Transcript Mild_Cognitive_Impairment

Understanding Mild Cognitive
Impairment
Objectives
• Understand the concept of MCI
• Identify risk factors for progression to
dementia
• Review clinical trial data regarding CHEI
in patients with MCI
• Develop a clinical approach to
recognition and management of MCI
Case of Mr. T.
• 80 yo male c/o 2 years of difficulty
recalling names and phone numbers
• Concerned that his memory was
“getting worse”
• Managing money, medications,
shopping and all IADLs without difficulty
• Initial MMSE 29/30, 1 off for recall 3/3
with cueing
Questions
•
•
•
•
Should you be concerned?
What would you do at this point?
Is the patient demented?
Is there evidence for cognitive
impairment?
Cognitive Changes With Aging
Preserved (crystallized)
– Language
– Vocabulary
– Semantic memory
– Factual knowledge
Decline (fluid)
– Working memory
– Psychomotor
speed
– Complex problem
solving
– Memory retrieval
Crystallized Vs. Fluid
Intelligence in Aging
Dementia (DSM IV)
• Memory impairment
• Associated impairment in abstract thinking,
judgment, other disorders of cortical function
or personality change
• Significant severity to cause impairment in
social or occupational functioning
• Decline from a previously higher level of
functioning
• NOT occurring exclusively during delirium
Spectrum of Cognitive Impairment
Mild Cognitive Impairment
• Complaint of memory problem ideally
corroborated by informant
• Objective evidence of memory
impairment
• Preserved global cognitive function
• Preserved social & occupational
function
Petersen Arch Neur 1999
Controversies in MCI
• A label or a diagnosable condition?
• How much memory impairment and
which tests?
• What about other cognitive domains?
• Definition of preserved social and
occupational function?
MCI Classification-Revised
Cognitive complaint
Not normal for age
Not demented
Cognitive decline
Essentially normal functional activities
Mild Cognitive Impairment
Impairment in memory?
Yes
No
Only memory impaired?
More than one domain impaired?
Yes
Amnestic MCI
No
Multidomain
Amnestic MCI
Yes
Multidomain MCI
Non-amnestic
No
Single domain
Non-amnestic MCI
J Int Med 2004
Mild cognitive
impairment
Amnestic
Mild cognitive
impairment
Multiple domains
slightly impaired
Mild cognitive
impairment
Single nonmemory domain
Alzheimer’s disease
Alzheimer’s disease
? normal aging
Frontotemporal dementia
Lewy body dementia
Parkinson’s disease
Alzheimer’s disease
Vascular dementia
Case of Mr. T.
• Returned 8 months later complaining of
further “worsening memory”
• Still managing all his IADLs,
medications, taxes, money, shopping,
etc.
• MMSE 30/30 up from 29/30
• What would you do now?
Case of Mr. T.
• Labs all normal
• MRI “mild cortical atrophy appropriate
for age”
• Learned 5/6 words after 3 trials, 1/6 on
delayed recall after 15 minutes
• No benefit from cueing, several
intrusion errors
Case of Mr. T. Continued
• Slightly diminished category fluency
– 13 supermarket items one minute, down
from 19
– Clock drawing showed misplacement of
hands
• Impaired visual memory with impaired
recognition
Visuospatial Skills
Visual Memory
Visual Memory-recognition
Questions
• Is the patient demented?
• What is your diagnosis at this point?
• What is the risk for developing
dementia?
• Can we predict the likelihood of
developing dementia?
• Is treatment indicated and what is the
role of cholinesterase inhibitors?
Can We Predict Who Will
Develop Alzheimer’s Disease?
