Functional Connectivity Associations With Markers of Disease Progression in GRN Pathogenic Variant Carriers

Area of Science:

• Neuroscience
• Genetics
• Neurology

Background:

• Autosomal dominant progranulin (GRN) variants cause frontotemporal lobar degeneration.
• Biomarkers are needed to predict symptom onset and track disease progression in GRN carriers.
• Previous work showed age-related thalamocortical hyperconnectivity in asymptomatic GRN carriers.

Purpose of the Study:

• To investigate the relationship between functional connectivity and neurodegenerative markers in GRN variant carriers.
• To determine if hyperconnectivity precedes or coincides with markers of neurodegeneration.

Main Methods:

• Used T1 and resting-state fMRI in 49 asymptomatic and 26 symptomatic GRN carriers.
• Assessed functional connectivity using voxelwise whole-brain degree.
• Correlated connectivity with plasma neurofilament light chain, CSF complement levels, OCD severity, and gray matter volume.

Main Results:

• In asymptomatic carriers, neurofilament light chain correlated with hyperconnectivity and reduced gray matter in specific regions.
• Symptomatic carriers showed atrophy in regions associated with hyperconnectivity and complement levels.
• Obsessive-compulsive disorder severity linked to hypoconnectivity across all carriers.

Conclusions:

• Co-occurrence of hyperconnectivity, high neurofilament light chain, and low gray matter in asymptomatic carriers suggests impending clinical decline.
• Functional hyperconnectivity may serve as a biomarker for approaching symptomatic onset in GRN-related frontotemporal dementia.