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

Petersen Arch Neur 1999

Mild Cognitive Impairment

• Complaint of memory problem ideally corroborated by informant

• Objective evidence of memory impairment

• Preserved global cognitive function

• Preserved social & occupational function

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?

J Int Med 2004

M CI C lassification-Revised

YesAm nestic M C I

N oM ultidom ain

Am nestic M C I

O nly m em ory im paired ?

Yes

YesM ultidom ain M C I

N on-am nestic

N oSingle dom ain

N on-am nestic M C I

M ore than one dom ain im paired?

N o

Im pairm ent in m em ory?

M ild C ognitive Im pairm ent

N ot norm al for ageN ot dem ented

C ognitive declineEssentia lly norm al functional activ itie s

C ognitive com pla in t

Mild cognitiveMild cognitiveimpairmentimpairment

AmnesticAmnestic

Mild cognitiveMild cognitiveimpairmentimpairment

Multiple Multiple

domainsdomainsslightly impairedslightly impaired

Mild cognitiveMild cognitiveimpairmentimpairmentSingle non-Single non-

memory domainmemory domain

Alzheimer’s diseaseAlzheimer’s disease

Alzheimer’s diseaseAlzheimer’s disease? normal aging? normal aging

Frontotemporal dementiaFrontotemporal dementiaLewy body dementiaLewy body dementiaParkinson’s diseaseParkinson’s diseaseAlzheimer’s diseaseAlzheimer’s diseaseVascular dementiaVascular 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 MCI AD 12%/yrAD 12%/yr Control Control AD 1-2%/yrAD 1-2%/yr

Petersen RC et al: Arch Neurol 56:303-308, 1999Petersen RC et al: Arch Neurol 56:303-308, 1999

50

60

70

80

90

100

50

60

70

80

90

100

Initial 12 24 36 48exam

MCI ADMCI AD Controls ADControls AD

Months

Initial 12 24 36 48exam Months

Petersen Arch Neur 1999

0

20

40

60

80

100

0 1 2 3 4 5 6 7 8 9

StableStable(%)(%)

YearsYears

MildMildCognitiveCognitiveImpairmentImpairment

Risk of Progression to AD

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

• Neuropsychological measures

• Genetic factors

• Neuroimaging findings

• Risks factors for progression mimic risk factors for development of AD

NeuropsychologicalPredictors

• 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

Petersen Oxford Press 2003

MCI: Conversion to Dementia

%%

YearsYears

0

20

40

60

80

100

0 1 2 3 4 5 6

APOE 4 APOE 4 non carriernon carrier

APOE 4 carrierAPOE 4 carrier

Neuroimaging Predictors

• Medial temporal lobe atrophy

• Hippocampal atrophy

• Global atrophy

• Parietal hypometabolism on FDG-PET

Petersen Oxford Press 2003

0

25

50

75

100

0 1 2 3 4 5 6

StableStable(%)(%)

YearsYears

W W 00

-2.5 < W <-2.5 < W <00

W W -2.5-2.5

Hippocampal Atrophy & Risk of AD

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

Petersen et. al NEJM 2005

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

Vitamin E & Donepezil for the Treatment of MCI

Risk for Progression to AD

Jelic J. Neur Neurosurg Psych 2006

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%

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

Ancelin, M. L et al. BMJ 2006;332:455-459

Mean z scores for consistent users of anticholinergic drugs vs. non-users

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/

Nasreddine ZS. J Am Geriatr Soc 2005

MOCA Vs. MMSE in MCISensitivity 87% Vs. 18%

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