are the absence of a therapeutic endpoint in treating Lyme disease and the presence of tick-borne coinfections that may complicate the course of the illness. Stricker RB, Lautin A, Burrascano JJ. Chemotherapy Feb 22;52(2):53-59

Tick-Borne/Borreliosis Infections and Psychiatric Illness

Higher prevalence of antibodies to Borrelia burgdorferi in psychiatric patients than in healthy subjects 166 (33%) of the psychiatric patients and 94 (19%) of the healthy comparison subjects were seropositive in at least one of the four assays for Borrelia burgdorferi. 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] Hajek T et al. Am J Psychiatry 2002 Feb;159(2):

BI/TBI & Neuropsychiatric Disorders
Fallon BA, Schwartzberg M, Bransfield R, Zimmerman B, Scotti A, Weber CA, Liebowitz MR. Late-Stage Neuropsychiatric Lyme Borreliosis: Differential Diagnosis and Treatment. Psychosomatics 1995;36: Adams WV, Rose CD, Eppes SC, Klein JD. Long-term cognitive effects of Lyme disease in children. Appl Neuropsychol 1999;6(1):39-45. Fallon BA, Nields JA. Lyme Disease: A Neuropsychiatric Illness. Am J Psych 1994;151(11): Fallon BA, Bird H, Hoven C, Cameron D, Liebowitz MR, Shaffer S. Psychiatric aspects of Lyme disease in children and adolescents: A community epidemiologic study in Westchester, New York. JSTD 1994;1: Waniek C, Prohovnik I, Kaufman MA, Dwork AJ. Rapidly progressive frontal-type dementia associated with Lyme disease J Neuropsych Clin Neurosci 1995;7(3):345-7. Fallon BA, Kochevar JM, Gaito A, Nields JA. The Underdiagnosis of Neuropsychiatric LYD in Children and Adults. Psych Clinics No Am, 1998; 21: Bransfield RC. Case Report: LYD and Complex Seizures. JSTD 1999;6:123-5. Massei F, Gori L, Macchia P, Maggiore G. The expanded spectrum of bartonellosis in children. Infect Dis Clin North Am. 2005;19(3): Murakami K, Tsukahara M, Tsuneoka H, et al. Cat scratch disease: analysis of 130 seropositive cases. Infect Dis Clin North Am. 2005;19(3):

Neuroactive Kynurenines in Lyme Borreliosis
We conclude that CSF quinolinic acid is significantly elevated in B burgdorferi infection-- dramatically in patients with CNS inflammation, less in encephalopathy. 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. title: Neuroactive kynurenines in Lyme borreliosis. Authors: Halperin JJ, Heyes MP Source: Neurology 1992 Jan;42(1):43-50 Organization: Department of Neurology SUNY Stony Brook. Abstract: Although neurologic dysfunction occurs frequently in patients with Lyme borreliosis, it is rarely possible to demonstrate the causative organism within the neuraxis. This discordance could arise if neurologic symptoms were actually due to soluble neuromodulators produced in response to infection. Since immune stimulation is associated with the production of quinolinic acid (QUIN), an excitotoxin and N-methyl-D-aspartate (NMDA) agonist, we measured levels of CSF and serum QUIN, and lymphokines. Samples were obtained from 16 patients with CNS Borrelia burgdorferi infection, eight patients with Lyme encephalopathy (confusion without intra-CNS inflammation), and 45 controls. CSF QUIN was substantially elevated in patients with CNS Lyme and correlated strongly with CSF leukocytosis. In patients with encephalopathy, serum QUIN was elevated with corresponding increments in CSF QUIN. Lymphokine concentrations were not consistently elevated. We conclude that CSF QUIN is significantly elevated in B burgdorferi infection-- dramatically in patients with CNS inflammation, less in encephalopathy. 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. Keywords: Brain Diseases, BL, CF, MI, Human, Kynurenine, AN, CF, ME, Lyme Disease, BL, CF, ME, Lymphokines, BL, CF, Multiple Sclerosis, BL, CF, Nervous System Diseases, CF, ME, Quinolinic Acids, BL, CF, ME, Support, Non-U.S. Gov't, Medline File Language: German Unique ID: Halperin JJ, Heyes MP. Neuroactive kynurenines in Lyme borreliosis. Neurology 1992 Jan;42(1):43-50 100

Proinflammatory Cytokines Increase Indoleamine 2,3-dioxygenase (IDO)
The IDO enzyme converts tryptophan into kynurenine, because IDO activation leads to reduced levels of tryptophan, the precursor of serotonin (5-HT), and thus to reduced central 5-HT synthesis. Kynurenine metabolites such as 3-hydroxy-kynurenine (3-OH-KYN) and quinolinic acid (QUIN) have toxic effects on brain function. 3-OH-KYN is able to produce oxidative stress by increasing the production of reactive oxygen species (ROS), and QUIN may produce overstimulation of hippocampal N-methyl-D-aspartate (NMDA) receptors, which leads to apoptosis and hippocampal atrophy. Both ROS overproduction and hippocampal atrophy caused by NMDA overstimulation have been associated with depression. J Psychiatry Neurosci Jan;29(1):11-7. Related Articles, Links The role of indoleamine 2,3-dioxygenase (IDO) in the pathophysiology of interferon-alpha-induced depression. Wichers MC, Maes M. Department of Psychiatry and Neuropsychology, Maastricht University, Maastricht, the Netherlands. The mechanisms by which administration of interferon-alpha induces neuropsychiatric side effects, such as depressive symptoms and changes in cognitive function, are not clear as yet. Direct influence on serotonergic neurotransmission may contribute to these side effects. In addition, the enzyme indoleamine 2,3-dioxygenase (IDO), which converts tryptophan into kynurenine, may play an important role, first, because IDO activation leads to reduced levels of tryptophan, the precursor of serotonin (5-HT), and thus to reduced central 5-HT synthesis. Second, kynurenine metabolites such as 3-hydroxy-kynurenine (3-OH-KYN) and quinolinic acid (QUIN) have toxic effects on brain function. 3-OH-KYN is able to produce oxidative stress by increasing the production of reactive oxygen species (ROS), and QUIN may produce overstimulation of hippocampal N-methyl-D-aspartate (NMDA) receptors, which leads to apoptosis and hippocampal atrophy. Both ROS overproduction and hippocampal atrophy caused by NMDA overstimulation have been associated with depression. PMID: [PubMed - indexed for MEDLINE] Wichers MC, Maes M. J Psychiatry Neurosci Jan;29(1):11-7. 101

Tryptophan metabolites and brain disorders
Tryptophan is metabolised primarily along the kynurenine pathway, of which two components are now known to have marked effects on neurons in the central nervous system. Quinolinic acid is an agonist at the population of glutamate receptors which are sensitive to N-methyl-D-aspartate (NMDA), and kynurenic acid is an antagonist at several glutamate receptors. Consequently quinolinic acid can act as a neurotoxin while kynurenic acid is neuroprotectant. A third kynurenine, 3-hydroxykynurenine, can generate free radicals and contribute to, or exacerbate, neuronal damage. Changes in the absolute or relative concentrations of these kynurenines have been implicated in a variety of central nervous system disorders such as the AIDS-dementia complex and Huntington's disease Clin Chem Lab Med Jul;41(7): Related Articles, Links Tryptophan metabolites and brain disorders. Stone TW, Mackay GM, Forrest CM, Clark CJ, Darlington LG. Institute of Biomedical & Life Sciences,Division of Neuroscience & Biomedical Systems, West Medical Building, University of Glasgow, Glasgow, UK. Tryptophan is metabolised primarily along the kynurenine pathway, of which two components are now known to have marked effects on neurons in the central nervous system. Quinolinic acid is an agonist at the population of glutamate receptors which are sensitive to N-methyl-D-aspartate (NMDA), and kynurenic acid is an antagonist at several glutamate receptors. Consequently quinolinic acid can act as a neurotoxin while kynurenic acid is neuroprotectant. A third kynurenine, 3-hydroxykynurenine, can generate free radicals and contribute to, or exacerbate, neuronal damage. Changes in the absolute or relative concentrations of these kynurenines have been implicated in a variety of central nervous system disorders such as the AIDS-dementia complex and Huntington's disease, raising the possibility that interference with their actions or synthesis could lead to new forms of pharmacotherapy for these conditions. Publication Types: Review Review, Tutorial PMID: [PubMed - indexed for MEDLINE] Stone TW, Mackay GM, Forrest CM, Clark CJ, Darlington LG. Clin Chem Lab Med Jul;41(7):852-9 102

