MCI in Lewy Body Disorders: MCI in Lewy Body Disorders: Definition, Frequency, Progression and Definition, Frequency, Progression and

Differentiation from Other MCI Differentiation from Other MCI

Alexander I. Tröster, Ph.D.

Department of Neurology

University of North Carolina, Chapel Hill

Tröster 2009

OverviewOverview• Nomenclature of Lewy body disorders• Factors leading to consideration of “MCI” as

an entity in Parkinson’s disease (PD)• Potential benefits of identifying MCI in PD• Frequency and subtypes of MCI in PD• Conversion of MCI to PDD and DLB• Dementia and the neuropsychological

characteristics of the PDD prodrome• Comparisons of neuropsychological

characteristics of early PDD/DLB and Alzheimer’s disease

• Challenges facing the concept of MCI in Lewy body disorders

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Nomenclature of Lewy Body Nomenclature of Lewy Body DisordersDisorders

DLB/PDD Work Group (Lippa et al. 2007)DLB/PDD Work Group (Lippa et al. 2007)

• Lewy body disorders» Parkinson’s disease (PD)» Parkinson’s disease with dementia (PDD)» Dementia with Lewy bodies (DLB)

• Lewy body dementias» Parkinson’s disease with dementia (PDD)» Dementia with Lewy bodies (DLB)

• Distinction in temporal sequence of onset of motor symptoms and dementia in PDD and DLB retained in recent criteria (12 Month Rule)

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Cognitive Impairment in PDCognitive Impairment in PD

• Cognitive changes in PD without dementia recognized for decades

• Cognitive changes near time of diagnosis recognized only recently (Foltynie et al. 2004, Muslimovic et al., 2005)

• First to refer to MCI in PD was review by Fernandez et al. 2005

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Possible Factors Prompting Possible Factors Prompting Consideration of MCI in PDConsideration of MCI in PD

• Acknowledgement of MCI heterogeneity and subtypes (Petersen 2004)

• Recognition of a) heterogeneous, and b) very early cognitive decrements in PD (Muslimovic et al. 2005)

• Neuropathologic staging of PD compatible with pre-diagnostic non-motor symptoms (Braak et al.2003)

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Possible Advantages of MCI Possible Advantages of MCI Diagnosis in PDDiagnosis in PD

• Early detection and treatment of cognitive decline, and consequent enhancement of functioning

• Evaluation of DLB/PDD distinction• Greater precision in identifying course of

cognitive decline, risk factors for these declines, and underlying mechanisms

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Evaluation and MCI SubtypesEvaluation and MCI Subtypes

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Montreal Cognitive Assessment Montreal Cognitive Assessment (MOCA)(MOCA)

Nasreddine et al. 2005Nasreddine et al. 2005

MCI Subtypes and Frequency in MCI Subtypes and Frequency in Parkinson’s DiseaseParkinson’s Disease

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Cognitive Impairment in Newly Cognitive Impairment in Newly Diagnosed PDDiagnosed PDMuslimovic et al. 2005Muslimovic et al. 2005

• N=115• 24% (27) 3+ tests impaired; 38% 2+ tests

impaired

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Progression of MCI to Parkinson’s Progression of MCI to Parkinson’s Disease with Dementia (PDD)Disease with Dementia (PDD)

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MCI Progression to Dementia in PDMCI Progression to Dementia in PD

• Foltynie et al. (2004) did not define MCI but found 36% of newly diagnosed PD had cognitive impairment per one or more of MMSE and CANTAB Tower and Pattern Recognition

• Follow-up 3-5 years later (Williams-Gray et al. 2007) found the cognitive groupings were not informative of subsequent dementia, but dementia was associated with deficits on cognitive tests of “posterior” cortical functions (semantic fluency, pattern recognition, pentagon copying).

Dementia and the Neuropsychological Dementia and the Neuropsychological Characteristics of the PDD ProdromeCharacteristics of the PDD Prodrome

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A Transition in Grouping PD A Transition in Grouping PD Patients by Cognitive ImpairmentPatients by Cognitive Impairment

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Neuropsychological Predictors of PDD Neuropsychological Predictors of PDD Studies with Limited Assessment InstrumentsStudies with Limited Assessment Instruments

• Piccirilli et al. (1989):» 6/8 with (but only 1/22 without) “frontal

dysfunction” per Luria tasks at baseline developed dementia at 4-year follow-up

• Biggins et al. (1992):» Baseline WAIS Verbal & MMSE (but not WMS

or WAIS Picture Completion) lower in 10 patients (of 82) developing dementia (54 months) than in 41 patients not developing dementia over 36 months

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Neuropsychological Predictors of PDDNeuropsychological Predictors of PDDStudies with Multiple Assessment InstrumentsStudies with Multiple Assessment Instruments

• Jacobs et al. (1995):» 23 of 111 (122) developed dementia

» at least 1 year follow-up

» predictors: lexical and semantic verbal fluency (without covariates, also immediate recall)

• Mahieux et al. (1998): » 19 of 81 (89) developed dementia

» 3.5 year follow-up

» predictors: WAIS-R Picture Completion, Stroop interference, and lexical verbal fluency

