Mild Cognitive Normal Impairment (MCI) Mild Cognitive Impairment Douglas W. Scharre, MD Director, Division of Cognitive Neurology Ohio State University Dementia Dementia Definition • Syndrome of acquired persistent intellectual impairment • Persistent deficits in at least three of the following: Definitions 9 Memory 9 Language 9 Visuospatial 9 Personality or emotional state 9 Cognition • Resulting in impairment in Activities of Daily Living (ADL) 1 Mild Cognitive Impairment MCI Related (MCI) Definition Conditions • Definitions vary - be careful! AAMI: Age-Associated Memory Impairment • Petersen criteria • Non-disease, aging-related decline in – Memory complaint memory – Memory loss on testing greater that 1.5 standard • Diagnostic criteria are ambiguous deviations below normal for age • Complaints of memory loss more related – Other non-memory cognitive domains normal or to affect/personality than test scores mild deficits (language, visuospatial, executive, personality or emotional state) • Prevalence in the elderly varies from 18% up to 38% depending on the study – Mostly normal activities of daily living Barker et al. Br J Psychiatry 1995;167:642-8 Arch Neurol 1999;56:303-8 Hanninen et al. Age and Aging 1996;25:201-5 MCI Related MCI Related Conditions Conditions • Age-Associated Memory Impairment Benign Senescent Forgetfulness or Mild (AAMI) Memory Impairment (MMI) • Memory tests > 2 s.d. below normal age and • Benign Senile Forgetfulness or Mild education matched individuals Memory Impairment (MMI) • Normal non-memory cognitive domains • Amnestic Mild Cognitive Impairment (MCI) • Normal activities of daily living • Multiple Domain Impairment (MDI) • No know disease causing impairments • Single (non-memory) Domain Impairment • Incipient AD may start this way (SDI) • Fairly similar to Petersen’s MCI definition Kral 1978 2 Amnestic Mild Cognitive Impairment (aMCI) MCI Related • Memory complaint usually corroborated by an Conditions informant Multiple Domain Impairment (MDI) • Objective memory impairment for age - that represents a change in function for the person • Mild impairment in several cognitive domains • Essentially preserved general cognitive function • Normal activities of daily living • Largely intact functional activities • Incipient Alzheimer’s disease often starts like this with deficits in memory, language, and • Not demented visuospatial domains • Vascular dementia and other dementias often • Alzheimer’s disease may start like this but many present this way non-AD conditions present like this also Petersen J Int Med 2004;256;183-194 Morris et al. Arch Neurol 2001;58:397-405 MCI Classification MCI Related MCI Conditions Memory Impaired? Yes No Single (non-memory) Domain Impairment (SDI) • Mild impairment in one non-memory cognitive Amnestic MCI Non-Amnestic MCI domain • Normal activities of daily living Memory Impairment Single non-memory cognitive domain Only? impaired? • Frontotemporal dementia and other non- Alzheimer’s dementias often present this way Yes No Yes No Amnestic MCI Amnestic MCI Non-amnestic MCI Non-amnestic MCI • Most, but not all AD patients start with amnestic Single domain Multiple domain Single domain Multiple Domain memory problems initially Petersen J Int Med 2004;256;183-194 3 Treatment of Alzheimer’s Disease 5 Early Diagnosis 4 of MCI 3 2 Patients (millions) 1 0 Prevalence Diagnosed Treated* * Any drug treatment, not limited to acetylcholinesterase inhibitors. Source: Decision Resources, March 2000. Importance of Early Early Diagnosis: Diagnosis of MCI and Clinical Dementia • Early treatment depends on identification of MCI and prediction of progression to • Plaques and tangles start 20 years before dementia clinical symptoms of AD • First, look for clues of MCI - forgetfulness, • Disease modifying agents are coming word finding, date disorientation, slow • Patients with MCI and early dementia have thinking, impaired judgment, getting impaired insight turned around • Preventing or delaying AD could save • Assess cognition and function with patient billions of dollars and lead to improved and caregiver quality of life for patients and families • Alternative diagnoses ruled out 4 Early Diagnosis of Cognitive Screening: MCI and Dementia MMSE • 0 (worst) - 30 (best) • Cognitive Screening Tests • Tests