Immune Responses in ASD, Borreliosis and Mycoplasma Infections

Natural Killer Cell CD-57
Autistic children are known to have many metabolic dysfunctions which are shared by victims of LD, in particular, chronically low counts of CD57 natural-killer (NK) cells. Lyme disease: a leaky brain Lyme disease is still barely recognized by orthodox medicine, but new, explosive evidence links this worldwide epidemic with certain types of mental illness, including autism. The first cases of Lyme disease (LD) occurred in the US, but it’s now acknowledged to be a worldwide problem. Britain had its first official death due to LD in December 2005: “liver disease due to Lyme sepsis”, according to the autopsy. In May of this year, a 38-year-old British pro-fessor committed suicide after developing dementia brought about by LD. It’s particularly prevalent at this time of the year—late spring and early summer. The number of diagnosed cases of Lyme disease are now rising—and not just because doctors are finally beginning to recognize it, but also possibly as a result of global warming. And, as with many new-disease discoveries, a whole raft of previously mysterious conditions are now being laid at the door of LD, including chronic fatigue (CFS/ME), multiple sclerosis (MS) and even autism. Could we be witnessing the start of a new epidemic? “Many of the diseases that are considered incurable by conven-tional medicine may have some kind of Lyme component,” says American alternative practitioner Dr Lee Cowden. What is Lyme disease? In essence, it’s a kind of malaria, although it emerges not from the swampy jungle, but from temperate forests. Like malaria, the disease is transmitted by being bitten by a blood-feeding creature—in the case of LD, not by an insect, but a tick, an arachnid, that lives on animals such as cattle, birds and even mice, but primarily deer. Where it all began Lyme disease first appeared more than 30 years ago as a mysterious disease outbreak in an American town called Lyme, in Connecticut. In the spring of 1975, there was a cluster of cases of what appeared to be juvenile arthritis. Children as young as 10 began to develop severe joint pain. Doctors from nearby Yale University were called in to investigate, and were puzzled by the appearance of odd rashes on the children’s skin. Months of detective work finally led the doctors to connect the symptoms to a disease that had first been described in Europe almost a century before as ‘sheep-tick fever’. After years of further detective work, researchers traced the illness to a rogue spirochaetes bacterium in the patients’ blood known as Borrelia burgdorferi—hence, the alternative name of ‘Lyme borreliosis’. But where had it come from? Already alerted to the fact that it might be due to a tick bite, the scientists began a hunt among the local animal population. The Borrelia microorganism was finally tracked down to a tick of the genus Ixodes that lives on deer. This tiny arachnid—related to mites, spiders and scorpions, having eight legs—has a correspondingly tiny mouth, so its bite is rarely felt, which may be one reason why it was able to elude detection for so long. Ixodes is also cleverly able to inject its prey with a local anaesthetic, further disguising its attack. In fact, most victims of Lyme disease have no idea they were ever on the tick’s hit list. In fact, it’s likely that Ixodes has to remain undetected because it’s believed to be an inefficient feeder. It needs to be plugged in to its prey for hours to obtain sufficient nourish-ment. One indication of this is the probability that B. burgdorferi is not transmitted until the tick has been attached for at least 12 hours. Initially, medicine treated the disease just like any other bacterial infection—with antibiotics. These appeared to work, and doctors patted themselves on the back for having put paid so easily to this novel disease. But the story hasn’t turned out to be that simple. Although this medical field is still relatively small, there is already a schism appearing among LD clinic-ians; indeed, some would call it a war. One army of experts believe that Lyme disease can be easily cured by a short course of antibiotics, whereas the opposing side says no, LD is a complex, potentially long-term illness (see box, page 6). The problems begin with the diag-nosis. If LD is spotted early on, then antibiotics can prove helpful. But, in practice, LD turns out to be very diffi-cult to diagnose (see box, page 8), and the later stages of the disease are much harder to treat with the usual drugs. What’s more, these antibiotics can sometimes make things even worse. Any Borrelia bacteria that are not totally killed off by the drugs don’t just develop resistance—which is bad enough—but also become what is referred to as ‘cell-wall deficient’. This makes them very elusive as, without walls, they can hide inside of healthy cells, thereby avoiding direct attack by the drugs (Infection, 1996; 24: 218–26). Lyme patients also find that the types of antibiotics used to treat them may actually exacerbate their symp-toms. This is thought to be the result of changes due to the drugs in the genetic sequencing of Borrelia, causing them to release toxins into the body. These toxins often get into the brain and nervous system, precipitating what is called the Jarisch–Herxheimer reaction (named after Karl Herx-heimer, the German dermatologist who first observed it). J–H reactions can be life-threatening, and are seen in one in seven Lyme borreliosis patients treated. The leaky brain In fact, it has also been suggested that LD in itself—whether treated by antibiotics or not—may be neurotoxic. The idea is that Lyme disease creates ammonia in the brain, causing a ‘leaky-brain syndrome’. Among the first to propose the idea was LD specialist Dr David Jernigan. As ammonia can alter permeability of the blood–brain barrier, he says, it would allow large molecules to reach the brain, causing ‘cerebral allergies’. Jernigan believes that this may be a major cause of a variety of LD symptoms (Townsend Lett Docs, 2007; April: 141–8; online only). Confirmation of this hypothesis has come from animal studies. Using radioactive tracers, researchers have shown that laboratory animals, when infected by Borrelia, lose the pro-tection of the blood–brain barrier after just two weeks (Schutzer SE, ed. Lyme Disease: Molecular and Immunologic Approaches, Series 6. Current Communications in Molecular and Cell Biology. Plainview, NY: Cold Spring Harbor Press, 1992). How does Borrelia do this? It’s thought that the bacteria burrow their way between the cells of the brain’s outermost membrane, causing a localized inflammation that, in turn, releases proteins to fight against the bacterial invasion; this then results in holes in the cerebral membrane. It’s much the same mechanism as seen in the leaky-gut syndrome but, in this case, it’s potentially more serious as it involves the brain. In addition, there is now laboratory evidence that Borrelia can “attach to or invade human cortical neuronal cells”, say researchers at the National Center for Infectious Diseases in Colorado, part of the US Centers for Disease Control and Prevention (CDC). This makes the bacteria difficult to kill by the immune system (Microbes Infect, 2006; 8: 2832–40). It also helps to explain why Lyme disease can be both relaps-ing and resistant to treatment. Incidentally, the spirochaetes bac-terium that causes syphilis has a similar mode of action and can also lodge in the brain, potentially remain-ing active for years. Brain abnormalities The leaky-brain theory also accounts for some of the highly specific neur-ological abnormalities found in Lyme patients—including Bell’s palsy, lymphocytic meningitis, meningo-encephalitis and cranial neuritis—not to mention the less specific CFS/ME and ‘brain fog’. “The neurological and psychiatric manifestations of Borrelia are so numerous that it is called the ‘new great imitator’,” says Dr Frederic Blanc, of the University of Strasbourg, France. “Every part of the nervous system can be involved: from central to peripheral nervous system, and even muscles” (Med Mal Infect, 2007; Mar 8; Epub ahead of print). In fact, as long as 10 years ago, LD was firmly characterized as a ‘neuro-psychiatric illness’. Reviewing the whole history of the disease, a team of psychiatrists at New York’s Colum-bia University found Lyme disease to be responsible for “a broad range of psychiatric reactions”, including paranoia, dementia, schizophrenia, bipolar disorder, panic attacks, major depression, anorexia nervosa and obsessive–compulsive disorder (Am J Psychiatry, 1994; 151: 1571–83). Since then, tests have discovered reduced blood flow in the brains of chronic LD sufferers, explaining the impaired mental functioning that afflicts so many victims of the disease (Neuro-psychiatry Clin Neurosci, 2003; 15: 326–32). The autism connection The most dramatic mental condition thought to be caused by Lyme disease is autism. A rare condition 50 years ago, autism now affects one in every 150 American children, according to the latest figures from the CDC. But why should Lyme disease be implicated? One of the first clues was that the psychological symptoms of LD are similar to those of autism. Six years ago, the above-mentioned Columbia University psychiatrists found that children with Lyme disease have “significantly more cognitive and psychiatric disturbances resulting in psychosocial and academic impair-ments” (J Neuropsychiatry Clin Neurosci, 2001; 13: 500–7). There are other clues, too. As already mentioned, syphilis, which is caused by a similar spirochaetes as in LD, in the womb is known to cause autism. Furthermore, autistic children are known to have many metabolic dysfunctions which are shared by victims of LD, in particular, chronically low counts of CD57 natural-killer (NK) cells. Of course, scores of theories have been proposed for the cause of autism, among which vaccine damage is perhaps the best known. But LD may be involved there, too. “It is possible that the two are conjoined in damage, and the long-term effects of Borrelia could hamper the body’s ability to mount a significant, timely response to vaccines,” says Dr Geoffrey Radoff, of the Alternative Medical Care Center of Arizona. “This could explain the higher incidences of adverse reactions to vaccinations in children with autism (Townsend Lett Docs, 2007; April: 78–81; online only). However, some children appear to be born with autism, so how could Lyme disease be involved there? Although the research has yet to be done in humans, studies of farm animals have shown that Borrelia can pass through the placental barrier into the womb and even into breast milk. This makes it possible for an infected mother to pass on the disease to her newborn child, in whom it could present as autism. Do the numbers stack up? With autism now so widespread, is it likely that so many children—or their mothers—could have been bitten by a relatively uncommon tick? One answer is that ticks, it appears, are not the only cuplrits. Mosquitoes, fleas and lice may also carry Borrelia (Agric Environ Med, 2002; 9: 257–9), thus vastly increasing the risk of infection. Another theory is that there may be a ‘Borrelia-related complex’ wherein the bacteria pass unnoticed from generation to generation, and only present when the immune system is under stress. Autistic children are known to suffer from a plethora of autoimmune and metabolic disorders (J Autism Dev Disord, 2000; 30: 475–9), and these could turn latent Borrelia infect-ion into a full-blown attack—with no tick in sight. Such theories were recently aired at a January 2007 meeting of the newly formed Lyme-Induced Autism Foundation, held in San Diego. Texas physician Dr William Harvey reported that he had many patients who tested positive for Borrelia, and yet, “our part of Texas is not an endemic region of Lyme disease”, he said. “No patient had the typical skin rash, but most had been ill for many years, with similarly ill family members.” Other delegates agreed. “There may be two forms of Borrelia infection: Lyme disease and epidemic borreliosis—disease spread directly between humans,” said fellow LD physician Dr Radoff. “It is quite possible that the prevalence of autoimmune disorders found in families with autism is an infection that has existed chronically in the body for years, if not decades.” Dr Warren Levin, another LD practitioner, has reported that, in the 10 children with autism he has seen, all tested positive for Lyme disease. Predictably, medicine’s knee-jerk reaction to such findings has been to dismiss them, but one group of researchers is taking them seriously. Yet again, that pioneering team of psychiatrists at Columbia University, led by Dr Brian Fallon, has already taken up the challenge and embarked on a huge epidemiological study of Lyme disease and autism. Fallon believes that two things will emerge from his study: that regions with very high rates of Lyme disease will also have higher-than-normal rates of autism; and that at least some of those autistic children will respond to LD therapy. “In our work with children with LD, we have encountered a few children with autistic-like disorders,” says Dr Fallon. “When they received intensive antibiotic therapy, the autistic syn-dromes dramatically improved and, in some cases, resolved.” Lyme disease: a leaky brain.

Gene expression changes in children with autism
The objective of this study was to identify gene expression differences in blood differences in children with autism (AU) and autism spectrum disorder (ASD) compared to general population controls. Transcriptional profiles were compared with age- and gender-matched, typically developing children from the general population (GP). The AU group was subdivided based on a history of developmental regression (A-R) or a history of early onset (A-E without regression). Total RNA from blood was processed on human Affymetrix microarrays. Thirty-five children with AU (17 with early onset autism and 18 with autism with regression) and 14 ASD children (who did not meet criteria for AU) were compared to 12 GP children. Unpaired t tests (corrected for multiple comparisons with a false discovery rate of 0.05) detected a number of genes that were regulated more than 1.5-fold for AU versus GP (n=55 genes), for A-E versus GP (n=140 genes), for A-R versus GP (n=20 genes), and for A-R versus A-E (n=494 genes). No genes were significantly regulated for ASD versus GP. There were 11 genes shared between the comparisons of all autism subgroups to GP (AU, A-E, and A-R versus GP) and these genes were all expressed in natural killer cells and many belonged to the KEGG natural killer cytotoxicity pathway (p=0.02). A subset of these genes (n=7) was tested with qRT-PCR and all genes were found to be differentially expressed (p<0.05). We conclude that the gene expression data support emerging evidence for abnormalities in peripheral blood leukocytes in autism that could represent a genetic and/or environmental predisposition to the disorder. Genomics Jan;91(1):22-9. Epub 2007 Nov 14. Links Gene expression changes in children with autism. Gregg JP, Lit L, Baron CA, Hertz-Picciotto I, Walker W, Davis RA, Croen LA, Ozonoff S, Hansen R, Pessah IN, Sharp FR. Department of Pathology, University of California at Davis Medical Center, Sacramento, CA 95817, USA. University of California at Davis, Davis, CA 95616, USA. The objective of this study was to identify gene expression differences in blood differences in children with autism (AU) and autism spectrum disorder (ASD) compared to general population controls. Transcriptional profiles were compared with age- and gender-matched, typically developing children from the general population (GP). The AU group was subdivided based on a history of developmental regression (A-R) or a history of early onset (A-E without regression). Total RNA from blood was processed on human Affymetrix microarrays. Thirty-five children with AU (17 with early onset autism and 18 with autism with regression) and 14 ASD children (who did not meet criteria for AU) were compared to 12 GP children. Unpaired t tests (corrected for multiple comparisons with a false discovery rate of 0.05) detected a number of genes that were regulated more than 1.5-fold for AU versus GP (n=55 genes), for A-E versus GP (n=140 genes), for A-R versus GP (n=20 genes), and for A-R versus A-E (n=494 genes). No genes were significantly regulated for ASD versus GP. There were 11 genes shared between the comparisons of all autism subgroups to GP (AU, A-E, and A-R versus GP) and these genes were all expressed in natural killer cells and many belonged to the KEGG natural killer cytotoxicity pathway (p=0.02). A subset of these genes (n=7) was tested with qRT-PCR and all genes were found to be differentially expressed (p<0.05). We conclude that the gene expression data support emerging evidence for abnormalities in peripheral blood leukocytes in autism that could represent a genetic and/or environmental predisposition to the disorder. Gregg JP, Sharp FR et al. Genomics Jan;91(1):22-9. Epub 2007 Nov 14.

