Transcript A MINUTE ALZHEIMER SCREEN

Recent Advances in
Alzheimer’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 Center
September 24, 2002
Slides at: www.medafile.com/ascr924.ppt
(some slides removed for space reduction)
Collaborations
General 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, Delirium
4. Ethanol
5-15%
5. Medical / Metabolic Systems
6. Endocrine (thyroid, diabetes), Ears, Eyes, Envir
7. Neurologic (other primary degenerations, etc.)
8. Tumor, Toxin, Trauma
9. Infection, Idiopathic, Immunologic
10. 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
2% of
4% of
8% of
16% of
60 - 65
65 - 70
70 - 75
75 - 80
80 - 85
(10.7m)
( 9.4m)
( 8.7m)
( 7.4m)
( 5.0m)
=
=
=
=
=
107,000
188,000
350,000
595,000
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 year
Care of AD patients costs $80 billion per year
With 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 AD
NEUROPLASTIC 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
Family history - Downs
Family history - Parkinson’s
Maternal age > 40 years
Head trauma (with LOC)
History of depression
History of hypothyroidism
History of severe headache
History of “statin” use
NSAID use
Use of NSAIDs, ASA, H2-blcks
3.5 (2.6 - 4.6)
2.7 (1.2 - 5.7)
2.4 (1.0 - 5.8)
1.7 (1.0 - 2.9)
1.8 (1.3 - 2.7)
1.8 (1.3 - 2.7)
2.3 (1.0 - 5.4)
0.7 (0.5 - 1.0)
0.3
0.2 (0.05 – 0.83)
0.09
Genes and Alzheimer’s disease
(60% - 80 % of causation)
(all known genes relate to bamyloid)
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 e4
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 risk
46 Million in US > 60 y/o //// 4 Million have AD
(data from Saunders et al., 1993; Farrer et al., 1997)
GenT %pop %AD
#pop
E2/2
0.5M .004M 0.8%
.4 M
5.5M .18M 3.2%
1.5 M
1% 0.1%
4%
#AD
risk If all US
E2/3
12 %
E3/3
60%
35% 27.6M 1.4M 5.1%
2.3 M
E3/4
21%
42%
8.2 M
E4/4
2%
16%
9.6M 1.7M 18%
.9M
.6M 67%
30.7M
Age at Onset
age of onset for e3/3 vs e4/4, p<0.02; for e3/3 vs e3/4, p<0.05
(in preparation, Ashford, Kindy, Shih, Aleem, Cobb, Tsanatos, Cool)
APOE
Number
genotype
Mean age Standard
of onset deviation
(years)
(years
e3/3
20
73.6
4.7
e3/4
20
69.5
6.7
e4/4
10
68.3
5.6
ONLY SUCCESSFUL INTERVENTION
CHOLINESTERASE INHIBITION






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



(1st double blind study – Ashford, Soldinger, Schaefer, Cochran, Jarvik, 1981)
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?
Assessment
History 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 History
Family History (of dementia)
Physical Examination
Neurological Examination
Psychological 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,
Encephalomalacia
Confirmation of atrophy pattern
Estimation of severity of brain atrophy
MRI 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 infarction
Helps 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 respond
Memory 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 know
Specific treatments now available, may delay
nursing home placement longer if started earlier
AD is Underdiagnosed
Early Alzheimer’s disease is subtle – it is easy for
family members and physicians to miss the initial
signs and symptoms
Less 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 problems
Early diagnosis and appropriate intervention may
lessen disease burden
No 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 Association
AD 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 Approaches
possible considerations
Genetic vulnerability testing
Early 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 Signs
Top Ten
Alzheimer Association
1. Recent memory loss affecting job
2. Difficulty performing familiar tasks
3. Problems with language
4. Disorientation to time or place
5. Poor or decreased judgment
6. Problems with abstract thinking
7. Misplacing things
8. Changes in mood or behavior
9. 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 WorldWide 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 TREATMENTS
FOR PREVENTING ALZHEIMER’S DISEASE
www.medafile.com
1.
2.
3.
4.
5.
6.
7.
8.
9.
Take your blood pressure regularly, keep systolic pressure always less than 130.
Watch your cholesterol; if your cholesterol is elevated, get treated with “statin” drugs and
be sure your cholesterol is fully controlled.
Exercise your body and mind regularly. Physical exercise best 10-30 mins after each meal
for 10-30 mins (3x/d).
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).
If you have diabetes, make sure that your blood sugar is optimally controlled.
Consult your doctor about arthritis pain (treat with ibuprofen, sulindac, or indomethacin).
Take your vitamins daily (folate - 400mcg, B12 - 25mcg, C - 250 mg, and E - 400iu's).
Discuss sex-hormone replacement therapy with your physician (only women for now).
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