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ALZHEIMER’S DISEASE
DIAGNOSIS and TREATMENT
J. Wesson Ashford, M.D., Ph.D.
Stanford / VA Alzheimer’s Center
VAMC, Palo Alto, California
San Francisco, California
October 5, 2004
Slides at: www.medafile.com (Dr. Ashford’s lectures)
Alzheimer Issues




Definition of dementia, differential diagnosis
Epidemiology (why diagnosis is important)
Diagnosis of Alzheimer’s disease (how to)
Treatment options
The need to treat
 The benefits of cholinesterase inhibitors
 The advantage of galantamine (Reminyl)

Dementia Definition

Multiple Cognitive Deficits:



Memory dysfunction
 especially new learning, a prominent early
symptom
At least one additional cognitive deficit
 aphasia, apraxia, agnosia, or executive
dysfunction
Cognitive Disturbances:


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
(commonly used mnemonic device: AVDEMENTIA)
1.
2.
3.
4.
5.
6.
7.
Alzheimer Disease (pure ~40%, + mixed~70%, ? dLbd)
Vascular Disease, MID (5-20%)
Drugs, Depression, Delirium
Ethanol (5-15%)
Medical / Metabolic Systems
Endocrine (thyroid, diabetes), Ears, Eyes, Environ.
Neurologic (other primary degenerations, fronto-temporal
- Consider diffuse Lewy body dementia, Parkinson component)
8. Tumor, Toxin, Trauma
9. Infection, Idiopathic, Immunologic
10. Amnesia, Autoimmune, Apnea, AAMI
Adapted from Yesavage, 1979
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

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) = 107,000
( 9.4m) = 188,000
( 8.7m) = 350,000
( 7.4m) = 595,000
( 5.0m) = 800,000
U.S. Census 2000 by age
www.census.gov
Males,
138,053,563
Females,
143,368,343
2,500,000
2,250,000
# people
2,000,000
1,750,000
1,500,000
1,250,000
Total = 281,421,906
>60 = 45,809,291
>65 = 35,003,844
>85 = 4,251,678
>100=
62,545
1,000,000
750,000
500,000
250,000
0
0
10
JW Ashford, MD PhD, 2003
20
30
40
50
Age
60
70
80
90 100
U.S. mortality by age - 1999
www.cdc.gov
Males, 1,175,460
45,000
Number of people
40,000
Females, 1,215,939
35,000
30,000
25,000
20,000
15,000
10,000
5,000
0
0
10
20
JW Ashford, MD PhD, 2003
30
40
50
Age
60
70
80
90
100
U.S. mortality rate by age
1999 CDC / 2000 census
Males
Females
Alzheimer incidence
probability
1.0000
0.1000
0.0100
0.0010
0.0001
0
10 20
JW Ashford, MD PhD, 2003
30 40 50 60 70
Age
80 90 100
Mortality Equations
t = age in years
Td = time for mortality rate to double
Ro = mortality rate at time zero
alpha = ln(2) / Td

Mortality rate u(t)
R = Ro x exp (alpha x t)

Survival curve s(t)
S = exp ( - Ro/alpha x (exp (alpha x t) –1 ))

Number of deaths per year d(t)
D = -ds/dt = ( Ro + alpha x ln (1/s(t) )) x s(t)
= u(t) x s(t)
Proportion of population
Probability Not Demented
1
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
50
60
70
80
Age
JW Ashford, MD PhD, 2003
90
100
# / yr
U.S.
Alzheimer Incidence
(4 million / 8yr)
male=170,603
16000
14000
12000
10000
8000
6000
4000
2000
0
female=329,115
50
JW Ashford, MD PhD, 2003
60
70
80
Age
90
100
Genes and Alzheimer’s disease
(60% - 80 % of causation)

Familial AD (onset < 60 y/o) (<5%)
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all known autosomal dominant genes relate to b-amyloid
Presenilin I, II (ch 14, 1)
APP (ch 21)
Non-familial (late onset)

