1	Alzheimer’s Disease – Past, Present & Future Talk to the Medical Staff of St. Clare’s Hospital Schenectady, NY July 11, 2006 by Robert S. Stall MD, Geriatrician Clinical Assistant Professor UB School of Medicine / Division of Geriatrics
2	OBJECTIVES Know and understand: Dementia from a historical perspective Diagnosis of Alzheimer’s Disease Pharmacological and nonpharmacological treatment of Alzheimer’s Disease Future of Alzheimer’s Disease
3	Cicero De Senectute “... many old men are so feeble that they can perform no function that duty or indeed any position in life demands. True, but that is not peculiar to old age; generally it is a characteristic of ill-health.” July 17, 44 BC
4	Shakespeare As You Like It 1599
5	Napoleonic Code Article 10 “There is no crime when the accused is in a state of dementia at the time of the alleged act.” 1808
6	Thomas Jefferson Letter to John Adams “Bodily decay is gloomy in prospect, but of all human contemplations the most abhorrent is body without mind.” August 1, 1816
7	Jean Etienne Esquirol Des Maladies Mentales “...a cerebral disease characterized by an impairment of sensibility, intelligence and will... a demented man has lost the goods he used to enjoy; he is a wealthy person turned poor...” 1838
8	Sir William Osler July 12, 1849 – December 29, 1919 The Principles and Practice of Medicine 1892
9	Alois Alzheimer June 14, 1864 – December 19, 1915 Alzheimer A (1907) Ueber eine eigenartige Erkrankung der Hirnrinde [On a peculiar disease of the cerebral cortex]. Zeitschrift fuer Psychiatrie 64, 146; 3 pages
10	Diagnostic and Statistical Manual of Mental Disorders (DSM) DSM ‘Organic brain syndrome’ 1952 DSM II ‘Senile and presenile dementia’ 1968
11	STATISTICS
12	SCHENECTADY DEMOGRAPHICS
13	WHAT IS DEMENTIA? An acquired syndrome of decline in memory and other cognitive functions sufficient to affect daily life in an alert patient Progressive and disabling Not an inherent aspect of aging
14	MEMORY SYSTEMS (from “Current Concepts: Memory Dysfunction”, NEJM Vol 352(7), 17 Feb 2005, pp 692-699)
15	EPISODIC MEMORY (from “Current Concepts: Memory Dysfunction”, NEJM Vol 352(7), 17 Feb 2005, pp 692-699)
16	SEMANTIC, PROCEDURAL, AND WORKING MEMORY (from “Current Concepts: Memory Dysfunction”, NEJM Vol 352(7), 17 Feb 2005, pp 692-699)
17	PREDISPOSING FACTORS (from “Genetics Factors in Alzheimer’s Disease”, NEJM Vol 352(9), 3 Mar 2005, pp 862-864)
18	GENETICS Mutations of chromosomes 1, 14, 21 Rare early-onset (before age 60) familial forms of dementia Down syndrome Apolipoprotein E4 on chromosome 19 Late-onset AD APOE4 allele risk & ¯ onset age in dose-related fashion APOE2 allele may have protective effect
19	DIFFERENTIAL DIAGNOSIS Normal aging Mild cognitive impairment Delirium Depression Vascular (multi-infarct) dementia Dementia associated with Lewy bodies Other (alcohol, Parkinson's disease, Lewy-body disease, Pick’s disease, frontal lobe dementia, neurosyphilis) Alzheimer’s disease
20	NORMAL AGING No consistent, progressive deviations on testing of memory Some decline in processing and recall of new information: slower, harder Reminders work—visual tips, notes Absence of significant effects on ADLs or IADLs due to cognition
