Brain Imaging Phenotypes Associated with Polygenic Risk for Essential Tremor.

Area of Science:

• Neuroscience
• Genetics
• Medical Imaging

Background:

• Essential tremor (ET) is a prevalent movement disorder with a significant genetic component.
• Current understanding of how genetic predisposition leads to ET pathogenesis is limited.
• Brain imaging techniques like MRI have identified structural abnormalities in ET patients.

Purpose of the Study:

• To investigate presymptomatic brain vulnerabilities associated with essential tremor genetic risk.
• To explore the relationship between ET polygenic risk scores (PRS) and brain structural/microstructural differences in healthy individuals.
• To identify early neurobiological markers of ET susceptibility.

Main Methods:

• Utilized data from approximately 30,000 UK Biobank participants.
• Analyzed associations between ET-PRS and diffusion-weighted MRI (dMRI) and T1 MRI metrics (morphometry, white/grey matter microstructure).
• Included secondary analysis comparing low PRS individuals with a small cohort of ET patients.

Main Results:

• Significant associations found between ET-PRS and white matter integrity (mean diffusivity, fractional anisotropy, etc.) in motor control pathways.
• ET-PRS correlated with grey matter microstructure in key areas like the red nucleus, caudate, putamen, and motor thalamus.
• Reduced grey matter volumes were observed in ET-PRS individuals, particularly in the cerebellum and other cortical/subcortical regions. Structural anomalies mapped to networks relevant to ET surgical treatments.

Conclusions:

• High genetic risk for ET is linked to structural brain vulnerabilities, including white and grey matter alterations, even in asymptomatic individuals.
• These findings suggest that genetic factors can disrupt brain networks relevant to ET pathology before the onset of clinical symptoms.
• Identified brain structural changes in at-risk individuals may serve as early indicators of ET development.