Gene Expression Profile Distinctions In Autistic Children Identified: Genomic analysis could add biological certainty to behavioral diagnosis A group of genes with known links to natural-killer cells -- the first to attack viruses, bacteria and malignancies -- are expressed at high levels in the blood of children with autism when compared to children without the disorder. researchers also found gene expression distinctions in children with early onset and regressive forms of the disorder. "What we found were 11 specific genes with expression levels that were significantly higher in the blood of children with autism when compared to the blood of typically developing children," Those 11 genes are all known to be expressed by natural-killer cells, which are cells in the immune system necessary for mounting a defense against infected cells. There is a pattern of 140 genes differentially expressed in children with the early onset form of the disorder and a pattern of 20 genes differentially expressed in children with the regressive form of the disorder. These separate experiences offers biological evidence that there are at least two types of autism -- early onset and regressive. In addition to being expressed by natural-killer cells, some of the 11 genes found to be expressed at higher levels in children with autism are also expressed by CD8+ T lymphocytes -- cells that target infected cells and, once bound to them, destroy them. "What we are seeing can reflect something in the environment that is triggering the activation of these genes…” "Such an immune response could be caused by exposure to a virus, another infectious agent or even a toxin. Another possibility is that these changes represent a genetic susceptibility factor that predisposes children to autism when they are exposed to some environmental factor.“ "If the natural-killer cells are dysfunctional, this might mean that they cannot rid a pregnant mother, fetus or newborn of an infection, which could contribute to autism." From the Desk of Rick Rollens: Gene Expression Profile Distinctions In Autistic Children Identified Genomic analysis could add biological certainty to behavioral diagnosis A group of genes with known links to natural-killer cells -- the first to attack viruses, bacteria and malignancies -- are expressed at high levels in the blood of children with autism when compared to children without the disorder, according to a new study from the UC Davis M.I.N.D. Institute. Researchers also found gene expression distinctions in children with early onset and regressive forms of the disorder. The outcomes, published in the January issue of Genomics, offer hope that gene expression analyses can provide biological evidence of autism, currently diagnosed only through behavioral assessments, in some children. "What we found were 11 specific genes with expression levels that were significantly higher in the blood of children with autism when compared to the blood of typically developing children," said Frank Sharp, senior author of the study and professor of neurology with the M.I.N.D. Institute. "Those 11 genes are all known to be expressed by natural-killer cells, which are cells in the immune system necessary for mounting a defense against infected cells. We were surprised by our results because we were not looking for these particular genes. And while a number of studies have shown immune system dysregulation to be an important factor in autism, ours is one of the first to implicate these particular cells." In conducting the study, Sharp, molecular pathologist Jeff Gregg and their M.I.N.D. Institute colleagues used blood samples from 35 children diagnosed with autism, 14 with development delay but not autism and 12 typically developing children. The samples were subjected to gene expression analysis using microarrays and compared for common patterns. In addition to finding the 11 genes with natural-killer cell connections shared by all of the children with autism, they identified a pattern of 140 genes differentially expressed in children with the early onset form of the disorder and a pattern of 20 genes differentially expressed in children with the regressive form of the disorder. The team is the first to use genomic profiling of blood to observe differences in children with autism. A serious and increasingly prevalent neurodevelopmental disorder, autism is characterized by language impairments, social deficits and limited, repetitive behaviors. While some parents report they knew something was wrong with their child close to birth, others report their children progressed just like others and then lost social and/or language skills later, usually between the ages of 1 and 2. These separate experiences led clinicians to hypothesize that there are at least two types of autism -- early onset and regressive. This study offers biological evidence of those two subtypes. Microarrays are used to examine the expression levels of thousands of genes simultaneously. Because of its accuracy, the technology may become an important diagnostic tool for a variety of neurological conditions, including ischemic stroke and multiple sclerosis. To perform the analysis, RNA is isolated from cells in the blood. Complimentary strands of DNA (cDNA) are then created using the RNA as a template. Fluorescently labeled cRNA is next made from the cDNA and hybridized with the DNA on the array. Scanners using laser technology then read the array, revealing which genes are expressed and at what levels. In addition to being expressed by natural-killer cells, some of the 11 genes found to be expressed at higher levels in children with autism are also expressed by CD8+ T lymphocytes -- cells that target infected cells and, once bound to them, destroy them. It is not yet clear whether autism involves a primary problem in natural-killer cells, CD8+ lymphocytes or both. "What we are seeing can reflect something in the environment that is triggering the activation of these genes or something genetic that the children have from the time they were conceived," Sharp explained. "Such an immune response could be caused by exposure to a virus, another infectious agent or even a toxin. Another possibility is that these changes represent a genetic susceptibility factor that predisposes children to autism when they are exposed to some environmental factor." He added that the current study also does not identify whether or not the natural-killer cells are functioning abnormally, which further work by M.I.N.D. Institute immunologists will reveal. "If the natural-killer cells are dysfunctional, this might mean that they cannot rid a pregnant mother, fetus or newborn of an infection, which could contribute to autism." Gregg and Sharp consider the findings preliminary until they can be replicated, but still believe the study results point them in a new research direction that will shed light on the biological foundations of autism and eventually lead to new therapeutic targets. The study, "Gene Expression Profiles in Children with Autism," was funded by the National Institutes of Environmental Health Sciences and the U.S. Environmental Protection Agency through the UC Davis Center for Children's Environmental Health and the UC Davis M.I.N.D. Institute. A copy can be downloaded at Sharp F et al.

Invasion and cytopathic killing of human lymphocytes by spirochetes
Lyme disease is a persistent low-density spirochetosis caused by Borrelia burgdorferi sensu lato. Although spirochetes causing Lyme disease are highly immunogenic in experimental models, the onset of specific antibody responses to infection is often delayed or undetectable in some patients. The properties and mechanisms mediating such immune avoidance remain obscure. To examine the nature and consequences of interactions between Lyme disease spirochetes and immune effector cells, we coincubated B. burgdorferi with primary and cultured human leukocytes. We found that B. burgdorferi actively attaches to, invades, and kills human B and T lymphocytes. Significant killing began within 1 hour of mixing. Cytopathic effects varied with respect to host cell lineage and the species, viability, and degree of attenuation of the spirochetes. Both spirochetal virulence and lymphocytic susceptibility could be phenotypically selected, thus indicating that both bacterial and host cell factors contribute to such interactions. These results suggest that invasion and lysis of lymphocytes may constitute previously unrecognized factors in Lyme disease and bacterial pathogenesis. Clin Infect Dis Jul;25 Suppl 1:S2-8. Links Invasion and cytopathic killing of human lymphocytes by spirochetes causing Lyme disease. Dorward DW, Fischer ER, Brooks DM. National Institute of Allergy and Infectious Diseases, Rocky Mountain Laboratories, Hamilton, Montana 59840, USA. Lyme disease is a persistent low-density spirochetosis caused by Borrelia burgdorferi sensu lato. Although spirochetes causing Lyme disease are highly immunogenic in experimental models, the onset of specific antibody responses to infection is often delayed or undetectable in some patients. The properties and mechanisms mediating such immune avoidance remain obscure. To examine the nature and consequences of interactions between Lyme disease spirochetes and immune effector cells, we coincubated B. burgdorferi with primary and cultured human leukocytes. We found that B. burgdorferi actively attaches to, invades, and kills human B and T lymphocytes. Significant killing began within 1 hour of mixing. Cytopathic effects varied with respect to host cell lineage and the species, viability, and degree of attenuation of the spirochetes. Both spirochetal virulence and lymphocytic susceptibility could be phenotypically selected, thus indicating that both bacterial and host cell factors contribute to such interactions. These results suggest that invasion and lysis of lymphocytes may constitute previously unrecognized factors in Lyme disease and bacterial pathogenesis. Dorward DW, Fischer ER, Brooks DM. Clin Infect Dis Jul;25 Suppl 1:S2-8.

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:

ASD & BI/TBI both have: Been associated with a combination of inflammatory and autoimmune pathophysiology. Elevated TNF and IL-6 & reduced NKC Antibodies against neural tissue Microglial activation Oxidative stress Greater susceptibility to herpes and other viral infections HLA-DR4 genotypes frequently

ASD & BI/TBI & Inflammation
Wilner. Elevated TNF Found in CSF of Autistic Children. CNS News. 2007;9:4 Patterson P. International neuroscience conference Melbourne. Accessed Cohly HH, Panja A. Immunological findings in autism. Int Rev Neurobiol. 2005;71:317-41 Vargas DL, Nascimbene C, Krishnan C, Zimmerman AW, Pardo CA. Neuroglial activation and neuroinflammation in the brain with autism. Ann Neurol. 2005;57(1):67 Rasley A, Anguita J, Marriott I. Borrelia burgdorferi induces inflammatory mediator production by murine microglia. J. Neuroimmunol. 2002;130(1-2):22-31. Alaedini A, N. Latov N. Antibodies against OspA epitopes of Borrelia burgdorferi cross-react with neural tissue. J. Neuroimmunol. 2005;159:192-5 MacDonald AB. Spirochetal cyst forms in neurodegenerative disorders,..hiding in plain sight. Med Hypotheses. 2006;67(4):819-32 Lee LC, Zachary AA, Leffell MS, Newschaffer CJ, Matteson KJ, Tyler JD, Zimmerman AW. HLA-DR4 in families with autism. Pediatr Neurol. 2006;35(5):303-7. Steere AC, Klitz W, Drouin EE, et al. Antibiotic-refractory Lyme arthritis is associated with HLA-DR molecules that bind a Bb peptide. J Exp Med. 2006;203(4):961 Nicholson G. The Role of Chronic Intracellular Infections in ASD. LIA Conf. 2007 Rawadi, G., Roman-Roman, S, et al., Effects of Mycoplasma fermentans on the Myelomonocytic Lineage: Different Molecular Entities with Cytokine-inducing and Cytocidal Potential. J Immunol. 1996;156(2):670-8 Latov N, Wu AT, Chin RL, Sander HW, Alaedini A, Brannagan TH 3rd. Neuropathy and cognitive impairment following vaccination with the OspA protein of Borrelia burgdorferi. J Peripher Nerv Syst. 2004;9(3):165-7. Scott DW. Mycoplasm: The linking pathogen in neurosystemic dis. Nexus Perry VH, Cunningham C, Holmes C. Systemic infections and inflammation affect chronic neurodegeneration. Nat Rev Immunol. 2007;7(2):161-7 Kern JK, Jones AM. Evidence of toxicity, oxidative stress, and neuronal insult in autism. J Toxicol Environ Health B Crit Rev. 2006;9(6):485-99

Inflammation and Cognitive Deficits I
Wilson CJ, Finch CE, Cohen HJ. Cytokines and cognition-the case for a head-to-toe inflammatory paradigm. J Am Geriatr Soc 2002; 50(12): Eskandari F, Webster JI, Sternberg EM. Neural immune pathways and their connection to inflammatory diseases. Arthritis Res Ther 2003; 5(6): Hopkins SJ. Central system recognition of peripheral inflammation: a neural, hormonal collaboration. Acta Biomed 2007; 78 Suppl 1: Watkins LR, Maier SF. Immune regulation of central nervous system functions: from sickness responses to pathological. J Intern Med 2005; 257(2): Maier SF, Watkins LR. Immune-to-central nervous system communication and its role in modulating pain and cognition: Implications for cancer and cancer treatment. Brain Behav Immun 2003; 17 Suppl 1: S Banks WA, Farr SA, Morley JE. Entry of blood-borne cytokines into the central nervous system: effects on cognitive processes. Neuroimmunomodulation ; 10(6): Viljoen M, Koorts AM. A role for proinflammatory cytokines in the behavioral disturbances and cognitive decline in chronic renal failure patients. Clin Nephrol 2004; 61(3): Wolfe F, Michaud K. Fatigue, rheumatoid arthritis, and anti-tumor necrosis factor therapy: an investigation in 24,831 patients. J Rheumatol 2004; 31(11): Yaffe K, Kanaya A, Lindquist K, Simonsick EM, Harris T, Shorr RI, Tylavsky FA, Newman AB. The metabolic syndrome, inflammation, and risk of cognitive decline. JAMA 2004; 292(18): Tonelli LH, Postolache TT. Tumor necrosis factor alpha, interleukin-1 beta, interleukin-6 and major histocompatibility complex molecules in the normal brain and after peripheral immune challenge. Neurol Res 2005; 27(7): Tonelli LH, Postolache TT, Sternberg EM. Inflammatory genes and neural activity: involvement of immune genes in synaptic function and behavior. Front Biosci 2005; 10: Licinio J, Kling MA, Hauser P. Cytokines and brain function: relevance to interferon-alpha-induced mood and cognitive changes. Semin Oncol 1998; 25(1 Suppl 1): Shoemaker R

