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Michael A Hill, MD Professor Of Psychiatry

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1 Michael A Hill, MD Professor Of Psychiatry
Dementia Michael A Hill, MD Professor Of Psychiatry

2 Dementia An acquired syndrome characterized by:
Short-term memory impairment (i.e. learning) AND At least one of the following: Aphasia - language memory impairments Apraxia - motor memory impairments Agnosia - sensory memory impairments Abstract thinking / Exec. function impairments Impairment in social and/or occupational fn Sxs not explainable by another disorder

3 Etiology & Pathogenesis
Dementia results from impaired functioning of multiple brain systems in both cortical and sub-cortical areas that are associated with short-term memory (i.e. learning) and other higher cognitive functions. Generally this is due to structural brain damage that is often progressive and relatively irreversible

4 Delirium vs Dementia (summary)
General rules of thumb: Delirium Dementia acute chronic reversible irreversible physiological structural primary attention primary memory deficits deficits Delirium and dementia can coexist; in fact delirium is very common in demented patients CAUSES OF DELIRIUM: Infectious - encephalitis, meningitis, UTI - also systemic infections with sepsis, fever Withdrawal Acute Metabolic - electrolyte changes, dehydration, blood sugsr changes, acidosis, hepatic or renal failure Trauma CNS pathology - seizures, tumors, strokes, etc. Hypoxia Deficiencies - b12, thiamine Endocrine Acute Vascular Toxins,Drugs Heavy Metals I WATCH DEATH

5 Clinical Presentation of Dementia
Always associated with cognitive disturbances and functional impairments Visuospatial impairments and behavioral disturbances are usually seen as well Specific symptoms will vary by type of dementia (Frontal lobe dementias present with personality change and executive dysfunction to a much greater degree than memory impairment)

6 Memory Impairments Difficulty learning or retaining new information (repeated conversations) Information retrieval deficits (can’t recall names, list generation deficits) Personal episodic memory impairment (misplacing items) Declarative (semantic) memory (WHAT) > procedural memory (HOW)

7 Language Deficits List-generation deficits – verbal fluency (esp. in AD) Word-finding difficulties (naming problems) Less complex sentence structure Relatively preserved auditory comprehension (can understand directions)

8 Visuospatial impairments
Visual recognition impairments (trouble recognizing familiar faces - CAPGRAS syndrome possible) Spatial deficits (getting lost in familiar surroundings, 3-D drawing deficits, constructional apraxia)

9 Functional Impairments
Deficits appear first in IADLs (managing finances, driving, shopping, working, taking medications, keeping appointments) Eventually problems with ADLs (feeding, grooming, dressing, eating, toileting) Rate and specific pattern of loss will vary by individual and somewhat by diagnosis NB: Functional impairment and performance on cognitive testing may not correlate strongly early in the course of dementia

10 Behavioral Symptoms PERSONALITY CHANGE: Occurs early
Nearly universal and often the main focus of treatment. Inability to manage these symptoms is highly correlated with institutional placement. PERSONALITY CHANGE: Occurs early passivity (apathy, social withdrawal) disinhibition (inappropriate sexual behavior or language, loss of social graces, aggression) self-centered behaviors (childishness, loss of generosity)

11 Epidemiology: Prevalence increases with age
*Lower numbers represent moderate to severe dementia

12 Incidence Of Alzheimer’s Disease by Age

13 Diagnostic Approach Early Detection & Screening
Careful history from patient and reliable informant PE with focus on neurological exam and cognitive testing Cognitive testing tools such as MMSE are helpful. Score below often concerning depending on premorbid abilities Functional Assessment tools such as the Functional Activities Questionnaire

14 Primary Care Screening Tools
MMSE (‘normal’ varies somewhat by age and educational level – an 80 y/o with only 4 years of education would be expected to only get a 19/30) Clock Test – easy to do, quick. Draw a clock, put numbers in correct locations, set hands to ‘10 til 2’. List generation – number of animals that can be named in 60 seconds. <12 is definitely abnormal, is marginal. Can also do words beginning with letter ‘F’ in one minute is normal. Often very impaired in Alzheimer’s and some types of FTDs. Trails B testing is useful if frontal lobe deficits suspected (e.g. fronto-temporal dementias, AIDS dementia) ‘Go No-Go’ Testing (inability to inhibit responses)

