Development of an Objective Assessment of the Cognitive, Posturographic, and Electrophysiological Phenotype of the Fragile X Premutation, and analysis of their contribution to Postural Instability.

Abstract

The Fragile X Premutation is a complex genetic anomaly which affects one in 260 females and 400 males and results in a broad range of symptoms and distinct conditions. The premutation phenotype involves cognitive and motor impairment as well as increased risk of developing the neurodegenerative movement disorder Fragile X Associated Tremor Ataxia Syndrome (FXTAS). FXTAS is characterised by clinically significant cognitive and motor impairments as well as balance deficits, subsequently leading to falls, injuries, and even hospitalisation. However, due to the relatively recent discovery of FXTAS and the premutation phenotype, the pathophysiology and progression of motor symptoms towards the development of FXTAS are not clear and current evaluations of motor and neurological health involve subjective rating scale based assessments or time-consuming neuroimaging techniques, therefore there is an urgent clinical need for objective, time-efficient clinical assessments of patient health to allow for early interventions. In this thesis, a protocol, with foundations based on posturography based measures of stability, was developed to objectively assess balance and postural control in younger Premutation Carriers without FXTAS. Posturographic measures were recorded during altered cognitive and sensory conditions to emulate situations experienced during daily life. Both clinically interpretable measures of postural sway were assessed as well as more complex entropy-based measures of postural control. Furthermore, electrophysiological imaging methods were employed to investigate potential alteration in neural activity which may underlie the changes in motor functioning, providing new insight into the Fragile X Premutation related pathomechanisms of instability. The central aim of this thesis was to employ a multimodal approach to objectively assess and characterise premutation related cognitive and motor symptoms in younger, seemingly asymptomatic Fragile X Premutation Carriers. The main findings of the studies presented in this thesis suggest that the protocol developed is effective in probing deficits in cognitive and sensory functioning experienced by carriers to elicit decreased stability in younger female Premutation Carriers, and that classical sway parameters, alongside entropy-based measures of sway, are effective in detecting disparities in postural control of Premutation Carriers and unaffected Control subjects. Furthermore, the relationship between activation of specific electrophysiological frequency bands and postural performance, which has been established in unaffected control subjects, was lacking in Premutation Carriers, suggesting altered neural activation connectivity in carriers may contribute to aberrant postural control. It was shown that a combination of cognitive, posturographic and electrophysiological based methods provide an objective and information-rich assessment of motor functioning and neurophysiology of Fragile X Premutation Carriers. This highlights the efficacy and utility of a multimodal approach to assessments in clinical practice. In conclusion, the original contribution to knowledge of this thesis lies in the development of a simple but comprehensive, easily administered, protocol for the objective assessment of stability and postural control and neurological health of young, asymptomatic Fragile X Premutation Carriers. The main findings of this thesis, therefore, can provide significant value for future research into the effects of the Fragile X Premutation. The cognitive, posturographic and electrophysiological based methods described in this thesis may yield information which can then be used to instigate conversations with patients surrounding health-related behaviours, personalised strategies for behavioural changes and preclusive measures to potentially delay onset or progression of symptoms, subsequently improving quality of life.