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Keys to Care Alzheimer Disease

Alzheimer’s Burden 4 Million Americans 14 Million Projected by 2050 1/10 over 65 85+ one of three has AD Life expect: 8 years in U.S .$110 B. in yr 2000 Half of all NH patients $12500-70000/person year, avg lifetime cost=$174000

Alzheimer’s Burden (cont’d) Prevalence doubles every 5 years after 65 360,000 new cases/yr Higher in non-Caucasians whose numbers are growing in population 65+ now 13% but will reach 18% by 2025 Sltly more than 50% receive care at home

Neurological Diseases Alzheimer’s             4 Million                $110 Bn Affective Disorders 17 Million              $44Bn Drug & etoh             15Million              $240Bn Intractable Pain                                      $65 Bn Parkinson’s               500,000                 $5.6Bn Schizophrenia            2 Million              $30Bn Stroke                      700,000/yr              $30Bn MS                           350,000 Source:JAMA 285:594(2001)

Neurological Disease (Prevalence) Alzheimer Disease:        4 million Stroke:                            3-4 Million Traumatic Brain Inj:       2.5-3.7 Million Epilepsy:                         1.75 Million Parkinson’s:                    1.5 Million

Alzheimer Genes 21: Abn APP Gene 14: Presenilin 1 1 : Presenilin 2 19:APOE-epsilon 4: Incr risk in Caucasions 19:APOE-epsilon2 on Chr 19: decr risk

Future Burden 2011: first baby boomers turn 65 18% of population by 2025 85+ now 4 million, 8.5 million by 2030 50% of Alz pts are at home, 50% in care

Risks Age ApoE4 Down’s Head injury ?Low education ?Family History

Alzheimer Disease Dissolution of the Personality Inexorable Progression

Keys of Therapy Early Recognition of Disease Cholinesterase Blockers Treatment of Ancillary Symptoms Maintaining Patient in own Environment Family Support

Diagnosis Index of Suspicion Age! Sensitivity to Patients and Family

Vigilance Now Important because there are now early treatments that help.

10 Warning Signs: Dysfunction on Job Problem with Language function Difficulty performing Familiar Tasks Disorientation Poor Judgment Altered Abstract thinking

More Signs Misplacing Objects Personality Change Altered Mood and Behavior Loss of initiative

Diagnostic Criteria for Dementia Multiple Cognitive Deficits with Both Memory Impairment plus one or more of foll’g: Aphasia, Apraxia, Agnosia, Executive function Impaired abstraction, judgement Impaired Social or Occupational Function DSM IV (1994), 133-35

Diagnostic Criteria (cont) Cognitive Deficits are not due to other processes incl Substances Systemic processes Delirium and acute conditions Not better accounted for by another Axis I disorder

Diagnosis: Keys Not patient, but Persons Other than  patient  complain of decreased cognitive function. Backing away  from or ceasing to participate in previous hobbies and activities Take spouse, signif other, employer reports seriously!!

Alzheimer Dementia Often “anosognosia” unawareness of problem on part of sufferer Also denial

Pseudo-Dementia Often patient will themselves complain of memory loss Younger patient Memory problem complained of Spouse and co-worker find no problem Pre-occupation Anxiety is the enemy of recall

Pseudo-Dementia Some sharp or compulsive persons notice a normal slipping with age Ready recall Word-finding Again, no complaints from others Difficult distinction May require psychometrics to distinguish

Pseudo-Dementia Associated with severe depression Lack of reactivity “psychomotor retardation” More abrupt onset Some old folks have combined organic dementia and severe depression

Stages: Mild Routine loss of recent memory Mild aphasia or word-finding difficulty Seeks familiar and avoids unfamiliar places Some difficulty writing and using objects Apathy and depression Needs reminders for some ADL’s

Stages: Moderate Chronic loss of recent memory Moderate Aphasia Gets lost at times even inside home Repetitive actions, apraxia Possible mood and behavioral disturbances Needs reminders and help with most ADL’s

Late Stage Mixes up past and present Expressive and receptive aphasia Misidentifies familiar persons and places Parkinsonism and falls risk More mood and behavioral disturbances Needs help with all ADL’s, Incontinent

Evaluation Thorough Hx/Pex Mental Function Evaluation CBC, Chems, RPR, LFT’s,Thyroid, B12 HIV testing in selected cases Imaging (CT, MRI) in most cases Neuropsych testing if dx is uncertain LP in doubtful cases Tau and amyloid beta Apolipoprotein genotype??