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Neuropsychological Predictors of PDDNeuropsychological Predictors of PDDStudies with Multiple Assessment InstrumentsStudies with Multiple Assessment Instruments

• Woods & Tröster (2003)» 20 developed dementia after 1 year, 18

studied and compared to 18 PD not developing dementia

» PDD had poorer baseline performance in:• Memory (CVLT Immediate recall & recognition) • Executive function (WCST Perseverative

Errors)• Working memory (Digits backwards)

» Each of the 4 scores had good sensitivity in predicting PDD, but ≥ 2 of 4 scores impaired per ROC curve had 0.75 overall predictive power

Progression of MCI to Dementia Progression of MCI to Dementia with Lewy Bodies (DLB)with Lewy Bodies (DLB)

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Progression from MCI to DLBProgression from MCI to DLB• No MCI studies with DLB focus; two MCI

studies incidentally/secondarily mention DLB• Jicha et al. (2006)

» 34 amnestic-MCI developing dementia came to autopsy

» 1 had final clinical diagnosis of DLB

» 3 had neuropathologic diagnosis of Lewy body disease

• Fischer et al. (2007)» 141 MCI and 440 normal followed 30 mos.

» Possible DLB in 10 patients with AD• Baseline: 4 normal, 4 non-amnestic MCI, 2

amnestic MCI

Neuropsychological Differentiation of Neuropsychological Differentiation of LBD MCI and Other MCILBD MCI and Other MCI

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Retrospective Comparison of Retrospective Comparison of MCI-AD and MCI-DLBMCI-AD and MCI-DLB

Jicha et al. 2009Jicha et al. 2009

• Neuropathological database search » 15 neuropathologically confirmed DLB (without

significant comorbidity); 9 with predementia cognitive decline data

» 12 of 16 neuropathologically confirmed AD with predementia cognitive decline data

• MCI required memory complaint and impairment with intact functioning

• MCI-DLB: worse phonemic fluency• MCI-AD: worse immediate paragraph recall• Trends

» MCI-DLB slower on Trailmaking Part A» MCI-AD worse on BNT, delayed wordlist recall

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Neuropsychological Comparisons Neuropsychological Comparisons of DLB, PDD and AD & Inferences of DLB, PDD and AD & Inferences

about MCI Characteristicsabout MCI Characteristics

• Caution needed in assuming neuropsychological differences in early dementia parallel those in MCI

• Assumes rate of progression of different deficits is similar

• Assumes linear progression of deficits

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Neuropsychological Comparison of Neuropsychological Comparison of DLB/PDD vs. ADDLB/PDD vs. AD

• AD involves greater impairment of memory, especially verbal (e.g., Noe et al., 2004; Simard et al. 2002), probably related to greater temporal lobe pathology» AD hallmarks: rapid rates of forgetting and

intrusions

• DLB involves greater visuoperceptual and constructional deficits (e.g., Simard et al. 2003; Calderon et al. 2001), which may be linked to posterior cortical hypometabolism and vissal hallucinations

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Neuropsychological Comparison of Neuropsychological Comparison of DLB/PDD vs. ADDLB/PDD vs. AD

• DLB/PDD perform worse than AD on complex attention tasks (Stroop, Trailmaking) (Calderon et al. 2001) but not on simple tasks (e.g., digit span) (Salmon et al. 1996)

• DLB/PDD perform worse on executive function tasks (e.g., card sorting) than AD (Simard et al. 2000; Paolo et al. 1995). Executive dysfunction linked to basal forebrain cholinergic deficits

• Language data more equivocal: same naming and fluency deficits in AD and DLB, worse naming in AD, worse letter fluency in DLB

Summary of MCI in LBDSummary of MCI in LBD

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Summary of MCI in LBDSummary of MCI in LBD

• MCI is present in 19% to 53% of PD, with most reports in the 20%-30% range

• In PD, MCI single domain more common than multiple domain

• Executive/attention seems most common domain of MCI in PD

• Executive/attention, and to lesser extent, immediate recall impairments are associated with development of dementia

• Virtually nothing known about MCI in DLB• LBD MCI is neuropsychological differentiable

from MCI/early AD

Challenges to MCI in LBDChallenges to MCI in LBD

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Challenges to the Concept Challenges to the Concept of MCI in LBDof MCI in LBD

• Problems of studying MCI especially in DLB – low yield of DLB in MCI up to now. Will subtyping help? Should we start with MCI with parkinsonism?

• Many clinicians and patients think of MCI as a disease (or early AD) vs. a syndrome, thus risking confusion and fear of AD in PD

• Should behavioral abnormalities be considered in MCI given the PDD criteria?

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Challenges to the Concept Challenges to the Concept of MCI in LBDof MCI in LBD

• Definition of MCI: which tests, which scores?• How will MCI diagnosis aid treatment in PD?• Role of PD medications in producing and

alleviating/masking MCI?• Should we call it PDCI analogous to vascular

CI?• Is memory impairment primary or secondary

– affects definition of single vs. multiple domain MCI?

• Are subtypes too gross for prognostic purposes?