15 MMSE ‘norms’ by Age and Educational Level
18-24 23 28 29 30 35-39 27 50-54 22 70-74 21 26 80-84 19 25

16 Diagnostic Work-Up This is done to
(1) rule out disorders besides dementia (e.g. delirium) (2) to identify reversible/treatable dementias (13+%) (3) to clarify the specific dementia syndrome Routine Assessment: CBC with diff, serum electrolytes, Ca++, glucose, BUN/CR, LFTs, TFTs, B12 & folate, U/A, RPR, head imaging When indicated: Sed. rate, HIV, CXR, heavy metals, LP, EEG, functional imaging, Lyme titers, endocrine studies, rheumatologic studies, Neuropsychological Testing

17 Guidelines For Use of Specialized Testing
LP: Suspicion of metastatic CA, CNS infections, neuropsyphilis, hydrocephalus, vasculitis. Also for dementia <55 and rapidly progressive dementias Neuroimaging - consider in all new cases. However without focal symptoms or signs, seizures or gait disturbances in an individual over age 70 - consider this optional Functional Imaging (SPECT, PET, MRS, fMRI): to clarify type of dementia when necessary (and in the future to track course of illness and response to tx) EEG - can help distinguish delirium from dementia, can help with seizure disorder and JCD

18 Neuropsychological Testing
Cognitive testing and functional testing are at odds or there is suspicion of early dementia in a high IQ individual with normal MMSE Mild impairment in a person with: low IQ or limited education, trouble with English, impairments less than 6 months Determining capacity for legal purposes when deficits are mild

19 Mild Cognitive Impairment
Some cognitive deficits apparent on testing but not to dementia level (MMSE 24-29) range Minimal, if any, functional impairments 13-15% per year progress to dementia (A.D.) but not all progress and some improve Predictors of progression: ApoE4 alleles, poor performance on cued recall and hippocampal atrophy by MRI

20 Pseudodementia More appropriately called ‘reversible dementia’
The classic case is ‘depressive pseudodementia’ with ‘overstated’ cognitive impairments due to decreased concentration and poor effort However, depression may be a risk factor for dementia 50% of elderly patients with depressive pseduodementia have Alzheimer’s at 5 year follow-up

21 Late-Life Depression Def’n: First Major Depressive Episode occurs after age 65 High correlation with dementia (50% go on to develop dementia within 3 years!) Many of these depression may be vascular or post-stroke depressions

22 Most Common Dementias Alzheimer’s Disease (AD) (50-75%)
Lewy Body Dementias (DLB) (10-30%) Vascular Dementias (VaD) (15-20%) Alcohol-related dementias (including Korsakoff’s (infrequent) and etoh-induced)) HIV dementia - most common dementia in those under age 55

23 Classification of Dementias
Primary versus secondary based on the pathophysiology leading to damaged brain tissue Cortical versus sub-cortical depending on the cerebral location of the primary deficits Reversible versus irreversible depending on optimal treatment expectations Early (before age 65) versus late onset

24 Economic Burden $80 to $100 billion per year in total treatment costs
Alzheimer’s disease is the third most expensive disease to treat in the United States, following cancer and heart disease Currently 4 million people have Alzheimer’s disease in the U.S. More than $213,000 per family for the remainder of the patient’s life, including direct and indirect treatments costs ($47,000 per patient per year)

25 General Treatment Principles
Treatment Of Underlying Disease Process (Primary Treatment) Management Of Behaviors and Symptoms (Secondary Treatment) Caregiver Support and Education

26 Reversible Dementias May become irreversible if not treated soon enough Many dementias may be arrestible if not fully reversible Rule out ‘depressive pseduodementia’ and delirium which can mimic dementia Some reversible dementias include: hypoT4, B12 def., some infections and tumors, drug-induced syndromes, etc.

27 Primary Treatment Strategies (for progressive dementias)
1. Prevention Identify risks and mitigate Develop neuroprotective strategies for those at risk 2. Slow or halt progression of illness Understanding pathophysiology leads to treatment ideas 5 year delay in onset ---> 1/3 decrease in prevalence Delaying institutionalization by 1 month saves $1.2 billion/yr 3. Reverse symptoms Compensate through augmentation of remaining neurons or other systems Reversal of destructive processes & regeneration of tissue

28 Delayed Onset Incidence

29 ALZHEIMER’S Pathophysiology
Neuritic plaques -extracellular - abnormal insoluble amyloid protein fragments Neurofibrillary tangles - intracellular - disturbed tau-microtubule complexes (hyperphosphorylated tau) Cholinergic system degeneration with significant loss of neurons in certain areas (such as Nucleus Basalis of Meynert) Degeneration often begins in enterorhinal cortex and progresses to other limbic structures