Mild Cognitive Impairment (MCI)
MCI AD 12%/yr
Control AD 1-2%/yr
100
100
90
90
80
80
70
70
60
60
50
50
Initial
exam
12
24
36
Months
MCI
48
AD
Petersen RC et al: Arch Neurol 56:303-308, 1999
Initial
exam
12
24
36
Months
Controls
AD
48
Risk of Progression to AD
Mild
Cognitive
Impairment
100
80
Stable
(%)
60
40
20
0
0
1
2
3
4
5
6
7
8
9
Years
Petersen Arch Neur 1999
Progression to AD
• Highly varied progression rates across
studies related to study population
• Ranges from 11-33% over 2 years
• Up to 44 % return to normal cognition at
one year
• Risk factors predicting transition to AD
are only partially understood
Predictors of Progression
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•
•
•
Neuropsychological measures
Genetic factors
Neuroimaging findings
Risks factors for progression mimic risk
factors for development of AD
Neuropsychological
Predictors
• Poor performance on tests of free
recall
• Impaired executive functioning
• Depression/dysexecutive syndrome
• Apathy and social withdrawal may
be early behavioral markers for
cognitive dysfunction
Genetic Predictors of
Progression
• APOE allele status
• APOE 4 allele positivity increases risk of
AD
• APOE E 4 positivity increases risk for
conversion from MCI to AD
MCI: Conversion to Dementia
100
APOE 4 non
80
carrier
60
%
APOE 4 carrier
40
20
0
0
1
2
3
Years
4
5
6
Petersen Oxford Press 2003
Neuroimaging Predictors
•
•
•
•
Medial temporal lobe atrophy
Hippocampal atrophy
Global atrophy
Parietal hypometabolism on FDGPET
Hippocampal Atrophy & Risk of AD
100
75
W 0
Stable
(%)
50
25
-2.5 < W < 0
W -2.5
0
0
1
2
3
4
5
6
Years
Petersen Oxford Press 2003
What Is the Role of
Cholinesterase Inhibitors in MCI?
Cholinesterase Inhibitors in MCI
• 5 completed randomized clinical trials
– 2 for donepezil
– 2 for galantamine
– 1 for rivastigmine
• Duration from 24 weeks to 3 years
• Widely varying conversion rates to AD
• High dropout rates and adverse effects
Donepezil and Vitamin E
• Fewer donepezil treated patients converted to
AD at 6 and 12 months but effect was lost
over three years
• ~16% annual conversion rate
• APOE 4 allele was a strong predictor of
conversion
• Donepezil associated with lower risk of
conversion among APOE 4 positive
throughout first 24 months
Petersen et. al NEJM 2005
Vitamin E & Donepezil for the
Treatment of MCI
Risk for Progression to AD
Galantamine for MCI
• Gal-INT-11
• Gal-INT-18
– 24 month RCT placebo controlled studies
– 2000 patients included in both studies
• No effect on rate of conversion to AD in
either study
• Rates 13% vs. 18% and 17% vs. 21%
Jelic J. Neur Neurosurg Psych 2006
Galantamine for MCI
• Greater mortality in the galantamine
treated groups
• 5 deaths placebo vs. 15 with
galantamine
• RR death 3.04 (95% CI 1.26-7.32)
• Recent “Dear Doctor” letter and change
to labeling
Returning to Mr. T.
• Seen again in 2004 after several episodes of
getting lost from his way back home
• Increasing troubles managing medications
and some troubles with finances
• Family expressing concerns about his safety
• Diagnosed with probable Alzheimer’s disease
and begun on cholinesterase therapy
MRI Showing Bilateral
Hippocampal Atrophy
Evaluation of MCI in Clinical
Practice
• Take memory complaints seriously
• Don’t attribute to simply “getting older”
• Review medications and stop those with
significant anticholinergic effects
• Screen for depression
• Evaluate and treat cardiovascular risk
factors
Mean z scores for consistent users of
anticholinergic drugs vs. non-users
Ancelin, M. L et al. BMJ 2006;332:455-459
Evaluation of MCI in Clinical
Practice
• Consider usual lab w/u for dementia
– TSH, vitamin b12/folate, cmp, cbc
• Consider neuroimaging, particularly MRI
• Neuropsychological testing if available
• Further bedside testing can also be very
useful
Montreal Cognitive Assessment (MOCA)
http://www.mocatest.org/
MOCA Vs. MMSE in MCI
Sensitivity 87% Vs. 18%
Nasreddine ZS. J Am Geriatr Soc 2005
Summary
• MCI is a concept still in evolution
• Most will ultimately develop dementia but
many will not
• Treatment remains speculative and focuses
on close attention to general health and
cardiovascular risk factors
• Thoroughly assess and follow older patients
with memory complaints no matter how slight