orientation, attention, mental control, calculations, delayed memory, • Structural Neuroimaging language, and constructional praxis • Easy to use, available, well known • Functional Neuroimaging • No clueing of memory words Folstein et al. J Psychiat Res 1975;12:189-98 Feher et al. Arch Neurol 1992;49:87-92 Early Diagnosis: Cognitive Screening: Cognitive Screening MMSE Short Screening Tests • MMSE • Not great for frontal or executive functions • Clock Drawing Test • Sensitivity 78% and specificity 84% for • 7-minute Screen dementia with a cutoff of 26/30 • Montreal Cognitive Assessment (MOCA) • Takes 5 to 10 minutes; needs examiner • Self-Administered Gerocognitive Examination (SAGE) Detailed evaluation if screen positive • Neuropsychological batteries Folstein et al. J Psychiat Res 1975;12:189-98 Feher et al. Arch Neurol 1992;49:87-92 5 Cognitive Screening: Clock Drawing Test • 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 Shulman et al. Int Geriatr Psychiatry 1986;1:135-40 Cahn et al. Arch Clin Neuropsych 1996;11:529-39 Early Diagnosis: Cognitive Screening 6 Cognitive Screening: Cognitive Screening: Montreal Cognitive Assessment 7 Minute Screen (MOCA) • Special scoring calculator required • Tests orientation, memory, clock drawing, • Tests orientation, memory, clock drawing, constructions, verbal fluency, naming, verbal fluency repetition, attention, abstraction, calculations, executive (trails B) • Not easy to use in primary care office • Not easy to give in primary care office • Low scores very specific for AD • Sensitivity 100% and specificity 87% for • Sensitivity 92% and specificity 96% for AD AD vs normal controls vs normal controls • Takes 7 - 12 minutes; needs examiner • Takes 10-15 minutes; needs examiner Solomon et al. Arch Neurol 1998;55:349-55 Nasreddine et al. J Am Geriatr Soc 2005;53:695-699 7 Minute Screen 7 Cognitive Screening: SAGE Modified Trails B Self-Administered Review this e xample (this first one is done for you) then go to question 10 below: Draw a line from one circle to another starting at 1 and alternating numbers and letters (1 to Gerocognitive Exam (SAGE) A to 2 to B to 3 to C). A C • Tests orientation, memory, language, verbal 1 2 fluency, naming, visuospatial/constructional B praxis, abstraction, calculations, executive Start functioning (trails B), and problem solving 3 10. Do the following: Draw a line from one circle to another starting at 1 and • Self-administered, easy to use; not yet available alternating numbers and letters in order before ending at F (1 to A to 2 to B and so on). nor well known - due out in 2008 1 4 F Start C • Limited memory evaluation; impressive End executive measures 6 A • Sensitivity 88% and specificity 92% for dementia 3 D vs non-dementia B 2 • Takes 15 minutes; needs no examiner E Scharre 2007 5 SAGE Naming Early Diagnosis: Examples 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;46:678-81 Golomb et al. Neurology 1996;47:810-3 Whitaker et al. Society for Neuroscience 2001 8 Alzheimer’s Disease Early Diagnosis: Neuroimaging Initiative (ADNI) Functional Neuroimaging • To identify serial biomarkers and neuroimaging techniques that are • Single photon emission computed sensitive and change quickly as the subject goes from normal to MCI to AD tomography (SPECT) studies • Academia - Industry Partnership • Positron emission tomography (PET) studies • $60 million for 5 years at about 50 sites • Functional MRI (fMRI) studies • Data available to all researchers Gray Matter Reductions in AD Using Voxel Based Functional Morphometry Neuroimaging: SPECT • 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 Bonte et al. Semin Nucl Med 1990;20:342-52 Holman et al. J Nucl Med 1992;33:181-5 Alexander GE et al., ADNI MRI Core Team, 2007 Johnson et al. Neurology 1998;50:1563-71 9 Functional SPECT in AD Neuroimaging: PET • PET shows hypometabolism in bilateral parietal, temporal, and posterior cingulate cortex 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;36:1238-48 Minoshima et al. Ann Neurol 1997;42:85-94 Small et al. JAMA 1995;273:942-47 SPECT in AD Typical AD PET Scan Normal Brain AD Brain Provided courtesy of M. Mega, MD, PhD, Department of Neurology, UCLA School of Medicine. 10 Preliminary FDG PET Comparisons: Regional Hypometabolism in Functional Probable AD (purple) & MCI (blue)