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Clinical Aspects of Dementia: Emphasis on Alzheimer Disease

A L P E R T M E D I C A L S C H O O L. Clinical Aspects of Dementia: Emphasis on Alzheimer Disease. Summer School of Neuroscience and Aging Venice, Italy 10-14 June, 2013 Richard W. Besdine , MD,FACP Professor of Medicine Professor of Health Services Policy and Practice

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Clinical Aspects of Dementia: Emphasis on Alzheimer Disease

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  1. ALPERT MEDICAL SCHOOL Clinical Aspects of Dementia:Emphasis on Alzheimer Disease • Summer School of Neuroscience and Aging • Venice, Italy 10-14 June, 2013 Richard W. Besdine, MD,FACP Professor of Medicine Professor of Health Services Policy and Practice Greer Professor of Geriatric Medicine • Director, Division of Geriatrics and Palliative Medicine • Director, Center for Gerontology and Healthcare Research

  2. Population Aging Average life expectancy (ALE) at birth in ancient Rome for a citizen was ~25 years; 35 years in Padova when Morgagni was dissecting In 1900 America, 48: 50 for, 47 for; in 2013, 81 and 76, respectively – 1900 years for 1st 25-year gain in ALE, <100 years for the next For Italians reaching adulthood in 2013, ALE is nearly 90 for women and >80 for men Maximum life span increase, though slower than increase in ALE, has not slowed since 1950s

  3. Nine Themes of Aging1 • These themes are the conceptual basis for understanding the interactions of aging changes with diseases and risk factors • Themes explain relationships of symptoms, signs and diagnostic tests to disease and changes in organ function in older persons - special knowledge base of geriatric medicine • The themes facilitate analysis and understanding of the most complex and challenging clinical problems of older patients

  4. Nine Themes of Aging2 • Pure Aging – Changes in organ function due only to aging – presbyopia • Reduced capacity to maintain homeostasis if stressed – delirium, falls in hospitalized elders • Geriatrics Syndromes – Disease-age interactions produce specific common function losses – falls, delirium, syncope, dizziness, UI, weight loss • Interaction of disease with pure aging produces changes in disease behavior beyond syndromes – SDH more frequent

  5. Nine Themes of Aging3 • Pure aging misinterpreted as disease – slow information retrieval called dementia • Disease misinterpreted as pure aging effect – obvious dementia symptoms called “old age” • Medication Hazards – pure aging & disease ↑↑risks of adverse drug effects – CNS, CV toxicity • Multimorbidity – Interactions of multiple diseases accelerate potential for harm • Diseases Special in Aging – Common only in elders; geriatricians must know – DCHF, AD

  6. What is Human Aging? • Not nearly as important as we thought? • A set of predictable, gradual and inevitable changes in biological and psychological function, usually decremental, that occur in healthy persons with the passage of time

  7. Age-related Structural Brain Changes Enlarged Subdural space predisposes to SDH Narrower gyri Wider sulci Enlarged ventricles

  8. Neurologic Exam Changes of Aging •  arm swing,  tone -  Dopamine neurons •  DTRs in feet •  Gag reflex •  Ability to prevent postural sway •  Ability to prevent orthostatic hypotension •  Baroreflex sensitivity • Reemergence of primitive reflexes •  Hand- and foot-tapping speed • Restricted upward gaze

  9. Pure Aging Changes in Memory1 Most memory functions change little with pure aging – mild in attention; elders more easily distracted, so avoid competing tasks Processing speed (reaction, retrieval, timed tasks, perceptual), free recall, multi-tasking all decline with age Retrieval of names, persons especially, and objects often transiently lost

  10. Pure Aging Changes in Memory2 • Sensory memory - earliest stage (visual, auditory, tactile) - unstable, rapid decay; no age-related change • Primary, or working (short-term) memory - rehearsal transfers sensory to short term memory - no loss with age • Long term (secondary) - hours, days, years • Declarative (explicit) memory: either semantic (facts, meanings; no Δ), or episodic (events, time, place; autobiography), aging decline • Procedural (implicit) – biking, music, knots - no Δ

  11. Quality of Scientific Evidence Concerning Risk Factors for AD

  12. Declines in Special Senses • Vision -  accommodation (presbyopia), low-contrast acuity, glare tolerance, adaptation, color discrimination, attentional visual field all decline, due to changes in the eye peripherally and in central processing • Hearing - Neural, conductive and sensory losses (presbycusis); primarily high tones (consonants) – 50% clinically significant

  13. Strength and Balance Major confounders are disuse and disease Muscle mass, strength ; modifiable by training – at best ~15%  by 80; fast twitch type 2  Sarcopenia (>50% ) common, NOT pure aging Strength, cerebellar integrity, hearing and vision all play a role in balance Vestibular portion of 8th CN – degeneration of otoconia (otolith granules) – multiple diseases, 8th N sensitivity to drugs are confounders Single stance, eyes closed a powerful discriminator

  14. Alois Alzheimer - 1906 Auguste D “…only a tangle of fibrils indicates the place where a neuron was previously located.” “Soon she developed a rapid loss of memory...”

