Mild cognitive impairment MCI

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Mild cognitive impairment (MCI)

• Henry Brodaty
• Professor of Older Age Mental Health
• Director, Dementia Collaborative Research Centre,
  University of New South Wales
• Katrin Seeher
• Research Psychologist, POWH and UNSW

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Retrenched Lehman Bank employees staged a protest
by blockading the entrance to the Bank's
Headquarters for unfair and below-the-market
compensations
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Outline

• What is MCI?
• Why MCI?
• Definitional confusion a concept in evolution
• How common is MCI?
• What happens to people with MCI?
• Future directions

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What is MCI?
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What is MCI?

• There is usually a period between appearance of
  first symptoms and a clinical diagnosis of
  dementia
• e.g. Subjects who report subjective memory loss
  more likely to develop AD1
• ? MCI refers to transitional zone between normal
  aging and dementia 2

1Tyas et al, 2001 2Artero et al (2006). Dement
Geriatr Cogn Disord. 22465-470
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Mild Cognitive Impairment
Cognitive Performance
MCI refers to the state of cognition and
functional ability between normal aging and very
mild AD (Petersen, 2001)
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MCI concepts
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Pre-dementia
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Pre-dementia
Cognitive Performance
Normal
Pro-drome
AD
Pro-dromes?
VaD, LBD, FTD
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Normal gt MCI gt AD

• On all measures, MCI is intermediate
• between normal controls and Alzheimers
• disease
• Neuropsychology
• Neuroimaging
• Neuropsychiatry
• Neuropathology

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MCI Challenging issues

• Mary Ganguli Ron Petersen, 2008
• Pts can only be diagnosed with they had reached
  threshold of dementia
• But most appropriate time to intervene might be
  before then.
• ? Imperative to develop criteria with good
  predictive validity for progression to clinical
  dementia

Ganguli Petersen (2008). Am J Geriatr
Psychiatry165339-342
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Why MCI?

• Why make the diagnosis of MCI?
• Possibility of intervention next talk
• MCI may be too late maybe need pre-MCI?!
• Planning and advice
• would need high diagnostic accuracy
• Baby boomers caring for ageing parents worried
  about themselves Alzheimer phobia
• Pharma seeking expanded market?

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Global increase in dementia
Cognitive Impairment 5X more common in the
community than dementia (Unverzagt et al, 2001)
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Definitional Confusion
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Pre-dementia syndromes

• Age Associated Memory Impairment (AAMI)
• Age Related Memory Decline (ARMD)
• Age Related Cognitive Decline (ARCD)
• Benign Senescent Forgetfulness (BSF)
• Cognitive Impairment No Dementia (CIND)
• Memory Impairment
• Mild Cognitive Disorder (MCD)
• Mild Cognitive Impairment (MCI)
• Mild Neurocognitive Disorder (MND)
• Questionable dementia (QD)

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MCI criteria according to Flicker et al (1991)

• Based on GDS rating
• MCI GDS 3 2
• i.e. subtle deficits in cognition and possibly
  some impairment in executive functioning that
  affects complex occupational and social
  activities
• But GDS severity ranking and diagnostic
  instrument 3

Flicker et al (1991). Neurology. 411006-1009 2
Gauthier et al (2006). Lancet. 3671262-1270 3
Petersen et al (1999). Arch Neurol 56303-08
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Amnestic MCI (Petersen, 1995)

• Cognitive complaint, usually memory
• Cognitive screening test in normal range for age
  (eg MMSE)
• 1.5 SDs below age-appropriate norms on memory
  tests or memory component of other cognitive
  tests - clinician judgement
• ADLs not significantly affected
• Not meeting DSM dementia criteria

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MCI criteria according to Petersen

• Subjective memory complaint
• Objective memory impairment
• Normal general cognitive function
• Normal IADLs/ADLs
• No dementia

Petersen et al (1999). Arch Neurol. 55303-308
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Definition by Gauthier et al (2006)

• MCI is a syndrome defined as
• cognitive decline greater than expected for an
  individuals age and education level
• but that does not interfere notably with
  activities of daily life.

