1	Pennsylvania Neurological Associates www.pneuro.com
2	The Death of Alzheimer’s Disease
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4	This Talk is About: Pipe dreams and practical matters The end of Alzheimer’s disease in time to be useful to “baby-boomers” (ME) Some useful new treatments
5	To get to Amyloid Hypothesis: The death of Alzheimer’s in our day Cholinergic Hypothesis and current treatments
6	Alzheimer Disease Dissolution of the Personality Inexorable Progression
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10	Artistic Regression Distortion – comic-grotesque representation Condensation – filling to overflowing Transformation (neomorphism) – anatomic changes and strange facial features (physiognomy) Stereotype – ornamental stereotype and repetition of particular motives Woodenness – geometrical and diagrammatic design and pictures enclosed with a frame, lack of depth (lack of shading) and lack of movement (wooden rigidity) Disintegration – neglect of spacial relationships between objects and loosening of physiognomy of human beings and animals. Regression – relapse into primitive or child-like drawings and lack of perspective Maurer K, Frolich L, ALZHEIMER INSIGHTS Paintings of and Artist With Alzheimer Disease
11	Clock Drawing
12	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
13	Life expectancy with Dementia 3.3 years, comparable to some malignancies In patients diagnosed with dementia Wolfson et al NEJM 2001;344:1111-1116
14	Time course in deterioration
15	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
16	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
17	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
18	Alzheimer Brain Atrophy
19	Risks Age ApoE4 Down’s Head injury ?Low education ?Family History
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21	Stanley Prusiner Nobel 1997
22	Thesis: Degenerative Disease is caused by the accumulation of toxic substances Deranged metabolism over long pds of time. Primarily diseases of elderly As in cholesterol and homocysteine in atherosclerosis
23	Neurologic Diseases attributed to Protein deposition Alzheimer disease: Aβ42 Amyloid Angiopathy: Aβ42 Huntington Disease: Huntingtin Prion Disease: PrP sc “Tauopathies: Pick’s, FT dementia, PSP Parkinson Disease, Lewy body Dementia (alpha synuclein) Spino-cerebellar Degenerations: Ataxins ALS: Neurofilament Macular Degeneration: A2E
24	Macular Degeneration=“Age Related Maculopathy” 5% of 60 year olds, 20% of 80 year olds Disorder of Phagocytosing cells in Retinal Pigment epithelium Accumulation of drusen or lipofuscin in Retinal Pigment Epithelium Genetic forms: may be “A2E” accumulation Retinal Alzheimer’s Disease
25	Macular Degeneration
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27	First Hints to Causation Genetics Familial Alzheimer Disease Trisomy 21
28	Alzheimer Genes: Chromosome #s 21: Abn APP Gene <5%* 14: Presenilin 1 18-50%* 1 : Presenilin 2 <1%* 19:APOE-epsilon 4: Incr risk in Caucasions 19:APOE-epsilon2 on Chr 19: decr risk *of early-onset Disease
29	Apolipoprotein E4 Variant alleles E2,E3 Variants differ by only 1 amino acid E4 is present in 64% of late-onset Alz patients as 34% of unaffected controls 2 copies (homozygote) of E4 increases risk of Alz from 45% to 91%
30	All have in Common: Increased Accumulation of b Amyloid Abnormal Accumulation Defective Degradation
31	Alzheimer Disease Cerebral Amyloidosis
32	The Amyloid Hypothesis
33	Pathogenesis Beta-Amyloid Accumulation Decrease in Acetylcholine, AchE Injury Free-Radical Formation Genetics Polygenic ApoE4 FAD
34	Characteristic Changes Pathology Tangles, plaques, Granulo-vacuolar degeneration, Atrophy,neuronal loss Biochemistry Decreased Ach, AchE Imaging Atrophy Decreased metab activity in post’r cerebral association Cortices
35	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.
36	Amyloid Plaques Between Cells (extra-cellular) Appear before Tangles do Associated with Microglia (inflammation) (microglia are phagocytes of the brain)
37	Amyloid Precursor Protein 695-770 Amino Acids Transmembrane protein Beta-Amyloid is snipped out precursor protein Beta-Amyloid- transmembrane component
38	Cast of Characters Amyloid Precursor Protein (APP) Secretases – alpha, beta, Gamma Enzymes that cut up Amyloid Precursor Protein Beta-Amyloid (or Aβ42) Beta-Amyloid is the villain Setting: The neuron cell membrane
39	Secretase Steps Alpha then Gamma – OK Beta then Gamma – yields Beta Amyloid 40 Amino Acid fragment is OK but minority cut into toxic 42 Amino acid fragment which constitutes plaque (Aβ42)
40	Presenilins Early Onset Alzheimer's Trans-membrane Protein Cleavers PreI: Chr 14, PreII:Chr 1 Knockout for these proteins: No Beta Amyloid Forms of Gamma-Secretase??
