Transcript Document

The Management of Alzheimer’s
Disease and Related Dementias
The Treatment of Alzheimer’s Disease
and Disease Progression Modification
Alzheimer’s Disease (AD): Overview
 Progressive, degenerative CNS disorder
 Characterized by memory impairment plus one or more
additional cognitive disturbances
 Gradual decline in three key symptom domains
– Activities of daily living (ADL)
– Behavior and personality
– Cognition
 Most common cause of dementia in people
aged 65 and over
Alzheimer’s Disease:
Economic Consequences
 Third most expensive disease in the US
 Costs over $100 billion/year
 Further $33 billion in lost productivity
and other employer costs
 3/4 of patients admitted to residential care
within 5 years of diagnosis
Evans DA, Scherr PA, Smith LA, et al. Aging (Milano). 1990(Sept);2(3):298-302; Ernst RL, Hay
JW. Am J Public Health. 1994(Aug);84(8):1261-1264; Alzheimer’s Association, 2002
Potential Impact of Interventions
to Delay Onset of Alzheimer’s Disease
Delay (Years)
0
1
5
8
6
4
2
2017 2027
2007
1997
Adapted from Brookmeyer et al, 1998.
0
2047
2037
Number of Patients
Potential to Increase Diagnosis
and Treatment Across Disease Stages
Number of patients1
Diagnosed2
Treated with AChE
inhibitor3
1,400,000
1,200,000
1,000,000
800,000
600,000
400,000
200,000
0
Mild4
Moderate4
Disease Stages
Severe4
AChE = acetylcholinesterase
1Mattson Jack; 2MMI MDAD, 2001; 3On CHeI—midpoint of last year’s treatment by severity
rates and rates reported in Reminyl uptake, 2001; 4Decision Resources.
Long-term Effects of Tacrine
on Nursing Home Placement
Probability of
Remaining at Home
1.0
0.8
80 mg
0.6
>80 to 120 mg
>120 to 160 mg
0.4
0
12
28
42
57
71
85
Time (Weeks)
Knopman D, Scheider L, Davis K et al. Neurology. 1996(July);47(1):166-177.
100
114
Dementia Increases the Costs of Caring for Common
Comorbidities in Managed Medicare Settings
Congestive Heart Failure
Diabetes with
Chronic Complications
Diabetes
Nondemented
19,300 matched
Chronic Pulmonary Disease
ADRD 3,934
Peripheral Vascular Disease
Cerebrovascular Disease
Renal Disease
0
5
10
15
20
Annual Cost (Thousands)
Hill JW, Futterman R, Duttagupta S, et al. Neurology. 2002(Jan 8);58(1):62-70.
25
Caregiver Burden in AD
 Compared with noncaregiver controls matched by age,
gender, race and marital status, caregivers of persons
with AD or related disorders require
– 46% more physician visits
– 71% more prescribed medications
– Higher diastolic blood pressure
– Hypercoagulable state
– Higher plasma norepinephrine
Haley WE, Levine EG, Brown SL, et al. Am J Geriatr Soc. 1987(May);35(5):405-411
Shaw et al., J Psychosom Res 2003; 54:293-302
vonKanel et al., Am J of Cardiol 2001(June);87:1405-1408
Grant I, Psychosom Med 1999; 61:420-423
Differential Diagnosis of Dementia
Other dementias
Frontal lobe dementia
Creutzfeldt-Jakob disease
Corticobasal degeneration
Progressive supranuclear palsy
Many others
Vascular dementias
Multi-infarct dementia
Binswanger’s disease
Dementia with Lewy bodies
Parkinson’s disease
Diffuse Lewy body disease
Lewy body variant of AD
Vascular dementias
and AD
AD and dementia
with Lewy bodies
AD
5% 10%
65%
Small et al, 1997; APA, 1997; Morris, 1994.