Gauthier et al (2006). Lancet. 3671262-1270
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Revised MCI criteria according to consensus
conference, Stockholm (2003)

• Not normal, absence of dementia
• Cognitive decline
• Subjective (self and/or informant report)
• Objective (1.5 SD)
• Some decline in function, but
• Preserved basic ADL/minimal impairment in complex
  IADLs

Winblad et al (2004). J Intern Med. 256240-246
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Subtypes of MCI

• Single-domain amnestic MCI
• Single-nonmemory MCI
• Multi-domain MCI amnestic
• Multi-domain MCI nonamnestic

Winblad et al (2004). J Intern Med. 256240-246
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Heterogeneity of MCI and potential multiple
aetiologies

• Possible aetiologies
• Degenerative
• Vascular
• Metabolic
• Traumatic
• Psychiatric
• Others?

• Clinical presentation
• MCI amnestic
• MCI multiple domains
• MCI single non-memory domain

from Winblad et al (2004). J Intern Med.
256240-246
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Gauthier et al (2006). Lancet. 3671262-1270
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Problems with criteria

• Multiple definitions
• Heterogenous criteria eg subjective, objective
• Vary in content and amount of detail eg which
  tests to use

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The problem with cognitive complaint

• Who complains?
• Patient or family member
• Does the person complain
• Spontaneously? or
• In response to interviewer asking about memory
  problems?
• Does the person seek assessment/ treatment or is
  s/he recruited from community survey?

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Problem with general cognition normal for age

• Usual to base this on a MMSE score above certain
  threshold, eg gt24
• Does not make allowance for effects of
  intelligence, education, language, culture
• Person of low intelligence is more susceptible to
  MMSE decline (than person with high IQ)

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Problem with memory impairment

• What is impairment?
• No specific cut-offs
• No standard memory tests prescribed
• Standard practice is to define 1.5 SD below
  population norms corrected for age, education
• BUT criterion then based on clinician judgement
• this is not operationalised but allows
  flexibility eg to allow for high intelligence,
  low education

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Problem with intact ADLs

• Intact ADLs can be as simple as still being able
  to dress, wash
• Or, intact IADLs e.g. driving car, managing
  housework, catching public transport
• But, are subtle impairments included?
• Eg ability to weigh up competing investment
  portfolios and make decisions about finance

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Impaired Financial ADLs1

• Subjects
• 21 cognitively normal
• 21 aMCI
• 22 mild AD
• The Financial Capacity Instrument (FCI) was
  administered to assess Financial ADLs
• FCI assesses financial ADLs in 9 domains, such as
  bill payment, investment decision making, and
  basic monetary skills

• Griffith et al (2003) Neurology 60449-57.

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Impaired Financial ADL Results1

• aMCI subjects impaired relative to controls in
• Cash transactions
• Bank statement management
• Bill payment
• Overall financial capacity
• The control and aMCI groups performed
  significantly better than mild AD subjects
• Suggests the aMCI diagnostic criteria should
  include impairments in higher order ADLs

• Griffith et al (2003) Neurology 60449-57.

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MCI-R now current Stockholm consensus conference

• Not normal
• Absence of dementia
• Cognitive decline
• Subjective (self and/or informant report)
• Objective (1.5 SD)
• Some decline in function, but
• Preserved basic ADL/minimal impairment in complex
  IADLs

Winblad et al (2004). J Intern Med. 256240-246
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John Morris Is MCI really early AD?

• Suggested to relabel MCI as early AD.

