mild cognitive normal impairment (mci) - pdf of slides.pdf · 2018. 11. 11. · 2 mild cognitive...

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Mild Cognitive Impairment (MCI)

Douglas W. Scharre, MDDirector, Division of Cognitive Neurology

Ohio State University

Definitions

Normal

Mild Cognitive Impairment

Dementia

Dementia Definition• Syndrome of acquired persistent

intellectual impairment• Persistent deficits in at least three of the

following: MemoryLanguageVisuospatialPersonality or emotional stateCognition

• Resulting in impairment in Activities of Daily Living (ADL)

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Mild Cognitive Impairment (MCI) Definition

• Definitions vary - be careful! • Petersen criteria– Memory complaint– Memory loss on testing greater that 1.5 standard

deviations below normal for age– Other non-memory cognitive domains normal or

mild deficits (language, visuospatial, executive, personality or emotional state)

– Mostly normal activities of daily livingArch Neurol 1999;56:303-8

MCI Related Conditions

• Age-Associated Memory Impairment (AAMI)

• Benign Senile Forgetfulness or Mild Memory Impairment (MMI)

• Amnestic Mild Cognitive Impairment (MCI)• Multiple Domain Impairment (MDI)• Single (non-memory) Domain Impairment

(SDI)


AAMI: Age-Associated Memory Impairment• Non-disease, aging-related decline in

memory• Diagnostic criteria are ambiguous• Complaints of memory loss more related

to affect/personality than test scores• Prevalence in the elderly varies from 18%

up to 38% depending on the studyBarker et al. Br J Psychiatry 1995;167:642-8 Hanninen et al. Age and Aging 1996;25:201-5


Benign Senescent Forgetfulness or Mild Memory Impairment (MMI)

• Memory tests > 2 s.d. below normal age and education matched individuals

• Normal non-memory cognitive domains• Normal activities of daily living• No know disease causing impairments• Incipient AD may start this way• Fairly similar to Petersen’s MCI definition

Kral 1978

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• Memory complaint usually corroborated by an informant

• Objective memory impairment for age - that represents a change in function for the person

• Essentially preserved general cognitive function

• Largely intact functional activities

• Not demented

• Alzheimer’s disease may start like this but many non-AD conditions present like this also

Amnestic Mild Cognitive Impairment (aMCI)

Petersen J Int Med 2004;256;183-194

MCI ClassificationMemory Impaired?

MCI

Amnestic MCI Non-Amnestic MCI

Memory Impairment Only?

Single non-memory cognitive domain impaired?

Amnestic MCI

Single domain

Amnestic MCI

Multiple domain

Non-amnestic MCI

Single domain

Non-amnestic MCI

Multiple Domain

Yes No

Yes No Yes No

Petersen J Int Med 2004;256;183-194


Multiple Domain Impairment (MDI)• Mild impairment in several cognitive domains

• Normal activities of daily living

• Incipient Alzheimer’s disease often starts like this with deficits in memory, language, and visuospatial domains

• Vascular dementia and other dementias often present this way

Morris et al. Arch Neurol 2001;58:397-405


Single (non-memory) Domain Impairment (SDI)• Mild impairment in one non-memory cognitive

domain

• Normal activities of daily living

• Frontotemporal dementia and other non-Alzheimer’s dementias often present this way

• Most, but not all AD patients start with amnesticmemory problems initially

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Early Diagnosis of MCI

Importance of Early Diagnosis of MCI and

Dementia• Plaques and tangles start 20 years before

clinical symptoms of AD

• Disease modifying agents are coming

• Patients with MCI and early dementia have impaired insight

• Preventing or delaying AD could save billions of dollars and lead to improved quality of life for patients and families

Treatment of Alzheimer’s Disease

Source: Decision Resources, March 2000.

0

1

2

3

4

5

Prevalence Diagnosed Treated*

Patie

nts

(mill

ions

)

* Any drug treatment, not limited to acetylcholinesterase inhibitors.