Inflammation and Cognitive Deficits II
Capuron L, Miller AH. Cytokines and psychopathology: lessons from interferon-alpha. Biol Psychiatry 2004; 56(11): Owens T, Babcock A. Immune response induction in the central nervous system. Front Biosci 2002; 7: d Chavarria A, Alcocer-Varela J. Is damage in central nervous system due to inflammation? Autoimmun Rev 2004; 3(4): Millward JM, Caruso M, Campbell IL, Gauldie J, Owens T. IFN-gamma-induced chemokines synergize with pertussis toxin to promote T cell entry to the central nervous system. J Immunol 2007; 178(12): Hagberg H, Mallard C. Effect of inflammation on central nervous system development and vulnerability. Curr Opin Neurol 2005; 18(2): Magaki S, Mueller C, Dickson C, Kirsch W. Increased production of inflammatory cytokines in mild cognitive impairment. Exp Gerontol 2007; 42(3): Lindberg C, Chromek M, Ahrengart L, Brauner A, Schultzberg M, Garlind A. Soluble interleukin-1 receptor type II, IL-18 and caspase-1 in mild cognitive impairment and severe Alzheimer’s disease. Neurochem Int 2005; 46(7): Dik MG, Jonker C, Hack CE, Smit JH, Comijs HC, Eikelenboom P. Serum inflammatory proteins and cognitive decline in older persons. Neurology 2005; 64(8): Boutin H, LeFeuvre RA, Horai R, Asano M, Iwakura Y, Rothwell NJ. Role of IL-1alpha and IL-1beta in ischemic brain damage. J Neurosci 2001; 21(15): Zhu Y, Saito K, Murakami Y, Asano M, Iwakura Y, Seishima M. Early increase in mRNA levels of pro-inflammatory cytokines and their interactions in the mouse hippocampus after transient global ischemia. Neurosci Lett 2006; 393(2-3): Sheng WS, Hu S, Ding JM, Chao CC, Peterson PK. Cytokine expression in the mouse brain in response to immune activation by Corynebacterium parvum. Clin Diagn Lab Immunol 2001; 8(2): Gelinas DS, McLaurin J. PPAR-alpha expression inversely correlates with inflammatory cytokines IL-1beta and TNF-alpha in aging rats. Neurochem Res 2005; 30(11): Shoemaker R

Inflammation and Cognitive Deficits III
Montalban X, Rio J. Interferons and cognition. J Neurol Sci 2006; 245(1-2): Pierson SH, Griffith N. Treatment of cognitive impairment in multiple sclerosis. Behac Neurol 2006; 17(1): Magaki S, Mueller C, Dickson C, Kirsch W. Increased production of inflammatory cytokines in mild cognitive impairment. Exp Gerontol 2007; 42(3): Wan Y, Xu J, Ma D, Zeng Y, Cibelli M, Maze M. Postoperative impairment of cognitive function in rats: a possible role for cytokine-mediated inflammation in the hippocampus. Anesthesiology 2007; 106(3): Rafnsson SB, Deary IJ, Smith FB, Whiteman MC, Rumley A, Lowe GD, Fowkes FG. Cognitive decline and markers of inflammation and hemostasis: the Edinburgh Artery Study. J Am Geriatr Soc 2007; 55(5): Dehghani F, Conrad A, Kohl A, Korf HW, Hailer NP. Clodronate inhibits the secretion of proinflammatory cytokines and NO by isolated microglial cells and reduces the number of proliferating glial cells in excitotoxically injured organotypic hippocampal slice cultures. Exp Neurol 2004; 189(2): Hailer NP, Vogt C, Korf HW, Dehghani F. Interleukin-1beta exacerbates and interleukin-1 receptor antagonist attenuates neuronal injury and microglial activation after excitotoxic damage in organotypic hippocampal slice cultures. Eur J Neurosci 2005; 21(9): Rothwell N. Interleukin-1 and neuronal injury: mechanisms, modification, and therapeutic potential. Brain Behav Immun 2003; 17(3): Simi A, Tsakiri N, Wang P, Rothwell NJ. Interleukin-1 and inflammatory neurodegeneration. Biochem Soc Trans 2007; 35(Pt 5): Lucas SM, Rothwell NJ, Gibson RM. The role of inflammation in CNS injury and disease. Br J Pharmacol 2006; 147 Suppl 1: S Clarkson AN, Rahman R, Appleton I. Inflammation and autoimmunity as a central theme in neurodegenerative disorders: fact or fiction? Curr Opin Investig Drugs 2004; 5(7): Cunningham C, Wilcockson DC, Campion S, Lunnon K, Perry VH. Central and systemic endotoxin challenges exacerbate the local inflammatory response and increase neuronal death during chronic neurodegeneration. J Neurosci 2005; 25(40): Shoemaker R

Inflammation and Cognitive Deficits IV
Perry VH. The influence of systemic inflammation on inflammation in the brain: implications for chronic neurodegenerative disease. Brain Behav Immun 2004; 18(5): Schultzberg M, Lindberg C, Aronsson AF, Hijorth E, Spulber SD, Oprica M. Inflammation in the nervous system-physiological and pathophysiological aspects. Physiol Behav 2007; 92(1-2): Ehrenreich H, Fischer B, Norra C, Schellenberger F, Stender N, Stiefel M, Siren AL, Paulis W, Nave KA, Gold R, Bartels C. Exploring recombinant human erythropoietin in chronic progressive multiple sclerosis. Brain 2007; 130(Pt 10): Guerreiro RJ, Santana I, Bras JM, Santiago B, Paiva A, Oliveira C. Peripheral inflammatory cytokines as biomarkers in Alzheiner’s disease and mild cognitive impairment. Neurodegener Dis 2007; 4(6): Robinson EK, Seaworth CM, Suliburk JW, Adams SD, Kao LS, Mercer DW. Effect of NOS inhibition on rat gastric matrix metalloproteinase production during endotoxemia. Shock 2006; 25(5): Suliburk JW, Helmer KS, Kennison SD, Mercer DW, Robinson EK. Time-dependent aggravation or attenuation of lipopolysaccharide-induced gastric injury by nitric oxide synthase inhibition. J Surg Res 2005; 129(2): de la Torre JC, Aliev G. Inhibition of vascular nitric oxide after rat chronic brain hypoperfusion: spatial memory and immunocytochemical changes. J Cereb Blood Flow Metab 2005; 25(6): Institoris A, Farkas E, Berczi S, Sule Z, Bari F. Effects of cyclooxygenases (COX) inhibition on memory impairment and hippocampal damage in the early period of cerebral hypoperfusion in rats. Eur J Pharmacol 2007; 574(1): Shibata M, Yamasaki N, Miyakawa T, Kalaria RN, Fujita Y, Ohtani R, Ihara M, Takahashi R, Tomimoto H. Selective impairment of working memory in a mouse model of chronic cerebral hypoperfusion. Stroke 2007; 38(10): Zhou YF, Stabile E, Walker J, Shou M, Baffour R, Yu Z, Rott D, Yancopoulos GD, Rudge JS, Epstein SE. Effects of gene delivery on collateral development in chronic hypoperfusion: diverse effects of angiopoietin-1 versus vascular endothelial growth factor. J Am Coll Cardiol 2004; 44(4): Moe CL, Turf E, Oldach D, Bell P, Hutton S, Savitz S, Koltai D, Turf M, Ingsrisawang L, Hart R, Ball JD, Stutts M, McCarter R, Wilson L, Haselow D, Grattan L, Morris JG, Weber DJ. Cohort studies of health effects among people exposed to estuarine waters: North Carolina, Virginia, and Maryland. Environ Health Perspect 2001; 109 Suppl 5: Hudnell HK, House D, Schmid J, Koltai D, Stopford W, Wilkins J, Savitz DA, Swinker M, Music S. Human visual function in the North Carolina clinical study on possible estuary-associated syndrome. J Toxicol Environ Health A 2001; 62(8): Shoemaker R

Inflammation and Cognitive Deficits V
Qin L, Liu Y, Wang T, Wei SJ, Block ML, Wilson B, Liu B, Hong JS. NADPH oxidase mediates lipopolysaccharide-induced neurotoxicity and proinflammatory gene expression in activated microglia. J Biol Chem 2004; 279(2): Qin L, Wu X, Block ML, Liu Y, Breese GR, Hong JS, Knapp DJ, Crews FT. Systemic LPS causes chronic neuroinflammation and progressive neurodegeneration. Glia 2007; 55(5): Sparkman NL, Buchanan JB, Heyen JR, Chen J, Beverly JL, Johnson RW. Interleukin-6 faclitates lipopolysaccharide-induced disruption in working memory and expression of other proinflammatory cytokines in hippocampal neuronal cell layers. J Neurosci 2006; 26(42): Huang Y, Henry CJ, Dantzer R, Johnson RW, Godbout JP. Exaggerated sickness behavior and brain proinflammatory cytokine expression in aged mice in response to intracerebroventricular lipopolysaccharide. Neurobiol Aging 2007; [Ebup ahead of print] Godbout JP, Chen J, Abraham J, Richwine AF, Berg BM, Kelley KW, Johnson RW. Exaggerated neuroinflammation and sickness behavior in aged mice following activation of the peripheral innate immune system. FASEB J 2005; 19(10): Pereira C, Agostinho P, Moreira PI, Cardoso SM, Oliveira CR. Alzheimer’s disease-associated neurotoxic mechanisms and neuroprotective strategies. Curr Drug Targarets CNS Neurol Disord 2005; 4(4): Ghavami A, Hirst WD, Novak TJ. Selective phosphodiesterase (PDE)-4 inhibitors: a novel approach to treating memory deficit? Drugs R D 2006; 7(2): Chen J, Buchanan JB, Sparkman NL, Godbout JP, Freubd GG, Johnson RW. Neuroinflammation and disruption in working memory in aged mice after acute stimulation of the peripheral innate immune system. Brain Behav Immun 2008; 22(3): Zhou HR, Harkema JR, Yan D, Pestka JJ. Amplified proinflammatory cytokine expression and toxicity in mice coexposed to lipopolysaccharide and the trichothecene vomitoxin (deoxynivalenol). J Toxicol Environ Health A 1999; 57(2): Lang CH, Silvis C, Deshpande N, Nystrom G, Frost RA. Endotoxin stimulates in vivo expression of inflammatory cytokines tumor necrosis factor alpha, interleukin-1beta, -6, and high-mobility-group protein-1 in skeletal muscle. Shock 2003; 19(6): Browne SE, Lin L, Mattsson A, Georgievska B, Isacson O. Selective antibody-induced cholinergic cell and synapse loss produce sustained hippocampal and cortical hypometabolism with correlated cognitive deficits. Exp Neurol 2001; 170(1): Shoemaker R

Inflammation and Cognitive Deficits VI
Semmier A, Frisch C, Debeir T, Ramanathan M, Okulla T, Klockgether T, Heneka MT. Long-term cognitive impairment, neuronal loss and reduced cortical cholinergic innervation after recovery from sepsis in a rodent model. Exp Neurol 2007; 204(2): Ponomarev ED, Maresz K, Tan Y, Dittel BN. CNS-derived interleukin-4 is essential for the regulation of autoimmune inflammation and induces a state of alternative activation in microglial cells. J Neurosci 2007; 27(40): Lyons A, Downer EJ, Crotty S, Nolan YM, Mills KH, Lynch MA. CD200 ligand receptor interaction modulates microglial activation in vivo and in vitro: a role for IL-4. J Neurosci 2007: 27(31): McIntyre RS, Soczynska JK, Woldeyohannes HO, Lewis GF, Leiter LA, MacQueen GM, Miranda A, Fulgosi D, Konarski JZ, Kennedy SH. Thiazolidinediones: a novel treatments for cognitive deficits in mood disorders? Expert Opin Pharmacother 2007; 8(11): Noble F, Rubira E, Boulanouar M, Palmier B, Plotkine M, Warnet JM, Marchand-Leroux C, Massicot F. Acute systemic inflammation induces central mitochondrial damage and mnesic deficit in adult Swiss mice. Neurosci Lett 2007; 424(2): Rosi S, Vazdarjanova A, Ramirez-Amaya V, Worley PF, Barnes CA, Wenk GL. Memantine protects against LPS-induced neuroinflammation, restores behaviorally-induced gene expression and spatial learning in the rat. Neuroscience 2006; 142(4): Ohta H, Nishikawa H, Kimura H, Anayama H, Miyamoto M. Chronic cerebral hypoperfusion by permanent internal carotid ligation produces learning impairment without brain damage in rats. Neuroscience 1997; 79(14): De Jong GI, Farkas E, Stienstra CM, Plass JR, Keijser JN, de la Torre JC, Luiten PG. Cerebral hypoperfusion yields capillary damage in the hippocampal CA1 area that correlates with spatial memory impairment. Neuroscience 1999; 91(1): Liu J, Jin DZ, Xiao L, Zhu XZ. Paeoniflorin attenuates chronic cerebral hypoperfusion-induced learning dysfunction and brain damage rats. Brain Res 2006; 1089(1): Ernst T, Chang L, Arnold S. Increased glial metabolites predict increased working memory network activation in HIV brain injury. Neuroimage 2003; 19(4): Shoemaker R

