Clinical phenotypes and pathology in neurodegeneration

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Copyright: Burrell, James R
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Abstract
Clinicopathological heterogeneity complicates the study of neurodegenerative diseases. In motor neuron disease (MND), variability in clinical phenotype and prognosis is well recognised. In frontotemporal dementia (FTD), three distinct clinical phenotypes are described, including the behavioural variant FTD, semantic dementia and progressive non-fluent aphasia (PNFA). Clinical and pathological overlaps between FTD and MND exist, and the recent discovery of a hexanucleotide repeat (C9ORF72) in a significant proportion of both sporadic and familial FTD and MND indicates the importance of this rapidly developing area. Heterogeneity also characterises corticobasal syndrome (CBS), which presents with multifaceted motor and cognitive deficits. In this thesis, several potential disease biomarkers, including threshold tracking transcranial magnetic stimulation (TMS), saccadometry, voxel-based morphometry analysis (VBM), and (11C) Pittsburgh Compound B positron emission tomography (PiB-PET) were used, to improve understanding of clinicopathological heterogeneity in MND, FTD and CBS. After describing the background of the disorders covered (Chapter 1) and the experimental design used (Chapter 2), Chapter 3 describes clinical and neurophysiological features of an isolated bulbar palsy phenotype (IBP) of MND. IBP patients were predominantly female with prominent upper motor neuron bulbar symptoms and normal cortical excitability, measured using threshold tracking TMS. Chapter 4 identified clinical and neurophysiological evidence of motor dysfunction in a significant proportion of FTD patients, most prominently in PNFA. Chapter 5 demonstrated prolonged median reflexive saccade latencies in FTD, despite an increased incidence of early saccades; both abnormalities correlated with frontal eye field atrophy. Chapter 6 demonstrated cortical dysfunction in CBS and correlated this with core clinical features (apraxia and visuospatial dysfunction) and atrophy of motor structures using VBM. Chapter 7 compared clinical and neuropsychological characteristics of CBS due to Alzheimer's pathology to other CBS, using PiB-PET to classify patients. Unravelling the heterogeneity underlying the complex clinical presentations across the spectrum of neurodegenerative diseases studied in this thesis will facilitate early diagnoses and the introduction of directed therapeutic approaches. Several clinical biomarkers developed in the present studies may serve to better differentiate disease groups, in addition to clarifying the underlying pathological basis.
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Author(s)
Burrell, James R
Supervisor(s)
Kiernan, Matthew
Hodges, John
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Publication Year
2012
Resource Type
Thesis
Degree Type
PhD Doctorate
UNSW Faculty
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