APOE
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Clinical studies suggest 40 – 50% due to e4
If e2 is considered, may be 95% of causation
Population studies suggest 10 – 20% cause
Evolution over last 300,000 to 200,000 years
At least 20 other genes suspected of relating to AD
Ashford & Mortimer, 2002, J. Alz. Dis. 4:1-9.
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%
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%
JW Ashford, MD PhD, 2003
4%
#AD
9.6M 1.7M 18%
.9M
.6M 67%
30.7M
Number of people/yr
Dementia rate, for Td = 5 yrs
mean rate
APOE 4/4
APOE 3/4
APOE 3/3
presenilin
1000
100
10
1
0.1
0.01
0.001
0.0001
50
J. W. Ashford, 2004
60
70
80
Age
90
100
Proportion of population
Probability Not Demented
1
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
mean rate
APOE 4/4
APOE 3/4
APOE 3/3
presenilin
50
60
70
80
Age
J. W. Ashford, 2004
90
100
Probability of Dementia Onset
probability / yr
0.06
0.05
0.04
0.03
0.02
0.01
0
50
60
mean rate
APOE 4/4
APOE 3/4
APOE 3/3
Presenilin
70
80
90
100
Age
J. W. Ashford, 2004
% Developing/Year
U.S. Dementia Incidence by APOE
(% of cases)
1
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
50
4/4
3/4
3/3
60
70
80
Age
JW Ashford, MD PhD, 2000
90
100
Estimated Number of New AD Cases, in Thousands
1200
959
1000
1000
820
800
600
400
615
377
411
454
491
200
0
1995
2000
2010
2020
2030
2040
2050
Reprinted with permission from Brumback, RA, Leech RW, J. Ohio State Med Assoc. 1994: 87, 103-111
ECONOMIC IMPACT OF AD

2 million AD patients in nursing homes
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Nursing homes cost - $120 to $160 per day
Annualized cost of nursing homes ranges
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
from $40,000 to $70,000 per year
Nursing Home Care of AD patients costs $80 billion per year

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Projection to California – 240,000
for life-time cost – about $175,000 per patient
The majority of patients live at home and
are cared for by family and friends
With lost wages of patients and families plus costs for nonnursing home patients:


Total costs: $120 billion annually (Am J Publ Hlth)
Projection to California – $14.5 billion annually!
AD Can Be Readily Diagnosed
A
diagnosis of Alzheimer’s disease can be
made with a high degree of certainty
 Using NINCDS-ADRDA criteria, accuracy in
autopsy-verified cases is approximately 90%
 Diagnosis is a 2-step process:
Detection through screening
 Confirmation through patient history and physical,
caregiver interview, brain imaging, and appropriate
laboratory studies

McKhann G et al. Neurology. 1984;34:939-944.
Kazee AM et al. Alzheimer Dis Assoc Disord. 1993;7:152-164.
Ashford JW et al, Psychiaric Annals, 1996;26:262-268.
AD Is Often Misdiagnosed
Patient’s first diagnosis
other than AD
Patient initially diagnosed
with AD
35%
14%
14%
No
72%
9%
7%
21%
Yes
28%
Dementia (not AD)
Stroke
Depression
No diagnosis
Normal aging
Other
Source: Consumer Health Sciences, LLC. Alzheimer’s Caregiver Project. 1999.
AD is Under-diagnosed

Early Alzheimer’s disease is subtle, the diagnosis continues to be missed



Less than half of AD patients are diagnosed




Estimates are that 25% to 50% of cases remain undiagnosed
Diagnoses are missed at all levels of severity: mild, moderate, severe
Undiagnosed AD patients often face avoidable social, financial, and
medical problems
Early diagnosis and appropriate intervention may lessen disease burden


it is easy for family members to avoid the problem and compensate for the patient
physicians tend to miss the initial signs and symptoms
Early treatment may improve overall course substantially
No definitive laboratory test for diagnosing AD exists

Efforts to develop biomarkers, early recognition by brain scan
Evans DA. Milbank Quarterly. 1990; 68:267-289
Assessment
History Of The Development Of The Dementia








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
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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
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 – Medicare will pay special cases)
EEG, Evoked Potentials (P300)
REACTION TIMES (slowed in the elderly, especially
when complex response is required
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)
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
Promotes advocacy for research and treatment development
Specific treatments now available



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
ALZHEIMER’S DISEASE
Estimate MMSE as a function of time
MMSE score
30
25
20
15
10
5
0
-10
-8
-6
-4
-2
0
2
4
6
8
10
Estimated years into illness
AAMI / MCI/ early AD -- DEMENTIA
Ashford et al., 1995
Need to Develop Better Screening
and Early Assessment Tools