41	Are “Pre-Senilins” forms of Secretase??
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43	Amyloid Plaque
44	Amyloid
45	Pathogenesis of Senile Plaque Toxic Beta Amyloid fragments build up outside the cell E4 may be selectively removed from the extracellular space in place of beta-amyloid Beta-Amyloid is toxic and leads to other pathology
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47	Cutting β-Amyloid Precursor Protein Alpha and Gamma Secretase give rise to harmless p3 protein Beta then Gamma secretase yield either: Harmless 40 amino acid residue of Beta-Amyloid OR Toxic 42 Amino Acid residue of Beta Amyloid
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49	Gamma Secretase: a trans-membrane protease
50	Beta Amyloid Mediated Damage Ca++ Deregulation Creation of Free Radicals Immune Aggregation
51	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
52	Mechanism of Amyloid destruction Liberating Calcium in Cells Damaging Mitochondria Enhancing inflammatory (Microglial) Response
53	New Strategies Beta-Amyloid Vaccine Beta and Gamma Secretase Blockers Zinc and Copper Chelators
54	Strategies to Prevent and treat Alzheimer’s 1. Inhibition of the proteases (enzymes) that produce Aβ42 ; 2. Inhibition of Aβ42 aggregation that precedes A deposition; 3. Inhibition of Aβ42 -induced neurotoxicity Vaccine or antibody to Aβ42
55	Dennis Selkoe & Howard Weiner
56	Mouse Trials of Vaccine Nasal Administration Genetically affected mice make excessive Beta Amyloid Mice show evidence of Dementia 50% reduction in plaque formation Improvement on tests Human phase II trials begin this year
57	Elan Pharmaceutical trial In PDAPP mouse (a genetically engineered mouse model with Alzheimer’s-like pathology) AN-1792, both reduces pre-existing deposits of amyloid and inhibits accumulation
58	Gene linkage Long arm of Chromosome 10 in late onset Alzheimer ?Connected with degradation of Beta Amyloid? Insulin processing protein Rudy Tanzi Dec22,2000 Science
59	Treatment Cornerstones Cholinesterase Inhibitors Ancillary Symptoms Anxiety Agitation Disorientation and Wandering Sleep Disturbance Placement Caring for Caretaker
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61	Cholinergic hypothesis Diffusely projecting area: Nucleus Basalis of Meynert Layers I and II major cholinergic cortical innervation Amygdala and hippocampus lgest innervation
62	Acetylcholine Correlation with Dementia and markers of ACh metabolism: CAT: choline acetyl transferase AChE: acetylcholinesterase (breaks down ACh)
63	Receptor Changes M1: post-synaptic intra-cortical cells M2: pre-synaptic asc cholinergic axon terminals: most reduced in Alz disease Nicotinic receptors: pre-synaptic but promote release of Acetylcholine
64	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.
65	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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67	Cholinesterase Blockers
68	Cholinesterase blockers
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70	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
71	Acetylcholine Formation: ChAT and Acetyl-CoA Degradation: AchE and Butyryl-cholinesterase
72	Butyrylcholinesterase Role is minor in normal brain Proportionate activity increases in Alzheimer brain
73	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
74	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%).
75	Reminyl Average approx. 4 pts on ADAS-Cog Scores
76	Galantamine Common snowdrop (Galanthus nivalis) Binds AChE Modulator of Nicotinic Receptors ?Enhanced Sexual Fxn Mythology Iliad, Circe, Atropine, Jimsonweed
77	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
78	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]
79	Rivastigmine Shown to improve: Global function, behavior, and Cognition
80	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.
81	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
82	Rivastigmine: GI Effects 18% Men, 26% Women at Max dose
83	ADAS-Cog Effects
84	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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86	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
87	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.
88	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)
89	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
90	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
91	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
92	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 patients on coumadin Selegiline, Vit E treatment - NEJM 1997
93	Behavior Problems Personality change: apathetic or more impulsive Anxiety: apprehension over upcoming events Aggression: physical or verbal
94	10 Warning Signs: Dysfunction on Job Problem with Language function Difficulty performing Familiar Tasks Disorientation Poor Judgment Altered Abstract thinking
95	More Signs Misplacing Objects Personality Change Altered Mood and Behavior Loss of initiative
96	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
97	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
98	Lab Supports of Diagnosis Test for Aβ42 and Tau in CSF (ADmark©) APOE E4 allele
99	Brain Activation f-MRI E4 dose effect on intensity of activation and number of areas activated NEJM Mazziota et al. 343:450, 8/17/2000
100	Other Pathology
101	Granulo-vacuolar Degeneration
102	Granulo-vacuolar degeneration 5 m clear intracytoplasmic vacuole Argyrophillic core Pyramidal cell region of hippocampus
103	Neurofibrillary Tangles
104	Neurofibrillary Tangles
105	Neurofibrillary Tangle
106	Neurofibrillary Tangles Paired Helical Filaments associated with Tau which binds to microtubules Phosphorylation of Tau inhibits its ability to stabilize microtubules Leads to microtubule agglomeration as PHF Test for Tau in CSF
107	Neurofibrillary Tangle Tau protein –Ass’d with microtubules Correlates more with degree of dementia Appear after than Senile plaque Not Specific for Alzheimer Disease
108	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.
109	Fuel and Longevity Daf-2 gene in C. elegans When not functioning lifespan increases from 10 to 30 days An insulin receptor gene in humans Rat experiments with caloric reduction Monkey and human receptors Gary Ruvkun, Harvard Med’l School
110	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
111	Multi-infarct dementia
112	Hachinski Score for Dx of Vascular Dementia Abrupt onset Stepwise deterioration Fluctuating course: improvement between strokes Relative preservation of personality Nocturnal confusion Depression
113	Hachinski Score (cont’d) Somatic complaints Emotional incontinence History of hypertension Evidence of atherosclerosis Pvd, MI Focal Neurological symptoms (TIA) Focal neurological signs
114	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
115	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
116	Agitation and Dementia Structure and routine. Follow regular, predictable routines. Keep things simple. Distract.
117	Behavior Why is depression relatively uncommon?? Anosognosia for dementia
118	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
119	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.
120	Sleep and Anxiety Nonpharmacologic: Daytime stimulation, adequate supervision, avoidance of napping. Neuroleptics: may be helpful for delusion and agitation. 20% may get worse.