# Trajectories and Markers of Neurodegeneration in Fragile X Premutation Carriers

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA AT DAVIS · 2021 · $617,594

## Abstract

FMR1 premutation carriers exhibit mild cognitive impairment and have an increased rate of 
psychiatric disorders.
Critically, they are at risk for developing a neurodegenerative disease, fragile X-associated 
tremor/ataxia syndrome (FXTAS), which is characterized by progressive gait ataxia, intention 
tremor, Parkinsonism, dementia, autonomic dysfunction, peripheral neuropathy and key 
neuropathological features. The disease has a variable and age-related penetrance, affecting 75% of 
male premutation carriers by the eighth decade of life. Given the high prevalence of the FMR1 
premutation in the population (about 1/468 males) this is a significant health issue that affects a 
large number of individuals. There is currently no treatment for FXTAS and no empirically evaluated 
interventions to prevent or slow the disease progression. Importantly, no biological or behavioral 
markers are available for predicting which premutation carrier will develop FXTAS before the 
clinical symptoms appear.  In the last funding period of our program of research (“Trajectories and 
Markers of Neurodegeneration in Fragile X Premutation Carriers”) we have successfully followed FMR1 
premutation carriers and age-matched controls for at least two, and in some cases 3 longitudinal 
time points, obtaining neuroimaging, neuropsychological, and molecular measurements as well as 
medical and neurological examinations. We have identified neuroimaging, behavioral and molecular 
markers that show promise for predicting, before the onset of clinical symptoms, which premutation 
carriers will convert to FXTAS, and for tracking changes during the early stages of disease. Ours 
remains the only prospective, longitudinal study of FMR1 premutation carriers being conducted, and 
understanding the prodrome of FXTAS remains critical for the early intervention and prevention of 
this neurodegenerative disease.  For the current project, we will continue to collect longitudinal 
neuroimaging, neuropsychological and molecular data from our existing cohort and a new cohort of 
carriers and controls with an overarching goal to define the prodrome of FXTAS, refining our 
protocol in accordance with what we learned in the last five years, and adding biomarkers and 
clinically sensitive measures and assessments of lifestyle factors to better address hypotheses 
about risk and resilience in this population.

## Key facts

- **NIH application ID:** 10179501
- **Project number:** 5R01NS110100-14
- **Recipient organization:** UNIVERSITY OF CALIFORNIA AT DAVIS
- **Principal Investigator:** DAVID R HESSL
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $617,594
- **Award type:** 5
- **Project period:** 2007-06-01 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10179501

## Citation

> US National Institutes of Health, RePORTER application 10179501, Trajectories and Markers of Neurodegeneration in Fragile X Premutation Carriers (5R01NS110100-14). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10179501. Licensed CC0.

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