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Is Alzheimers disease a myth?
If AD (and MCI) brain ageing giving a diagnosis
of AD (and MCI) raises false hopes and
expectations

• ISBN 9781429920711

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Does MCI-R have clinical validity?
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Validation of revised criteria for MCI

• Petersen vs MCI-R (Winblad)
• ROC analysis ? prediction of dementia onset in
  the following 2yrs
• 308 Ss (60 average 75.7 years)
• ? estimated prevalence for MCI-R 16.6
• ? yearly incidence for MCI-R 0.06

Artero et al (2006). Dement Geriatr Cogn Disord.
22465-470
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Validation of revised criteria for MCI
Artero et al (2006). Dement Geriatr Cogn Disord.
22465-470
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How common is MCI? And how often does it
progress to dementia?Or stay stable?Or improve?
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Different criteria give different prevalence
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MCI-R criteria prevalence in a GP population

• 3242 Ss of a German GP sample (75 mean age 80.1
  years)

MCI-R according to Winblad et al (2004) without
mandatory subjective cog complaint
MCI-R according to Winblad et al (2004)
vs
Luck et al (2007). Dement Geriatr Cogn Disord.
24307-316
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MCI-R criteria prevalence in a GP population
Objective cog impairment (N818)
no subjective cognitive complaint 319 Ss (39)
did not meet MCI-R-criterion
No objective impairment (N2424)
Luck et al (2007). Dement Geriatr Cogn Disord.
24307-316
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Luck et al (2007). Dement Geriatr Cogn Disord.
24307-316
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MCI in general population Occurrence and
progression to AD1

• 3 yr prospective population-based study
• Kungsholmen-Project
• 379 Ss without dementia (75-95yrs old)
• Standard modified criteria for MCI
• Main outcome (applying both criteria sets)
• 3-year progression to AD

Palmer et al (2008). Am J Geriatr Psychiatry.
16(7)603-611
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MCI in general population Occurrence and
progression to AD1

• Standard criteria
• Petersen et al, 1999
• Subjective memory ?
• Do you feel that your/ participants memory has
  declined? (?60 Y)
• Objective cognition ? (? 30 Y)
• gt1sd below age/educatn
• N function basic ADLs

• Modified criteria
• Normal general cognition not mandatory
• General cognition within 1 sd of MMSE corrected
  for age and education

Palmer et al (2008). Am J Geriatr Psychiatry.
16(7)603-611
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Occurrence of 3 MCI subtypes
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Proportion of people who developed AD at 3 year
follow-up
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Hazard ratios of developing AD _at_ 3y
HR for only global cognitive deficits at
baseline 9.1
Palmer et al (2008). Am J Geriatr Psychiatry.
16(7)603-611
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MCI in general population Occurrence and
progression to AD1

• Removing requirement for normal general cognitive
  functioning
• ? Doubles occurrence of MCI-amnestic and
  MCI-multi-domains, but .
• predictivity for future AD not diminished
• On the other hand, low general cognition without
  MCI also increases risk of AD

Palmer et al (2008). Am J Geriatr Psychiatry.
16(7)603-611
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Memory and Ageing Study, Sydney

• 1032 community-based people
• Aged 70-90 from electoral roll

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Preliminary results Memory Ageing Study
Rates of MCI are higher in NESB but difficult to
interpret
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Preliminary results Memory Ageing Study
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Preliminary results from Memory Ageing

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Sydney Memory Ageing Study

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Instability of MCI
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Instability of syndromes

• Memory impairment (lt10th percentile)1
• After 2 years, 35 improved
• After 5 years, 42 improved
• AACD2
• After 1 year, 76/174 improved (43)
• After 3 years, 69/170 improved (41)

1Visser et al, 2000 2Ritchie et al, 2001
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Prevalence and rate of progression from
epidemiological studies

• Prevalence between 3 and 19
• Incidence per 1000 per year 8-58
• Risk of progression after 2 yrs 11-33
• Risk of progression after 5 yrs gt50