Evaluation: compare betw visits Folstein Mini-Mental Status Clock-drawing Scale of level of Function as reported by family member Language function

Rule Out Alcohol Depression Drug s Metabolic Derangement Nutritional Deficiencies Infection

Causes of Dementia Alzheimer –55% Vascular -  20% Lewy Body –15% Pick’s and lobar atrophy –5% Other 5% Small,GW et al JAMA 1997,278:1363-71, APA, Am J Psychiatry 1997,154 (suppl)1-39; Morris JC Clin GeriatrMed. 1994,10:257-76

Hachinski Score for Dx of Vascular Dementia Abrupt onset Stepwise deterioration Fluctuating course: improvement between strokes Relative preservation of personality                            Nocturnal confusion Depression

Hachinski Score (cont’d) Somatic complaints Emotional incontinence History of hypertension Evidence of atherosclerosis Pvd, MI Focal Neurological symptoms (TIA)    Focal neurological signs

Vascular Dementia CT or MRI critical Either large volume of brain affected, preferably in both hemispheres or multi-infarcts in strategic locations Small Vessel Lacunar State, deep strokes Subcortical deficits Multiple Cortical Infarcts:aphasia, agnosia, apraxia

Pick’s Lobar atrophy Behavioral disturbances precede dementia Disinhibition Exaggeration of previous eccentricities Exhibitionism and overt sexuality Inappropriate humor, loss of social skills Ethnic jokes Slovenly behavior, decr hygiene and cleanliness Distractibility and impersistence Language dysfxn rather than memory

Pick’s Fronto-temporal atrophy on imaging or SPECT or PET scans show decr metabolism “Tau –opathy” Grouped with PSP etc May be familial

“Others” Creutzfeldt-Jakob Cortico-Basal Degen Progressive Supranuclear Palsy Frontal Lobe Dementia

Parkinson Related Dementia Late consequence of Parkinson Disease Hallucination prominent Dopaminergic Meds, anticholinergics are hallucinogenic Parkinson and age related perceptual changes

Parkinson’s and Dementia Diffuse Lewy Body Disease Alzheimer changes in the aged Parkinson-dementia complex Parkinson related diseases Anti-esterases seem effective here too

Treatment Cornerstones Cholinesterase Inhibitors Ancillary Symptoms Anxiety Agitation Disorientation and Wandering Sleep Disturbance Placement Caring for Caretaker

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Cholinergic hypothesis Diffusely projecting area: Nucleus Basalis of Meynert Layers I and II major cholinergic cortical innervation Amygdala and hippocampus lgest innervation

AChE inhibitors Establish a diagnosis of probable AD. Determine the stage of the patient (AChE-I are approved for mild to moderate AD). Discontinue agents with anticholinergic effects. Reduce dosage or discontinue if side effects are intolerable. Monitor efficacy by caregiver report, quantified mental status examination, effects on activities of daily living, or effects on behavior.

AChE’s Cont’d Continue for 6-12 months if any of the efficacy measures indicate benefit or there is stabilization in functional, cognitive, or behavioral deterioration. Continue AChE-I therapy until there is evidence of ongoing cognitive decline. If there is evidence of continuing cognitive decline, reduce the dosage and monitor to determine if there is an acceleration of deterioration.  If deterioration is accelerated, reintroduce AChE-I.

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Cholinesterase Blockers

Cholinesterase blockers

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Types of Cholinergic Receptors Muscarinic – excitatory M1 most common in cortex M2 presynaptic autorecptor governing release in basal forebrain Work via G proteins Nicotinic –Inhibitory Ligand-gated ion channels

Acetylcholine Formation: ChAT and Acetyl-CoA Degradation: AchE and Butyryl-cholinesterase

Butyrylcholinesterase Role is minor in normal brain Proportionate activity increases in Alzheimer brain

AChE inhibitors: Progression? Patients on AChE inhibitors had a slower rate of progression than placebo treated patients Raises the issue of possible biological effect of these agents to slow progression of disease

Galantamine (Reminyl)  Start at 4 mg BID (8 mg/day) for at least 4 weeks, then 8 mg bid  Available in 4 mg, 8 mg, and 12 mg tablets Most frequent adverse events that occurred with placebo, REMINYL 16 mg/day, and REMINYL 24 mg/day, respectively, were nausea (5%, 13%, 17%), vomiting (1%, 6%, 10%), diarrhea (6%, 12%, 6%), anorexia (3%, 7%, 9%), and weight decrease (1%, 5%, 5%).

