Background and objectives Fragile X–associated tremor/ataxia syndrome (FXTAS) is a late-onset neurodegenerative disorder that affects carriers of the FMR1 premutation (55–200 CGG repeats). It is characterized by motor and cognitive impairments. However, the mechanisms underlying individual susceptibility to FXTAS among carriers remain poorly understood. Emerging evidence suggests that neuroinflammation and glymphatic dysfunction may interact and play key roles in the pathological cascade leading to neurodegeneration. This study aimed to investigate potential glymphatic and/or inflammatory dysfunction in FMR1 premutation carriers with FXTAS using the diffusion tensor imaging analysis along the perivascular space (DTI-ALPS) index, as well as gene expression and functional enrichment analyses in individuals with FXTAS versus controls. Methods We analyzed the DTI-ALPS index in 14 participants with FXTAS and 25 age- and sex-matched controls, and assessed the expression and pathway dysregulation of genes related to neuroinflammation and glymphatic function using Reactome analysis in postmortem brain tissue from 3 individuals with FXTAS and 12 controls and skin fibroblasts from 6 individuals with FXTAS and 3 controls. Results The DTI-ALPS index was significantly lower in individuals with FXTAS compared to controls in the right but not left hemisphere ( p = 0.0051) and globally in both hemispheres ( p = 0.0473). There was no correlation between lower DTI-ALPS index and increasing CGG repeat length but a trend was observed in males. Reactome analysis revealed downregulation of aquaporin-mediated transport in brain tissue and fibroblasts, upregulation of multiple immune-related and inflammatory pathways, predominantly in brain tissue, and increased circadian-related pathway activity in fibroblasts. Discussion Our findings point at glymphatic system dysfunction and neuroinflammation in FXTAS pathophysiology, as evidenced by in vivo DTI-ALPS metrics and gene pathway dysregulation and expression in fibroblasts and in postmortem FXTAS brains.
Elias-Mas et al. (Thu,) studied this question.