Glymphatic dysfunction and neuroinflammation in FXTAS: evidence from DTI-ALPS and gene expression analysis

Area of Science:

• Neuroscience
• Genetics
• Biomedical Imaging

Background:

• Fragile X-associated tremor/ataxia syndrome (FXTAS) is a late-onset neurodegenerative disorder in FMR1 premutation carriers.
• Mechanisms of FXTAS susceptibility are poorly understood, with emerging evidence implicating neuroinflammation and glymphatic dysfunction.
• This study investigates glymphatic and inflammatory pathways in FXTAS.

Purpose of the Study:

• To assess glymphatic function in FMR1 premutation carriers with FXTAS using the diffusion tensor imaging analysis along the perivascular space (DTI-ALPS) index.
• To analyze gene expression and pathway dysregulation related to neuroinflammation and glymphatic function in FXTAS.
• To explore the interplay between glymphatic dysfunction and neuroinflammation in FXTAS pathophysiology.

Main Methods:

• Diffusion tensor imaging analysis along the perivascular space (DTI-ALPS) was performed on 14 FXTAS participants and 25 controls.
• Gene expression and Reactome pathway analysis were conducted on postmortem brain tissue and skin fibroblasts from FXTAS individuals and controls.
• Analysis focused on genes associated with neuroinflammation and glymphatic function.

Main Results:

• A significantly lower DTI-ALPS index was observed in FXTAS individuals compared to controls, indicating impaired glymphatic function.
• Gene expression analysis revealed downregulation of aquaporin-mediated transport and upregulation of immune/inflammatory pathways in FXTAS.
• Increased circadian-related pathway activity was noted in fibroblasts from FXTAS individuals.

Conclusions:

• The study provides evidence for glymphatic system dysfunction and neuroinflammation in FXTAS.
• DTI-ALPS metrics and gene pathway dysregulation in brain tissue and fibroblasts support these findings.
• These results highlight potential therapeutic targets for FXTAS.