IS MCI A MYTH?

1. IS MCI A MYTH? Edward Zamrini, MD Director, Clinical Core Alzheimer’s Disease Research Center University of Alabama at Birmingham Funded in part by NIA grant 1P50 AG16582

2. Acknowledgment • Diane Mansour • Alzheimer’s Association Lebanon • Alzheimer’s Association International • Ahmad Mohit – WHO • H.E. Mr. Issam Fares, deputy prime minister • Lilia Mendoza, Alzheimer Assoc Mexico • Sami Harik, M.D., Arkansas University • All the sponsors and audience

3. Speakers’ Bureau/ Minor consulting Pfizer/Eisai Novartis Janssen/Ortho-McNeill Astra-Zeneca Forest labs Research support NIH ADCS ONO Pharmaceuticals Neurochem Forest labs Marco/Hitech Collaborations UCSD UCSF Georgetown U. U Rochester Michigan U DISCLOSURE

4. OUTLINE • There is a transitional stage between normal aging and Alzheimer’s disease • Changes in aging • Functional change is critical to the diagnosis of AD • The transitional change: MCI

5. Memory Complaints in Normal Adults SituationPercentage of elderly Names 83 % Where you put things 60 % Knowing you have told someone 49 % something Forgetting a task after starting 41 % Losing the thread of conversation 40 % From: Boller et al, Arch Neurol 1991

6. Aging, memory and intellect Don’t changeDecrease Verbal IQ Speed of memory retrieval Vocabulary Speed of processing Store of information Multi-tasking ability Comprehension

7. Brain changes with aging • Brain weight: • decreases by about 0.5% per year after age 30 • Neuron loss: • region-specific • 10-25% loss in cerebellum, cortex, hippocampus, substantia nigra • Loss of synapses (connections between neurons) • Mild degree of Alzheimer-type pathology

8. Variability of aging depends on: • Heredity: • presence of longevity genes • absence of disease genes • Lifestyle: • diet • body weight • exercise • Luck: • avoiding disease and trauma

9. 2 2.8 4.7 13.1 20.1 25.6 Cognitive Impairment in Primary Care Clinics Prevalence of Cognitive Impairmentby Age, Corrected for Education* 60-65 N=206 66-70 Age in Years 71-75 76-80 81-85 >85 0 5 10 15 20 25 30 Percent *Short Portable Mental Status Questionnaire = 5 or more errors.Callahan CM et al. Ann Intern Med. 1995;122:422-429.

10. Rungruang et al., J. Am. Ger. Soc. 2003

11. Construct of MCI • Patient/relevant other expresses concern about the pt’s cognition, OR the examining physician detected a cognitive change. • Objective evidence for cognitive decline relative to peers (age, sex, education, background) • Essentially normal functional activities • Reversible/ arrestable causes are excluded (?)

12. Evolving definition? MCI naMCI md-naMCI aMCI md-aMCI

13. Subtypes of MCI? Petersen et al., Arch Neurol 2001

14. Diagnosis of AD • DSM-IV or NINCDS-ADRDA criteria • Memory impairment • Other relevant domain impairment (aphasia, apraxia, agnosia, executive dysfunction) • A significant impairment in social or occupational function • A change from a previous level of function • Other causes excluded (depression, schizophrenia…)

15. Dementia Normal AD MCI

16. Questions • How do we distinguish inflection points on the continuum: Normal - MCI - AD? • How do we distinguish: • Normal vs. MCI? • Normal Not At-Risk (NNR) vs. Normal At-Risk (NAR)? • At what point should we treat? With what? (efficacy, safety, cost)

17. -amyloid Plaques and Tangles

18. AD and the Brain Preclinical AD • Signs of AD are first noticed in the entorhinal cortex, then proceed to the hippocampus. • Affected regions begin to shrink as nerve cells die. • Changes can begin 10-20 years before symptoms appear. • Memory loss is the first sign of AD. Slide 20

19. AD and the Brain • AD spreads through the brain. The cerebral cortex begins to shrink as more and more neurons stop working and die. • Mild AD signs can include memory loss, confusion, trouble handling money, poor judgment, mood changes, and increased anxiety. • Moderate AD signs can include increased memory loss and confusion, problems recognizing people, difficulty with language and thoughts, restlessness, agitation, wandering, and repetitive statements. Mild to Moderate AD Slide 21