5%
7% 8%
Neuropathologic Changes
Characteristic of AD
Normal
AD
AP
AP=amyloid plaques; NFT=neurofibrillary tangles
Courtesy of George Grossberg M.D.; St. Louis University.
NFT
PET and Genetic Risk for
Alzheimer’s Disease
Normal Memory
Dementia
PET
Imaging
-6%
Genetic
Risk:
No APOE -4
-14%
APOE -4
Small GW, Ercoli LM, Silverman DH. Proc Natl Acad Sci. USA.
2000(May) 23);97(11):6037-6042 .
-28%
-31%
UCI Brain Imaging Center
Alzheimer’s Disease
Normal Control
Decreased
temporoparietal
Frontal
lobe
Occipital
lobe
Cerebellum
0.00
19.36
mg/100 g/min
PET in the Evaluation of Dementia
 284 dementia patients
(138 autopsy-confirmed diagnosis)
 Sensitivity 93%; specificity 76%
 Negative PET scan indicated chance of
cognitive progression <20% over 3 years
Silverman DH, Small GW, Chang CY, et al. JAMA. 2001 Nov 7;286(17):2120-2127
ADAS-Cog Sscore
Mean Change from Baseline
Model-based Analysis: ADAS-Cog Score
Mean Change from Baseline
Improvement
–6
0
6
Decline in ADAS-Cog score
based on the natural history of
untreated patients with moderate
AD*
12
18
0
6 12 14
N=133
26
38
50
62
74
Cumulative Weeks from Baseline
of the Double-blind Study
Rogers and Friedhoff, 1998; *Stern et al, 1994.
85
98
Decline
Major Cholinergic Changes in AD
 Depletion of acetylcholine (ACh): especially in
moderate to severe disease stages
 Decline in choline acetyltransferase (ChAT)
activity
 Loss of cholinergic neurons
– Loss of muscarinic (M2) receptors
– Loss of nicotinic receptors (nAChR)
  AChE
  Butylcholinesterase (BuChE)
Flynn et al, 1995; Perry et al, 1978; Rodriguez-Puertas et al, 1997; Whitehouse et al, 1982.
Normal Cholinergic Function
Presynaptic
neuron
Acetyl
CoA
+
Choline
Glial cell
Choline
ChAT
BuChE
MR1
MR2
Synaptic cleft
Postsynaptic
neuron
MR1 MR2
ACh
NR
BuChE
ACh
AChE
Choline
+
Acetate
NR
CoA=coenzyme A; MR=muscarinic receptor; NR=nicotinic receptor
Adapted from Adem, 1992.
AChE
Cholinesterase Inhibitors
H3C
ACh
H3CO
H3CO
O
N
N C
H2
Donepezil
mechanism: AChE-I
Physicians’ Desk Reference, 2003.
CH3
CH3
O
H3C
N
O
C
H2
O
CH3 O
CH3
CH3
H3C
Rivastigmine
N
mechanism: AChE/BuChE-I
CH3
H3C
+
N
.
HO
NEW
O
OCH3
Galantamine
mechanism: AChE-I
ChE Inhibitors: Overview
AChE Inhibitors
Dual AChE/
BuChE
Inhibitor
Characteristic
Donepezil
Galantamine
Rivastigmine
Doses per day
1
2
2
Maximum dose (mg/d)
10
24
12
Brain region selectivity
No
No
Yes
Reversibility
Reversible Reversible
Psuedoreversible
Nicotinic allosteric modulation No
Yes
No
Cytochrome P450 metabolism
Yes
No
Yes
Enz et al, 1992, 1993; Samochocki et al, 2000; Svensson and Nordberg, 1997;
Yamanishi et al, 1990; Cutler and Sramek, 1998; Inglis, 2002.