Maternal Immune Activation Alters Fetal Brain Development through Interleukin-6
Schizophrenia and autism are thought to result from the interaction between a susceptibility genotype and environmental risk factors. The offspring of women who experience infection while pregnant have an increased risk for these disorders. Maternal immune activation (MIA) in pregnant rodents produces offspring with abnormalities in behavior, histology, and gene expression that are reminiscent of schizophrenia and autism, making MIA a useful model of the disorders. However, the mechanism by which MIA causes long-term behavioral deficits in the offspring is unknown. Here we show that the cytokine interleukin-6 (IL-6) is critical for mediating the behavioral and transcriptional changes in the offspring. A single maternal injection of IL-6 on day 12.5 of mouse pregnancy causes prepulse inhibition (PPI) and latent inhibition (LI) deficits in the adult offspring. Moreover, coadministration of an anti-IL-6 antibody in the poly(I:C) model of MIA prevents the PPI, LI, and exploratory and social deficits caused by poly(I:C) and normalizes the associated changes in gene expression in the brains of adult offspring. Finally, MIA in IL-6 knock-out mice does not result in several of the behavioral changes seen in the offspring of wild-type mice after MIA. The identification of IL-6 as a key intermediary should aid in the molecular dissection of the pathways whereby MIA alters fetal brain development, which can shed new light on the pathophysiological mechanisms that predispose to schizophrenia and autism. Neurobiology of Disease Maternal Immune Activation Alters Fetal Brain Development through Interleukin-6 Stephen E. P. Smith,1 Jennifer Li,1 Krassimira Garbett,2 Karoly Mirnics,2 and Paul H. Patterson1 1Biology Division, California Institute of Technology, Pasadena, California 91125, and 2Department of Psychiatry and Vanderbilt Kennedy Center for Human Development, Vanderbilt University, Nashville, Tennessee 37203 Correspondence should be addressed to Dr. Paul H. Patterson at the above address. Schizophrenia and autism are thought to result from the interaction between a susceptibility genotype and environmental risk factors. The offspring of women who experience infection while pregnant have an increased risk for these disorders. Maternal immune activation (MIA) in pregnant rodents produces offspring with abnormalities in behavior, histology, and gene expression that are reminiscent of schizophrenia and autism, making MIA a useful model of the disorders. However, the mechanism by which MIA causes long-term behavioral deficits in the offspring is unknown. Here we show that the cytokine interleukin-6 (IL-6) is critical for mediating the behavioral and transcriptional changes in the offspring. A single maternal injection of IL-6 on day 12.5 of mouse pregnancy causes prepulse inhibition (PPI) and latent inhibition (LI) deficits in the adult offspring. Moreover, coadministration of an anti-IL-6 antibody in the poly(I:C) model of MIA prevents the PPI, LI, and exploratory and social deficits caused by poly(I:C) and normalizes the associated changes in gene expression in the brains of adult offspring. Finally, MIA in IL-6 knock-out mice does not result in several of the behavioral changes seen in the offspring of wild-type mice after MIA. The identification of IL-6 as a key intermediary should aid in the molecular dissection of the pathways whereby MIA alters fetal brain development, which can shed new light on the pathophysiological mechanisms that predispose to schizophrenia and autism. Stephen EP et al. The Journal of Neuroscience, October 3, 2007, 27(40):

Stereotypies and hyperactivity in rhesus monkeys exposed to IgG from mothers of children with autism
Four control rhesus monkeys were exposed to human IgG collected from mothers of multiple typically developing children. Five additional monkeys were untreated controls. Rhesus monkeys gestationally exposed to IgG class antibodies from mothers of children with ASD consistently demonstrated increased whole-body stereotypies across multiple testing paradigms. These monkeys were also hyperactive compared to controls. Brain Behav Immun Feb 7 [Epub ahead of print] Links Stereotypies and hyperactivity in rhesus monkeys exposed to IgG from mothers of children with autism. Martin LA, Ashwood P, Braunschweig D, Cabanlit M, Van de Water J, Amaral DG. Department of Psychiatry and Behavioral Sciences, Center for Neuroscience, California National Primate Research Center and The M.I.N.D. Institute, University of California-Davis, th Street, Sacramento, CA 95817, USA. Autism together with Asperger syndrome and pervasive developmental disorder not otherwise specified form a spectrum of conditions (autism spectrum disorders or ASD) that is characterized by disturbances in social behavior, impaired communication and the presence of stereotyped behaviors or circumscribed interests. Recent estimates indicate a prevalence of ASD of 1 per 150 (Kuehn, 2007). The cause(s) of most cases of ASD are unknown but there is an emerging consensus that ASD have multiple etiologies. One proposed cause of ASD is exposure of the fetal brain to maternal autoantibodies during pregnancy [Dalton, P., Deacon, R., Blamire, A., Pike, M., McKinlay, I., Stein, J., Styles, P., Vincent, A., Maternal neuronal antibodies associated with autism and a language disorder. Ann. Neurol. 53, ]. To provide evidence for this hypothesis, four rhesus monkeys were exposed prenatally to human IgG collected from mothers of multiple children diagnosed with ASD. Four control rhesus monkeys were exposed to human IgG collected from mothers of multiple typically developing children. Five additional monkeys were untreated controls. Monkeys were observed in a variety of behavioral paradigms involving unique social situations. Behaviors were scored by trained observers and overall activity was monitored with actimeters. Rhesus monkeys gestationally exposed to IgG class antibodies from mothers of children with ASD consistently demonstrated increased whole-body stereotypies across multiple testing paradigms. These monkeys were also hyperactive compared to controls. Treatment with IgG purified from mothers of typically developing children did not induce stereotypical or hyperactive behaviors. These findings support the potential for an autoimmune etiology in a subgroup of patients with neurodevelopmental disorders. This research raises the prospect of prenatal evaluation for neurodevelopmental risk factors and the potential for preventative therapeutics. PMID: [PubMed - as supplied by publisher] Martin et al. Brain Behav Immun Feb 7 [Epub ahead of print]

Maternal Immune Activation Alters Fetal Brain Development through Interleukin-6
Schizophrenia and autism are thought to result from the interaction between a susceptibility genotype and environmental risk factors. The offspring of women who experience infection while pregnant have an increased risk for these disorders. Maternal immune activation (MIA) in pregnant rodents produces offspring with abnormalities in behavior, histology, and gene expression that are reminiscent of schizophrenia and autism, making MIA a useful model of the disorders. However, the mechanism by which MIA causes long-term behavioral deficits in the offspring is unknown. Here we show that the cytokine interleukin-6 (IL-6) is critical for mediating the behavioral and transcriptional changes in the offspring. A single maternal injection of IL-6 on day 12.5 of mouse pregnancy causes prepulse inhibition (PPI) and latent inhibition (LI) deficits in the adult offspring. Moreover, coadministration of an anti-IL-6 antibody in the poly(I:C) model of MIA prevents the PPI, LI, and exploratory and social deficits caused by poly(I:C) and normalizes the associated changes in gene expression in the brains of adult offspring. Finally, MIA in IL-6 knock-out mice does not result in several of the behavioral changes seen in the offspring of wild-type mice after MIA. The identification of IL-6 as a key intermediary should aid in the molecular dissection of the pathways whereby MIA alters fetal brain development, which can shed new light on the pathophysiological mechanisms that predispose to schizophrenia and autism. Neurobiology of Disease Maternal Immune Activation Alters Fetal Brain Development through Interleukin-6 Stephen E. P. Smith,1 Jennifer Li,1 Krassimira Garbett,2 Karoly Mirnics,2 and Paul H. Patterson1 1Biology Division, California Institute of Technology, Pasadena, California 91125, and 2Department of Psychiatry and Vanderbilt Kennedy Center for Human Development, Vanderbilt University, Nashville, Tennessee 37203 Correspondence should be addressed to Dr. Paul H. Patterson at the above address. Schizophrenia and autism are thought to result from the interaction between a susceptibility genotype and environmental risk factors. The offspring of women who experience infection while pregnant have an increased risk for these disorders. Maternal immune activation (MIA) in pregnant rodents produces offspring with abnormalities in behavior, histology, and gene expression that are reminiscent of schizophrenia and autism, making MIA a useful model of the disorders. However, the mechanism by which MIA causes long-term behavioral deficits in the offspring is unknown. Here we show that the cytokine interleukin-6 (IL-6) is critical for mediating the behavioral and transcriptional changes in the offspring. A single maternal injection of IL-6 on day 12.5 of mouse pregnancy causes prepulse inhibition (PPI) and latent inhibition (LI) deficits in the adult offspring. Moreover, coadministration of an anti-IL-6 antibody in the poly(I:C) model of MIA prevents the PPI, LI, and exploratory and social deficits caused by poly(I:C) and normalizes the associated changes in gene expression in the brains of adult offspring. Finally, MIA in IL-6 knock-out mice does not result in several of the behavioral changes seen in the offspring of wild-type mice after MIA. The identification of IL-6 as a key intermediary should aid in the molecular dissection of the pathways whereby MIA alters fetal brain development, which can shed new light on the pathophysiological mechanisms that predispose to schizophrenia and autism. Stephen EP et al. The Journal of Neuroscience, October 3, 2007, 27(40):

Stereotypies and hyperactivity in rhesus monkeys exposed to IgG from mothers of children with autism
Rhesus monkeys gestationally exposed to IgG class antibodies from mothers of children with ASD consistently demonstrated increased whole-body stereotypies across multiple testing paradigms. These monkeys were also hyperactive compared to controls. Brain Behav Immun Feb 7 [Epub ahead of print] Links Stereotypies and hyperactivity in rhesus monkeys exposed to IgG from mothers of children with autism. Martin LA, Ashwood P, Braunschweig D, Cabanlit M, Van de Water J, Amaral DG. Department of Psychiatry and Behavioral Sciences, Center for Neuroscience, California National Primate Research Center and The M.I.N.D. Institute, University of California-Davis, th Street, Sacramento, CA 95817, USA. Autism together with Asperger syndrome and pervasive developmental disorder not otherwise specified form a spectrum of conditions (autism spectrum disorders or ASD) that is characterized by disturbances in social behavior, impaired communication and the presence of stereotyped behaviors or circumscribed interests. Recent estimates indicate a prevalence of ASD of 1 per 150 (Kuehn, 2007). The cause(s) of most cases of ASD are unknown but there is an emerging consensus that ASD have multiple etiologies. One proposed cause of ASD is exposure of the fetal brain to maternal autoantibodies during pregnancy [Dalton, P., Deacon, R., Blamire, A., Pike, M., McKinlay, I., Stein, J., Styles, P., Vincent, A., Maternal neuronal antibodies associated with autism and a language disorder. Ann. Neurol. 53, ]. To provide evidence for this hypothesis, four rhesus monkeys were exposed prenatally to human IgG collected from mothers of multiple children diagnosed with ASD. Four control rhesus monkeys were exposed to human IgG collected from mothers of multiple typically developing children. Five additional monkeys were untreated controls. Monkeys were observed in a variety of behavioral paradigms involving unique social situations. Behaviors were scored by trained observers and overall activity was monitored with actimeters. Rhesus monkeys gestationally exposed to IgG class antibodies from mothers of children with ASD consistently demonstrated increased whole-body stereotypies across multiple testing paradigms. These monkeys were also hyperactive compared to controls. Treatment with IgG purified from mothers of typically developing children did not induce stereotypical or hyperactive behaviors. These findings support the potential for an autoimmune etiology in a subgroup of patients with neurodevelopmental disorders. This research raises the prospect of prenatal evaluation for neurodevelopmental risk factors and the potential for preventative therapeutics. PMID: [PubMed - as supplied by publisher] Martin et al. Brain Behav Immun Feb 7 [Epub ahead of print]

