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

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA AT DAVIS · 2020 · $464,864

## Abstract

! 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...

## Key facts

- **NIH application ID:** 9944683
- **Project number:** 5R01NS107131-03
- **Recipient organization:** UNIVERSITY OF CALIFORNIA AT DAVIS
- **Principal Investigator:** Veronica Martinez-Cerdeno
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $464,864
- **Award type:** 5
- **Project period:** 2018-09-01 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9944683

## Citation

> US National Institutes of Health, RePORTER application 9944683, Fragile X-associated tremor/ataxia syndrome (FXTAS) pathology and anatomy: imaging and clinical correlates (5R01NS107131-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9944683. Licensed CC0.

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