Recent Advances in Alzheimer’s Disease - Understanding Neuropath - Evaluation - New Treatments - Early Detection J. Wesson Ashford, M.D., Ph.D. UNIVERSITY.

Recent Advances inAlzheimer’s Disease - Understanding Neuropath- Evaluation- New Treatments- Early Detection

J. Wesson Ashford, M.D., Ph.D.UNIVERSITY OF KENTUCKY

Depts. Of Psychiatry, Neurology, Sanders-Brown Center on Aging

Veterans Affairs Medical CenterSeptember 24, 2002

Slides at: www.medafile.com/ascr924.ppt(some slides removed for space reduction)

CollaborationsGeneral Support Bill Markesbery David Wekstein Mark Mattson Cathie Cool

Alzheimer Neuropath Jim Geddes Natalie Sultanian

Brief Screening Fred Schmitt Marta Mendiondo Dick Kryscio

Brain Imaging Wei-Jen Shih Gary Small (UCLA) David Kuhl (U.Mich)

Genetic Mark Kindy (MUSC) Wei-Jen Shih Bahar Aleem Doug Tsanatos Leah Cobb Jim Mortimar (USF)

Cholinesterase Rx Lissy Jarvik (UCLA)

DEMENTIA DEFINITION

Multiple Cognitive Deficits that include: Memory dysfunction (especially new learning)

a prominent early symptom

at least one additional cognitive deficit: (aphasia, apraxia, agnosia, or executive dysfunction)

Cognitive disturbances must be sufficiently severe to cause impairment of occupational or social functioning and must represent a decline from a previous level of functioning

Differential Diagnosis: Top Ten

1. Alzheimer Disease (pure ~40%, + mixed~70%)2. Vascular Disease, MID 5-20%3. Drugs, Depression, Delirium4. Ethanol 5-15%5. Medical / Metabolic Systems6. Endocrine (thyroid, diabetes), Ears, Eyes, Envir7. Neurologic (other primary degenerations, etc.)8. Tumor, Toxin, Trauma9. Infection, Idiopathic, Immunologic10. Amnesia, Autoimmune, Apnea, AAMI

DIAGNOSTIC CRITERIA FOR DEMENTIA OF THE ALZHEIMER TYPE

(DSM-IV, APA, 1994)

A. DEVELOPMENT OF MULTIPLE COGNITIVE DEFICITS

1. MEMORY IMPAIRMENT

2, OTHER COGNITIVE IMPAIRMENT

B. THESE IMPAIRMENTS CAUSE DYSFUNCTION IN

IN SOCIAL OR OCCUPATIONAL ACTIVITIES

C. COURSE SHOWS GRADUAL ONSET AND DECLINE

D. DEFICITS ARE NOT DUE TO:

1. OTHER CNS CONDITIONS

2. SUBSTANCE INDUCED CONDITIONS

F. DO NOT OCCUR EXCLUSIVELY DURING DELIRIUM

G. NOT DUE TO ANOTHER PSYCHIATRIC DISORDER

PREVALENCE of AD

Estimated 4 million cases in US (2000) (2000 - 46 million individuals over 60 y/o)

Estimated 500,000 new cases per year

Increase with age (prevalence) 1% of 60 - 65 (10.7m) = 107,000 2% of 65 - 70 ( 9.4m) = 188,000 4% of 70 - 75 ( 8.7m) = 350,000 8% of 75 - 80 ( 7.4m) = 595,000 16% of 80 - 85 ( 5.0m) = 800,000

ECONOMIC IMPACT OF AD

2 million AD patients in nursing homes Projection to Kentucky – 22,000 current cases Nursing homes cost - $120 to $160 per day

Annualized cost of nursing homes ranges from $40 to $70,000 per yearCare of AD patients costs $80 billion per yearWith lost wages of patients and families plus costs for non-nursing home patients: Total costs: $120 billion annually (Am J Publ Hlth) Projection to Kentucky – $1.5 billion annually!

