Mechanisms and biomarkers of disease progression in Fragile X-associated tremor/ataxia syndrome (FXTAS) - PROJECT SUMMARY/ABSTRACT Fragile X-associated tremor/ataxia syndrome (FXTAS) is a neurodegenerative condition that leads to profound declines in functional motor abilities and quality of life. It is estimated to be the most common single-gene form of ataxia in the aging population, but it remains understudied, poorly understood, and without effective treatment options. Elevated mRNA transcript caused by premutation expansions of the 5' untranslated region of the FMR1 gene serves as the primary molecular mechanism of FXTAS, though risk is modified by separate genetic and molecular alterations that are not yet well defined. One reason mechanistic pathways have been difficult to establish is that no quantitative markers of brain and behavioral changes in FXTAS are available to assess relationships between genetic/molecular factors and neurodegenerative processes. To address this need, we will 1) establish new biobehavioral markers sensitive to disease progression and 2) define molecular and genetic risk mechanisms associated with quantitative brain and sensorimotor changes in FXTAS. Premutation carriers with FXTAS (FXTAS+; n=60, including 30 females), carriers without FXTAS (FXTAS-; n=65; 30 females), and age- and sex- matched healthy controls (n=60) will be studied at two time points separated by 24-months. Aim 1A uses measures of multiple motor behaviors (manual, postural control, gait) and task-based functional magnetic resonance imaging (fMRI) to test the hypotheses that, relative to FXTAS- carriers and controls, FXTAS+ patients show elevated motor variability associated with reduced visual cortex-cerebellar Crus I functional connectivity. Exploratory analyses of task-free functional connectivity also are proposed. Aim 1B tests the prediction that sensorimotor deficits and reduced visual cortex – Crus I functional connectivity during motor behavior will become more severe over time in FXTAS, especially for males. Aim 2A uses structural and diffusion MRI to test the hypotheses that FXTAS+ carriers show reduced cerebellar volumes and reduced microstructural integrity of the primary input and output pathways of the cerebellum relative to FXTAS- carriers and controls. Aim 2B tests the hypothesis that FXTAS+ carriers will show more severe changes over time in cerebellar volumes and microstructure, especially for males. Aim 3A examines associations between FMR1 gene alterations (repeat length, mRNA, repeat instability) and quantitative biomarkers from Aims 1-2, as well as how associations are modified by ApoE allelic variants implicated in FXTAS. Aim 3B tests these relationships over time. This will be the first known quantitative analyses of sensorimotor behaviors as well as the function and structure of the primary brain locus of FXTAS, the cerebellum. By testing their change over time and their associations with genetic/molecular causes and risk modifiers of FXTAS, these studies hold promise for elucidating disease mechanisms and advancing urgently needed quantitative biomarkers for tracking FXTAS onset, progression, and treatment-related changes.
