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Abstract
Premutation (PM) expansions (55–200 CGG repeats) of the Fragile X Mental Retardation 1 (FMR1) gene confer risk for the development of fragile X-associated tremor ataxia syndrome (FXTAS), a neurodegenerative disorder affecting up to 45% of PM males aged over 50 years. Clinical and radiological features include intention tremor, gait ataxia, parkinsonism, cognitive dysfunction, diffuse white matter pathology and cerebral/cerebellar atrophy. The development of measures sensitive to the earliest indicators of FXTAS would have significant implications for determining risk, tracking progression, and monitoring treatment response. This thesis examined the interrelationships between neurobehavioural, radiological and FMR1 molecular measures among a final sample of 22 PM males (ages 26–80, seven with FXTAS) and 24 matched controls (ages 26–77). Comprehensive assessments included measures of cognitive function, psychiatric symptomatology, neuromotor function, structural brain imaging and FMR1 quantification. A number of clinical features including hearing loss, history of psychiatric disorder and psychomotor slowing were overrepresented among PM males compared to controls. Males with the PM also exhibited greater increases in motor symptom severity and greater reductions in cerebellar and subcortical volume with increasing age. Within the PM group, smaller thalamus and pallidum volumes were associated with poorer fine motor function. Significantly greater postural sway among PM males was associated with increasing CGG repeat length and decreasing cerebellar volume. The relationship between CGG repeat length and postural sway was mediated by a negative association between CGG repeat size and cerebellar volume. There was also preliminary evidence to suggest that reductions in cerebellar volume were associated with greater cognitive-motor interference of intra-individual variability in step width among PM males while performing a serial subtractions task. Further, increases in step width variability became more prominent among PM males with increasing age and CGG repeat length. Overall, this thesis provides strong evidence that subcortical pathology and CGG-related reductions in cerebellar volume contribute to specific decrements in neurobehavioural function among PM males. These findings have significant implications for guiding future research exploring the use of sensitive measures to track symptom progression and response to treatment.