BIOPSYCHOSOCIAL SYSTEMS AFFECTED BY ADNEUROPLASTIC MECHANISMS AFFECTED AT ALL LEVELS

(Ashford & Jarvik, 1985; Ashford, Mattson, Kumar, 1998)

SOCIAL SYSTEMS INSTRUMENTAL ADLs - EARLY BASIC ADLs - LATE

PSYCHOLOGICAL SYSTEMS PRIMARY LOSS OF SHORT-TERM MEMORY

LEARNING PROCESSES – CLASSICAL, OPERANT LATER LOSS OF LEARNED SKILLS

NEURONAL MEMORY SYSTEMS CORTICAL GLUTAMATERGIC STORAGE SUBCORTICAL

(acetylcholine, norepinephrine, serotonin) CELLULAR PLASTIC PROCESSES

APP metabolism – early, broad cortical distribution TAU hyperphosphorylation – late, focal effect, dementia related

Relative Risk Factors for Alzheimer’s Disease

Family history of dementia 3.5 (2.6 - 4.6)Family history - Downs 2.7 (1.2 - 5.7)Family history - Parkinson’s 2.4 (1.0 - 5.8)Maternal age > 40 years 1.7 (1.0 - 2.9)Head trauma (with LOC) 1.8 (1.3 - 2.7)History of depression 1.8 (1.3 - 2.7)History of hypothyroidism 2.3 (1.0 - 5.4)History of severe headache 0.7 (0.5 - 1.0)History of “statin” use 0.3NSAID use 0.2 (0.05 – 0.83)Use of NSAIDs, ASA, H2-blcks 0.09

Roca, 1994; ‘t Veld et al., 2001, Breitner et al., 1998, Wolozin et al., 2000

Genes and Alzheimer’s disease(60% - 80 % of causation)

(all known genes relate to amyloid)

Familial AD (onset < 60 y/o) (<5%) Presenilin I, II (ch 14, 1) APP (ch 21)

Non-familial (late onset) APOE

Clinical studies suggest 40 – 50% due to 4 Population studies suggest 10 – 20% cause Evolution over last 300,000 to 200,000 years

At least 20 other genes

APO-E genotype and AD risk46 Million in US > 60 y/o //// 4 Million have AD(data from Saunders et al., 1993; Farrer et al., 1997)

GenT %pop %AD #pop #AD risk If all US

E2/2 1% 0.1% 0.5M .004M 0.8% .4 M

E2/3 12 % 4% 5.5M .18M 3.2% 1.5 M

E3/3 60% 35% 27.6M 1.4M 5.1% 2.3 M

E3/4 21% 42% 9.6M 1.7M 18% 8.2 M

E4/4 2% 16% .9M .6M 67% 30.7M

Age at Onsetage of onset for 3/3 vs 4/4, p<0.02; for 3/3 vs 3/4, p<0.05(in preparation, Ashford, Kindy, Shih, Aleem, Cobb, Tsanatos, Cool)

APOE genotype

Number Mean age of onset (years)

Standard deviation (years

3/3 20 73.6 4.7

3/4 20 69.5 6.7

4/4 10 68.3 5.6

ONLY SUCCESSFUL INTERVENTION

CHOLINESTERASE INHIBITION (1st double blind study – Ashford, Soldinger, Schaefer, Cochran, Jarvik, 1981)

Presumably increases acetylcholine at functional synapses Improvement in cognition (? 6 months better)

Improvement in function (ADLs, variable)

Improvement in behavior (? basal ganglia)

Slowing of disease course Delays nursing home placement (by 2 years, maybe more if early rx) Not yet adequately characterized prospectively

Proposed need for early intervention

Need to divide effects of drug treatment into 2 groups

Acute effects of treatment e.g., 3 months are the acute effects related to severity

e.g., AChEases may work very well in mild patients, but not in nursing home patients

Chronic effects of treatment rate of change, after acute effects are the effects on rate of change related to severity

are very mild patients improved over time by AChEases? do early, chronic benefits suggest prevention?

