Smith, Callum R. (2020) Cognitive Impairment in Parkinson’S Disease: Impact and Identification of Comorbid Disease Mechanisms
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Smith, Callum R. (2020) Cognitive impairment in Parkinson’s disease: Impact and identification of comorbid disease mechanisms. PhD thesis. https://theses.gla.ac.uk/77862/ Copyright and moral rights for this work are retained by the author A copy can be downloaded for personal non-commercial research or study, without prior permission or charge This work cannot be reproduced or quoted extensively from without first obtaining permission in writing from the author The content must not be changed in any way or sold commercially in any format or medium without the formal permission of the author When referring to this work, full bibliographic details including the author, title, awarding institution and date of the thesis must be given Enlighten: Theses https://theses.gla.ac.uk/ [email protected] Cognitive impairment in Parkinson’s disease: Impact and identification of comorbid disease mechanisms. Callum R. Smith B.A. Psychology, MSc. Research Methods in Psychology Submitted in fulfilment of the requirements for the degree of Doctor of Philosophy Institute of Neuroscience and Psychology College of Medical, Veterinary, and Life Sciences University of Glasgow December 2019 © Callum R. Smith, 2019 2 Abstract Cognitive impairment is a common and debilitating feature of Parkinson's disease (PD). While it is primarily caused by cerebral propagation of α-synuclein protein, evidence of comorbid diseases is frequently found in autopsy samples. This includes tau and amyloid-β pathologies – the hallmarks of Alzheimer's disease (AD) – and cerebrovascular damage. Comorbid diseases may influence cognition in PD over and above the effects of α-synuclein alone, and this influence may interfere with the results of clinical trials of next-generation medical treatments that target α-synuclein. The primary aims of this thesis were to define the extent and the effects of comorbid disease mechanisms in PD, and to identify viable clinical strategies for detecting coexistent disorders in vivo. Methods included a systematic review of autopsy studies; a factor analysis of the Montreal Cognitive Assessment (MoCA); a regression analysis of two genes; and a cross-sectional neuropsychological study of 45 patients. The systematic review found significant tau pathology in around one-third of PD patients at death. Significant amyloid-β pathology affected over half, and conferred a worse prognosis. Other pathologies (e.g. cerebrovascular disease) were less common, and did not contribute to dementia in PD. The factor analysis showed that the MoCA has limited value for distinguishing cognitive profiles in PD, suggesting that it should be used only for screening. The genetic project found that variation in the APOE gene influenced cognitive decline in early PD; the effect varied between men and women. Variation in MAPT did not affect cognitive decline. Finally, the neuropsychological study found that over half of cognitively impaired PD patients could be clinically diagnosed with a coexistent cognitive disorder, with AD being the most common. Collectively, the results of this thesis show that comorbid diseases, particularly AD, are common in PD, and these contribute to the cognitive phenotype. Consequently, a clinical assessment incorporating selected neuropsychological tests can be used to identify comorbid diseases in PD patients. It is important to consider the potentially confounding impact of multimorbidity in the design and analysis of clinical trials that aim to modulate neurodegeneration in PD by targeting α-synuclein. 3 Table of Contents Abstract .....................................................................................................................2 Table of Contents .......................................................................................................3 List of Tables .............................................................................................................7 List of Figures ............................................................................................................8 List of Publications ....................................................................................................9 List of Conference Presentations .............................................................................. 10 Abbreviations ........................................................................................................... 11 Acknowledgements .................................................................................................. 13 Author’s declaration ................................................................................................. 14 1 General introduction ................................................................................... 1-15 1.1 Parkinson’s disease .................................................................................. 1-15 1.1.1 Epidemiology .............................................................................. 1-15 1.1.2 Neuropathology ........................................................................... 1-16 1.1.3 Clinical features .......................................................................... 1-18 1.2 Cognitive impairment .............................................................................. 1-21 1.2.1 Epidemiology of cognitive impairment in PD .............................. 1-23 1.2.2 Other causes of cognitive impairment .......................................... 1-25 1.2.3 Current treatment strategies ......................................................... 1-27 1.3 Aims and structure of the thesis ............................................................... 1-30 2 Neuropathology of PD and dementia disorders .......................................... 2-34 2.1 Lewy pathology ....................................................................................... 2-34 2.1.1 Pathological staging and diagnosis of Lewy body disease ............ 2-37 2.2 Tau and amyloid-β pathology................................................................... 2-41 2.2.1 Pathological staging and diagnosis of AD .................................... 2-45 2.3 Pathology associated with FTD ................................................................ 2-48 2.4 Cerebrovascular pathology ....................................................................... 2-49 2.5 Chapter summary ..................................................................................... 2-51 3 Systematic review of autopsy studies of dementia in PD ............................ 3-53 3.1 Introduction ............................................................................................. 3-53 3.2 Methods ................................................................................................... 3-56 3.2.1 Protocol and registration .............................................................. 3-56 4 3.2.2 Eligibility criteria ........................................................................ 3-56 3.2.3 Information sources ..................................................................... 3-57 3.2.4 Search strategy ............................................................................ 3-57 3.2.5 Study selection process ................................................................ 3-58 3.2.6 Data collection ............................................................................ 3-58 3.2.7 Data items ................................................................................... 3-58 3.2.8 Risk of bias assessment ............................................................... 3-58 3.2.9 Methods of analysis ..................................................................... 3-59 3.3 Results ..................................................................................................... 3-59 3.3.1 Study selection and characteristics ............................................... 3-59 3.3.2 Risk of bias ................................................................................. 3-63 3.3.3 Lewy pathology ........................................................................... 3-65 3.3.4 Coexistent Alzheimer pathology .................................................. 3-67 3.3.5 Coexistent TDP-43 and cerebrovascular pathology ...................... 3-71 3.3.6 Relative contribution of α-synuclein, amyloid-β, and tau ............. 3-72 3.3.7 The motor-cognitive interval and mortality .................................. 3-74 3.3.8 Intercorrelations between different pathologies ............................ 3-75 3.3.9 Genetic results ............................................................................. 3-75 3.4 Discussion ............................................................................................... 3-76 3.4.1 Role of APOE and MAPT genotypes ........................................... 3-81 3.4.2 Limitations .................................................................................. 3-82 3.4.3 Conclusions ................................................................................. 3-83 4 Clinical diagnostic criteria for dementia disorders .................................... 4-84 4.1 Clinical diagnostic criteria for AD dementia ............................................ 4-85 4.1.1 AD-MCI and preclinical AD ....................................................... 4-87 4.2 Clinical diagnostic criteria for Lewy body dementias ............................... 4-88 4.2.1 PDD and DLB ............................................................................