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.