Reduce Serum anticholinergic load Precursor strategies (e.g. lecithin and choline) Receptor/synaptic strategies Metabolic strategies (anticholinesterases)

31 Serum Anticholinergic Load & Cognitive Impairment
90% of community elderly sample had detectable SA levels An SA level >2.8 pmol/Ml was 13X more likely to be associated with an MMSE of 24 or less in the general elderly population than in those with undetectable SA levels Univ Of Pittsburgh, AAGP 5th Annual Meeting, 2002

32 Commonly Prescribed Non-Psyciatric Drugs with Significant Anticholinergic Activity
cimetidine & ranitidine prednisolone theophylline digoxin/Lanoxin furosemide nifedipine diphenhydramine (OTC) To a lesser extent: codeine, warfarin, dipyradimole, isosorbide dinitrate

33 Current AChE Inhibitors
*promotes binding of acetylcholine



36 Anticholinesterase Side Effects (i.e. procholinergic)
GI – nausea, vomiting, diarrhea, increased gastric acid secretion Muscle cramps Fatigue Insomnia Syncope (2% vs 1% for placebo) (?bradycardia)

Calcium channel modulation and excitatotoxic systems attenuation (such as memantine) Anti-inflammatory/immunosuppressive strategies(e.g. NSAIDs) Gene therapy for defective protein regulation Toxin removal (Desferroxamine, clioquinol) / Ventriculoperitoneal shunting (COGNIShunt) Amyloid Protein strategies Other Neuroprotective strategies NGF -- see previous discussion. NGF can’t cross blood-brain barrier so must be given intrathecally. Dr Winblad in Stockholm has used it on 2 patients “strongly improved memory”, side effects include pain, anorexia and wt. loss.

38 Neuroprotective Strategies
Nerve Growth Factor Acetyl-l(levo) carnitine (ALCAR) Estrogen Homocysteine reduction( folate, B6, B12) Antioxidants (Vit E, Gingko, deprenyl) ‘Statins’ (Lipitor, Pravachol) (may lower abnormal amyloid levels) Rosiglitazone (Avandia) -anti-inflammatory, amyloid processing modulation activities Nutraceuticals

39 Nutraceutical Strategies
Vitamin E (antioxidant) Homocysteine Reduction (folate, B6, B12) Beta-carotene – Physician’s Health Study II found a cognitive protective effect of 50 mg every other day over two decades of use Gingko (antioxidant) Resveratrol

40 Vitamin E Potent antioxidant properties
Has been shown to slow progression at least as much as Deprenyl in one head-to-head study Recent study showed no difference from placebo in preventing progression from MCI to AD over 3 yrs Few side effects even in high doses, though recent studies in Europe suggest a higher death rate in those on hi-dose Vitamin E Doses used in recent studies: up to 1000 IU bid Consider IU per day for prevention May work better if combined with Vitamin C

41 Days

42 Estrogen At this point the summary of many studies suggests that Hormone replacement therapy (HRT) is questionably effective in slowing the onset of AD in some women The earlier started, the better. Limited exposure may be best. Progesterone may be detrimental Tacrine response can be enhanced by Estrogen WHY? neurotrophic effects, incr. ChAT, high serum E2 suppresses Apo E

43 Statins Lovastatin(Mevacor), pravastatin(Pravachol), simvastatin(Zocor), atorvastatin(Lipitor) May prevent aggregation of B-amyloid* in the brain by preventing cholesterol build up. May activate alpha-secretase. Conflicting evidence – recent U of Wash study did not find a benefit, but looked at older individuals on statins only a short while. Earlier studies were more positive Not sure if all these drugs are equal… Ability to enhance tissue plaminogen activator (tPA) and thus production of plasmin may be important. Plasmin may activate alpha-secretase and can also increase production of BDNF. *AKA amyloid-beta peptide or ABeta

44 Memantine Glutamate is the principal excitatory neurotransmitter in brain regions associated with cognition and memory (i.e. it stimulates cholinergic neurons) Glutamate hypothesis of dementia suggests that overactivation of these neurons leads to excitatoxic damage to these brain areas (by allowing calcium to continuously ‘leak in’ to cells). It is post-synaptic receptor sensitivity rather than excess release of glutamate that is the problem. Memantine is a weak antagonist of glutamate-gated NMDA receptor channels which prevents overactivation during memory formation but allows normal function

45 NSAID Use & AD in Elderly Patients
2708 patients enrolled Examined NSAID use and prevalence of Alzheimer’s Disease NSAID users had ~50% lower risk of being affected by AD Aspirin trended this way but was not significant Treatment studies have not shown any consistent benefits yet however. Landi, et al, Am J Geriatric Psychiatry, March-April, 2003