Early Diagnosis: Clinical

• Early treatment depends on identification of MCI and prediction of progression to dementia

• First, look for clues of MCI - forgetfulness, word finding, date disorientation, slow thinking, impaired judgment, getting turned around

• Assess cognition and function with patient and caregiver

• Alternative diagnoses ruled out

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Early Diagnosis of MCI and Dementia

• Cognitive Screening Tests

• Structural Neuroimaging

• Functional Neuroimaging

Short Screening Tests• MMSE• Clock Drawing Test• 7-minute Screen• Montreal Cognitive Assessment (MOCA)• Self-Administered Gerocognitive Examination

(SAGE)Detailed evaluation if screen positive• Neuropsychological batteries

Early Diagnosis: Cognitive Screening

Cognitive Screening: MMSE

• 0 (worst) - 30 (best)

• Tests orientation, attention, mental control, calculations, delayed memory, language, and constructional praxis

• Easy to use, available, well known

• No clueing of memory words

Folstein et al. J Psychiat Res 1975;12:189-98Feher et al. Arch Neurol 1992;49:87-92

Cognitive Screening: MMSE

• Not great for frontal or executive functions

• Sensitivity 78% and specificity 84% for dementia with a cutoff of 26/30

• Takes 5 to 10 minutes; needs examiner

Folstein et al. J Psychiat Res 1975;12:189-98Feher et al. Arch Neurol 1992;49:87-92

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• Various scoring methods• Tests constructional praxis, visuospatial

skills, and executive functioning• Easy to use, available, well known• Limited in evaluating other cognitive

domains• Sensitivity 83% and specificity 72% for AD• Takes 1 minute; needs no examiner

Cognitive Screening: Clock Drawing Test

Shulman et al. Int Geriatr Psychiatry 1986;1:135-40Cahn et al. Arch Clin Neuropsych 1996;11:529-39

Early Diagnosis: Cognitive Screening

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Cognitive Screening: 7 Minute Screen

• Special scoring calculator required• Tests orientation, memory, clock drawing,

verbal fluency• Not easy to use in primary care office• Low scores very specific for AD• Sensitivity 92% and specificity 96% for AD

vs normal controls• Takes 7 - 12 minutes; needs examiner

Solomon et al. Arch Neurol 1998;55:349-55

7 Minute Screen

• Tests orientation, memory, clock drawing, constructions, verbal fluency, naming, repetition, attention, abstraction, calculations, executive (trails B)

• Not easy to give in primary care office

• Sensitivity 100% and specificity 87% for AD vs normal controls

• Takes 10-15 minutes; needs examiner

Cognitive Screening: Montreal Cognitive Assessment

(MOCA)

Nasreddine et al. J Am Geriatr Soc 2005;53:695-699

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• Tests orientation, memory, language, verbal fluency, naming, visuospatial/constructional praxis, abstraction, calculations, executive functioning (trails B), and problem solving

• Self-administered, easy to use; not yet available nor well known - due out in 2008

• Limited memory evaluation; impressive executive measures

• Sensitivity 88% and specificity 92% for dementia vs non-dementia

• Takes 15 minutes; needs no examiner

Cognitive Screening: Self-Administered

Gerocognitive Exam (SAGE)

Scharre 2007

SAGE Naming Examples

SAGE Modified Trails BReview this example (this first one is done for you) then go to question 10below:Draw a line from one circle to another starting at 1 and alternating numbers and letters (1 to

A to 2 to B to 3 to C).

Start

10. Do the following: Draw a line from one circle to another starting at 1 andalternating numbers and letters in order before ending at F (1 to A to 2 to B and so on).

1

A

2B

3

C

14

D

C

2 B

3A

5E

F

6Start

End

Early Diagnosis:Structural Neuroimaging

• Volumetric measurement of hippocampus and entorhinal cortex atrophy with MRI is sensitive (95%) but not specific (40%) for AD

• Change in MRI hippocampal volume may be predictive over time in both MCI and individuals at genetic risk for AD

• 7-Tesla and 8-Tesla MRI being used in AD research

Laakso et al. Neurology 1996;46:678-81Golomb et al. Neurology 1996;47:810-3Whitaker et al. Society for Neuroscience 2001

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Alzheimer’s Disease Neuroimaging Initiative (ADNI)• To identify serial biomarkers and

neuroimaging techniques that are sensitive and change quickly as the subject goes from normal to MCI to AD

• Academia - Industry Partnership

• $60 million for 5 years at about 50 sites

• Data available to all researchers

Gray Matter Reductions in AD Using Voxel Based

Morphometry

Alexander GE et al., ADNI MRI Core Team, 2007

Early Diagnosis: Functional Neuroimaging

• Single photon emission computed tomography (SPECT) studies

• Positron emission tomography (PET) studies

• Functional MRI (fMRI) studies

• SPECT shows hypoperfusion in bilateral parietal, temporal, and eventually frontal cortex in AD patients