AssessmentHistory Of The Development Of The Dementia

Ask the Patient What Problem Has Brought Him to See You Ask the Family, Companion about the Problem (necessary) Specifically Ask about Memory Problems Ask about the First Symptoms Enquire about Time of Onset Ask about Any Unusual Events Around the Time of Onset, e.g.,

stress, trauma, surgery Ask about Nature and Rate of Progression Ask about the current level of difficulites

Medical HistoryFamily History (of dementia)Physical ExaminationNeurological ExaminationPsychological Exam (MMSE-extended) and animal naming in 1 min, clock-draw, cube

LABORATORY TESTS (routine)

BLOOD TESTS electrolytes, liver, kidney function tests, glucose thyroid function tests (T3, T4, FTI, TSH) vitamin B12, folate complete blood count, ESR VDRL, HIV (if indicated)

EKG (if indicated)

CHEST X-RAY (if indicated)

URINALYSIS

ANATOMICAL BRAIN SCAN – CT (cheapest), MRI

SPECIAL LABORATORY TESTS

FUNCTIONAL BRAIN IMAGING (SPECT, PET)

EEG, Evoked Potentials (P300)

REACTION TIMES (slowed in the elderly, especially when complex response is required, e.g., driving)

CSF ANALYSIS - ROUTINE STUDIES ELEVATED TAU (future possible) DECREASED AMYLOID (future possible)

HEAVY METAL SCREEN (24 hr urine)

GENOTYPING APO-LIPOPROTEIN-E (for supporting dx) AUTOSOMAL DOMINANT (young onset)

Justification for Brain Scan in Dementia Diagnosis

Differential Diagnosis: Tumor, Stroke, Subdural Hematoma, Normal Pressure Hydrocephalus, EncephalomalaciaConfirmation of atrophy patternEstimation of severity of brain atrophyMRI shows T2 white matter changes Periventricular, basal ganglia, focal vs confluent These may indicate vascular pathology

SPECT, PET - estimation of regions of physiologic dysfunction, areas of infarctionHelps family to visualize problem

BEHAVIORAL PROBLEMS IN DEMENTIA PATIENTS

MOOD DISORDERS – depression – early in AD

PSYCHOTIC DISORDERS Particularly paranoia, e.g, people stealing things

INAPPROPRIATE BEHAVIORS (sexual

AGGRESSION: verbal, physical

PURPOSELESS ACTIVITY: verbal, motor

MEAL TIME BEHAVIORS

SLEEP DISORDERS

Age-Associated Memory Impairment(loss of memory without loss of social function)

vs

Mild Cognitive Impairment

Memory declines with age At what point is memory abnormal? How does age affect consideration of abnormality? Age - related memory decline corresponds with atrophy

of the hippocampus Older individuals remember more complex items and

relationships

Older individuals are slower to respondMemory problems predispose to development of Alzheimer’s disease

Why Diagnose AD Early?

Safety (driving, compliance, cooking, etc.)Family stress and misunderstanding (blame, denial) Early education of caregivers of how to handle patient (choices, getting started)Advance planning while patient is competent (will, proxy, power of attorney, advance directives)Patient’s and Family’s right to knowSpecific treatments now available, may delay nursing home placement longer if started earlier

AD is UnderdiagnosedEarly Alzheimer’s disease is subtle – it is easy for family members and physicians to miss the initial signs and symptomsLess than half of AD patients are diagnosed Estimates are that 25% to 50% of cases remain undiagnosed

Undiagnosed AD patients often face avoidable social, financial, and medical problemsEarly diagnosis and appropriate intervention may lessen disease burdenNo definitive laboratory test for diagnosing AD exists

Evans DA. Milbank Quarterly. 1990; 68:267-289

Early Recognition of AD - Consensus Statement -

(AAGP, AGS, Alzheimer’s AssociationAD continues to be missed as diagnosis

AD is unrecognized and under-reported patients do not realize families tend to compensate

Recent evidence of benefits of anti-cholinesterase agents in the treatment of mild Alzheimer’s disease Improvement of cognition Slowing of progression