21	MILD COGNITIVE IMPAIRMENT Memory problem without deficits in other domains No functional impairment 10%–12% per year progress to dementia
22	DELIRIUM Acute onset Cognitive fluctuations over hours or days Impaired consciousness and attention Altered sleep cycles
23	DSM-IV - VASCULAR DEMENTIA Development of cognitive deficits manifested by: Impaired memory and Aphasia, apraxia, agnosia, disturbed executive function Significantly impaired social, occupational function Focal neurologic symptoms & signs or evidence of cerebrovascular disease Deficits occur in absence of delirium
24	PSEUDODEMENTIA 1 (DEPRESSION) Impaired concentration Lack of motivation, loss of interest, apathy Psychomotor retardation Sleep disturbance ¯ motivation during cognitive testing Cognitive complaints exceed measured deficits Maintain language and motor skills
25	PSEUDODEMENTIA 2 (DEAFNESS)
26	LEWY BODY DEMENTIA Onset: gradual Cognitive symptoms: memory, visuospatial, hallucinations, fluctuations Motor symptoms: parkinsonism Progression: gradual, but usually faster than AD Lab tests: normal Imaging: possible global atrophy
27	FRONTO-TEMPORAL DEMENTIA Onset: gradual, usually age <60 Cognitive symptoms: executive: disinhibition, apathy, behavior changes Motor symptoms: none; may be associated with ALS in rare cases Progression: gradual but faster than AD Lab tests: normal Imaging: atrophy in frontal and temporal lobes
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29	ALZHEIMER’S DISEASE Onset: gradual Cognitive symptoms: primarily memory Motor symptoms: rare early, apraxia later Progression: gradual, over 8–10 yr on average Lab tests: normal Imaging: possible global atrophy, small hippocampal volumes
30	AD VS. AGE-RELATED MEMORY PROBLEMS (from http://www.alzwisc.org/)
31	DSM-IV - ALZHEIMER’S DISEASE Development of cognitive deficits manifested by: Impaired memory and Aphasia, apraxia, agnosia, disturbed executive function Significantly impaired social, occupational function Gradual onset, continuing decline Not due to CNS or other physical conditions (eg PD, delirium) Not due to an Axis I disorder (eg, schizophrenia)
32	PROBABLE AD – DIAGNOSTIC CRITERIA (from “Clinical diagnosis of Alzheimer's disease: Report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer's Disease”. Neurology. 34(7):939-944, July 1984.)
33	PROBABLE AD – SUPPORTIVE INFORMATION (from “Clinical diagnosis of Alzheimer's disease: Report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer's Disease”. Neurology. 34(7):939-944, July 1984.)
34	PROBABLE AD – OTHER CLINICAL FEATURES (from “Clinical diagnosis of Alzheimer's disease: Report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer's Disease”. Neurology. 34(7):939-944, July 1984.)
35	AD UNLIKELY (from “Clinical diagnosis of Alzheimer's disease: Report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer's Disease”. Neurology. 34(7):939-944, July 1984.)
36	POSSIBLE AD (from “Clinical diagnosis of Alzheimer's disease: Report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer's Disease”. Neurology. 34(7):939-944, July 1984.)
37	DEFINITE AD (from “Clinical diagnosis of Alzheimer's disease: Report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer's Disease”. Neurology. 34(7):939-944, July 1984.)