Autism: Maternally derived antibodies specific for fetal brain proteins
Autism is a profound disorder of neurodevelopment with poorly understood biological origins. A potential role for maternal autoantibodies in the etiology of some cases of autism has been proposed in previous studies. To investigate this hypothesis, maternal plasma antibodies against human fetal and adult brain proteins were analyzed by western blot in 61 mothers of children with autistic disorder and 102 controls matched for maternal age and birth year (62 mothers of typically developing children (TD) and 40 mothers of children with non-ASD developmental delays (DD)). We observed reactivity to two protein bands at approximately 73 and 37kDa in plasma from 7 of 61 (11.5%) mothers of children with autism (AU) against fetal but not adult brain, which was not noted in either control group (TD; 0/62 p= and DD; 0/40 p=0.0401). Further, the presence of reactivity to these two bands was associated with parent report of behavioral regression in AU children when compared to the TD (p=0.0019) and DD (0.0089) groups. Individual reactivity to the 37kDa band was observed significantly more often in the AU population compared with TD (p=0.0086) and DD (p=0.002) mothers, yielding a 5.69-fold odds ratio (95% confidence interval ) associated with this band. The presence of these antibodies in the plasma of some mothers of children with autism, as well as the differential findings between mothers of children with early onset and regressive autism may suggest an association between the transfer of IgG autoantibodies during early neurodevelopment and the risk of developing of autism in some children. Neurotoxicology Nov 6 [Epub ahead of print] Links Autism: Maternally derived antibodies specific for fetal brain proteins. Braunschweig D, Ashwood P, Krakowiak P, Hertz-Picciotto I, Hansen R, Croen LA, Pessah IN, Van de Water J. Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis, CA, USA; The M.I.N.D. Institute, University of California at Davis, CA, USA; NIEHS Center for Children's Environmental Health, University of California, Davis, CA 95616, USA. Autism is a profound disorder of neurodevelopment with poorly understood biological origins. A potential role for maternal autoantibodies in the etiology of some cases of autism has been proposed in previous studies. To investigate this hypothesis, maternal plasma antibodies against human fetal and adult brain proteins were analyzed by western blot in 61 mothers of children with autistic disorder and 102 controls matched for maternal age and birth year (62 mothers of typically developing children (TD) and 40 mothers of children with non-ASD developmental delays (DD)). We observed reactivity to two protein bands at approximately 73 and 37kDa in plasma from 7 of 61 (11.5%) mothers of children with autism (AU) against fetal but not adult brain, which was not noted in either control group (TD; 0/62 p= and DD; 0/40 p=0.0401). Further, the presence of reactivity to these two bands was associated with parent report of behavioral regression in AU children when compared to the TD (p=0.0019) and DD (0.0089) groups. Individual reactivity to the 37kDa band was observed significantly more often in the AU population compared with TD (p=0.0086) and DD (p=0.002) mothers, yielding a 5.69-fold odds ratio (95% confidence interval ) associated with this band. The presence of these antibodies in the plasma of some mothers of children with autism, as well as the differential findings between mothers of children with early onset and regressive autism may suggest an association between the transfer of IgG autoantibodies during early neurodevelopment and the risk of developing of autism in some children. HYPERLINK Contact: Karen Finney <HYPERLINK University of California - Davis - Health System <HYPERLINK " Some cases of autism may be traced to the immune system of mothers during pregnancy UC-Davis discovery could lead to prenatal identification and prevention (SACRAMENTO, Calif.) – New research from the UC Davis M.I.N.D. Institute and Center for Children’s Environmental Health has found that antibodies in the blood of mothers of children with autism bind to fetal brain cells, potentially interrupting healthy brain development. The study authors also found that the reaction was most common in mothers of children with the regressive form of autism, which occurs when a period of typical development is followed by loss of social and/or language skills. The findings, to be published in the March 2008 issue of Neurotoxicology, raise the possibility that the transfer of maternal antibodies during pregnancy is a risk factor for autism and, at some point, that a prenatal test and treatment could prevent the disorder for some children. “While a growing body of research is dedicated to finding distinctions in the immune systems of children with autism, this is one of the first studies to identify immunological factors in mothers that could be linked to autism in the very earliest stages of life,” said Judy Van de Water, senior author of the study and professor of rheumatology, allergy and clinical immunology. “Our results should lead to more research on the prenatal environment and the onset of autism. We are also optimistic that in the future a prenatal test and therapeutic intervention preventing IgG exposure during pregnancy could protect some children from ever getting autism.” Van de Water and her team began their research with blood samples from 123 mothers – 61 whose children have autism and 62 whose children are typically developing. They isolated IgG antibodies from the samples then exposed the antibody to fetal brain tissue by western blot analysis, which detects antibody reactivity to proteins. The outcome revealed a highly specific reactivity pattern to two fetal brain proteins in seven of the 61 samples from the autism group, six of which were from mothers of children who had regressive autism. None of the IgG samples from mothers in the control group produced this same result. “We’re not entirely sure why the IgG response against fetal brain proteins was so specific for later onset autism,” said Van de Water. “It’s possible that early exposure to maternal antibodies sets in motion a biological path to autism with the behavioral outcomes not apparent until much later. It’s also possible that an environmental exposure sometime after birth could be required to set this process in motion. We are hopeful that this study will help build our understanding of the foundations of the regressive form of the disorder.” Characteristic features of autism – social deficits, language impairments and limited, repetitive behaviors – are often clear early in an affected child’s life. Other children seem to progress normally until 12-to-24 months of age, when developmental milestones disappear. These distinct pathways have led clinicians to identify autism as one of two types – early onset or regressive – potentially with distinct causes and disease processes. IgG antibodies are responsible for long-term immune system responses to infection, but they can also contribute to autoimmune diseases such as arthritis, multiple sclerosis and lupus. IgG also crosses the placenta in order to provide key immune system protectants to a growing fetus and newborn child, which is a key reason why Van de Water decided to investigate the role of IgG as a potential factor in autism. Van de Water next wants to know if IgG in women during the time of their pregnancies produces the same response to fetal brain proteins. Women in the current study were two-to-five years beyond childbirth. She will now conduct the same study with women who are pregnant and already have a child with autism, because such women are much more likely to have another child with the disorder. “If women in this next phase of the study give birth to a child eventually diagnosed with autism, blood analyses from all stages of her pregnancy will give us a clear picture of the immune system factors that were in play during gestation and could have altered her child’s neurodevelopment,” Van de Water said. Other key next steps are to identify the specific proteins targeted by autism-specific maternal antibodies and their role in neurodevelopment and to determine whether or not exposure to maternal IgG during pregnancy leads to behavioral or social distinctions in offspring. Animal model studies are now under way to help answer these questions. “Our outcome leads autism science in many new and exciting directions,” said Daniel Braunschweig, pre-doctoral fellow of immunology in the Van de Water lab, lead author of the current study and recent recipient of an Autism Speaks mentor fellowship to further pursue this research. “We now know we should be looking for the clues to the onset and pathology of autism much earlier than was initially assumed. Future studies should consider the immune system interactions between mother and child as a focal point in creating greater understanding of, and eventually finding effective preventions for, this complex neurodevelopmental disorder.” “This finding is important because it provides important clues about the potential maternal contributions to autism risk in a subset of children who may develop autism,” said Isaac Pessah, director of the UC Davis Center for Children’s Environmental Health and professor of molecular biosciences. “We’re determined to find out what causes autism. Studies conducted in the Van de Water lab are giving us valuable insights as to when and where in the developmental process we should be looking for those causes.” “We’re very interested in understanding the underlying causes of autism,” said Cindy Lawler, scientific program director at the National Institute of Environmental Health Sciences. “This finding, in combination with other new research findings coming from NIH-funded studies, demonstrates the complexity of this disorder and underscores the importance of understanding how the mother’s immune system can influence early brain development.” ### The study, “Maternally Derived Antibodies Specific for Fetal Brain Proteins,” was funded by the National Institutes of Environmental Health Sciences, the U.S. Environmental Protection Agency and the M.I.N.D. Institute. A copy can be requested from <HYPERLINK or downloaded at HYPERLINK <HYPERLINK " . The UC Davis M.I.N.D. (Medical Investigation of Neurodevelopmental Disorders) Institute is a unique collaborative center that brings together clinicians, scientists, parents and educators for research on causes, treatments, preventions and cures for autism, fragile X syndrome, Tourette’s syndrome, attention-deficit/hyperactivity disorder and other neurodevelopmental disorders. For more information, visit HYPERLINK <HYPERLINK " . The UC Davis Center for Children’s Environmental Health and Disease Prevention is a multi-disciplinary research effort established to examine how toxic chemicals may influence the development of autism in children. Toward that goal, the center is conducting two large-scale research projects: the Childhood Autism Risks from Genetics and the Environment (CHARGE) study and Markers of Autism Risk in Babies—Learning Early Signs (MARBLES) study. For more information, visit HYPERLINK <HYPERLINK " . Editor’s note: B-roll of blood sample processing for immunological studies of autism in the Van de Water lab is available on request. Braunschweig D et al. Neurotoxicology Nov 6 [Epub ahead of print]

Regressive Autism Reactivity: 28% to 37-kDa & 25% to 73-kDa
Table 2 Summary and significant associations of maternal autoantibody reactivity patterns for human fetal brain proteins in autism Prevalence & 73 (kD) 37 (kD) 73 (kD) Total (n = 61) 7 (12%)* 15 (25%)* 10 (17%) Regressive (36) 6 (17%)* 10 (28%)* 9 (25%)* Early onset (25) 1 (4%) 5 (21%) 1 (4%) Braunschweig D et al. Neurotoxicology Nov 6 [Epub ahead of print]

What is associated with 37-kDa & 73-kDa antibodies?