46 Abnormal Amyloid Protein Strategies
Most genetic mutations associated with AD affect amyloid processing Senile plaques contain abnormal amyloid B fragments (that precipitate out of solution easily) Attack enzymatic pathways that lead to production of abnormal type and amount of amyloid ( beta or gamma-secretase inhibitors) Enhance alpha-secretase system to promote normal amyloid Prevent aggregation (NSAIDS may do this!) Alter the abnormal gene expression GAG mimetics (glycosaminoglycans) –Alzhemed – interferes with formation of insoluble amyloid protein fragments

47 Reversal Strategies Destroy the current plaques/amyloid
Vaccination Strategy: AN-1792 vaccine is in testing. This is an amyloid B protein fragment which can induce antibodies that bind to plaques and activate microglial destruction processes. Trial halted b/o menigoencephalopathies ‘Plaque busters’ Alzhemed prevents Amyloid B fragments from forming fibrils Clioquinol - A metal-protein-attenuating compound (MPAC) that inhibits zinc and copper ions from binding to beta-amyloid, thereby helping to dissolve it and prevent it from accumulating. Transthyretin shows promise at interfering with toxic effects Generate new tissue - neuroregeneration strategies (STEM cells) neurotransplantation strategies

48 Other Drugs in the Pipeline
Tau protein modulators (to prevent abnormal phosphorylated ‘tau’ protein Beta and gamma-secretase inhibitors Alpha secretase stimulators Bryostatin – CA drug that stimulates brain protein production. Reduces B-amyloid levels in mice, enhances memory and learning. New generation NSAIDS (flubiprofen) – testing in humans looks promising Immune enhancers (immunoglobulin) New vaccines and new anticholinesterases (huperzine)

49 Caregiver Burden Alzheimer’s caregivers spend an average of 69 to 100 hours per week providing care Caregivers of patients suffering from dementia(compared to control subjects) reported: 46% more physician visits Over 70% more prescribed drugs More likely to be hospitalized More than 50% of caregivers are at risk for clinical depression

50 Staging of Dementias MILD: difficulties with checkbook maintenance, complex meal preparations, complicated medication schedules MODERATE: difficulties with simple food preparation, household or yard work. May need some assistance with self-care SEVERE: Need considerable assistance with feeding, grooming and toileting PROFOUND: Largely oblivious to surroundings, totally dependent TERMINAL: Bed bound; require constant care

51 Common Associated Problems
depression (occurs in 20-40% - esp. AD and VaD) psychosis (occurs in %) - usually see paranoid delusions (theft, infidelity) wandering/purposeless activity agitation/threatening behavior sleep disturbances delirium - minor insults can lead to major decompensations Common Delusions ‘People are stealing things’ ‘The House is not one’s home’ ‘Spouse is an impostor’ - may lead to violence ‘Abandonment’ - may be based on awareness of burden ‘Infidelity’ purposeless activity is also known as cognitive abulia.

52 Behavioral Problems in AD
Almost universally a problem at some point 60% of AD at any one time exhibiting significant symptoms (usually delusions and/or agitation) Common problems by order of prevalence: agitation depression delusions/psychosis Additional behavioral problems disinhibition, apathy, personality change, anxiety, wandering, insomnia

53 Causes of Behavioral Problems
Biological (due to the disease process itself e.g.) Psychological (loss of function and autonomy, attempts to maintain some control, denial of deficits, etc.) Social (family distress, economic issues, family conflicts over care) Environmental (increased sensitivity to changes, issues of safety, etc.)

54 General Treatment Strategies
Define symptoms clearly Rule out other psychiatric illness (e.g. MDD) Rule out medical causes for the symptoms (e.g. intercurrent illness, medication reactions, etc.) Identify non-pharmacologic strategies Pharmacotherapy

55 Environmental Strategies
Identify provocations and rectify if possible Appropriate re-orientation strategies Optimize sensory input [i.e. correct visual and hearing impairments] Behavior management strategies that respect the patient’s need for control and autonomy (announcing intentions, single-step instructions e.g.) Optimize physical activity, social stimulation, reminiscing

56 Management Issues Alleviate patient’s distress
Reduce care-giver burden Delay institutionalization Assure safety Patient’s often become ‘more like themselves’

