Pattern of structural and functional brain abnormalities in asymptomatic granulin mutation carriers

Area of Science:

• Neuroimaging
• Genetics
• Neurology

Background:

• Investigating presymptomatic changes in GRN mutation carriers.
• Understanding early brain alterations in genetic neurodegenerative diseases.

Purpose of the Study:

• To identify brain atrophy, white matter (WM) tract changes, and functional connectivity (FC) abnormalities in asymptomatic GRN mutation carriers.
• To detect early neuroimaging markers for GRN-associated neurodegeneration.

Main Methods:

• Structural, diffusion tensor, and resting-state functional MRI in 10 cognitively normal subjects (5 GRN+ carriers, 5 GRN- noncarriers).
• Cortical thickness analysis for atrophy, tract-based spatial statistics for WM abnormalities, and independent component analysis for FC.
• Assessment conducted 12±7 years before estimated disease onset.

Main Results:

• GRN+ carriers exhibited reduced cortical thickness in specific frontal regions (right orbitofrontal, precentral gyrus; left rostral middle frontal gyrus).
• WM abnormalities in GRN+ included increased axial diffusivity in the right cingulum, superior longitudinal fasciculus, and corticospinal tract.
• No significant differences in resting-state functional connectivity were observed between groups.

Conclusions:

• Brain atrophy and WM tract abnormalities in frontal-parietal circuits are detectable in asymptomatic GRN mutation carriers.
• These neuroimaging changes precede estimated symptom onset by at least a decade, indicating early disease pathology.