Genetic vulnerability testing (trait risk)
Vulnerability factors (education, occupation, head
injury)
Early recognition (10 warning signs)
Screening tools (6th vital sign in elderly)
Positive diagnostic tests




CSF – tau levels elevated, amyloid levels low
Brain scan – PET – DDNP, Congo-red derivatives
Mild Dementia severity assessments
Detecting early change over time

predicting progression, measuring rate
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
Need for a Brief Screening Test for
Dementia, Alzheimer’s Disease

Recent evidence of benefits of anti-cholinesterase
agents in the treatment of mild Alzheimer’s disease





Improvement of cognition
Slowing of progression
Delay of conversion to diagnosis
How to get elderly, clinicians interested in screening
for dementia
How to handle positive screens sensitively and
efficiently

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.
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?


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!”


D = 1 if within 2 days.
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
(Mendiondo et al., 2003)
Dementia Screening Test


Need test to screen patients for Alzheimer’s disease
Test needs to be on multiple platforms:










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
MEMTRAX - Memory Test
(to detect AD onset)

New test to screen patients for AD:








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:

CHOLINESTERASE INHIBITION

(1st double blind study - Ashford et al., 1981)
Presumably increases acetylcholine at synapses
 Improvement in cognition (? 6-12 months better)
 Improvement in function (ADLs, variable)
 Improvement in behavior (? basal ganglia)
 Slowing of disease course

Treatment delays nursing home placement
 There is loss of benefit with delay of treatment


Need to consider early intervention
Treatment of Alzheimer’s Disease
Patients (millions)
5
4,523,100
4
3
2,261,600
2
904,600
1
543,800
0
Prevalence
Diagnosed
Treated*
* Any drug treatment, not limited to acetylcholinesterase inhibitors.
Source: Decision Resources, March 2000.
Treated
with AChEIs
Cholinergic Changes in AD

The most prominent neurotransmitter
abnormalities are cholinergic



Reduced activity of choline acetyltransferase
(synthesis of acetylcholine)1
Reduced number of cholinergic neurons in late
AD (particularly in basal forebrain)2
Selective loss of nicotinic receptor subtypes in
hippocampus and cortex1,3
1. Bartus RT et al. Science. 1982;217:408-414. 2. Whitehouse PJ et al. Science. 1982;215:1237-1239.
3. Guan ZZ et al. J Neurochem. 2000;74:237-243.
intracellular
extra cellular
Lipid raft
Formed by cholesterol
Transported by ApoE
From macroglia
Stimulated by acetylcholine
through muscarinic receptor
Favored when lipid
raft too large
NEXIN
? To establish
new connections
JW Ashford, MD PhD,
2003
? Free-radical generator
? To remove old synapses
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., 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


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?
are new AChEase molecules created which require dose increases?
does sudden discontinuation lead to catastrophic decline?
do early, chronic benefits suggest prevention?
Exelon Improves Cognitive Function:†
ADAS-Cog mean change from baseline
6–12 mg/day Exelon
1–4 mg/day Exelon
®
®
Placebo
Improvement
2
Mean change in
ADAS-Cog score
1
*
*
*
18
26
Weeks
0
–1
–2
12
*
4.94
*
–3
–4
–5
†B352
OC study analysis; *p<0.05 vs
placebo
Worsening
Corey-Bloom J et al, for the ENA 713 B352 Study Group. Int J Geriatr Psychopharmacol. 1998;1:55-65.
ADAS-Cog Mean Change
from Baseline
Exelon  Longterm Effects on Cognition:
Mean Change in ADAS-Cog from
Baseline at Week 52
*
1
0
-1
-2
-3
-4
-5
-6
-7
*
*
*
*
10
B352 Patients in B353 (OC) at Week 52
* p< 0.05 vs projected placebo
*
*
6-12 mg
1-4 mg
Placebo
Proj. PBO
0
*
20
All Patients
Taking Exelon
30
40
*
50
60
Study Week
Sohn et al. In: Proceedings of the CPNP. April 2000.
REMINYL® (galantamine HBr) Pooled Analysis:
Change in ADAS-cog Scores at 6 and 12 Months
Advanced Moderate AD Patients With Baseline ADAS-cog Scores >30
–6
*
*
*†
–4
–2
†‡
0
2
4
6
8
REMINYL 24 mg/d
10
Placebo from RCTs
12
Historical placebo
Baseline
1
3
6
Time (mo)
9
12
*p<0.001 vs placebo.
†p<0.001 vs historical placebo.
‡Not significant vs baseline.
Baseline ADAS-cog score: 37.3 (REMINYL 24 mg/d) vs 37.4 (placebo).
Adapted from Blesa R et al. Dement Geriatr Cogn Discord. 2003;15:79-87.
Improvement
Mean ( SE) Change in
ADAS-cog From Baseline
–8
GAL-GBR-2
MMSE: Change From Baseline
2.5
*
Mean MMSE change
(± SE) from baseline
2
.
*
1.5
1
Reminyl® (galantamine HBr)
(n = 94)
Aricept® (n = 87)
†
0.5
NS
0
–0.5
–1
–1.5
–2
–2.5
#
0
13
26
39
52
Weeks
* p  0.0001 vs baseline; † p = 0.0006 vs baseline; # p = 0.0003 vs baseline.
NS = p > 0.1.
Data on file, Janssen Pharmaceutica Products, L.P. Bullock R et al. Poster presented at the 41st Annual Meeting
of the ACNP, San Juan, Puerto Rico, December 8–12, 2002.
Benefits of Treatment of AD With
Acetylcholinesterase Inhibitors