• The probability of AD diagnosis was 82% with bilateral temporoparietal hypoperfusion on SPECT and only 19% with a normal SPECT image

• SPECT predicted the risk of progression to AD in 83% of questionable AD subjects

Functional Neuroimaging: SPECT

Bonte et al. Semin Nucl Med 1990;20:342-52Holman et al. J Nucl Med 1992;33:181-5Johnson et al. Neurology 1998;50:1563-71

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SPECT in AD

SPECT in AD

Functional Neuroimaging: PET

• PET shows hypometabolism in bilateral parietal, temporal, and posterior cingulatecortex in AD subjects and those who are asymptomatic but at increased risk for AD (those with Apo E ε4)

• PET predicted 94% of MCI subjects whose disease progressed to dementia during a 3 year period

Minoshima et al. J Nucl Med 1995;36:1238-48Minoshima et al. Ann Neurol 1997;42:85-94Small et al. JAMA 1995;273:942-47

Typical AD PET Scan

Provided courtesy of M. Mega, MD, PhD, Department ofNeurology, UCLA School of Medicine.

Normal Brain AD Brain

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Preliminary FDG PET Comparisons: Regional Hypometabolism in

Probable AD (purple) & MCI (blue)

Chen, K, et al., ADNI PET Coordinating Center, 2007

PET with Pittsburgh Compound B (PIB)

• PIB is a hydroxylatedbenzothiozole PET tracer

• Attaches to the amyloid beta peptide

• MCI patients have more amyloid than normals and less that AD patients

Klunk et al. Ann Neurol 2004;55(1)

• fMRI uses contrast dependent on blood oxygen

• Mild cognitively impaired and AD subjects had decreased brain activation during memory tasks after cholinesterase inhibitor treatment

• This may represent improved efficiency of neural processing

Functional Neuroimaging: fMRI

Smith et al. Neurology 1999;53:1391-96Bookheimer et al. N Engl J Med 2000;343:450-6

Backman et al. Neurology 1999;52:1861-70Narayanan et al. Neurology 2007;68(Suppl 1):A10

MCI:Predicting

Progression to Dementia

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MCI: Predicting Dementia Progression

• Older age and lower MMSE scores

• Disorientation to date

• Clock drawing impairments

• Lexical processing task and a working memory task correctly identified 85% of those progressing

Chertkow et al. Neurology 2001;56:B46

• ApoE E4 carrier status has been significant in some studies but not others

• MRI hippocampal volume is intermediate between normal controls and AD but does not reliably predict conversion

• Change in MRI hippocampal volume may be predictive over time


Petersen et al. Arch Neurol 1999;56:303-8 Chertkow et al. Neurology 2001;56:B46

Parnetti et al. JAGS 1995;44:133-8


Rates of Dementia Conversion• Vary from 1% - 25% per year to AD depending on

the definition used and measurement instruments

• 10% - 12% per year to AD is typical• 57% conversion to dementia after 3 years in one

study• 25% do not convert to dementia even with long

term follow-up

Chertkow et al. Neurology 2001;56:B46

• MCI definitions vary

• More study is needed to identify which MCI subjects will progress to dementia or AD

• Early diagnosis of MCI and AD is mostly done by clinical means; screening should be done

• Identification of genetic markers, biomarkers, and neuroimaging markers will be a great boost to early diagnosis

Summary

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Mild Cognitive Impairment

Maria Kataki, MD, PhDThe Ohio State University

Overview• Epidemiology of Mild Cognitive

Impairment (MCI)

• Neuroanatomy of Memory

• Differential Diagnosis of Memory loss

• Clinical Progression of MCI

• Current management

Prevalence of MCISelected Studies

• Canadian Study of Health and Aging-17%. Graham et al. Lancet 1997

• Cardiovascular Health Study-18%. Lopez et al. Arch Neurol. 2003

• Indianapolis study of Health and Aging- 12%-23%. Unverzag et al. Neurol 2001

• Kuopio Study. Hanninan et al. 5%. Acta NeurolScand. 2002

• Leipzig Longitudinal study of aging. 3%-38%. Busse et al. Act Neurol Scand. 2003

Neuroanatomy of Memory

N Engl J Med 2005; 352;692-9

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N Engl J Med 2005; 352;692-9

