PRACTICAL/ROYAL COLLEGE TYPE
APPROACH TO DEMENTIAS
Serge Gauthier, MD, FRCPC
McGill Center for Studies in Aging
Montréal, Canada
CONTENT
•
•
•
•
•
Diagnostic issues
Current status of pharmacotherapy
Studies under way
Considerations for use of future drugs
CCCDTD4
MoCA
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Alzheimer’s disease exists on a spectrum
from minimal symptoms to dementia
Increasing Alzheimer’s
pathology
No symptoms
Mild cognitive
symptoms
Dementia
Time
• Increasingly severe phenotype
• Biomarkers assist in identifying the underlying pathology
• Biomarker changes may precede clinically detectable changes
© JL Cummings, 2008
Dubois et al., Lancet Neurology 2007
Dubois et al., Lancet Neurology 2007
AD Diagnosis Marching Leftward
Presymptomatic
AD
Onset
of AD
path
No symptoms,
biomarker
evidence
of amyloid
dysregulation
Modified
Dubois criteria:
“earlier AD”
Very mild
symptoms
+ amyloid
biomarker
Aisen PS. Alzheimers Res Ther. 2009;1:2. doi:10.1186/alzrt2.
Dubois
research criteria:
“early AD”
Episodic
memory
impairment
+ any
biomarker
Standard
diagnosis
Dementia
PIB +ve
SPINAL FLUID (CSF) IN AD
A42
↓↓
↓ or N
N
AD
MCI
Cont
rol Phosphorylated tau
in tangles
Tau
↑↑
↑ or N
N
Ptau
↑↑
↑ or N
N
Total tau in
neuronal axons
A1-42 in senile
plaques
AD PROGRESSION USING BIOMARKERS
Abnormal
CSF Aβ42
Amyloid imaging
FDG-PET
MRI hippocampal
volume
CSF Tau
Cognitive performance
Function (ADL)
FDG-PET
MRI hippocampal
volume
Amyloid
imaging
CSF Aβ42
Cognitive performance
Function (ADL)
CSF Tau
Normal
Presymptomatic
eMCI
LMCI
Dementia
Aisen PS, Petersen RC, Donohue MC, et al. Alzheimers Dement. 2010;6:239-246.
Time
Comparison of Clinical, Cognitive, Structural, Metabolic, and Biochemical Changes as a
Function of Estimated Years from Expected Symptom Onset.
Bateman RJ et al. N Engl J Med 2012;367:795-804
DIAGNOSTIC CRITERIA FOR DEMENTIA
PROBABLY DUE TO AD USING BIOMARKERS
(Modified from McKhann et al, 2011)
Aß
• Probable AD with
high likelihood
• Probable AD with
intermediate likelihood
• Probable AD dementia
• Possible AD dementia
+
Neuronal injury
+
+ or untested untested or +
untested or conflicting results
+
+
(atypical clinical presentation)
* Unlikely AD dementia
-
-
DIAGNOSTIC CRITERIA FOR
MCI DUE TO AD USING BIOMARKERS
(Modified from Albert et al, 2011)
Aß
+
Neuronal injury
+
• MCI due to AD
high likelihood
• MCI due to AD
+
untested
intermediate likelihood untested
+
• MCI possibly due to AD
untested or conflicting
• MCI unlikely due to AD
-
DIAGNOSTIC CRITERIA FOR PRECLINICAL AD
USING BIOMARKERS
(Modified from Sperling et al, 2011)
• Asymptomatic
cerebral amyloidosis (ACA)
• ACA + evidence of neuronal
injury (NI)
• ACA + NI + subtle cognitive
decline
Aß Neuronal Symptoms
injury
+
+
+
-
+
+
+
CONTENT
•
•
•
•
•
Diagnostic issues
Current status of pharmacotherapy
Studies under way
Considerations for use of future drugs
CCCDTD4
NATURAL HISTORY OF AD AND CURRENT Rx
Normal
MCI
Early
L
o
s
s
Moderate
Severe
Terminal
1
2
3
4
5
6
7
8
Temps (ans) )
NATURAL HISTORY OF AD AND CURRENT Rx
No standard drug therapy
Normal
MCI
Early
L
o
s
s
Moderate
Severe
Terminal
1
2
3
4
5
6
7
8
Temps (ans) )
NATURAL HISTORY OF AD AND CURRENT Rx
No standard drug therapy
Normal
No standard drug therapy
MCI
Early
L
o
s
s
Moderate
Severe
Terminal
1
2
3
4
5
6
7
8
Temps (ans) )
NATURAL HISTORY OF AD AND CURRENT Rx
No standard drug therapy
Normal
No standard drug therapy
MCI
Antidepressants
CIs
Early
L
o