20. AD and the Brain Severe AD • In severe AD, extreme shrinkage occurs in the brain. Patients are completely dependent on others for care. • Symptoms can include weight loss, seizures, skin infections, groaning, moaning, or grunting, increased sleeping, loss of bladder and bowel control. • Death usually occurs from aspiration pneumonia or other infections. Caregivers can turn to a hospice for help and palliative care. Slide 22

21. Clinical Dementia Rating Scale • Rates the severity of dementia as: • 0= absent • 0.5= questionable (mild cognitive impairment) • 1= mild • 2= moderate • 3= severe

22. Clinical Dementia Rating Scale • Score is based on synthesis of: • objective performance on clinical batteries • subject’s responses • informant’s responses

23. CDR 0.5 Precursor of AD • 11/16 progressed or had AD on postmortem • Retrospective evaluation of 687 subjects conversion rates were 31% at 2y. and 44% at 3y. • 67 individuals followed over 54 mo., conversion = 44% at 3 y.

24. Delayed Recall • Best predictor of conversion to AD. (Flicker et al. 1991, Masur et al. 1994) • Best discriminator between between normal aging and mild AD. (Knopman & Ryberg 1989, Welsh et al.1991, Tierney et al. 1996) • Conversion in 2.4 y.

25. SUBJECTS

26. TANGLES

27. Plaques

28. IMPLICATIONS • Early detection helps track the course of the disease and test the effectiveness of potential treatments to slow its progression. • Could help prescribe drugs early and assist affected people and their families in planning for the future.

29. Development of Alzheimer’s Disease in Persons with MCI 100 75 Percentage with AD 50 25 0 Initial 12 24 36 48 Exam Months Petersen et al., Arch Neurol, 56:305-308, 1999

30. Changes in Super Aging, Normal Aging, andNeurodegenerative Diseases Start AD brain changes Clinically diagnosed AD MCI “Super” Aging Normal Aging Function AD Total loss independent function Birth 40 60 80 Death Life Course Source: NIA

31. Mortality Due to AD: Impact of Age 1,000 100 10 Rate per 100,000 population 1 0.1 0.01 Under45 45–54 65–74 85+ 75–84 55–64 Age (years) Modified from Hoyert DL et al. Natl Vital Stat Rep. 1999;47:1-104.

32. PARADIGM SHIFT • Shift towards prevention as a goal • To do so, need to determine • Risk factors • Safe preventative therapies • Surrogate markers for risk reduction/ efficacy of preventative strategies.

33. ALZHEIMER’S DISEASE TIMELINE Oxidative, nitrative & inflammatory damage Mis-folding & aggregation of Aβ & Tau, followed by SPs & NFTs AUTOPSY Genetic Risk Factors? Celldeath CLINICAL DIAGNOSIS MCI Probable AD YRS 0 20 40 60 80 100 PREVENTATIVE MODIFYING SYMPTOMATIC

34. Need better diagnosis • To do risk stratification • What affects results of tests. E.g. Neuropsychological Tests (NPTs) can be simple or complicated and time consuming affecting results. • Variations between individuals according to background, personality, race, etc. • Need to discover new risk factors and interactions between various risk factors.

35. Financial capacity • 1: Basic Monetary Skills: coins/currency: naming, relationships, counting • 2: Financial Conceptual Knowledge: financial concepts: Define, Apply • 3: Cash Transactions: 1& 3-item grocery purchase, Change/vending machine, Tipping • 4: Checkbook Management: Understand, Use • 5: Bank Statement Management: Understand, Use • 6: Financial Judgment: Detect mail and telephone fraud • 7: Bill Payment: Understand, Prioritize, Prepare for mailing • 8: Knowledge of Personal Assets/Estate Arrangements • 9: Investment Decision Making • Overall Financial Capacity Griffith et al., Neurology, 2003

36. UAB ADRC Lindy Harrell, Atiq Rahman Daniel Marson Randall Griffith Dept. of Neurology Ro Elgavish Steven Sawrie Robert Knowlton Center for Aging Richard Allman Patricia Baker Alan Stevens Rodney Go ADCS Leon Thal Mary Sano Steven Ferris Paul Aisen Jason Karlawish Nursing Linda Davis Other Mona Fouad Richard Powers ACKNOWLEDGMENT