Fragile X-associated tremor/ataxia syndrome (FXTAS) pathology and anatomy: imaging and clinical correlates

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! Program Director/Principal Investigator (Last, First, Middle): Martínez-Cerdeño, Verónica Abstract Fragile X-associated tremor/ataxia syndrome (FXTAS) pathology and anatomy: imaging and clinical correlates FXTAS is a late-onset neurodegenerative disorder associated with premutation alleles (55-200 CGG repeats) of the FMR1 gene. Larger expansions give rise to fragile X syndrome (FXS), the most common inherited form of cognitive impairment. The prevalence of premutation carriers in the general population (1: 400 males; 1: 200 females), and the fact that up to 40% of carriers develop FXTAS, underscores the a high personal and economic burden for society. Despite its importance, the number of pathology reports on FXTAS patients is currently very limited. Particularly, comprehensive histopathological studies with clinical and imaging correlation of FXTAS patients do not exist and to the best of our knowledge we are the only research group dedicated to study the pathology of FXTAS. Using our unique FXTAS brain repository, we will perform a thorough histopathological analysis of ~70 FXTAS cases and correlate their pathology to their radiological, clinical and molecular history. We hypothesize that FXTAS is a microhemorrhage white matter disease - in addition to a grey matter neurodegenerative disease as currently thought. Specifically, we propose that inclusion-bearing endothelial cells in white matter fail to maintain capillary integrity, resulting in the release of erythrocytes that, upon breakdown, release iron. Iron accumulates in the capillaries and white matter tissue inducing activation of microglia and astrocytes, cytokine and chemokine release, high oxidative state and/or mitochondrial dysfunction, all leading to myelin loss and axonal degeneration. We also hypothesize high signal (T2 hyper-intensities) regions in MRI correspond to white matter disease characterized by microhemorrhage, the presence astrocyte/microglia activation and iron deposition. Additionally, we hypothesize that the alteration of the pontocerebellar system is the main anatomical trait of FXTAS. We will determine if FXTAS is a micro-hemorrhage white matter disease (aim 1) by establishing the pathology of FXTAS, the level of oxidative stress, and the hemorrhagic nature of MRI hyperintensities. We will also determine if FXTAS presents with a chronic inflammatory state (aim 2) by evaluating if astrocytes and microglia are activated and if there is an increase in the levels of cytokines and chemokines. We will test if oligodendrocytes and Purkinje cells are the main cell population affected by cell death in FXTAS by performing quantification experiments for specific neural types. We will also investigate if the alteration of the pontocerebellar system is the main anatomical trait of FXTAS (aim 3). To do so we will verify the presence of intranuclear inclusions, determine level of atrophy in the brain areas associated with the pontocerebellar system, the anatomical distribution of the PC loss, and the number of fibers in the medial cerebellar peduncle and corpus callosum. The knowledge gained from this project will be a tremendous advance in the understanding of FXTAS and could change future treatments to address microhemorrhages and inflammation in FXTAS.