38	SENILE PLAQUES & NEUROFIBRILLARY TANGLES
39	PATHOLOGY
40	HISTORY Current symptoms Time course of changes (ask “when did you first notice a problem?”)
41	AD Warning Signs (from the Alzheimer’s Association)
42	AD Warning Signs (from the National Institute on Aging)
43	ATYPICAL EARLY FEATURES OF AD
44	PHYSICAL EXAM Examine: Neurologic status Cardiovascular status Mental status Psychiatric status Functional status Include: Quantified screens for cognition (eg MMSE, Mini-Cog, CDR, FAST) Consider: Neuropsychologic testing
45	LABS Complete blood cell count Comprehensive metabolic profile TSH B12
46	IMAGING Indications: Onset occurs at age <65 years Symptoms have occurred for <2 years Neurologic signs are asymmetric or focal Clinical picture suggests normal-pressure hydrocephalus Patient has had recent fall or other head trauma Modalities: Noncontrast computed topography head scan Magnetic resonance imaging Positron emission tomography
47	CT
48	MRI & PET (from “Drug Therapy: Alzheimer's Disease”, NEJM Vol 351(1), 1 July 2004, pp 56-67)
49	MMSE
50	“Close Your Eyes”
51	MINI-COG
52	CLOCK DRAWING INSTRUCTIONS
53	CLOCK DRAWING EXAMPLES
54	MINI-COG SCORING
55	Clinical Dementia Rating scale (CDR)
56	ALZHEIMER’S DISEASE ASSESSMENT SCALE (ADAS-cog) CLINICIAN’S INTERVIEW-BASED IMPRESSION OF CHANGE (CIBIC-plus)
57	FAST
58	TIME COURSE OF AD
59	POSSIBLE PROTECTIVE FACTORS Physical activity Intellectual activity NSAIDs Antioxidants Statins “The reported beneficial effect of statins in the prevention of dementia and Alzheimer's disease may be related to their capacity to increase NO synthesis and enhance the concentration of various BMPs [bone morphogenetic proteins] in the brain...” Canadian Medical Association Journal Vol 165(7), 2 Oct 2001, pp 908-909
60	PRIMARY GOAL OF TREATMENT Enhance quality of life and maximize functional performance by improving cognition, mood, and behavior
61	PHARMACOLOGIC MANAGEMENT Cholinesterase inhibitors: donepezil (Aricept), rivastigmine (Exelon), galantamine (Razadyne ER – formerly Reminyl) NMDA antagonist: memantine (Namenda) “Overstimulation of the N-methyl-D-aspartate (NMDA) receptor by glutamate is implicated in neurodegenerative disorders. Accordingly, we investigated memantine, an NMDA antagonist, for the treatment of Alzheimer's disease.” NEJM Vol 348(14), 3 Apr 2003, pp 1333-1341 Other cognitive enhancers: estrogen, NSAIDs, ginkgo biloba, vitamin E Antidepressants Psychoactive medications Other
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63	SYMPTOMS TO CONTROL Depression Psychoses (delusions, hallucinations, aggressive behavior, hypersexuality) Sleep disturbances Pain
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65	NONPHARMACOLOGIC MANAGEMENT Consistency Effective Communication Creativity Empathy, patience, and equanimity
66	The Geriatric Continuum of Care
67	CARING FOR ALZHEIMER’S FAMILIES (from “Ten Ways to Help an Alzheimer Family”, http://alzwisc.org/) Keep in touch Do little things (they mean a lot) Give them a break Be specific when offering assistance Be alert
68	CURE & PREVENTION Biochemistry Genetics Research
69	AMYLOID (from “Attacking Amyloid”, NEJM, Vol 352(7), 17 Feb 2005, pp 722-723)
70	CALPAINS (from “Mechanisms of Disease: Calpains and Disease”, NEJM Vol 352(23), 9 June 2005, pp 2413-2423)
71	PATHOLOGIC CONDITIONS ASSOCIATED WITH CALPAINS (from “Mechanisms of Disease: Calpains and Disease”, NEJM Vol 352(23), 9 June 2005, pp 2413-2423)
72	AMYLOID REVISITED (from “Tangles and Neurodegenerative Disease - A Surprising Twist”, NEJM, Vol 353(17), 27 Oct 2005, pp 1853-1855)
73	RESEARCH Messing with the Membrane? An Alternative Interpretation of the Amyloid-β Hypothesis. At a Crossroad of Amyloid-β Functional Pathways: Homeostasis of cholesterol and lipid peroxidation are integrated components of neural membrane neuroplasticity mechanisms and neurodegeneration Apolipoprotein E, Alzheimer Disease, and Cerebral Amyloid Angiopathy: Effects of ApoE on Amyloid-β Metabolism Suggest Underlying Mechanisms and Potential Treatments Axonal Transport Dysfunction "The Amyloid Cascade Hypothesis” "Connections, Cognition And Alzheimer's Disease“ "Alzheimer's disease: a re-examination of the amyloid hypothesis" "Does beta amyloid kill from within the cell or from the extracellular space?"
