Research Update in PD Related Cognition Saturday, November 3, 2018

1. Research Update in PD Related CognitionSaturday, November 3, 2018 Presenting: Greg Pontone, MD, MHS Associate Professor, Departments of Neurology and Psychiatry Johns Hopkins University

2. Disclosures • No relevant financial relationships with commercial interests. • The following talk includes unlabeled/unapproved use of medications.

3. Research Update in PD Related CognitionSaturday, November 3, 2018 Today’s Goals and Objectives: • Become familiar with the prevalence and range of cognitive impairment in Parkinson’s disease • Discuss the current definition and construct of mild cognitive impairment in Parkinson’s disease • Introduce a new research project using fMRI to better understand the role of medial temporal lobe structures including hippocampal sub-regions in amnestic mild cognitive impairment in Parkinson’s disease

4. I. Overview of cognitive impairment in Parkinson’s diseaseII. Mild Cognitive Impairment in Parkinson’sIII. fMRI and the hippocampus in amnestic mild cognitive impairment associated with Parkinson’s

5. Lewy bodies ascend to the cortex (Obeso et al. Nature Medicine 16, 2010:653–661)

6. Parkinson’s disease with dementia and dementia with Lewy bodies • Dementia with Lewy-body like inclusions -- first reported early 1960’s (Okazaki et al 1961) • Lewy-body-related dementias (PD-D and DLB) -- second most frequent cause of primary degenerative dementia; 15-20% of dementias • Neurodegenerative conditions with a common disorder of α-synuclein

7. Epidemiology of PD-Dementia • Point prevalence 40% (Cummings et al. 27 studies representing 4,336 pts with PD) • Incidence in a prevalent PD population ≈ 10% progress from non-demented to demented per year • However not uniform, as incidence and prevalence increase with age (e.g. incidence 0.6/100K age 50-59 to 47/100K age 80-99) Aarsland et al 2003, Hely et al 1999, Hobson et al 2015

8. Epidemiology of PD-Dementia • Dementia affects up to 50% of PD patients within 10 years of motor symptom onset and over 80% by 20 years • Longitudinal cohorts find that when patients are followed until death nearly all progress to dementia Aarsland et al 2003, Butler et al 2008, Hely et al 1999, 2008, Hobson et al 2015, Williams-Gray et al 2013

9. Risk factors for PD-Dementia • Relative risk for developing dementia in PD is up to 6 times greater than in the general population • Most Consistently Reported: • greater severity of motor symptoms • older age • cognitive impairment at baseline Levy et al 2002; Hughes et al 2000; Aarsland et al 2001, 2003

10. I. Overview of cognitive impairment in Parkinson’s diseaseII. Mild Cognitive Impairment in Parkinson’sIII. fMRI and the hippocampus in amnestic mild cognitive impairment associated with Parkinson’s

11. Diagnostic criteria for MCI in PD: MDS task force guidelines • Diagnosis of iPD • Subjective gradual decline in cognitive ability • Measured (objective) cognitive impairment • Cognitive deficits do not significantly interfere with functional independence (*although subtle difficulties on complex tasks may be present) Litvan et al 2012 MovDisord

12. Prevalence of MCI in PD • MCI present up to 42% of non-demented PD patients • mean prevalence of 27% across studies • MCI is often present early, up to a third of PD patients have cognitive impairment at diagnosis Aarsland et al 2010, Foltynie et al 2004), Litvan et al 2011, Yarnall et al 2014

13. PD MCI and risk of dementia • Risk of dementia is 4x greater in PD MCI than in cognitively normal PD • Risk varies by age and may vary based on cognitive domains affected • In non-PD populations, reversion rates MCI  normal cognition up to 41% even after 10 years; in PD variable but many fewer revert (*different studies: 25% at 3 yrs, <10% at 5yrs, and 1 of 166 at 6yrs and that 1 demented at 12yrs) Boyle et al 2006, Broeders et al 2013, Larrieu et al 2002, Mitchell et al 2009, Hobson et al 2015

14. Age and cognitive decline in PD Reid et al 2011

15. Impact of cognitive impairment and dementia in PD • Functional impairment, especially for more complex tasks • Neuropsychiatric symptoms more common; up to 70% in MCI (*aMCI>naMCI) and up to 90% in PDD • Lower quality of life • Greater caregiver distress • More likely to be placed in nursing home • Health-related costs are >3X higher in PDD and increased in cognitive impairment • Predicts earlier mortality Aarsland et al 2014, Leroi et al 2012, Monastero et al 2013, Oosterveld et al 2015, Pirogovsky et al 2012, Schrag et al 2006, Vossius et al 2011

16. I. Overview of cognitive impairment in Parkinson’s diseaseII. Mild Cognitive Impairment in Parkinson’sIII. fMRI and the hippocampus in amnestic mild cognitive impairment associated with Parkinson’s

17. Memory earliest, most frequently affected cognitive domain in PD • Memory impairment most common - 13% to 15% of non-demented PD • Memory impairment predicts greater cognitive decline across several studies • Memory deficits remain after adjusting for the effect of impaired attention and executive function Aarsland et al 2010, Muslimovic et al 2007, Sollinger et al 2010, Yarnall et al 2014

18. Episodic memory performance differs between disease states • AD, HD, and PD correctly assigned to disease group 79% based on memory performance; AD distinguished from HD and PD 91% of the time • In PD memory function there is differential performance between recognition and free recall Aretouli and Brandt 2010, Weintraub et al 2004, Yarnell et al 2014

19. File Cabinet Example

20. Differential hippocampal pathology in PD by subregion • The CA1 region is often spared in PD • Lewy bodies are greatest in CA2 and CA3 regions in PD • Volume changes appear to differ between hippocampal subregions Armstrong et al 2014, Beyer et al 2013, Churchyard et al 1997, Mak et al 2014, Pereira et al 2013

21. High-resolution functional MRI

22. Models of memory – pattern separation task • Pattern separation: transform similar, overlapping representations into distinct non-overlapping representations (tax the DG-CA3 regions); allows encoding of new information • Pattern completion: transforming incomplete or “distorted” representations into complete patterns based on pre-existing knowledge (CA1 and others)

23. Pattern separation in PD • Pattern separation task • Respond with “old”, “similar”, or “new” 3 s .5 s Pattern Separation “Similar” (CR) … Pattern Completion “Old” (FA) “New” (Miss) First Presentation Lure

24. Anatomy of the medial temporal lobe Pattern separation Pattern completion Adapted from Lavenex et al. 2000 and Wilson et al. 2006

25. aMCI PD10 controls vs. 8 iPD aMCI

26. Pattern separation in PD aMCI

27. Hyperactivation left DG/CA3 in PD aMCI

28. Acknowledgements • Arnold Bakker • Catherine Bakker • Alana Gold • Zoltan Mari • Kate Perepezko • Caroline Speck

29. Questions?

30. Volume changes in PD aMCI

31. Lewy body-related dementias

32. PDRC – Neuropathological Diagnosis (clinical diagnosis of PD) Halliday et al 2014, Kalaitzakis et al 2009, Sabbagh et al 2009

33. Pattern separation – LurePD aMCI vs non-PD aMCI (presumed AD)

34. Hyperactivation in non-PD aMCI also left DG/CA3 Bakker et al 2015