Allosteric Nicotinic Receptor Modulation
ACh-Induced Current (pA)
1,000
NEW
800
600
Galantamine
Rivastigmine
Metrifonate
Tacrine
Donepezil
400
200
Response amplitude
to 100 µM ACh
0
0.001
0.010
0.100
1.000
Concentration (µM)
Samochocki M, Zerlin M, Jostock R, et al. Acta Neurol Scand Suppl. 2000;176:68-73
10.000
Distribution of Cholinesterases in the
Healthy Human Brain
Figure 2†
Figure 1*
Amygdala
AChE
BuChE
Hippocampus
 BuChE neurons are less abundant than AChE neurons
 BuChE is very rich in cortical and limbic areas (amygdala and
hippocampus)
 BuChE accumulations in neuritic plaques
*Darvesh S, Grantham DL, Hopkins DA. J Comp Neurol. 1998(April 13);393(3):374-390. †Mesulam,
2000.
Distribution of Cholinesterases
in the Healthy Human Thalamus
Darvesh S, Hopkins DA. J Comp Neurol. 2003;463(1):25-43.
150
Rivastigmine 3 mg po
100
50
0
0
2.5 5.0 7.5 10.0 12.5
Time (Hours)
AChE in CSF
Cognitive Performance CNTB
CNTB summary score
Paired assoc. learning
Paired assoc. learning/delayed recall
Visual memory
*P<.01; **P<.05
CNTB=computerized neurophysiological test battery
CSF=cerebrospinal fluid
Percentage of Baseline
mean ± SEM
Percentage of Baseline
mean ± SEM
Rivastigmine Inhibition of CSF BuChE/AChE:
Correlation with CNTB Scores
150
Rivastigmine 3 mg po
100
50
0
0
2.5 5.0 7.5 10.0 12.5
Time (Hours)
BuChE in CSF
AUC
BuChE Activity AChE Activity
-0.65*
-0.56*
-0.53**
-0.22
-0.69*
-0.36
-0.52**
-0.42
Cutler et al, 1998; Costa et al, 1999;
Giacobini et al, 2002.
Relation between Activity and Numbers
of Senile Plaques in the Cerebral Cortex
Percentage of activity in
group with no plaques
200
BuChE
180
160
140
120
100
80
60
AChE
40
ChAT
20
0
0
1-5
6-10
11-20 21-30 30-42
Mean Plaque Count
Perry, 1978.
Compact Plaque Formation
Guillozet et al, 1997.
Activity of ChEs and b-amyloid (Ab)
Deposition in AD Cortex
G1 nmol/Min. x mg Protein
1.50
1.25
1.00
0.75
AChE
BuChE
0.50
0
Arendt et al, 1992.
50
100
150
200
Density of Ab Deposition
Long-term CSF Inhibition: Upregulation of AChE by
Tacrine, Donepezil, and Galantamine
50
700
P=.0013
CSF AChE Protein
AChE Activity mmol/mL/Min.
800
40
30
20
10
600
500
400
300
200
100
0
0
Baseline
12 months
Tacrine (80–160 mg/day)
0
12 0
6
0
6
0
12
months
Donepezil Galantamine Placebo
10 mg
Nordberg et al, 1999.
12 0
5 mg 32 mg 24 mg
Davidsson et al, 2001.
Long-term CSF Inhibition: Sustained Inhibition of AChE
and BuChE by Rivastigmine
60
50
40
30
20
10
0
-10
0
3
6
9
12
Treatment Length (Months)
Darreh-Shori et al, 2002.
Inhibition of CSF BuChE (%)
Inhibition of CSF AChE (%)
High-dose rivastigmine
Low-dose rivastigmine
80
70
60
50
40
30
20
10
0
-10
0
3
6
9
12
Treatment Length (Months)
ADAS-Cog Score
mean Change from Baseline
Model-based Analysis: ADAS-Cog Score
Mean Change from Baseline
Improvement
–6
0
6
Decline in ADAS-Cog score
based on the natural history of
untreated patients with moderate
AD*
12
18
0
6 12 14
26
38
50
62
74
Cumulative Weeks from Baseline
of the Double-blind Study
Rogers and Friedhoff, 1998; *Stern et al, 1994.
