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Title: Heterogeneity in the natural history of Parkinson's disease
Author: Evans, J. R.
Awarding Body: University of Cambridge
Current Institution: University of Cambridge
Date of Award: 2011
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The aim of my thesis has been to improve understanding of the character and determinants of phenotypic heterogeneity in PD. The following data is presented: Methods used in the identification of a novel, representative cohort of individuals newly diagnosed with parkinsonism in the Cambridgeshire area. Multiple sources of referral were used to maximise ascertainment over a 21 month case collection period. A crude incidence of PD of 13.0 / 100,000 person-years, and of all-cause parkinsonism 15.9 / 100,000 person-years is estimated. A comparative analysis with data from a previous incidence study in the same population is presented. An analysis of cognitive heterogeneity in this cohort using the results of a comprehensive neuropsychological assessment. A classification system for defining mild cognitive impairment in PD (PD-MCI) is presented and discussed. PD-MCI is identified in 17.4% of participants at their baseline assessment, and shown to be associated with lower pre-morbid IQ and a greater burden of axial symptoms. A descriptive analysis of the use of two tests which have predictive utility in other neurodegenerative dementias, Paired Associates Learning (PAL) and the Addenbrookes Cognitive Examination (ACE), is also presented. An exploration of the frequency and concomitants of neuropsychiatric disturbance in this representative population, with particular emphasis upon apathy and sleep disturbance. Apathy is identified in 22.8% and shown to be independently associated with increased age, depression and impairment in executive function. Figures for impairment of nocturnal sleep and excessive daytime somnolence are also presented, the first such description in an unselected PD population. A data-driven analysis of the natural history of progression in PD using data from a previously established incident cohort, followed longitudinally for up to 7.9 years. A multivariate statistical model is employed to derive a mean rate of motor progression on the commonly used UPDRS-3 scale of 2.24 points/year. Axial (gait and postural) PD symptoms are shown to progress most rapidly. Survival analysis methods are used for model progression to a major axial milestone (loss of postural stability) and risk factors for an adverse prognosis are evaluated. Investigations into the genetic basis of cognitive heterogeneity in PD. The MAPT H1/H1 genotype, which has previously been linked with increased dementia risk in PD, is shown to be associated with an altered pattern of tau transcription in post-mortem PD cortex, a novel finding which contributes to our understanding of the pathogenesis of dementia in PD. The influence of a common polymorphism in the gene encoding Butyrylcholinesterase upon cognition in PD is also investigated.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available