N Engl J Med 2005; 352;692-9

Episodic Memory• Alzheimer’s Disease

• Mild Cognitive Impairment, amnestic type

• Encephalitis

• Frontal Variant of Frontotemporal Dementia

• Korsakoff’s syndrome

N Engl J Med 2005; 352;692-9

Episodic Memory• Transient Global Amnesia• Concussion• Traumatic Brain Injury• Seizure• Hypoxic-Ischemic injury• Cardiopulmonary bypass• Side effects of medication• Space occupying lesions

N Engl J Med 2005; 352;692-9

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• Deficiency of B12• Hypoglycemia• Anxiety• Temporal lobe surgery• Vascular Dementia• Multiple Sclerosis• Normal Pressure hydrocephalus• Obstructive Sleep Apnea

Episodic Memory

N Engl J Med 2005; 352;692-9

Semantic Memory• Alzheimer’s Disease• Semantic Dementia• Traumatic brain injury• Encephalitis

N Engl J Med 2005; 352;692-9

Procedural Memory• Parkinson’s Disease• Huntington’s Disease• Progressive Supranuclear Palsy• Olivopontocerebellar Degeneration• Depression• Obsessive-Compulsive Disorder

N Engl J Med 2005; 352;692-9

Working Memory• Normal Aging• Vascular Dementia• Frontal Variant of Frontotemporal

Dementia• Alzheimer’s Disease• Dementia with Lewy bodies• Multiple Sclerosis

N Engl J Med 2005; 352;692-9

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• Traumatic Brain Injury

• Side effects of Medications

• Attention deficit-hyperactivity disorder

• Obsessive Compulsive Disorder

• Schizophrenia

Working Memory

N Engl J Med 2005; 352;692-9

• Parkinson’s Disease

• Huntington’s Disease

• Progressive Supranuclear Palsy

• Cardiopulmonary bypass

• Deficiency of B12

Working Memory

N Engl J Med 2005; 352;692-9

Copyright restrictions may apply.

Petersen, R. C. et al. Arch Neurol 2006;63:665-672.

Representative images of the middle frontal cortex and hippocampal sector CA1 from a healthy individual (patient 29), a patient with amnestic

mild cognitive impairment (aMCI) (patient 3), and a patient withAlzheimer disease (AD) (patient 51) stained with antibodies to beta-amyloid and tau (AT8), respectively (original magnification, x100)

Jack, C. R. et al. Neurology 1999;52:1397

Neuroanatomic Boundaries

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Theoretical Progression of a Person Developing Alzheimer's Disease (AD)


Comparison of the clinical diagnoses of normal aging, mild cognitive impairment (MCI), and Alzheimer's disease (AD), compared with the approximate stages on the rating

scales, Clinical Dementia Rating (CDR) and Global Deterioration Scale (GDS)


Heterogeneity of the Term Mild Cognitive Impairment

Grundman, M. et al. Arch Neurol 2004;61:59-66.

Mean Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) subscores for controls, patients with

mild cognitive impairment (MCI), patients with Alzheimer disease (AD) and global Clinical Dementia Rating (CDR) 0.5,

and patients with AD and global CDR 1.0

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Relative performance among 4 groups: controls, subjects with mild cognitive impairment (MCI) (Clinical Dementia Rating [CDR] 0.5), and

patients with Alzheimer disease (AD) (CDR 0.5; CDR 1), on measures of global cognitive functioning, Mini-Mental State Examination (MMSE), and full-scale IQ compared with performance on measures of delayed recallfor verbal materials (Logical Memory II) and nonverbal materials (Visual

Reproductions II)

Bennett, D. A. et al. Neurology 2002;59:198-205

Predicted 7-year paths of change in five different cognitive domains in typical participants with mild cognitive impairment

(dotted line) compared with those without cognitive impairment (solid line)

Markesbery, W. R. et al. Arch Neurol 2006;63:38-46.

Scatter plots of neuritic plaque counts in ventromedial temporal lobe structures of normal control subjects (NRM), patients with mild cognitive impairment (MCI), and patients

with early Alzheimer disease (EAD) in the amygdala (A), entorhinal cortex (B), CA1 (C), and subiculum (D)

Markesbery, W. R. et al. Arch Neurol 2006;63:38-46.

Scatter plots of neurofibrillary tangle counts in ventromedial temporal lobe structures of normal control subjects (NRM), patients with mild cognitive impairment (MCI), and patients with early Alzheimer disease (EAD) in the

amygdala (A), entorhinal cortex (B), CA1 (C), and subiculum (D)

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Copyright restrictions may apply.