  15. -amyloid Plaques Immunocytochemical staining (anti-amyloid antibody) of neuritic plaques in the hippocampus of an AD patient

  16. Neurofibrillary Tangles Immunocyto-chemical staining (anti-tau antibody) of neurofibrillary tangles in hippocampus of an AD patient

  17. Epidemiology of AD1 • 10% > age 65, ~40% > age 85 • No clear ethnic or racial patterns – China data: 2.6% 65-67, 60% 95-99 (Chan KY et al. Lancet 2013; 381: 2016–23) • Is it getting more common? – probably not • AD is a women’s problem • Majority of AD patients women; lifetime risk 32%, 18% men;prevalence > in 11 studies, up to 2:1 • Women live longer once they have the disease • Women are caregivers for AD victims

  18. Epidemiology of AD2 • 60-80% of dementia >65 is AD (US studies) • >5 million now, 3-fold increase as baby boomers turn 70 and 80 beyond 2025 • Costs of care in US $157-215 billion/yr(Hurd MD et al. NEJM. 2013;368:1326-34). • 5th leading cause of death • Survival after diagnosis <4 years (length bias), like aggressive cancer or severe CHF; should be on everyone’s hospice list • Wolfson C, et al. NEJM 2001;344:1111-6

  19. Prevalence of Dementia by Age 45 All types of dementia Alzheimer's disease Vascular dementia 40 35 30 25 Prevalence (%) 20 15 10 5 0 60–64 65–69 70–74 75–79 80–84 85–89 > 90 Age (years)

  20. Worldwide dementia: the numbers will double every twenty years!! Million Ferri et al., 2005, Lancet 366:2112-17

  21. If We Live Long Enough, Will We All be Demented? • Dementia prevalence doubles ~ every 5 years between age 65-85 • Prevalence levels off in later years, as censoring by death from other causes outstrips rising incidence; does risk diminish? • ~ 47% at 85 years (Evans,1989) • ~ 58% at >95 years (Ebly,1994) • Universal cognitive aging - WAIS-R IQ “normal” at age 85 is 50% of correct answers at age 21

  22. Life Expectancy in Years Year We And Many Of Our Patients Will Live Long Enough To Develop AD Median survival of women in the longest-lived countries has increased 3 months/year since 1840 Oeppen J et al. Science. 2002;296:1029-1031

  23. What is Dementia? • An acquired disorder producing decline in memory and other cognitive functions sufficient to affect daily life in an alert patient • Progressive and disabling • NOT a part of pure aging • Very different from normal cognitive lapses • AD by far the most common cause

  24. When to be Concerned • Sometimes it is the psychomotor slowing of aging • Recall of words or names temporarily lost • Misplacing the car keys • Worrying about memory • Why are you in front of the refrigerator? • Never retrieving names or words • Losing the car, major financial mistakes • Forgetting entire conversations or events • Not recognizing that there is a memory problem • Repetition not just for emphasis

  25. AD Is Often Underdiagnosed • Early AD is subtle - the initial signs and symptoms are easily missed • Fewer than half of AD patients (autopsy) are accurately diagnosed • Undiagnosed AD patients face unnecessary added social, financial and medical problems • Early diagnosis and appropriate intervention may lessen disease burden Sano M et al. N Engl J Med. 1997:336:1216-1222

  26. Patient initially diagnosed with AD AD Often Misdiagnosed Patient’s first diagnosis other than AD 35% 14% 14% No 72% 9% Yes 28% 7% 21% Dementia (not AD) Stroke No diagnosis Depression Normal aging Other

  27. Clinical Picture • Insidious, progressive, global decline in cognitive abilities – peak onset ~75, but as young as 30s • Prominent specific cortical deficits, personality changes, executive troubles, catastrophic reactions • Behavioral disturbances very common • Depression occurs in > 50% • More than 1/3 of incident cases do not fit classic picture; thus less likely diagnosed

