University of Otago Doctoral Thesis Cognitive Impairment and Conversion to Dementia in Parkinson's Disease: An Imaging Study of Amyloid PET and Diffusion MRI Supervisors: Dr. Tracy R. Melzer (Primary) Author: Dr. Daniel J. Myall Megan Rebecca Stark Prof. Tim J. Anderson Prof. John C. Dalrymple-Alford Dr. Steven H. Marsh A thesis submitted in fulfilment of the requirements for the degree of Doctor of Philosophy at the University of Otago Department of Medicine June 2020 Abstract Cognitive Impairment and Conversion to Dementia in Parkinson's Disease: An Imaging Study of Amyloid PET and Diffusion MRI by Megan Rebecca Stark Objective To investigate the association between amyloid deposition or white matter degeneration with cognitive impairment and conversion to dementia in Parkinson's disease (PD). Background Cognitive decline and dementia are common in Parkinson's disease, however the patho- physiological basis of cognitive impairment in PD is unresolved. The time-course from diagnosis to development of dementia is highly variable, and imaging biomarkers are ur- gently needed to assist estimation of long-term cognitive outcomes, and enable targeted therapeutic interventions in early disease. Misfolded beta-amyloid protein aggregates, or amyloid plaques, are a significant pathology in Alzheimer's disease, and may play a part in future cognitive decline in PD. Measures of cerebral blood flow and white mat- ter micro- and macro-structural degeneration may correlate more directly with current cognitive impairment, and may interact with amyloid to affect cognitive decline in PD. This thesis comprehensively investigates these measures in PD and aims to differentiate pathology and age-related effects, using both cross-sectional and longitudinal (three-year) study designs. Methods We acquired [18F]-Florbetaben (FBB) amyloid PET, arterial spin labelling perfusion MRI, and structural MRI in 115 patients with Parkinson's disease, recruited from the Movement Disorders clinic at the New Zealand Brain Research Institute. Movement Disorders Soci- ety level II criteria were used to classify PD patients as having normal cognition (PDN, n=23), mild-cognitive impairment (PD-MCI, n=76), or dementia (PDD, n=16), at study baseline and over the course of three-year neuropsychological follow-up. The relationship between amyloid deposition and cognitive classification, global cognitive ability, cerebral blood flow, and conversion to dementia during the three-year follow-up was assessed us- ing both Bayesian regression and whole-brain voxel-wise analysis. High angular resolution diffusion imaging (HARDI) MRI was acquired in a wider cohort of 123 PD participants and 37 controls, for the investigation of white matter integrity in PD across the cogni- tive spectrum (PDN, n=46; PD-MCI, n=66; PDD, n=11). Cross-sectional fixel-based ii analysis investigated measures of fibre density, fibre cross-section, and combined fibre- density-cross-section across PD, controls, and PD cognitive subgroups. Clinical measures of global cognitive ability and motor impairment were also assessed for association with these fixel-based metrics. Results We observed significantly higher cortical amyloid accumulation in our PDD group relative to other cognitive subgroups, but model comparison indicated this was due to an effect of age. Cortical amyloid was seen to be present in PD at levels comparable to healthy ageing. Longitudinal assessment identified that, while increased cortical and subcortical amyloid was associated with conversion to dementia within three years, this did not represent a clinically relevant effect. There was no evidence of an interactive effect of amyloid with cerebral blood flow to affect cognition. Reduced fibre density in the substantia nigra correlated with disease, however age exhibited the most widespread association with white matter metrics in this cohort. Conclusions This thesis investigated the effect of amyloid on cognitive impairment within a large, well-characterised, longitudinal PD cohort, and subsequently challenged existing charac- terisations of regional amyloid deposition relating to cognitive decline. This work also represents the largest application to-date of fixel-based analysis for the investigation of white matter degeneration across the cognitive spectrum in PD. Research Outputs and Activities ◦ Journal Publication: Tracy R. Melzer, Megan R. Stark, Ross J. Keenan, Daniel J. Myall, Michael R. MacAskill, Toni L. Pitcher, Leslie Livingston et al. (2019). Beta amyloid deposition is not associated with cognitive impairment in Parkinson's disease. Frontiers in Neurology, 10, 391. doi: 10.3389/fneur.2019.00391 ◦ Poster presentation: Australasian Winter Conference on Brain Research (AWCBR), Queenstown (Sep 2017). Abstract title: Parkinson's