Medline Search for 37 & 73-kDa Antibodies
Mycoplasma agalactiae [1] Mycoplasma gallisepticum [2] Mycoplasma arthritidis [3] 73-kDa Chlamydia [4] Streptococcus pneumoniae [5] Mycoplasma conjunctivae [6] 37-kDa & 73-kDa Bartonella henselae and Bartonella quintana [7] Borrelia burgdorferi Microbiol Immunol. 1993;37(6):495-8.Cited in PMC, LinkOut Antigenic characterization of Chlamydia pneumoniae isolated in Hiroshima, Japan. Kanamoto Y, Iijima Y, Miyashita N, Matsumoto A, Sakano T. Division of Microbiology, Hiroshima Prefectural Institute for Health and Environmental Science, Japan. The morphology and antigenic property of elementary bodies (EBs) of new Chlamydia pneumoniae YK-41 strain isolated in Hiroshima, Japan, were compared with those of C. pneumoniae strains TW-183 and AR-39, C. trachomatis L2/434/Bu strain and C. psittaci Cal 10 and Budgerigar-1 strains by SDS-PAGE and immunoblotting techniques. In spite of a clear difference in EB morphology between the YK-41 and the other C. pneumoniae strains used, protein profile of the YK-41 strain in SDS-PAGE was similar to that of the other strains. However, some quantitative difference in 200 and 98 kDa peptides and a faint difference in SDS-PAGE pattern was also observed in the molecular masses from 42 to 50 kDa. Immunoblot analysis with the patient serum at the convalescent stage revealed the presence of genus-specific and species-specific antigens in YK-41 EBs: i.e., the major outer membrane protein and 73 kDa peptides were genus-specific and the peptides of 43, 46, 53, 60 and 98 kDa appeared to be C. pneumoniae-specific. PMID: [PubMed - indexed for MEDLINE] Infect Immun Apr;75(4): Epub 2007 Feb Cited Articles, CoreNucleotide (RefSeq), Gene, HomoloGene, Nucleotide (RefSeq), Protein (RefSeq), Substance (MeSH Keyword), Taxonomy via GenBank, UniGene, GEO Profiles, Free in PMC, LinkOut Inflammatory lipoproteins purified from a toxigenic and arthritogenic strain of Mycoplasma arthritidis are dependent on Toll-like receptor 2 and CD14. Hasebe A, Mu HH, Washburn LR, Chan FV, Pennock ND, Taylor ML, Cole BC. Division of Rheumatology, Department of Internal Medicine, University of Utah School of Medicine, 30 North 1900 East, Salt Lake City, UT 84132, USA. Mycoplasma arthritidis is a naturally occurring murine pathogen, and the disease model has been used extensively to understand inflammatory mechanisms. Recently, Triton X-114 extracts of a virulent strain of M. arthritidis were found to be more potent in activating macrophages than were those from an avirulent strain, suggesting a role in disease. Here, octyl glucoside extraction of cells was used to identify four distinct bioactive moieties, with molecular masses of approximately 41, 37, 34, and 17 kDa. Their bioactivities were resistant to proteinase K but were destroyed by alkaline hydrolysis and oxidation. As for MALP-2, all were dependent upon Toll-like receptor 2, but unlike MALP-2, they were also dependent upon CD14. The M. arthritidis lipoproteins exhibited infrared absorbances at 2,900 cm(-1) and 1,662 cm(-1), similar to those seen in Pam(3)-Cys-Ser-(Lys)(4). Edman degradation failed to reveal N-terminal sequences, suggesting that they were blocked and therefore might be triacylated. However, mass spectrometry of fragments revealed that the 41-kDa moiety, which binds to serum apolipoprotein A-1, had similarity with the recently described MlpD lipoprotein of M. arthritidis. FEMS Microbiol Lett Oct 1;155(1): Substance (MeSH Keyword), Cited in PMC, LinkOut Antibody-mediated selection of a Mycoplasma gallisepticum phenotype expressing variable proteins. Gorton TS, Geary SJ. University of Connecticut, Department of Pathobiology, Storrs, USA. A variant phenotype of Mycoplasma gallisepticum S6 was isolated from an in vitro antibody-culture system utilizing metabolism-inhibiting antibodies against the 64 kDa lipoprotein (LP64). M. gallisepticum populations grown in medium alone or medium containing normal rabbit serum maintained expression of the parental phenotype. This paper describes the identification of proteins which undergo variable expression. Several of these were integral membrane proteins, with estimated molecular masses of 91, 43, 41, 38, 37, and 18 kDa, which were expressed in the variant phenotype but not in the parental phenotype. Three proteins (LP64, p63 and p47) were expressed in the parental phenotype, but not in the variant phenotype. The data suggest that the interaction of specific immunoglobulins with target epitopes resulted in the selection of a subpopulation of organisms expressing an alternative array of membrane proteins which, lacking the target epitopes, was able to escape the metabolism-inhibiting effects of the specific antibodies. Immun Oct;70(10): Cited Articles, CoreNucleotide, Protein Clusters, Taxonomy via GenBank, Nucleotide, Protein, Free in PMC, Cited in PMC, LinkOut Characterization of P40, a cytadhesin of Mycoplasma agalactiae. Fleury B, Bergonier D, Berthelot X, Peterhans E, Frey J, Vilei EM. Unité Mixte de Recherche ENVT-INRA 959, Ecole Nationale Vétérinaire de Toulouse, F Toulouse Cedex 3, France. An immunodominant protein, P40, of Mycoplasma agalactiae was analyzed genetically and functionally. The gene encoding P40 was cloned from type strain PG2, sequenced, submitted to point mutagenesis in order to convert mycoplasma-specific TGA(Trp) codon to the universal TGG(Trp) codon, and subsequently expressed in Escherichia coli. Nucleotide sequence-derived amino acid sequence comparisons revealed a similarity of P40 to the adhesin P50 of Mycoplasma hominis and to protein P89 of Spiroplasma citri, which is expected to be involved in adhesion. The amino acid sequence of P40 revealed a recognition site for a signal peptidase and strong antigenic and hydrophilic motifs in the C-terminal domain. Triton X-114 phase partitioning confirmed that P40 is a membrane protein. Fab fragments of antibodies directed against recombinant purified P40 significantly inhibited adherence of M. agalactiae strains PG2 to lamb joint synovial cells LSM 192. Sera taken sequentially from sheep infected with PG2 revealed that P40 induced a strong and persistent immune response that gave strong signals on immunoblots containing recombinant P40 even 3 months after infection. The gene encoding P40 was present in a single copy in all of the 26 field strains of M. agalactiae analyzed and was not detected in closely related mycoplasma species. P40 was expressed as a protein with an apparent molecular mass of 37 kDa on sodium dodecyl sulfate-acrylamide gels by all M. agalactiae strains except for serotype C strains, which showed nonsense mutations in their p40 genes. J Wildl Dis Apr;36(2): Cited in PMC, LinkOut Immune responses to Mycoplasma conjunctivae in alpine ibex, alpine chamois, and domestic sheep in Switzerland. Degiorgis MP, Abdo EM, Nicolet J, Frey J, Mayer D, Giacometti M. Centre for Fish and Wildlife Health, Institute of Animal Pathology, University of Berne, Switzerland. The humoral immune response of three alpine chamois (Rupicapra rupicapra rupicapra), two alpine ibex (Capra ibex ibex) and three domestic sheep naturally affected with infectious keratoconjunctivitis (IKC), and four ibex and two sheep experimentally infected with Mycoplasma conjunctivae was analysed. In addition, the local immune response to M. conjunctivae was analysed using conjunctival washes from chamois and sheep. Immunoblot analysis of sera using whole cell antigens of M. conjunctivae revealed the major immunogenic proteins which had molecular masses of 175, 83, 68, 60, 50, 42, 36, and 33 kDa. Major antigens were found at 83, 68, 60, and 42 kDa in both sera and conjunctival washes from naturally infected animals of all three Caprinae species. In experimentally infected animals, antibodies to the 68 and 60 kDa antigens were dominant. Naturally infected animals showed much stronger immune reactions than those experimentally infected, and specific antibodies appeared 2 to 4 wk after experimental infection. To evaluate possible cross-reactions, whole cell antigen of M. conjunctivae was analysed by immunoblot against hyperimmune sera of closely related Mycoplasma spp. Antibodies to the 175, 73, 68, 60, and 33 kDa antigens appeared to be specific to M. conjunctivae. Cross-reactions mainly with 83, 50, and 42 kDa antigens were detected, in particular with M. ovipneumoniae and M. bovoculi hyperimmune sera, but also with antisera against M. capricolum capricolum and M. putrefaciens. Microbiol Immunol. 1999;43(8): Cited in PMC, LinkOut Limited stress response in Streptococcus pneumoniae. Choi IH, Shim JH, Kim SW, Kim SN, Pyo SN, Rhee DK. College of Pharmacy, Sungkyunkwan University, Suwon, South Korea. In Streptococcus pneumoniae, heat shock induces the synthesis of 65-, 73-, and 84-kDa proteins, and ethanol shock induces a 104-kDa protein. In this study, the 65-, 84-, and 104-kDa proteins were identified as members of the GroEL, ClpL and alcohol dehydrogenase families, respectively, and the general properties of the stress response of S. pneumoniae to several other stresses were characterized. However, several stresses which are known to induce stress responses in Escherichia coli and Bacillus subtilis failed to induce any high molecular weight heat-shock proteins (HSPs) such as GroEL and DnaK homologues. A minor temperature shift from 30 to 37 C triggered induction of the homologues of DnaK and GroEL of E. coli. These features may provide a foundation for evaluating the role of heat-shock proteins relative to the physiology and pathogenesis of pneumococcus. J Med Microbiol Sep;48(9): Cited in PMC, LinkOut Seroprevalence of Bartonella henselae in cats in Germany. Haimerl M, Tenter AM, Simon K, Rommel M, Hilger J, Autenrieth IB. Max von Pettenkofer-Institut für Hygiene und Medizinische Mikrobiologie, Ludwig Maximilians-Universität Müchen, Germany. Bartonella henselae and B. quintana infections in man are associated with various clinical manifestations including cat-scratch disease, bacillary angiomatosis and bacteraemia. While cats are the natural reservoir for B. henselae, the source of B. quintana is unclear. In this study, the sera of 713 cats from Germany were examined for the presence of antibodies against B. henselae, B. quintana or Afipia felis by an indirect immunofluorescence assay (IFA). Bartonella-specific antibody titres of > or =50 were found in 15.0% of the cats. There was substantial cross-reactivity among the various Bartonella antigens, although single sera showed high titres against B. henselae but not against B. quintana and vice versa. Antibodies against A. felis were not detected in any of these cats. Statistical analysis indicated that there is no correlation between Bartonella infections and the sex, age or breed of the cat or its hunting behavior. There was also no correlation between bartonella and toxoplasma infections in cats. However, whereas 16.8% of cats from northern Germany had B. quintana-specific antibodies, only 8.0% of cats from southern Germany were seropositive for B. quintana. No statistically significant difference was found for B. henselae. IFA-positive and IFA-negative sera were used for immunoblot analysis including B. henselae and B. quintana. Marked reactivity was observed with protein bands at 80, 76, 73, 65, 37, 33 and 15 kDa. The results of this study suggest that B. henselae, and possibly a B. quintana-related pathogen, but not A. felis, are common in cats in Germany, and that there are differences in the geographic distribution of bartonella infections in cats. [1] Fleury B et al. Infect Immun Oct;70(10): [2] Gorton TS et al. FEMS Microbiol Lett Oct 1;155(1):31-8. [3] Hasebe A et al. Infect Immun Apr;75(4): [4] Kanamoto Y et al. Microbiol Immunol. 1993;37(6):495-8. [5] Choi IH et al. Microbiol Immunol. 1999;43(8): [6] Degiorgis MP et al. J Wildl Dis Apr;36(2): [7] Haimerl M et al. J Med Microbiol Sep;48(9):