Gauthier et al (2006). Lancet. 3671262-1270
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Instability of MCI
Back to normal at 4yr follow-up (n1067 37)
MCI at baseline (n2882 42)
MCI (n1626 56)
Normal cognition at baseline (n4010 58)
Dementia at 4yr follow-up (n189 7)
Artero et al (2008). JNNP 79979-984
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Instability of syndromes

• MCI
• Petersen 12 pa ? dementia, robust
• Ritchie (2001)
• After 1 year, 25/27 improved (93)
• After 3 years 19/23 improved (83)
• Wahlund (2003)
• After 3 years, 5/43 improved (11)

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Rates of conversion

• Vary between 0 and 34 p.a.
• Depends on
• Sample source clinic vs community vs population
• Age of sample, higher if older
• Criteria for defining sample
• Exclusion criteria

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Explanation of discrepancy between Petersen and
Ritchie

• Peterson MCI Dx based on clinical judgement
• ?memory by 1.5 SDs is guide not definitive.
• Ritchie used a number of tests many people fell
  below this threshold on gt 1 test but these would
  not be considered MCI by Petersen
• How is clinical judgement operationalised?
• Would Petersens MCI patients be considered early
  dementia in other settings?

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Conversion from MCI to AD-Consistently reported

• ? age1-3
• Apoe4 genotype3-6
• ? general cognition1-3,7
• ? memory1,2,5,8-11
• ? function5,10-12

• Lower education13
• ? Recall
• ? executive function

1Visser et al, 2000 2Devanand et al, 1997
3Petersen et al, 1995 4Petersen et al, 1996
5Morris et al, 2001 6Tierney et al, 1996
7Devanand et al, 2000 8Flicker et al, 1991
9Marquis et al, 2002 10Wentzel et al, 2001
11Hanninen et al, 1995 12Artero et al, 2001
13Tervo et al, 2004
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Other predictors

• Hippocampal atrophy3 volume loss4-6
• Medial temporal lobe loss6
• Neuropsychiatric Sx 7
• ? SPECT perfusion 8
• PIB ve on PET 9
• CSF tau/P-tau

• ? baseline olfaction and no complaints of
  smelling problems1
• Taking longer to walk 30 ft 2
• Female gender1
• Non-drinking and frequent drinking2

1Devanand et al, 2000 2Marquis et al, 2002
3Anttila et al, 2004 4Jack et al, 1999 4Jack et
al, 2000 5Marquis et al, 2002 6Visser et al,
2002 7 8Johnson et al, 19989Rowe et al 2008
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Risk for MCI
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Risk profiles for MCI and progression to dementia

• 4yr population cohort study in France
• N 6892, Ss aged 65, 3 cities
• 42 MCI at baseline
• Aims Risk factors for MCI ApoE4, stroke, low
  education, loss of IADL, age
• Risk factors different for males and females

Artero et al (2008). JNNP 79979-984
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Risk profiles for MCI by gender

• Men
• BMI gt 27
• Diabetes
• Stroke

• Women
• Poor subjective health
• Being disabled
• Socially isolated
• Insomnia

Artero et al (2008). JNNP 79979-984
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Conclusions 1

• Pre-dementia syndromes heterogenous
• Higher risk of dementia
• Predictors of conversion similar to AD
• Validity questionable
• Specificity not known
• No intervention proven to work but many trials
  current to prevent AD (next talk)

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Future directions

• A clinical judgement? (including family
  informant)
• Focus on decline rather than impairment
• informant
• estimate premorbid level
• longitudinal assessment
• Retrospective derivation of best pre-dementia
  variables
• May be specific to dementia types
• eg probable AD pre-dementia
• Imaging biomarkers PET, CSF, blood??

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Conclusions 3

• MCI is a diagnosis in evolution
• Search for holy grail of pre-dementia diagnosis
  continues

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Thank youhttp//www.dementia.unsw.edu.au/

• Happiness is nothing more than good health and
  a bad memory
• Albert Schweitzer (1875-1965)