disease: Association between amyloid PET imaging and cognitive status. ◦ Oral presentation: UOC Open Day, Christchurch, NZ (Oct 2017). Title: Parkinson's disease: Cognitive decline, amyloid and the ageing brain. ◦ Poster presentation: Human Amyloid Imaging (HAI), Miami, USA (Jan 2018). Abstract Title: Parkinson's disease: Association between amyloid PET imaging and cognitive status. ◦ Attended the BRNZ Early Career Researcher workshop, Auckland (Feb 2018). ◦ Three-month study period in New Haven, CT, USA, working with Dr. John Seibyl at the Institute for Neurodegenerative Disorders (May - Aug 2018). Generously funded by the The MacGibbon PhD travel fellowship. ◦ Attended Alzheimer's Association International conference, Chicago USA (Jul 2018). ◦ Attended the Global burden of Disease Brain Summit, Auckland (Oct 2018). ◦ Attended the BRNZ Early Career Researcher workshop, Auckland (Mar 2019). ◦ 3-Minute Thesis Competition: Presented at the BRNZ Conference, Auckland (Mar 2019). ◦ Attended Computational Anatomy Toolbox (CAT12) workshop, Auckland (Apr 2019). ◦ Public outreach: Presentation and panel discussion at the Christchurch Brain Aware- ness Day event, Turanga Library, Christchurch (Aug 2019). ◦ Poster presentation: The International Congress of Parkinson's disease and Move- ment Disorders (MDS), Nice, France (Sep 2019). Abstract Title: Amyloid load and cognitive decline in Parkinson's disease: preliminary longitudinal findings. ◦ Attended the BRNZ Early Career Researcher workshop, Dunedin (Feb 2020). iii Authorship Attribution Statement Work presented in Chapter 5 of this thesis has been published in Frontiers of Neurology (Melzer et al., 2019). Contributing Authors Megan Stark (MS), Tracy Melzer (TM), Ross Keenan (RK), Daniel J. Myall (DJM), Michael MacAskill (MM), Toni Pitcher (TP), Leslie Livingston (LL), Sophie Grenfell (SG), Kyla-Louise Horne (K-LH), Bob Young (BY), Maddie Pascoe (MP), Mustafa Al- muqbel (MA), Jian Wang (JW), Steven Marsh (SM), David H. Miller (DHM), John Dalrymple-Alford (JD-A), Tim Anderson (TA). Chapter 5 - Beta Amyloid Deposition Is Not Associated With Cognitive Im- pairment in Parkinson's Disease MS performed the image processing, statistical analyses and interpretation of results in this chapter, and produced the primary manuscript. TM and DJM contributed to image processing, statistical analyses, results interpretation, and draft manuscript. All authors contributed to acquisition, analysis, or interpretation of data. All authors contributed to manuscript revision, read, and approved the submitted version. Chapter 6 - Beta Amyloid Deposition and Future Cognitive Outcomes MS performed the image processing, statistical analyses and interpretation of results in this chapter, with guidance from TM and DJM. Chapter 7 - Diffusion Imaging of White Matter Degeneration - a Fixel-Based Analysis MS performed all image processing, statistical analyses and interpretation of results in this chapter. TM and MA acquired the MR image data for this study. The NZBRI Study of Parkinson's Disease The larger study of Parkinson's disease at the New Zealand Brain Research institute was conceptualised and designed by TM, DJM, MM, TP, DHM, JD-A, and TA. TM, MM, DHM, RK, DJM, LL, JD-A, and TA obtained funding for the study. RK, LL, DJM, MM, TP, and SM provided administrative, technical, and material support. Contributing Institutions New Zealand Brain Research Institute, Christchurch, New Zealand Department of Medicine, University of Otago, Christchurch, New Zealand Brain Research New Zealand Rangahau Roro Aotearoa Centre of Research Excellence, Christchurch, New Zealand Pacific Radiology Group, Christchurch, New Zealand Department of Neurology, Huashan Hospital, Fudan University, Shanghai, China Department of Physics and Astronomy, University of Canterbury, Christchurch, New Zealand Institute of Neurology, University College London, London, United Kingdom Department of Psychology, University of Canterbury, Christchurch, New Zealand Department of Neurology, Christchurch Hospital, Christchurch, New Zealand iv Acknowledgements I am incredibly grateful for the exceptional support and encouragement I have received from my supervisors, Dr. Tracy Melzer, Dr. Daniel Myall, Prof. Tim Anderson, Prof. John Dalrymple-Alford, and Dr. Steve Marsh. Thank you all, for your continued guidance and expertise. Tracy and Daniel, thank you for helping me navigate the mine-field that is statistical analysis, and for basically teaching me everything I know about neuroimaging. Tracy, I thank you three times - it was your optimism, endless patience, and sheer breadth of knowledge that got me through. Thank you to my colleagues and friends at the New Zealand Brain Research Institute. The research we do at NZBRI wouldn't be possible without the team