  28. The Impact of Dementia • 75% of AD victims go to NH, stay >3 years • Economic • ~$200 billion annually for care and lost productivity – most expensive of all • In the US, Medicare, Medicaid, private insurance provide only partial coverage • Families bear greatest burden of expense • Emotional • Direct toll on patients • Nearly half of caregivers suffer depression

  29. Mortality of Dementia Noale M et al. Dement Geriatr Cogn Disord 2003

  30. Evaluation of Dementia1 Screening • At annual physical >70 or earlier if red flags • Ask patient about any new problems with memory, mood, behavior and driving • Baseline MMSE and clock drawing or 3-word recall and clock (mini-cog) Evaluation for positive screen • Add reliable informant to interview • Structured criteria – DSM or NINCDS-AD • Search for causes • Identify and manage co-morbidities • Genetic testing not recommended in 2012

  31. Evaluation of Dementia2 • Chemistries (BUN/Creatinine, electrolytes, BS, calcium), CBC, Liver function tests • Thyroid, pituitary-adrenal axis • Vitamin levels – B12, folic acid (?) • Serology for Lyme, HIV, Syphillis • Brain image (CT without contrast) if <65, symptoms recent (<2yrs), focal neurologic signs, suspicion of NPH, or recent trauma • Neuropsychological testing if diagnosis unclear Small GW, et al. JAMA. 1997;278:1363-1371

  32. Criteria for Diagnosis of Dementia Global cognitive impairment with clear sensorium • Development of multiple cognitive deficits, with memory impairment, and one or more of: • Aphasia • Apraxia • Agnosia • Disturbance in executive functioning • Cognitive deficits are a significant decline from baseline and cause significant functional impairment • Deficits are not caused by delirium (R/O by work up)

  33. Accuracy of NINCDS Criteria for AD • In academic referral centers, accuracy of probable AD diagnosis is 81-100% (Galaskoet al, 1994; Morris et al, 1988; Tierney, 1988) • In one post-mortem series, 77% of cases of “possible” AD had AD (Galaskoet al, 1994) • In a community-based post-mortem series, accuracy of probable AD diagnosis was 75% (Lim et al, 1999)

  34. Risk Factors for AD • DefinitePossible/Probable • AgeFamily History • Head Injury Diabetes • Atherosclerosis (stroke) History of depression • Hypertension (stroke) HSV • Apolipoprotein E4 Education (-) • Down’s Syndrome Mediterranean diet (-) • Female Gender Exercise (-) • Multiple mutations Intellectual work (-) • Smoking Apolipoprotein E2 (-)

  35. -amyloid precursor protein Extracellular space TM Cytoplasm A peptide COOH NH2 -secretase -secretase Proteolytic Cleavages of Amyloid Precursor Protein (APP) That Produce A42Peptide alpha-secretase Selkoe DJ et al. JAMA. 2000;283:1615-1617.

  36. ~10 years Courtesy of Dr. Mark Mintun

  37. Cascade Model of Neurodegeneration in AD Jack et al. Lancet Neurology, 2010

  38. 6-Year Changeof Mild Cognitive Impairment Over time, persons with amnestic MCI are at risk of developing AD dementia Petersen RC et al. Current concepts in Mild Cognitive Impairment. Arch Neurol 2001;58:1985-1992.

  39. “The Prevention Paradigm” Cognitive function Preclinical MCI An intervention here might “prevent” people from developing MCI or dementia Dementia Years

  40. The Genetics of AD • Mutations on chromosomes 1, 14, 21 (APP regions) are associated with: • Rare early-onset (<60) familial forms of AD • Down syndrome • Apolipoprotein E alleles on chromosome 19 • APOE4 allele a powerful risk for AD (1 allele 3X, 2 alleles 10X), and earlier by ~10 years • APOE2 allele probably has protective effect • APOE in -amyloid plaques and neurofibrillary tangles; affect protein–protein interactions?