85
98
Decline
ADAS-Cog Score
Mean Change from Baseline
ADAS-Cog: Mean Change from Baseline during up to
36 Months’ Treatment with Galantamine
–6
–4
–2
0
2
4
6
8
10
12
14
16
18
20
22
24
Estimated decline: Stern equation
12 months placebo
Galantamine 24–32/24 mg/d
Baseline 3
Number of Patients
6
9
12
Baseline
165
Truyen and Kershaw, 2002; Stern et al, 1994.
18
Time (Months)
3
165
24
Time (Months)
6
9
12
165
165
160
30
36
24
124
36
81
Discrimination between Disease
Modification and Symptomatic Benefit
Withdrawal Design
Randomized
phase
Placebo
phase
Active
Disease-modifying
effect
Placebo
Performance
Performance
Randomized
phase
Staggered-start Design
Placebo
phase
Active
Placebo
Symptomatic
effect
Symptomatic
effect
Disease-modifying
effect
Time
Leber, 1997.
Time
ADAS-Cog Mean Change from
Baseline
Effects of Donepezil on Cognition
-3
***
-2
Improvement
***
***
-1
**
0
*
1
2
3
4
Baseline
***
10 mg/day (n=157)
5 mg/day (n=154)
Placebo (n=162)
6
12
18
Weeks on Therapy
Endpoint
30
Decline
Placebo
washout
*P<.0012; **P<.0007; ***P<.0001 vs placebo; mean MMSE score=19
Rogers SL, Farlow MR, Doody RS, Mohs R, Friedhoff LT. Neurology. 1998(Jan);50(1):136-145
Long-term Effects of Galantamine on Cognition:
ADAS-Cog Change from Baseline
Galantamine 24 mg/
Galantamine 24 mg (n=116)
(n=135)
Double-blind
Galantamine 32 mg/
Galantamine 24 mg (n=102)
Open-label
–4
ADAS-Cog mean (± SEM)
Change from Baseline
Placebo/
Galantamine 24 mg
Improvement
–3
–2
–1
*
0
1
2
All patients
receive galantamine
3
4
Baseline
13
26
Time (Weeks)
OC analysis; *P=.03 vs placebo/galantamine 24 mg
Raskind et al, 2000.
39
Decline
52
ADAS-Cog Mean Change
(± SEM) from Baseline
Long-term Effects of Rivastigmine
on Cognition: ADAS-Cog
Rivastigmine 6–12 mg
Placebo
Rivastigmine 1–4 mg
Projected placebo
2
1
0
–1
–2
–3
–4
–5
–6
–7
–8
–9
All patients
taking rivastigmine
0
*P<.05 vs projected placebo
Farlow et al, 2000.
12
18
26
Study Week
38
44
52
Effect of Long-term Rivastigmine
Therapy on Cognition in Patients GDS ≥5
Rivastigmine 6–12 mg/d
Rivastigmine 1–4 mg/d
Placebo treatment
up to 26 weeks
Projected
placebo
All patients taking rivastigmine 2–12 mg/d
ADAS-Cog Mean Change
from Baseline (± SEM)
–5
***
*** ***
***
*** ***
***
* ***
0
5
***
***
*
*
10
*
15
20
*P<.05; ***P<.001 vs projected placebo
OC data set
Baseline GDS 5
25
30
*
0
Doraiswamy et al, 2000.
26
38 44
52
Study Week
78
104
Mean Change in ADAS-Cog
Rivastigmine Effect on Cognitive
Function: Return Dropouts at Week 26
–2
–1
0
1
2
3
4
5
6
7
8
9
6–12 mg/day
1–4 mg/day
Placebo
*
RDO Population
*P<.05
Farlow et al, 2003.
