Mild cognitive impairment

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Mild cognitive impairment

• October 6th, 2005
• Chantanij Leemingsawat MD.

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Mild cognitive impairment

• New concept ( between normal ageing and very
  early dementia )
• Transitional period between normal ageing and the
  diagnosis of clinically probable very early AD
• variety of terms such as
• mild cognitive impairment (MCI), dementia
  prodrome, incipient dementia, isolated memory
  impairment
• Mild cognitive impairment or MCI

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Hypothetical change in function as an individual
develops Alzheimer's disease
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Cognitive continuum showing the overlap in the
boundary between normal ageing andMCI and AD
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• Several terms have been used to describe an
  intermediate stage of cognitive impairment
• Age-associated memory impairment (AAMI)
• - characterize memory changes in ageing which
  were felt to be a manifestation of normal
  cognition
• Age-associated cognitive decline (AACD)
• - refer to multiple cognitive domains
  presumed to decline in normal ageing
• Mild conitive impairment
• - pathological condition

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Clinical characterization

• No agreement in the field on a single set of
  criteria for MCI
• Cognitive impairment but of insufficient severity
  to constitute dementia
• Slight degrees of functional impairment
• Difficulty distinguishing these functional
  problems from those encountered by normal
  individuals as they age

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Clinical characterization

• Typical MCI patient is one who has a memory
  impairment beyond what is felt to be normal for
  age but is relatively intact in other cognitive
  domains.
• The concept of MCI has been expanded to include
  other types of cognitive impairment beyond memory

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Outcome

• Mayo Alzheimer's Disease Research Center
• - 220, mean age 79 yrs, F/U 3-6 yrs
• - Progressed to dementia at a rate of
• 12 per year
• - Progressed form normal to dementia
• at a rate of 1- 2 per year
• Followed for up to 6 years
• approximately 80 of them
• will have converted to dementia

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Annual rates of change on the MMSE ,Dementia
Rating Scale and Global Deterioration scale
Journal of Internal MedicineVol 256 Issue 3 Page
183, Sep2004
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Outcome

• The Religious Order Study
• nuns and priests who constitute a volunteer
  cohort
• 211 of these individuals and diagnosed them with
  MCI
• F/U mean of 4.5 years
• MCI subjects developed AD at a rate 3.1 times
  those subjects who did not meet criteria for MCI.

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Prevalence

• Prevalence of mild cognitive impairment vary from
  17 to 34
• Annualised rates of conversion from mild
  cognitive impairment to dementia range from 4 to
  25

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Classification of MCI

• Several clinical subtypes of MCI
• Anestic-MCI ( a-MCI ) Most
  research has focused
• Multiple domain MCI ( md MCI )
• - md MCI
• - md MCI
• 3. Nonmemory domain MCI
• least common type of MCI

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Classification of MCI

• a-MCI subtype of a presumed degenerative
  aetiology
• Prodromal form of AD
• md-MCI  a since this subtype has a high
  likelihood of progressing to AD
• Other subtypes ( impairments in nonmemory domains
  ) may have a higher likelihood of progressing to
  a non-AD dementia such as DLB

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Classification of clinical subtypes of mild
cognitive impairment with presumed aetiology
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a-MCI criteria

• Memory complaint, preferably corroborated by an
  informant
• Objective memory impairment for age
• Normal general cognitive function
• Intact activity of daily living
• Not demented

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Application of a-MCI criteria

• First criteria refers to the subjective memory
  complaint.
• Second criteria refers to an objective memory
  impairment for age.
• - neuropsychological testing
• - no particular test or cutoff score is
• specified
• - score 1.5 SD below their age-mates

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Application of a-MCI criteria

• Third criteria regarding general
• intellectual function.
• - General intellectual function (other
• nonmemory cognitive domains, e.g.
• language, executive function,
• visuospatial skills )
• - no specific instruments or cutoff
• scores
• - Neuropsychological testing can be
• very useful

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Application of a-MCI criteria

• Activities of daily living
• The criterion requires that the functional
  impairment can be difficult to determine in older
  subjects who may have several medical
  comorbidities and physical limitations.
• Last criteria, 'not demented', is also made on
  the basis of the clinician's best judgement.