Reminyl Average approx. 4 pts on ADAS-Cog Scores

Galantamine Common snowdrop (Galanthus nivalis) Binds AChE Modulator of Nicotinic Receptors ?Enhanced Sexual Fxn Mythology Iliad, Circe, Atropine, Jimsonweed

Rivastigmine Exelon Approved in April 2000 for treatment of mild to moderate Alzheimer's disease. Benefits:  Improved activities of daily living, including eating, dressing, and household chores.  Reduce behavioral symptoms, such as delusions and agitation. Improved cognitive function Reduced use of psychotropic medications

Faster Progression yields Increased response Patients with moderate-stage AD (Mini-Mental State Examination [MMSE] scores = 10-17) have a naturally faster rate of disease progression when taking placebo and a larger magnitude of response to cholinesterase inhibitors; patients with mild-stage AD (MMSE scores = 18-26) have a lesser magnitude of response.[28] In addition, a subanalysis of a large rivastigmine trial found that a faster rate of progression before therapy initiation (regardless of disease stage at baseline) predicted a more robust response to treatment.[29]

Rivastigmine Shown to improve: Global function, behavior, and Cognition

Rivastigmine Temporarily inactivates Cholinesterase by forming a Covalent Bond 3 mg bid decreases AChE in CSF by 46% 6mg  bid decreases AChE by 62% Duration of signif inhibition lasts up to 6 hours.

Alzheimer Scales CIBIC-Plus: 1-7 Clinician’s interview-based impression of change with caregiver input 1=marked improvement, 4=nc, 7=marked worsening ADAS-Cog:0-70 Higher scores=greater cognitive impairment Mild to moderate=15-25 6-12 points/yr average deterioration

Rivastigmine: GI Effects 18% Men, 26% Women at Max dose

ADAS-Cog Effects

Rivastigmine Dose: titrate dosage to achieve optimal effect.  Usual dose: 6 to 12 mg/day given BID. Start 1.5 mg bid, increase by 3 mg every 2 weeks.  Available in capsule doses of 1.5, 3, 4.5, 6 mg. Half life: 2 hours Few interactions with other drugs Side effects:  No hepatotoxicity GI disturbances, occur mainly during dose adjustment.

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Aricept (donepezil)  Indicated for mild to moderate Alzheimer's dementia More selective for acetylcholinesterase, the cholinesterase common in the brain, believed to account for the low incidence of GI side effects 5 mg qd for 4 to 6 wk, if tolerate increase to 10 mg qd

Aricept Pharmacology:   Half life: 72-hour Steady states are achieved in 15 days. 94% protein-bound metabolized by the hepatic P450 enzyme system, but few drug interactions have been identified. Adverse effect:   nausea, vomiting, gastrointestinal cramping, diarrhea and muscle cramping. Does not have hepatoxicity.

Behavior Problems  Personality change: apathetic or more impulsive Anxiety: apprehension over upcoming events Aggression: physical or verbal

Behavior cont’d Wandering: can be dangerous, medications not effective  provide a "sheltered freedom". Example: Cover door knob with shoe boxes. Screaming: very disturbing, may be related to pain, delusion or Neuroleptic induced akathisia. ? background music may be helpful. Sleep disruption & Sundowning: very common

Agitation and Dementia  Structure and routine.  Follow regular, predictable routines. Keep things simple. Distract.