Annual rates of conversion from mild cognitive impairment (MCI) to

dementia over 48 months


H Braak et al. Neurobiology of aging, vol 18, No 4, pp 351-357, 1997

Frequency of Stages of Alzheimer-Related Lesions in Different Age Categories

Bennett, D. A. et al. Neurology 2005;64:834-841

Percentages of persons with no cognitive impairment (NCI), mild cognitive impairment (MCI), and dementia by Braak Stage, modified Consortium to

Establish a Registry for Alzheimer's Disease neuropathologic criteria, and National Institute on Aging-Reagan neuropathologic criteria

Copyright ©2004 by the National Academy of Sciences

Reiman, Eric M. et al. (2004) Proc. Natl. Acad. Sci. USA 101, 284-289

Regions of the brain with abnormally low CMRgl in young adult carriers of the APOE {epsilon}4 allele and their relation to brain regions with

abnormally low CMRgl in patients with probable AD

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Copyright ©2000 by the National Academy of Sciences

Small, Gary W. et al. (2000) Proc. Natl. Acad. Sci. USA 97, 6037-6042

Cerebral metabolic and cognitive decline in persons at genetic risk

for Alzheimer’s disease

Normal Cholinergic Function

Acta Neurol Scand Suppl. 1992;139:69-74.

Mild Cognitive Impairment Clinical Trials

• Donepezil Vitamin E769 patients3 years durationPrimary outcome ADProgression Rate 16%Result: Partially Positive

Treatment of Mild Cognitive Impairment: Leon Thal. Syllabus AAN 2007


• Rivastigmine1018 patients3-4 years durationPrimary outcome ADProgression Rate 9%Result: Negative


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• Galantamine2048 patients2 years durationPrimary outcome CDR 1Progression Rate 5%Result: Negative



• Rofecoxib1457 patients3-4 years durationPrimary outcome ADProgression Rate 5%Result: Negative


MCI Clinical Trials• Vitamin E and Donepezil in the treatment of

Mild Cognitive Impairment.Alzheimer’s Disease cooperative Study Trial769 amnestic MCI patients treated with Donepezil10mg po qd, Vit E 2000iu qd or placebo3 year follow upProgression to clinical ADDonepezil delays clinical diagnosis of AD for up to 12 months. Treatment effect persisted for 36 months in ApoE 4 carriers.

Petersen et al: New Engl. J M. Vol 352:2379-2388 June 9, 2005Number 23: Vitamin E and Donepezil for the Treatment of Mild Cognitive Impairment

Efficacy of donepezil in mild cognitive impairment

A randomized placebo-controlled trial

• 270 patients with MCI

133 treated with donepezil10mg po qd and 137 with placebo

• Primary efficacy measures of the NYU Paragraph Recall test and the ADCS CGIC-MCI did not show significant treatment effects

S. Salloway, MD MS, S. Ferris, PhD, A. Kluger, PhD, R. Goldman, PhD, T.Griesing, PhD, D. Kumar, MS and S. Richardson, PhD for the Donepezil "401" Study Group*NEUROLOGY 2004;63:651-657

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Efficacy of donepezil in mild cognitive impairment

A randomized placebo-controlled trial

• More donepezil-treatedpatients showed improvements in ADAS-cog total scores, in tests of attention and psychomotor speed, and in PGA scores.

S. Salloway, MD MS, S. Ferris, PhD, A. Kluger, PhD, R. Goldman, PhD, T.Griesing, PhD, D. Kumar, MS and S. Richardson, PhD for the Donepezil "401" Study Group*NEUROLOGY 2004;63:651-657

Current Prevention• Screening of patients elderly 65 years old by

health care providers.

• Standardized questionnaires assessing cognition, function, mood, behaviors

• Early diagnosis and treatment

Clinical and financial benefit

Alleviate patient and caregiver burden

Fillit. Neurology:65, 6,suppl 3, S5-9

Current Prevention• Decrease Homocysteine, with Folic acid, B6, B12

• Maintain Physical exercise

• Oral antioxidants

• Anti-inflammatory agents

• Low Cholesterol, low fat diet

• Prevention of Hypertension, Vascular disease

Dekosky: Clinical trial, syllabus AAN 2005

Conclusions• Mild Cognitive impairment represents the

pathology of common degenerative illnesses.

• Early diagnosis is appropriate.• It has a risk of progressing to Alzheimer’s

disease and other dementias.• Can be associated with behavioral features• Follow up is recommended.• Prevention.

mild cognitive normal impairment (mci) - pdf of slides.pdf · 2018. 11. 11. · 2 mild cognitive...

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