Natural Progression of AD over 6 Months
vs the Effects of Rivastigmine
Rivastigmine
responders
minus baseline
Placebo
Increase
No change
Decrease
Increased
frontal
cortex
Potkin SG et al., Int J Neuropsychopharmacol. 2001;4(3):223-230
Increased
hippocampus
Glucose Metabolism in Cortical Association
Areas for AD Patients with and without
Rivastigmine Treatment
Glucose metabolism
Baseline
Untreated (n=12)
44
42
40
38
36
34
32
30
28
26
24
22
P<0.05
all brain regions
Brain region
Nordberg.
12 months
Treated (n=11)
44
42
40
38
36
34
32
30
28
26
24
22
Brain region
AChE and BuChE Activities
in Human Postmortem AD Brain
ChE Activity % of Respective
Control Values ± SEM
200
AChE
BuChE
100
0
Cortex
Hippocampus Cortex
AD Brain Region
Perry EK, et al. Neuropathol Appl Neurobiol. 1978;(4):273-277
Hippocampus
Selective Association of BuChE
with Amyloid Plaques in Cortex AD
BuChE staining in plaques,
tangles, dystrophic
neurites, and glia in AD
BuChE staining primarily
glial in nondemented
Guillozet AL, Smiley JF, Mash DC, Mesulam MM. Ann Neurol. 1997(Dec);42(6):909-918
AChE and BuChE Inhibitors Decrease
Endogenous b-APP Levels in Rats
Secreted b-APP Levels in
Rat CSF (Control ± SEM %)
Nonlesion
Nucleus basalis lesion
200
150
100
50
0
Control
Phenserine
AChEI
Haroutunian V, et al. Brain Res Mol Brain Res. 1997;46(1-2):161-168
Cymserine
BuChEI
Disease Progression: Rate of Cognitive Decline
in DLB Correlated with BuChE Levels at Autopsy
MMSE Decline/Year
12
10
8
6
4
2
R=0.88
P<.002
0
–2
0
0.7
0.8
0.9
BuChE Level in Medial Temporal Cortex
N=9
Perry et al, in press.
1.0
Correlation between CSF [Phospho-tau]
and MMSE Decrease in MCI
Annual MMSE Decrease
10
0
–10
–20
0
RHO=-.30
P<.01
Buerger et al, 2002.
300
600
900
1,200
1,500
CSF p-tau231 (pg/mL)
1,800
2,100
CSF Tau Levels in Treated and Untreated
AD Patients
Baseline
1,300
Followup (12 months)
CSF tau Level
(pg/mL)
1,100
900
P=.04*
700
P=.005*
P=.16
500
300
100
Control
Stefanova et al, 2003.
Tacrine
Rivastigmine
Greater Awareness May Lead to Earlier
Diagnosis and Treatment
Physician would have been
consulted sooner if caregiver or
others had known about
early signs
Yes
45%
No
32%
Physician would have been
consulted sooner if caregiver or
others had known about
prescription medication
47
Not
Sure
23%
 50% cases of moderate AD remain undiagnosed
 70% cases of mild AD remain undiagnosed
Harris Interactive Inc., 2001.
53
Summary
 Both AChE and BuChE can contribute to the loss of ACh,






which underlies many of the symptoms in AD
Inhibition of CSF AChE and BuChE with rivastigmine
correlates with clinical benefits
BuChE increases with severity of AD
BuChE may play a role in plaque maturation and APP
processing
Both AChE and BuChE are pharmacological targets
Lack of upregulation with rivastigmine implies that
cognitive benefits are sustained during long-term treatment
Increased AChE protein following galantamine and
donepezil is of uncertain clinical importance
Summary (cont’d)
 AD is an expensive illness in human and economic terms






for patient and care givers
Diagnosis is often not made, especially in early and mild AD
Frequently treatment is not initiated or sustained
Early treatment pays off; delaying treatment has long-term
consequences
Functional imaging can aid in early diagnosis of dementia
Moderately ill patients can robustly respond to tx
Cholinesterase inhibitors attenuate symptomatic decline
and may modify disease progression