73-kDa & 37-kDa Amtibodies & LYD
73-kDa proteins of Borrelia burgdorferi are dominant immunogens and expressed in all strains of B. burgdorferi. The humoral response to this antigen occurs relatively early during the course of infection.[1] A 37-kDa protein from Borrelia burgdorferi (the agent of Lyme disease) was identified as a target for immune-mediated resolution of Lyme arthritis. [2] 37-kDa is a marker for neuroborreliosis. [3] J Immunol Apr 15;146(8): Cited in PMC, LinkOut Immunologic and structural characterization of the dominant 66- to 73-kDa antigens of Borrelia burgdorferi. Luft BJ, Gorevic PD, Jiang W, Munoz P, Dattwyler RJ. Department of Medicine, SUNY, Stony Brook The 66- to 73-kDa proteins of Borrelia burgdorferi are dominant immunogens and expressed in all strains of B. burgdorferi. The humoral response to these Ag occurs relatively early during the course of infection. Two-dimensional Western blot analysis of this group of Ag revealed them to consist of a tetrad of proteins with apparent molecular mass of 66, 68, 71, and 73 kDa. Furthermore, in this study we demonstrate the 66-kDa protein to be a potent inducer of lymphoproliferation in the patient immune to B. burgdorferi. Monospecific polyclonal antibodies and mAb demonstrate that each of these proteins was immunologically distinct. However, direct amino acid sequence of the 66- and 68-kDa Ag was almost identical and had a high level of sequence similarity to the GroEL heat-shock protein (Hsp60) of Escherichia coli and the 60-kDa immunodominant protein of Treponema pallidum. The amino terminal sequence of the 71- and 73-kDa proteins of B. burgdorferi was almost identical and these proteins had remarkable sequence similarity to the DnaK heat-shock protein of E. coli (Hsp70). It appears likely, therefore, that proteins related to the heat-shock family are potent immunogens of B. burgdorferi. PMID: [PubMed - indexed for MEDLINE] Immunol Med Microbiol Jun;14(2-3): Substance (MeSH Keyword), Cited in PMC, LinkOut IgM and IgG significant reactivity to Borrelia burgdorferi sensu stricto, Borrelia garinii and Borrelia afzelii among Italian patients affected by Lyme arthritis or neuroborreliosis. Cinco M, Murgia R, Ruscio M, Andriolo B. Istituto di Microbiologia, Università degli Studi, Trieste, Italy. This survey evaluates the specificity of band patterns in immunoblot of sera taken from clinically defined cases of Lyme arthritis and neuroborreliosis, towards three locally isolated strains of Borrelia burgdorferi, belonging to the three species: Borrelia sensu stricto, Borrelia garinii and Borrelia afzelii. To assess specificity, patient sera were statistically (X2, P < or = 0.05) compared with blood donors sera samples. Both IgG and IgM antibodies were considered. The overall reactivity of the three Borrelia strains in IgG immunoblots indicated that ten protein bands were significant, with a different prevalence of some of them in the two groups of patient sera: bands at 60-58, 30-33, and kDa were markers for neuroborreliosis sera; proteins at , and kDa behaved like markers for Lyme arthritis. The IgM Immunoblots revealed significant bands at , 72-70, 51, and kDa only with neuroborreliosis sera. Though there were variable band reactivities in each strain, a correlation emerged between the three genospecies and the clinical symptoms: in fact B. afzelii and B. garinii were prevalent in Lyme arthritis sera, (IgG Immunoblots); B. garinii was associated to neuroborreliosis (IgG and IgM Immunoblots); B. sensu stricto was strongly reactive with neuroborreliosis in IgM immunoblots. These data indicate that the three locally strains of Borrelia representing the three genospecies should be used together in immunoblot to detect antibodies elicited in neuroborreliosis and Lyme arthritis. PMID: [PubMed - indexed for MEDLINE] Immun Jul;68(7): Cited Articles, CoreNucleotide, Gene, Protein (RefSeq), Protein Clusters, Taxonomy via GenBank, Nucleotide, Protein, GEO Profiles, Free in PMC, Cited in PMC, LinkOut Lyme arthritis resolution with antiserum to a 37-kilodalton Borrelia burgdorferi protein. Feng S, Hodzic E, Barthold SW. Center for Comparative Medicine, Schools of Medicine and Veterinary Medicine, University of California, Davis, California 95616, USA. A 37-kDa protein from Borrelia burgdorferi (the agent of Lyme disease) was identified as a target for immune-mediated resolution of Lyme arthritis. Studies in a mouse model have shown that arthritis resolution can be mediated by antibodies (against unknown target antigens) within immune sera from actively infected mice. Immune sera from infected mice were therefore used to screen a B. burgdorferi genomic expression library. A gene was identified whose native product is a putative lipoprotein of approximately 37 kDa, referred to here as arthritis-related protein (Arp). Active and passive immunization of mice with recombinant Arp or Arp antiserum, respectively, did not protect mice from challenge inoculation. However, when Arp antiserum was administered to severe combined immunodeficient (SCID) mice with established infections and with ongoing arthritis and carditis, treatment selectively induced arthritis resolution without affecting the status of carditis or influencing the status of infection, including spirochetemia. The selective arthritis-resolving effect of Arp antiserum mimics the activity of immune serum from immunocompetent mice when such serum is transferred into SCID mice with established infections. The arp gene could not be amplified from unrelated B. burgdorferi isolates but hybridized with those isolates only under very-low-stringency conditions. Arp antiserum reacted against proteins of similar size in a wide range of B. burgdorferi isolates. PMID: [PubMed - indexed for MEDLINE] PMCID: PMC101718 [1] Luft BJ et al. J Immunol Apr 15;146(8): [2] Feng S et al. Immun Jul;68(7): [3] Cinco M et al. Immunol Med Microbiol Jun;14(2-3):

Antibodies against fetal brain in sera of mothers with autistic children
Serum antibodies in 100 mothers of children with autistic disorder (MCAD) were compared to 100 age-matched mothers with unaffected children (MUC) using as antigenic substrates human and rodent fetal and adult brain tissues, GFAP, and MBP. MCAD had significantly more individuals with Western immunoblot bands at 36 kDa in human fetal and rodent embryonic brain tissue. The density of bands was greater in fetal brain at 61 kDa. MCAD plus developmental regression had greater reactivity against human fetal brain at 36 and 39 kDa. Data support a possible complex association between genetic/metabolic/environmental factors and the placental transfer of maternal antibodies in autism. Neuroimmunol Feb;194(1-2): Epub 2008 Feb 21. Related Articles, Links Antibodies against fetal brain in sera of mothers with autistic children. Singer HS, Morris CM, Gause CD, Gillin PK, Crawford S, Zimmerman AW. Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, United States. Serum antibodies in 100 mothers of children with autistic disorder (MCAD) were compared to 100 age-matched mothers with unaffected children (MUC) using as antigenic substrates human and rodent fetal and adult brain tissues, GFAP, and MBP. MCAD had significantly more individuals with Western immunoblot bands at 36 kDa in human fetal and rodent embryonic brain tissue. The density of bands was greater in fetal brain at 61 kDa. MCAD plus developmental regression had greater reactivity against human fetal brain at 36 and 39 kDa. Data support a possible complex association between genetic/metabolic/environmental factors and the placental transfer of maternal antibodies in autism. PMID: [PubMed - in process] Singer HS et al. Neuroimmunol Feb;194(1-2): Epub 2008 Feb 21.

Residual serologic reactivity in children with resolved Lyme arthritis
“The 41, 39, and 60 kDa were the most commonly observed reactive bands.” J Rheumatol Feb;23(2): Links Residual serologic reactivity in children with resolved Lyme arthritis. Rose CD, Fawcett PT, Gibney KM, Doughty RA. Division of Rheumatology, Alfred I. duPont Institute, Wilmington, DE, USA. OBJECTIVE: To define the pattern of persistent antibody response in children with resolved Lyme arthritis. METHODS: From a cohort of 67 children with Lyme arthritis followed in our department since 1989, 19 were selected using these criteria: All patients (1) were asymptomatic; (2) had an ELISA titer < or = 1:160; (3) had been in treatment a minimum of 6 months. Their initial and late samples were assessed by Western blot and the pattern of reactivity was analyzed. RESULTS: The mean interval between treatment and last sample was 9.6 months (6-23). Analysis of the last sample showed that only 5/19 were negative by ELISA and 4/19 were at the cutoff limit (1:80). Only 6 patients had fewer than 4 reactive bands, 4 had 4 bands, and 9 had 5-11 bands on Western blot. The 41, 39, and 60 kDa were the most commonly observed reactive bands at last evaluation. 31 and 34 kDa bands, while relatively common in initial samples (36%), became uncommon (5%) on late samples. A significant finding was the absence of IgM reactivity in 18/19: 1/19 had 41 kDa reactivity. Only 4 patients had both ELISA (< 1:80) and Western blot tests negative (< 5 reactive bands). CONCLUSION: All patients with resolved Lyme arthritis continue to show serologic reactivity beyond 6 months of therapy. 68% of the patients satisfy Western blot criteria for positivity in our laboratory. IgM reactivity to any antigen was minimal and IgG reactivity against the 41 kDa antigen, considered diagnostic of infection in initial samples by some laboratories, is very common (16/19). Rose CD et al. J Rheumatol Feb;23(2):367-9.

The antibody response in Lyme disease
“These polypeptides had molecular weights of 62, 60, 47, 37, 22, 18, and 15 kDa, and were not recognized by control sera.” Yale J Biol Med Jul-Aug;57(4): Links The antibody response in Lyme disease. Craft JE, Grodzicki RL, Shrestha M, Fischer DK, García-Blanco M, Steere AC. We determined the antibody response against the Ixodes dammini spirochete in Lyme disease patients by indirect immunofluorescence and an enzyme-linked immunosorbent assay (ELISA). The specific IgM response became maximal three to six weeks after disease onset, and then declined, although titers sometimes remained elevated during later disease. Specific IgM levels correlated directly with total serum IgM. The specific IgG response, often delayed initially, was nearly always present during neuritis and arthritis, and frequently remained elevated after months of remission. Although results obtained by indirect immunofluorescence and the ELISA were similar, the ELISA was more sensitive and specific. Cross-reactive antibodies from patients with other spirochetal infections were blocked by absorption of sera with Borrelia hermsii, but titers of Lyme disease sera were also decreased. To further characterize the specificity of the humoral immune response against the I. dammini spirochete, 35S-methionine-labeled spirochetal antigens were identified by immunoprecipitation with sera from Lyme arthritis patients. These polypeptides had molecular weights of 62, 60, 47, 37, 22, 18, and 15 kDa, and were not recognized by control sera. We conclude that the ELISA, without absorption, is the best method to assay the humoral immune response in Lyme disease, and we have identified methionine-containing spirochetal polypeptides that may be important in Lyme arthritis. PMID: [PubMed - indexed for MEDLINE] Craft JE et al. Yale J Biol Med Jul-Aug;57(4):561-5

What is the significance of these bands?
39 kDa is highly specific for Lyme disease 36/37 kDa is a Lyme disease band 60/62 kDa is a Lyme disease band

The MMR Debate & TBD In 1998, Dr. Wakefield "postulated in the Lancet that the vaccine might cause autism." Patients with TBD often report symptom flares following vaccinations. Is there an association between vaccines, patients infected with TBD’s & ASD?

Vaccines a risk for pregnant women?
“Vaccinating a pregnant woman may be risky if her immune response interferes with neuronal growth in her unborn baby’s brain.” Wenner M. Infected with insanity. Scientific American Mind. April/May 2008

Economic Issues It may cost $3.2 million to care for one autistic person in their lifetime and the preliminary data suggests Borreliosis may be a contributor in 20–30% of ASD, and pathogenic Mycoplasma may be a contributor in 58%. If 20% or 58% of the 560,000 recognized cases of ASD in the US can be prevented or more effectively treated, this could result in a savings of $358 billion to $1 trillion in addition to incalculable human impact of this disease. Bransfield RC, Wulfman JS, Harvey WT, Usman AI. Medical Hypotheses. 2007

Assessment When a patient has been diagnosed with childhood bipolar illness, ADHD, autism and other comorbidity, consider the presence of Tick-borne disease/Lyme disease and perform an adequate evaluation. Evaluating the possibility of TBI/BI should be considered in the evaluation of autism

Treatment Strategies Since ASD is caused by an interaction of genes and environment Should treatment be focused upon changing: Genes? Environment contributors? When TBI/BI is a possibility, consider a course of antibiotic treatment

Antibiotic Treatment “In our work with children with LD, we have encountered a few children with autistic-like disorders,” says Dr Fallon. “When they received intensive antibiotic therapy, the autistic syndromes dramatically improved and, in some cases, resolved.” Lyme disease: a leaky brain.

Further evaluation of the hypothesis
It is important to research this association further and to address the other environmental contributors that increase the impact of these infections diseases. Narrow and restrictive opinions on the diagnosis and treatment of Lyme disease may have contributed to the increased incidence of ASD. It is imperative to research all possible causes, prevent every preventable case and treat every treatable case of ASD.

Summary A broad base of research & clinical observations supports the conclusion that Lyme disease, other tick-borne diseases and other infectious diseases are significantly associated with a growing epidemic of autism spectrum disorder. Now greater attention needs to be focused upon the pathophysiology, prevention, early diagnosis and treatment.

Thanks for Your Attention

Robert C Bransfield, MD, DFAPA

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Robert C Bransfield, MD, DFAPA

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