Effective management techniques are available

Small et al., JAMA, 1997

Early Detection Approachespossible considerations

Genetic vulnerability testingEarly recognition (10 warning signs – Alz Assoc)Screening tools (6th vital sign in elderly)Regular memory check-ups BLT/Ashford Memory Test – on the web

Early positive diagnostic tests CSF – ?tau levels elevated, ?amyloid levels low ?Brain scan – PET – DDNP, Congo-red derivatives

Alzheimer Warning SignsTop Ten

Alzheimer Association

1. Recent memory loss affecting job2. Difficulty performing familiar tasks3. Problems with language4. Disorientation to time or place5. Poor or decreased judgment6. Problems with abstract thinking7. Misplacing things8. Changes in mood or behavior9. Changes in personality 10. Loss of initiative

Brief Alzheimer Screen (BAS)

Repeat these three words: “apple, table, penny”.So you will remember these words, repeat them again.What is today’s date?

D = 1 if within 2 days.

Spell the word “WORLD” backwards S = 1 point for each word in correct order

“Name as many animals as you can in 30 seconds, GO!” A = number of animals

“What were the 3 words I asked you to repeat?” (no prompts)

R = 1 point for each word recalled

BAS = 3 x R + 2/3 x A + 5 x D + 2 x S

CONCLUSIONS on the BAS

A single cut-off score provides reasonable sensitivity and specificity for the diagnosis of AD

Two cut-off points divide the population into 3 tiers the first cut-off indicates a low likelihood of dementia the second indicates a high likelihood of dementia the remaining group falls into a ‘gray area’ in need of

closer scrutiny, follow-up, and more extensive testing

A suitably short screen can be administered yearly to individuals over 60 y/o as a 6th vital sign

A-Screen (see www.medafile.com)

Repeat these three words: “apple, table, penny”.So you will remember these words, repeat them again, twice.What is today’s date?

1 point if within 2 days.

“Name as many animals as you can in 30 seconds, GO!” 1 point for naming 10 animals

“What were the 3 words I asked you to repeat?” (no prompts) 1 for each word,

TOTAL (max = 5) A score of 4 or 5 indicate a very low likelihood of dementia. A score of 2 or 3 suggests that more testing is needed. A score of 0 or 1 indicate a very high likelihood of dementia. (palm-pilot administration – www.medafile.com)

If score of 2 or 3: Spell World Backwards Draw a Clock (gives some impression of visuospatial problems)

If continued difficulties, ask questions about ADLs, depression

BLT/Ashford Memory Test

New test to screen patients for Alzheimer’s disease using the World-Wide Web – based testing

Test only takes 1-minute

Test can be repeated often (quarterly)

Any change over time can be detected

Test is at: www.ibaglobal.com/BLT

For info, see: www.medafile.com

THE TOP TEN TREATMENTSFOR PREVENTING ALZHEIMER’S DISEASE

www.medafile.com

1. Take your blood pressure regularly, keep systolic pressure always less than 130.

2. Watch your cholesterol; if your cholesterol is elevated, get treated with “statin” drugs and be sure your cholesterol is fully controlled.

3. Exercise your body and mind regularly. Physical exercise best 10-30 mins after each meal for 10-30 mins (3x/d).

4. Wear your seat-belt.  Wear a helmet when you are riding a bicycle or participating in any activity where you might hit your head (head injury is associated with Alzheimer’s disease).

5. If you have diabetes, make sure that your blood sugar is optimally controlled.

6. Consult your doctor about  arthritis pain (treat with ibuprofen, sulindac, or indomethacin).

7. Take your vitamins daily (folate - 400mcg, B12 - 25mcg, C - 250 mg, and E - 400iu's).

8. Discuss sex-hormone replacement therapy with your physician (only women for now).

9. If you have difficulty getting to sleep, consider trying 6 milligrams of melatonin at bedtime.

10. If you have significant memory difficulty, talk to your doctor about cholinesterase inhibitors.

See - latest version in Long Island Alzheimer Foundtion Newsletter, 7/2002