57 Caregiver information and support
Caregivers should: Encourage independence for the Alzheimer’s patient without sacrificing security Assist the patient, but only if necessary (i.e. allow the patient as much control as possible) Learn to compromise Develop ways to share activities Establish a support network; get other family involved Educate themselves (

58 Depression and Alzheimer’s
Common early in the course of the illness Incidence 40-50% Use SSRIs first; avoid anticholinergic antidepressants ECT can be helpful but may temporarily worsen cognitive symptoms

59 Treatment of Depression
Recognize that irritability and/or apathy /withdrawal may be indicative of depression Allow patient choices and control Identify pleasurable activities (such as singing old songs, pet therapy, etc.) Cognitive enhancers (e.g. Aricept) may help Consider Ritalin for apathy, poor appetite

60 Agitation Non-aggressive Aggressive
verbal: complaining, constant requests for attention, repetition of words, constant talk, screaming physical: pacing, disrobing, stereotypies, trying to get to a different place Aggressive Verbal: threats, name calling, obscenities Non-verbal: biting, scratching, spitting, kicking, pushing, swinging fists

61 Treatment of Agitation/Violence
Identify and reduce provocative stimuli if possible Optimize communication with patient Environmental modifications Pharmacotherapy - target underlying cause (neuroleptics, antidepressants, mood stabilizers, beta blockers, buspirone, trazodone)

62 Medications for Agitation
Buspirone – Takes a while to work Antidepressants (SSRIs, Trazodone) Anticonvulsants (esp. valproate) Atypical Antipsychotics (stroke risk concerning) Low dose narcotics? Marinol? Estrogen? Benzos – ataxia, worsening memory and disinhibition are problematic.

63 Treatment of Psychosis
Recognize common delusions as relating to impaired STM (improving memory may help - e.g. donepezil) Delusions often fade with time even without tx Traditional antipsychotics Low potency (chlorpromazine)– orthostasis, sedation, anticholinergic High potency (haloperidol)– EPS/TD but otherwise well tolerated New generations drugs (e.g. olanzapine, quetiapine, risperidone)- less EPS/TD but still see anticholinergic, BP and sedative effects

64 Atypical Antipsychotics & Risk of Serious Adverse Events
Retrospective review revealed a small (2-3%) but ~2 fold increase in risk of stroke in demented patients receiving these agents compared to placebo.12 FDA required ‘Black Box’ warning due to 1.6 to 1.7-fold increase in mortality in pooled sample of >5000 persons with dementia exposed to these agents (in particular this was found in studies of olanzapine, risperidone and aripiprazole) 12Hermann N, et al. CNS Drugs 2005;19(2):91-103

65 Atypical Antipsychotics & Risk of Serious Adverse Events
The risk with traditional antipsychotics may be even higher.13 Recent meta-analysis of 15 trials (some unpublished) by Schneider in JAMA14 confirmed a small increase in death with these agents compared with placebo. This was significant for the pooled data but not the individual drug data. The OR was 1.54 13Gill S, et al. BMJ 2005;330(7489): Schneider LS, et al. JAMA 2005;294(15):

66 Recommendations on Use of Antipsychotic Agents in Dementia
Have a justifiable use -> severe, distressing psychotic symptoms e.g. Do not use first-line for non-psychotic behavioral disturbances. Use lowest amounts for shortest possible times Caution patients and family about risk but remember that older agents may be worse, and there is little data on other psychotropics to suggest that they are safe.

67 Treatment of Wandering
Lock doors (but in a way that is confusing for AD patient but not others) Wander guards Decrease agitation (see above) Environmental changes (such as using visual patterns to redirect wandering, wander gardens)

68 Treatment of Insomnia Sleep hygiene (avoid caffeine, etc.)
Treat causative psychiatric or medical disorders Phsysiological remedies - melatonin, warm milk, lavendar oil Medications - Benadryl, benzos, sedating antidepressants or antipsychotics (all these drugs can make memory and confusion worse) Light Therapy - to reset natural circadian rhythms for sleep

69 Sexually Disinhibited Behavior
Includes: sexual talk, sexual acts, implied sex acts, false reporting Treatment or sexual aggression and/or disinhibition Psychosocial : reminders, move to private room, clothing modification, staff education Pharmacological: SSRIs, antiandrogens (medroxyprogesterone acetate, cyproterone acetate), estrogen patches

70 Wandering Behavior 4-26% of dementia patients in Nursing Homes wander
If not located within 24 hours, 46% will die (usually of hypothermia or dehydration) TX: Vigilance, wander guards, complicated exits, reduce agitation Safe Return – nationwide identification program – alert system for law enforcement officials, TV stations

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