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 Flow chart of decision process for
making diagnosis of subtypes of MCI
Journal of Internal MedicineVol 256 Issue 3 Page
183, Sep2004
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Neuropathology of early AD

• The principal hallmarks of AD include
• - Aß deposition in extracellular plaques and
  vascular walls,
• - the accumulation of intracellular
  neurofibrillary tangles (NFT),
• - synaptic reductions?
• - neuronal loss
• - volume loss (atrophy)

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Neuroimaging

• Essential part of general evaluation in MCI
  subject
• - Identifying specific and treatable cause
  of cognitive impairment (DDx)
• - Prediction probability of devoloping AD
  in MCI Atrophy of

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Neuroimaging

• Predict future development of AD
• - Atrophy Hippocampus
• entorhinal cortex ( MRI )
• - Evidence deficits in
• - regional cerebral blood flow
• as measured by SPECT
• - regional cerebral glucose
• as measured by FDG-PET

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 Arrow highlights the body of the hippocampus.
Image on right is from a patient with atrophy.
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Arrows mark the entorhinal cortex on MRI.
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(CSF) biomarkers

• 3 cerebrospinal fluid (CSF) biomarkers
• - total-tau (T- )
• - phospho-tau (P- ) and the
• - 42 amino acid form of ß-amyloid
• (A 42)
• may differentiatedearly AD from
• normal aging

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(CSF) biomarkers

• Tau- Protein is a microtubule-associated protein
  located in the
• neuronal axons.
• Tau binds to tubulin in the
• microtubules in the axons, thereby
• promoting microtubule assembly and stability.
• In AD abnormally hyperphosphorylated form of
  tau.
• Tau ?

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(CSF) biomarkers

• These CSF markers have high sensitivity to
  differentiate early and incipient AD from
• normal ageing, depression, alcohol dementia
  and Parkinson's disease,
• but lower specificity against other
  dementias, such as frontotemporal and Lewy body
  dementia.

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(CSF) biomarkers

• ß -Amyloid (Aß or ß/A4 protein) is the main
  protein constituent of plaques
• Aß is generated by proteolytic cleavage of its
  precursor, the amyloid precursor protein (APP)
• A is metabolized along two pathways
• a-secretase
• ß-secretase
• ? ß -Amyloid

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The generation of ß-amyloid from its precursor
amyloid precursor protein
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(CSF) biomarkers

• Invasive procedure
• Lack of normative data no change of these CSF
  markers with age
• Effect of drugs on change in
• CSF markers

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Genetic

• There may be several prognostics gene that may
  help to identify persons with high risk for
  progressive from MCI to AD.
• A few studies have suggested that the APOE e4
  allele is associated with greater likelihood of
  progressing from MCI to AD.

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Management

• 3 Level
• 1. General population
• - increase knowledge on modifiable
• risk factor of cognitive impairment
• - Screening MCI at population level

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Management

• 2. General practitioners
• - Attention to subjective cognitive
• compliant
• - identify treatable cause
• - modified cerebrovascular risk
• - persistent impairment refer to
• specialist

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Management

• 3. Specialist level
• - clinical examination
• - investigation for determine cognitive
• subtype of MCI

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Treatment

• There were no systematic investigations on the
  effects of these drugs on cognition in healthy
  adults or patients with MCI.
• Reduce risk of dementia
• - antihypertensive medication
• - cholesterol lowering drugs
• - antioxidants
• - anti inflammatories
• - estrogens

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Treatment

• In healthy adults as well as in individuals
  categorized as having MCI, Ginkgo biloba EGb 761
  improved cognition in some but not all
  neuropsychological tests.
• The single positive result with donepezil raises
  hope that other drugs may also contribute to
  cognitive improvement, even in healthy adults.

Pharmacopsychiatry. 2003 Jun36 Suppl 1S38-43.
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Folic acid vitamin B12

• 4 randomized controlled trials
• Recruited people with mild to moderate cognitive
  impairment or dementia.
• Mini-Mental State Examination (MMSE) and Global
  Deterioration Scale
• Analysis of the included trials found
• no benefit from folic acid with or
• without vitamin B12

The Cochrane Database of Systematic Reviews
2003, Issue 4.
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Thank you