# T2-FLAIR hyperintensities in the inferior cerebellar peduncles and their association with clinical symptoms, molecular and MRI markers in male FMR1 premutation carriers

## TL;DR

This study identifies new brain imaging signs in a genetic disorder linked to tremors and ataxia, showing their connection to symptoms and genetic factors.

## Contribution

The study introduces ICP hyperintensities as a novel MRI marker for FXTAS and links them to clinical and genetic features.

## Key findings

- ICP hyperintensities were found only in FXTAS carriers and not in controls or non-FXTAS carriers.
- ICP hyperintensities correlated with brain atrophy, white matter disease, and cognitive and gait impairments.
- Carriers with ICP hyperintensities had longer CGG repeat lengths, suggesting a genetic link.

## Abstract

FMR1 premutation carriers (55–200 CGG repeats) are at risk of developing fragile X-associated tremor/ataxia syndrome (FXTAS), a neurodegenerative disorder associated with motor and cognitive impairment. Bilateral hyperintensities of the middle cerebellar peduncles (MCP sign) are the major radiological hallmarks of FXTAS. The inferior cerebellar peduncles (ICP) contain fibers related to proprioception and vestibular functions (such as the rostral and posterior spinocerebellar tracts and the juxta restiform body), which are clinically associated with cerebellar gait ataxia, a major clinical criterion for FXTAS diagnosis. However, the ICP hyperintensity has yet to be studied in FXTAS.

We evaluated 588 MRI scans (mean 2.05 visits/participant) from 202 male premutation carriers (164 with FXTAS and 38 without FXTAS at last visits) and 85 controls. Two radiologists, independently, rated as absent or present the signal of the right and left ICP in T2-Fluid-attenuated inversion recovery (FLAIR) scans. Mixed-effects models were used for statistical analysis adjusting for age.

Only carriers with FXTAS revealed ICP hyperintensities at last visits. Furthermore, ICP hyperintensity was associated with brain atrophy, increased white matter disease, the MCP sign, FXTAS stage, abnormal gait, lower cognitive functioning and faster age-related increase in anxiety and depression scores. Finally, carriers with ICP hyperintensities had significantly higher CGG repeat length than carriers without ICP hyperintensities.

This study describes ICP hyperintensity as a new potential radiological finding in FXTAS, suggests involvement of the vestibulo-cerebellar, rostral, and posterior spinocerebellar tracts, and the vestibular system in FXTAS physiopathology, and reinforces the association of CGG expansion in the range of brain changes seen in FXTAS.