s
s
Moderate
Severe
Terminal
1
2
3
4
5
6
7
8
Temps (ans) )
NATURAL HISTORY OF AD AND CURRENT Rx
No standard drug therapy
Normal
No standard drug therapy
MCI
Antidepressants
CIs
CIs
Memantine
Early
L
o
s
s
Moderate
Severe
Terminal
1
2
3
4
5
6
7
8
Temps (ans) )
NATURAL HISTORY OF AD AND CURRENT Rx
No standard drug therapy
Normal
No standard drug therapy
MCI
Antidepressants
CIs
CIs
Memantine
Early
Memantine; CIs
Atypical neuroleptics
L
o
s
s
Moderate
Severe
Terminal
1
2
3
4
5
6
7
8
Temps (ans) )
NATURAL HISTORY OF AD AND CURRENT Rx
No standard drug therapy
Normal
No standard drug therapy
MCI
Antidepressants
CIs
CIs
Memantine
Early
Memantine; CIs
Atypical neuroleptics
L
o
s
s
Memantine; CIs
Atypical neuroleptics
Moderate
Severe
Terminal
1
2
3
4
5
6
7
8
Temps (ans) )
EXAMPLE OF MCI STUDY
Conversion to AD by Treatment Group
1 yr
1.0
2 yr
3 yr
0.9
0.8
Probability
of not
0.7
converting
to AD
0.6
Donepezil
Vitamin E
Placebo
0.5
D–P P=0.416
E–P P=0.912
0.4
0
200
400
600
800
1,000
1,200
Time on MCI study (days)
CP1157990-7
EXAMPLE OF MILD TO
MODERATE DEMENTIA STUDY
DONEPEZIL VS PLACEBO
COGNITION (ADAS-cog)
Least squares mean change from
baseline (±SE)
–2.5
**
–2.0
**
–1.5
–1.0
–0.5
**
**
**
**
**
**
**
**
0.0
**
**
**
Clinical improvement
**
0.5
1.0
Clinical decline
1.5
2.0
US Study†
Study‡
2.5
Placebo
3.0
Aricept:
3.5
5 mg/day
Multinational
10 mg/day
4.0
0
6
12
18
Study week
Endpoint
30
Placebo
washout
ITT-LOCF analysis; **p0.001 for Aricept versus placebo
†Rogers et al. Neurology 1998;50:136–145; ‡Burns et al. Dement Geriatr Cogn Disord 1999;10:237–244
EXAMPLE OF MODERATE TO
SEVERE DEMENTIA STUDY
CONCLUSION ABOUT
AVAILABLE DRUGS
• Current symptomatic drugs are useful in
AD, from mild to severe stages of
dementia
• The advantage of combination of drug
classes has not been conclusively
demonstrated
• The value of CIs in MCI has not been
conclusively demonstrated
CONTENT
•
•
•
•
•
Diagnostic issues
Current status of pharmacotherapy
Studies under way
Considerations for use of future drugs
CCCDTD4
Treating AD: The Amyloid Cascade
Hypothesis
AGE
30
40
50
60
70
80
90
100
-amyloid
deposition
Microglial
activation Neurofibrillary
Neuronal loss/
tangles
neurochemical
changes
DEMENTIA
APP
gene
-Amyloid treatment strategies under study
Production
APP
Antisense
Secretase
inhibitors &
modulators
A
Monomer
Immunotherapy
A
Oligomer
Aggregation
A
Fibril
Deposition
Fibrillogenesis
modulators
Diffuse
Plaque
Antiinflammatory
Senile
Plaque
Some recent negative trials in
AD
• Targeting A production
– Semagestat (g-secretase inhibitor)
– Rosiglitazone (-secretase inhibitor)
• Targeting A aggregation
- Scyllo-inositol
• Targeting A plaques
- Bapineuzumab
Bengt Winblad
Aug, 2012
35
Original Article
Clinical and Biomarker Changes in Dominantly
Inherited Alzheimer's Disease
Randall J. Bateman, M.D., Chengjie Xiong, Ph.D., Tammie L.S. Benzinger, M.D.,
Ph.D., Anne M. Fagan, Ph.D., Alison Goate, Ph.D., Nick C. Fox, M.D., Daniel S.
Marcus, Ph.D., Nigel J. Cairns, Ph.D., Xianyun Xie, M.S., Tyler M. Blazey, B.S., David
M. Holtzman, M.D., Anna Santacruz, B.S., Virginia Buckles, Ph.D., Angela Oliver, R.N.,
Krista Moulder, Ph.D., Paul S. Aisen, M.D., Bernardino Ghetti, M.D., William E.
Klunk, M.D., Eric McDade, M.D., Ralph N. Martins, Ph.D., Colin L. Masters, M.D.,
Richard Mayeux, M.D., John M. Ringman, M.D., Martin N. Rossor, M.D., Peter R.
Schofield, Ph.D., D.Sc., Reisa A. Sperling, M.D., Stephen Salloway, M.D., John C.
