Alexander I. Tröster, Ph.D. Department of Neurology University of North Carolina, Chapel Hill

1. MCI in Lewy Body Disorders: Definition, Frequency, Progression and Differentiation from Other MCI Alexander I. Tröster, Ph.D. Department of Neurology University of North Carolina, Chapel Hill

2. Overview • 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 Tröster 2009

3. Nomenclature of Lewy Body DisordersDLB/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) Tröster 2009

4. Cognitive 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 Tröster 2009

5. Possible Factors Prompting Consideration 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) Tröster 2009

6. Possible Advantages of MCI Diagnosis 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 Tröster 2009

7. Evaluation and MCI Subtypes Tröster 2009

8. Montreal Cognitive Assessment (MOCA)Nasreddine et al. 2005 Tröster 2009

9. MCI Subtypes and Frequency in Parkinson’s Disease

10. Cognitive Impairment in Newly Diagnosed PDMuslimovic et al. 2005 • N=115 • 24% (27) 3+ tests impaired; 38% 2+ tests impaired Tröster 2009

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

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16. MCI 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). Tröster 2009

17. Dementia and the Neuropsychological Characteristics of the PDD Prodrome

18. A Transition in Grouping PD Patients by Cognitive Impairment Tröster 2009

19. Neuropsychological Predictors of PDD Studies 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 Tröster 2009

20. Neuropsychological Predictors of PDDStudies 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 Tröster 2009

21. Neuropsychological Predictors of PDDStudies 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 Tröster 2009

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

23. Progression 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 Tröster 2009

24. Neuropsychological Differentiation of LBD MCI and Other MCI

25. Retrospective Comparison of MCI-AD and MCI-DLBJicha 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 Tröster 2009

26. Neuropsychological Comparisons of DLB, PDD and AD & Inferences about 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 Tröster 2009

27. Neuropsychological Comparison of DLB/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 Tröster 2009

28. Neuropsychological Comparison of DLB/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 Tröster 2009

29. Summary of MCI in LBD

30. Summary 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 Tröster 2009

31. Challenges to MCI in LBD

32. Challenges to the Concept of 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? Tröster 2009

33. Challenges to the Concept of 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? Tröster 2009