  41. Presenilins and Their Role in AD • Presenilin 1 (PS1) and presenilin 2 (PS2) on chromosome 14 – mutations in the proteins coded by these genes are most common genetic cause of familial Alzheimer’s Disease • PS1 and PS2 cause increased secretion of the more amyloidogenic form of -amyloid (A42)

  42. Diagnosis of AD - CSF Aβ42,Tau • >100 subjects each of clinically characterized (research criteria) elders as AD, MCI or normal • Low amyloid 1-42 (Aβ42) level, high total tau protein (T-tau), and elevated phosphorylated tau protein 181 (P-tau 181) in >90% of AD patients, 73% MCI, 39% controls (↑↑ AD pattern, Apo E4) • Sensitivity 90% for AD, specificity 64% in 3 distinct data sets, by post-mortem • AD CSF pattern (low Aβ42, high P-tau 181) identified all MCI cases progressing to AD in 5 yrs Meyer GD et al. Arch Neurol. 2010;67(8):949-956

  43. Vascular Dementia • 2nd or 3rd (DLB) most common dementia • Affects ~5-10% of the population >90 • Associated with stroke, cerebrovascular disease (white matter hyperintensities) • Often coexists with AD neuropathology; undetected stroke makes dementia symptoms much worse (Snowdon DA. JAMA. 1997;277:813-817) • Decline in cognition, function, and behavior

  44. Dementia With Lewy Bodies • 15%–25% of all dementia in the elderly • Onset ~75–80 years • Survival ~3.5 years (<1–20) • Slight male predominance • Characterized by • Fluctuating cognitive impairment (~80%) • Visual hallucinations, nightmares (>60%) • Parkinsonism (65%–70%) • Frequent severe neuroleptic side effects

  45. DLB Biology • Alpha-synuclein (α-syn), normally a soluble CNS protein of unknown function, encoded by SNCAgene, can aggregate abnormally to form insoluble fibrils (primary Lewybody structure) in synucleinopathies (DLB, PD, multiple system atrophy) • An α-syn fragment, known as the non-Aβcomponent (NAC) of AD amyloid, originally found in an amyloid-enriched fraction, is fragment of its precursor, NACP (human α-syn) • Occasionally, Lewy bodies contain tau; α-synand tau are two distinct filament subsets in same inclusion bodies • α-synpathology is also found occasionally in both sporadic and familial cases of AD disease

  46. Behavioral Symptoms in DLB Ranked by Frequency of Occurrence (% of Patients) Symptoms >50% of Patients (%) Symptoms <50% of Patients (%) Apathy/indifference 72.5 Appetite; eating disorder 34.2 Anxiety 70.0 Elation/euphoria 18.3 Depression/dysphoria 65.8 Disinhibition 16.7 Delusions 58.3 Agitation/aggression 55.0 Irritability/lability 55.0 Aberrant motor 53.3 McKeithIG et al. Neurology. 2000;54:1050-58

  47. Symptoms in DLB versus AD *P<.05 80 DLB 70 AD 60 50 Percentage of Patients with Symptoms * 40 30 20 * * * 10 0 Depression Delusions AuditoryHallucinations VisualHallucinations Misidentification Ballard C et al.Curr Psychiatry Rep. 1999;1:49-60

  48. Cholinesterase Inhibitor (AChEI) Effects on Behavioral Symptoms in DLB NPI 10-Item Score—Percentage of Patients Improving by ³30% from Baseline Neuro-psychiatric Inventory (NPI) 10-Item Score –8 –7 –6 –5 –4 –3 –2 –1 0 70 60 50 40 30 20 10 0 * * * AChEI Placebo Improvement Mean Change from Baseline Patients Improving (%) 12 20 Week 20 Baseline Weeks AChEI3–12 mg/d (n=59) Placebo (n=61) *P<.01 vs placebo; **P<.001 vs placebo Adapted from McKeith, et al, 2000.

  49. Parkinson’s Disease and Dementia • At least one-third of Parkinson’s Disease (PD) patients develop dementia • Patients with PD show degeneration of the nucleus basalis of Meynert and low brain choline acetyl transferaselevels • The dementia of PD is not improved by dopaminergic drugs (e.g., L-DOPA, pergolide, bromocriptine, bupropion, dopamine) • Cholinesterase inhibitor therapy in PD appears to be beneficial Perry, et al, 1985; Korczyn, 2001

  50. Fronto-temporal Dementia • FTD is most common fronto-temporal neuro-degeneration; rarer than AD, Vascular and DLB • Characterized more by pattern of behavioral deficits than by neuropsychological impairment • Clinical features: 1) distractibility, impersistence, 2) ↓in personal hygiene, grooming; 2) inflexibility, mental rigidity; 3) hyper-orality, diet change; 4) utilization behavior; and 5) perseverative, stereotyped behavior • Current treatment only for symptoms; no evidence of benefit from any drug class, including AChEIs • Serotonin deficit may play a role in behavior Perry RJ. Neurology. 2001;56:46-51. Neurology. 2000;54:2277-84. Morris JC. Neurology. 2001;57:173-174.

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