Transcript Calabasas, CA - 10/14/2004

ALZHEIMER’S DISEASE
DIAGNOSIS and TREATMENT
J. Wesson Ashford, M.D., Ph.D.
Stanford / VA Alzheimer’s Center
VAMC, Palo Alto, California
Calabasas, California
October 14, 2004
Slides at: www.medafile.com (Dr. Ashford’s lectures)
Diagnostic Criteria For Dementia Of
The Alzheimer Type (DSM-IV, APA, 1994)
A. Multiple Cognitive Deficits
1. Memory Impairment
2. Other Cognitive Impairment
B. Deficits Impair Social/Occupational
C. Course Shows Gradual Onset And Decline
D. Deficits Are Not Due to:
1. Other CNS Conditions
2. Substance Induced Conditions
E. Do Not Occur Exclusively during Delirium
F. Not Due to Another Psychiatric Disorder
PREVALENCE of AD
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Estimated 4 million cases in US (2000)
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(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
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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
Assessment
History Of The Development Of The Dementia
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Ask the Patient What Problem Has Brought Him to See You
Ask the Family, Companion about the Problem
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, Activities of Daily
Living
Physical Examination
Neurological Examination
Neuropsychological Assessment
Routine Laboratory Tests
Brain Scan
Why Diagnose AD Early?
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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
Promotes advocacy for research and treatment development
Specific treatments now available
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May slow underlying disease process, the sooner the better
May delay nursing home placement longer if started earlier
May prevent conversion from Mild Cognitive Impairment to AD
Dementia Screening Test
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Need to get elderly, clinicians interested in screening for dementia
Need test to screen patients for Alzheimer’s disease
Test needs to be on multiple platforms:
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Doctor’s offices
Best if computerized for rapid, objective assessment
World-Wide Web – based testing,
CD-distribution
KIOSK administration – drug stores, shopping malls
Test needs to be very brief (about 1-minute)
Multiple test forms needed so it can be repeated often (quarterly)
Screening should be done yearly after age 50, and repeated every
3 months for individuals over 65 years of age or with concerns
Any change over time needs to be detected
The test should be free
Need program to handle positive screens sensitively and efficiently
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Doctors have been reluctant to diagnose Alzheimer’s disease because
of the time required to explain the problem to the family and to
coordinate treatment.
MEMTRAX - Memory Test
(to detect AD onset)
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New test to screen patients for AD:
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World-Wide Web – based testing,
CD-distribution
KIOSK administration
Determine level of ability / impairment
Test takes about 1-minute
Test can be repeated often (e.g., quarterly)
Any change over time can be detected
Free test is at: www.medafile.com
FIRST SUCCESSFUL TREATMENT:
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CHOLINESTERASE INHIBITION
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Presumably increases acetylcholine at synapses
Improvement in cognition (? 6-12 months better)
Improvement in function (ADLs, variable)
Improvement in behavior (stabilization? basal ganglia)
Slowing of disease course
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(1st double blind study - Ashford et al., 1981)
Treatment delays nursing home placement
Loss of benefit with delay of treatment
Need to consider early intervention
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Prevent conversion from Mild Cognitive Impairment to AD
Need to divide effects of drug
treatment into 2 groups
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Acute effects of treatment
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e.g., 3 months
are the acute effects related to severity?
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e.g., do AChEases may work very well in mild patients,
and in nursing home patients?
do these medications work in very early phases of the disease?
Chronic effects of treatment
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rate of change, after acute effects
are the effects on rate of change related to severity
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are very mild patients improved over time by AChEases?
are new AChEase molecules created which require dose
increases?
does sudden discontinuation lead to catastrophic decline?
do early, chronic benefits suggest prevention?
Benefits of Treatment of AD With
Acetylcholinesterase Inhibitors
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AChEIs may improve, maintain, or slow the decline of
cognitive, behavioral, and functional performance in
patients with mild-to-moderate AD
Delay of treatment leads to loss of potential benefit
AChEIs may delay nursing home placement over 20
months, and potentially much more when started early.
AChEIs have demonstrated consistent efficacy and
safety in maintaining cognitive function, as measured by
ADAS-cog in patients with mild-to-moderate AD for up to
1 year – relative to placebo!!
 Donepezil1
38 weeks
 Rivastigmine2
38–42 weeks
 Galantamine3
52 weeks (25-30% better)
1. Rogers SL et al. Eur Neuropsychopharmacol. 2000;10:195-203. 2. Farlow M et al. Eur Neurol. 2000;44:236-241.
3. Raskind MA et al. Neurology. 2000;54:2261-2268.
Reminyl® (galantamine HBr):
Proposed Mechanisms of Action
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Increases amount of acetylcholine available in synaptic
cleft by inhibiting breakdown of acetylcholine
By modulating activity at nicotinic receptors, it may
increase release of acetylcholine from surviving
presynaptic nerve terminals
Combination action may diminish cholinesterase
supersensitivity from developing, prolonging the benefit.
May provide greatest delay of illness progression
May require increase of dose after patient declines below
initial baseline, to maintain benefit for longer term.
Maelicke A, Albuquerque EX. Eur J Pharmacol. 2000;393:165-170.
®
Reminyl (galantamine
HBr):
Dosing
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Available in 4-mg, 8-mg, and 12-mg tablets and oral solution (4 mg/mL)
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Dose escalation
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8 mg/day starting dose
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16 mg/day maintenance dose
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for at least 4 weeks (8 mg bid)
The flexibility to increase to 24 mg/day
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for 4 weeks (4 mg bid)
(12 mg bid) – can try after 12 weeks if further benefit sought
Increase from 8 to 12 mg bid in moderate dementia
Take initially with morning and evening meals
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Later, better with morning meal, mid-afternoon snack.
(Avoid nocturnal cholinergic activation which may hasten the progression
of Alzheimer’s disease!! – advantage over donepezil)