Longitudinal Analysis of Neuroradiological Biomarkers for Fragile X-Associated Tremor/Ataxia Syndrome and Implications for Clinical Trials.

Abstract

The objective of this study was to show the capacity of structural brain magnetic resonance imaging (MRI) measures to serve as monitoring biomarkers for Fragile X-Associated Tremor/Ataxia Syndrome (FXTAS). From 2 longitudinal studies of male FMR1 premutation carriers, 2 brain MRI scans were selected from each participant, collected within a period of 2 years (12 healthy controls, 17 carriers without FXTAS, and 51 carriers with FXTAS; all men, ages 40 to 80 years), along with clinical measurements and FMR1 cytosine-guanine-guanine (CGG) repeat numbers. Candidate MRI biomarkers included whole brain white matter hyperintensity (WMH) and cerebellar, brainstem, and whole brain volumes. In the FXTAS group, mixed-effects models demonstrated significant volume loss across an average interval of 1.32 years for the whole brain, cerebellum and brain stem volumes, and significant increases in WMH, with large magnitude effects for whole brain and WMH volumes. All MRI measures showed deterioration with advancing FXTAS stage, with the strongest pattern shown in WMH volume. CGG repeat number showed significant nonlinear associations with all 4 brain MRI metrics, with mid-range CGG repeat carriers evidencing the worst brain atrophy and WMHs. Structural brain MRI measurements, especially those capturing white matter deterioration, are correlated with FMR1 premutation size of CGG repeat length and sensitive to FXTAS disease progression across a relatively short interval of less than 2 years, making them potentially suitable as surrogate end points for clinical trials. ANN NEUROL 2025;98:471-481.