Morris, M.D., for the Dominantly Inherited Alzheimer Network
N Engl J Med
Volume 367(9):795-804
August 30, 2012
The Dominantly Inherited Alzheimer
Network (DIAN)
Admin – JC Morris
Genetics – AM Goate
Clinical – RJ Bateman
Imaging – T Benzinger
Biomarkers – AM Fagan
– D Marcus
Therapeutic Trials Informatics
Unit
Randy Bateman
(Director), Virginia Buckles,Neuropathology
Matt Carril, Dave
Clifford,
Biostatistics
– C Xiong
– NJ
CairnsDenise
Levitch, Susan Mills, Pam Millsap, John Morris, Krista Moulder, Angela Oliver, Anne
Ragland, Anna Santacruz, Natalie Selsor, Wendy Sigurdson, Joy Snider
http://www.dian-info.org/
batemanr@neuro.wustl.edu
DRUGS SELECTED BY DIAN
• Gantenerumab, antibody against
aggregated amyloid, from Roche
• Solanezumab, monoclonal antibody
against soluble amyloid, from Lilly
• New beta-secretase inhibitor, from Lilly
•
•
•
•
•
•
•
proposed preclinical autosomal dominant trial
design
300 participants in Colombia
– 200 carriers to study efficacy of
treatment by comparing change on
composite cognitive battery, other
clinical measures & biomarkers
– cohort study of 100 placebo-treated
carrier& non-carriers
crenezumab 300 mg SC every 2 weeks
up to 18mo for enrollment
duration 280 weeks: 6-week screening
period, 260-week, double-blind
treatment period, and a 14-week f/u
(16 weeks after the last dose of study
drug)
decision-making interim analysis after
104 weeks
Smaller US group with variable
mutations (n about 30), in collaboration
with DIAN
Under review by FDA, INVIMA,
EC’s/IRB’s
CONTENT
•
•
•
•
•
Diagnostic issues
Current status of pharmacotherapy
Studies under way
Considerations for use of future drugs
CCCDTD4
USE OF BIOMARKERS
MON ITORING FOR
NEUROLOGIC COMPLICATIONS
New Treatments:
SURPRISES WITH ANTI-AMYLOID
IMMUNOTHERAPY
CD3 T-cell meningeal
Vasculitis
response to AN-1792
Posterior Reversible
Encephalopathy
Syndrome (PRES)
Accelerated Brain
Atrophy
Intra-cerebral
Microhemorrhage
RISKS WITH ANTI-AMYLOID Rx
Amyloid Imaging Related Abnormalities
(ARIA)
• Transient cerebral edema (ARIA-E)
• Micro-bleeds (ARIA-H)
POSSIBLES RESTRICTIONS IN THE USE
OF NEW DRUGS
• Stage of disease (MCI vs early dementia)
• Diagnosis confirmed by biomarker (MCI)
• Responder status confirmed by age,
phenotype and genotype (ApoE)
• Availability of MRI and neurology
resources for short-term complications
• Availability of infusion services
NEW ETHICAL ISSUES
• Early diagnosis in persons with full insight
can lead to catastrophic reactions
• Access to new treatments will be restricted
by the studies inclusion and exclusion
criteria
• Costs will be high
• Stopping rules for treatments are needed
CONTENT
•
•
•
•
•
Diagnostic issues
Current status of pharmacotherapy
Studies under way
Considerations for use of future drugs
CCCDTD4
CCCDTD4
• Definition (MCI due to AD)
• Early onset dementias (need for registry)
• Rapidly progressive dementias (need for
specialized centers)
• Neuroimaging (not ready for prime time)
• Liquid biomarkers (CSF more cost-efficient
but not popular)
• Symptomatic drugs & discontinuation of
CIs
RECOMMENDATIONS FROM
CCCDTD4 ON STOPPING CIs
Discontinuing CIs in patients with moderate to severe
AD may lead to worsening of cognitive function and
greater functional impairment as compared to continued
therapy (Grade 2B). This must be balanced with the risk
for known side-effects and drug costs if therapy
continues. It is suggested that CIs be discontinued when:
a) The patient and/or their proxy decision-maker decide
to stop after being appraised of the risks and benefits of
continuation and discontinuation
b) The patient is sufficiently non-adherent with the
medication that continued prescription of it would be
useless, and it is not possible to establish a system for
the administration of the medication to rectify the
problem;
RECOMMENDATIONS FROM
CCCDTD4 ON STOPPING CIs
c) The patient’s rate of cognitive, functional, and/or
behavioural decline is greater on treatment compared to
that prior to being treated;
d) The patient experiences intolerable side effects that
are definitely or probably related to the CI;
e) The comorbidities of the patient make continued use
of the agent either unacceptably risky or futile (e.g.,
terminally ill);
f) The patient's dementia progresses to a stage (e.g.,
Global Deterioration Scale stage 7) where there would
be no clinically meaningful benefit from continued
therapy.
RECOMMENDATIONS FROM
CCCDTD4 ON STOPPING CIs
When a decision has been made to
discontinue therapy because of a
perceived lack of effectiveness, it is
suggested that the dose be tapered before
stopping the agent and that the patient be
monitored over the next 1-3 months for
evidence of an observable decline. If this
occurs, it is suggested that consideration
be given to reinstating therapy. (Grade 2C)