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.
Indications

REMINYL® (galantamine HBr) is approved for the
treatment of patients with mild-to-moderate dementia of
the Alzheimer’s type

The most frequent adverse events associated with
REMINYL included nausea, vomiting, diarrhea, anorexia,
and weight loss; most were generally transient and mild to
moderate in severity

REMINYL is available in 4-mg, 8-mg and 12-mg tablets
and an oral solution (4 mg/mL) and is taken twice a day,
preferably with morning and evening meals

May benefit very early cases, particular APOE-e4 carriers
Reminyl® (galantamine HBr):
Proposed Mechanisms of Action





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)
GI Tolerability

Nausea and vomiting: typically transient and
related to treatment initiation and dose escalation


Among patients experiencing nausea, median
duration was 5 to 7 days
Weight loss: reported as an adverse event in 
5% of patients, with none discontinuing
treatment due to weight loss
REMINYL Full Prescribing Information, 2001. Data on file, Janssen Pharmaceutica Products, L.P.
Reminyl® (galantamine HBr)
Pharmacokinetics



Linear pharmacokinetics
Bioavailability: 90%
Half-life: 7 hours




- can provide decrease inhibition at night!!
Low (18%) plasma protein binding
Hepatic metabolism via multiple
pathways, primarily CYP2D6 and
CYP3A4
Renal excretion
Reminyl® (galantamine HBr):
Dosing

Simple, one-step dose escalation

8 mg/day starting dose


16 mg/day maintenance dose


(12 mg bid) – should try after 12 weeks if further benefit sought
Taken preferably with morning and evening meals



for at least 4 weeks (8 mg bid)
The flexibility to increase to 24 mg/day


for 4 weeks (4 mg bid)
Later, better with morning meal, mid-afternoon snack.
(Avoid nocturnal cholinergic activation!!)
Available in 4-mg, 8-mg, and 12-mg tablets and
oral solution (4 mg/mL)
Switching Guidelines (cont)

Switching from Aricept® to Reminyl® (galantamine HBr)


No washout period of Aricept® should be
undertaken before initiating REMINYL. The standard dose
escalation should be undertaken the next day after the last
Aricept® administration
Switching from Exelon® to REMINYL

No washout period of Exelon® should be undertaken before
initiating REMINYL. The standard dose escalation should be
undertaken the next day after the last Exelon® administration
Morris JC et al. Clin Ther. 2001;23(suppl A):A31-39.
Switching guidelines (cont)

Exceptions



For patients who are experiencing poor tolerability on Aricept®
or Exelon®, a washout period of up to 7 days should be
undertaken, or until symptoms resolve
The standard dose escalation of Reminyl® (galantamine HBr)
should then be undertaken
Combined dosing


Combination therapy with AChEIs is not recommended by the
manufacturing company
Galantamine may be combined with Namenda® (memantine)


Evidence suggests additional efficacy
Combination appears to be at least as effective as combination of
donepezil and memantine
Morris JC et al. Clin Ther. 2001;23(suppl A):A31-39.