74	RESEARCH Two Hits and You're Out? A Novel Mechanistic Hypothesis of Alzheimer Disease Aluminosilicate Precipitation and Alzheimer's Disease Is Alzheimer's an Autoimmune Disease? Disruption of Glial (oligodendrocyte and astrocyte) Cellular Function The Combination of Nicotine with Galantamine Is Expected to Have Enhanced Therapeutic Effects in Patients with Alzheimer's Disease Viruses and Dementia, and the Role of Apolipoprotein E (ApoE) Polymorphisms in Inflammatory Genes Enhance the Risk of Alzheimer Disease Advanced Aging Plus "Risk Factors" May Explain Late-Onset Spordic Alzheimer's Disease "Calcium Signaling Deficit" Hypothesis for Alzheimer's Disease The "Coblaminergic" Hypothesis
75	RESEARCH Dementia as a neocortical disconnection syndrome: morphological and biochemical characterization of the vulnerable neurons Alzheimer changes in hypothalamic nuclei: Their relationship to neuronal activity and clinical symptoms "Apoptosis in Alzheimer's Disease“ “Frameshift mutants of beta amyloid precursor protein and ubiquitin-B in Alzheimer's and Down's syndrome patients” "Alzheimer Presenilins in the Nuclear Membrane, Interphase Kinetochores, and Centrosomes Suggest a Role in Chromosome Segregation”
76	RESEARCH "Herpes simplex virus type 1 is a risk factor for Alzheimer’s disease" "Towards an animal model of Alzheimer's disease: Can phorbol esters fan the flames?" "The cause of neuronal pathology in Alzheimer's disease" "Oxidative Stress Is Central To The Pathogenesis Of Alzheimer Disease" "The Role of the Carboxyl-Terminal fragment of APP in the Neurodegeneration and Cognitive Loss in Alzheimer Disease“ "NMDA Receptor Dysfunction And Alzheimer's Disease“ Debate: Multi-Infarct Dementia: Disease Entity or Alzheimer's Lesion?
77	REFERENCES Alzheimer’s Association http://www.alz.org/ Alzheimer‘s Association – Northeastern NY http://www.alzneny.org/ Alzheimer's Disease Education and Referral Center (ADEAR) http://www.alzheimers.nia.nih.gov Alzheimer’s Research Forum http://www.alzforum.org/ Geriatric Review Syllabus (AGS GRS) http://www.americangeriatrics.org/products/grs6.shtml Merck Manual of Geriatrics http://www.merck.com/mrkshared/mmg/home.jsp National Institute on Aging http://www.nia.nih.gov/ National Institute of Neurological Disorders and Stroke (NINDS) http://www.ninds.nih.gov/ The 36-Hour Day, Nancy L. Mace MA & Peter V. Rabins MD MPH, Johns Hopkins University Press.
78	LOCAL RESOURCES Alzheimer‘s Association – Northeastern NY http://www.alzneny.org/ Alzheimer's Disease Assistance Center of the Capital Region http://www.nehealth.com/html/NEH_Eddy_Alzheimers_ADAC.asp Beacon Pointe Memory Care Community / The Harbor at Clifton Park (8 miles) 1 Emma Lane Clifton Park, NY 12065 Phone: (518) 371-2200 http://www.beaconpointememorycare.com/ Clare Bridge of Niskayuna (4 miles) 2861 Troy-Schenectady Road Niskayuna NY 12309-1629 Phone: (518) 782-7381 http://www.brookdaleliving.com/brookdale2004/propertydefault.aspx?tabid=657
79	Contact Info Robert S. Stall MD, Geriatrician Office Address: 350 Greenhaven Terrace Tonawanda NY 14150 Phone: 716-213-4345 FAX: 1-888-387-1238 E-mail: drstall@stallgeriatrics.com Web: stallgeriatrics.com