Age-related functional brain changes in FMR1 premutation carriers.

Area of Science:

• Neuroscience
• Genetics
• Neurology

Background:

• The Fragile X premutation (FMR1) gene increases the risk of developing Fragile X-associated Tremor Ataxia Syndrome (FXTAS), a neurodegenerative disorder.
• FXTAS is characterized by late-onset progressive tremor, ataxia, and cognitive decline, potentially leading to dementia.
• It remains unclear if brain function alterations are detectable in motor areas before overt FXTAS symptoms manifest.

Purpose of the Study:

• To investigate for the first time, using functional magnetic resonance imaging (fMRI), whether asymptomatic FMR1 premutation carriers exhibit detectable changes in brain function related to motor tasks.
• To identify early neurodegenerative changes in motor regions that may precede the clinical diagnosis of FXTAS.

Main Methods:

• A cross-sectional study involving 17 asymptomatic FMR1 premutation carriers and 17 healthy male controls, aged 24-68.
• Utilized fMRI with a finger-tapping task (sequential, random, rest) to assess brain activation differences between groups.
• Collected molecular data (FMR1 mRNA levels) and clinical data (tremor, coordination, balance).

Main Results:

• Asymptomatic premutation carriers showed significantly reduced cerebellar activation compared to controls during a sequential versus random finger-tapping task.
• A significant age-by-group interaction was observed in the hippocampus, inferior parietal cortex, and temporal cortex.
• Brain activation showed a more negative relationship with age in carriers compared to controls, particularly in these regions.

Conclusions:

• This study provides the first functional imaging evidence of early, movement-related neurodegeneration in male carriers of the FMR1 premutation.
• These detected brain changes occur prior to the clinical onset of FXTAS.
• The findings suggest that these preclinical alterations may indicate vulnerability to developing FXTAS, especially in older carriers.