Behavior Why is depression relatively uncommon?? Anosognosia for dementia

Simple and Active Break down complex tasks into many small, simple steps that the person can handle Folding towels while one is doing the laundry.  Allow time for frequent rests.  Redirect.   Get the person to do something else as a substitute. A person who is restless and fidgety can be asked to sweep, dust, rake, fold clothes, or take a walk or a car ride with the caregiver. Repetitive simple movement

Distract Offer a snack Put on a favorite videotape or some familiar music  Be flexible.   Know when to back away from a task- a bath or dressing and reapproach later Soothe.   When agitated, do simple, repetitive activities such as massage, hair brushing, or giving a manicure.  Reassure.  Let the person know that you are there and will keep him or her safe.

Sleep and Anxiety Nonpharmacologic: Daytime stimulation, adequate supervision, avoidance of napping. Neuroleptics: may be helpful for delusion and agitation. 20% may get worse.

For Sleep Chloral hydrate, 500 to 1000 mg prn up to 2/d or 10/wk Zolpidem (Ambien), 5 to 10 mg hs prn Lorazepam (Ativan), 0.5 to 1 mg prn (up to 2/d or 10/wk) Buspirone (Buspar), 5 to 10 mg tid for short-term (few weeks) Trazodone (Desyrel), 50 mg hs, may increase gradually to 50 mg bid or tid Melatonin, 1 to 2 mg hs prn (investigational)

Agitation Olanzapine (Zyprexa): 2.5 mg qhs; Max: 10-20 mg/day given in bid. *Quetiapine (Seroquel): 12.5 mg bid; Max: 75 mg bid. More sedating, may cause transient orthostasis.  Risperidone (Risprdal)  0.25-1 mg qd to bid, EPS may occur at 2 mg. Little use for older neuroleptics: Haldol etc

Agitation (cont) Trazadone 25 mg hs, increase as tolerated, Prozac 10-20 mg qam *Sertraline 25-100 mg qam Desipramine 25-100 mg qhs Nortriptyline 10-100 mg qhs *Celexa 20 mg: Citalopram

Agitation (Cont) Anxiolytics: for short term use, long term use may worsen cognitive function  Lorazepam 0.5 - 2 mg Buspar: Takes long to act. Anticonvulsants: Use is common, but questionable. May ameliorate mood fluctuations, impulsiveness  Carbamazepine 100 mg bid, titrate Depakene 125 mg bid, titrate Beta blockers: ?behavioral outbursts

Vit E + Selegiline Slow the progression of AD (Sano et al, 1997). Rate of progression -25% less than the rate in placebo Dose used in study: Vitamin E 2000 I.U. Selegiline 5 mg am, 5 mg noon. Long-term effects unknown. Side effects:  Selegiline: insomnia, confusion, and psychosis. Vitamin E: Can potentially cause a prolonged prothrombin time for pateints on coumadin Selegiline, Vit E treatment - NEJM 1997

Time course in deterioration

Pathogenesis Beta-Amyloid Accumuation Decrease in Acetylcholine, AchE Injury Free-Radical Formation Genetics Polygenic ApoE4 FAD

Characteristic Changes Pathology Tangles, plaques, Hirano bodies, Atrophy,neuronal loss Biochemistry Decreased Ach, AchE Imaging Atrophy Decreased metab activity in post’r cerebral associaation Corices

Senile Plaque A hallmark pathologic lesion specific for AD is senile plaque. Plaques are composed of amyloid-beta (A-beta), which is found in soluble form in the body fluids of patients with AD. Initially, A-beta aggregates into diffuse plaques that lack definite borders. Later, it matures into compact plaques formed of A-beta fibrils that may be toxic to surrounding neurons.

Amyloid

Amyloid Plaque

Neurofibrillary Tangle Abnormal intracellular structure caused by  phosphorylation of the tau protein in the cytoskeleton of the neuron.  Microglial cell proliferation, especially in association with senile plaques, suggests  inflammatory processes play a role in the disease process.

Neurofibrillary Tangles

Beta Amyloid 4.2 kD fragment, 42-43 Abnormal cleavage of Beta Amyloid precursor protein (APP) APP part of family of 70kD transmembrane proteins Beta-Secretase, APP cleaving Protein Injury, ischemia incr APP Amyloid is neurotoxic

New Strategies Beta-Amyloid Vaccine Beta and Gamma Secretase Blockers Zinc and Copper Chelators

Evolving Therapies Vaccine Secretin inhibitors Blocking Amyloid Accumulation