Longitudinal functional network connectivity changes across the clinical stages of C9orf72 hexanucleotide repeat...

Area of Science:

• Neuroscience
• Genetics
• Neurology

Background:

• Abnormalities in intrinsic functional connectivity networks are present in C9orf72 hexanucleotide repeat expansion carriers during the asymptomatic phase.
• Longitudinal studies investigating these changes across different clinical stages are limited.

Purpose of the Study:

• To examine cross-sectional and longitudinal functional connectivity changes in C9orf72 carriers across asymptomatic, prodromal, and symptomatic stages.
• To assess associations between longitudinal connectivity changes, gray matter decline, baseline neurofilament light chain (NfL) concentrations, and symptom severity.

Main Methods:

• Analysis of task-free fMRI and structural MRI data from 36 asymptomatic (aSxC9), 17 prodromal (proC9), and 29 symptomatic (SxC9) C9orf72 carriers, alongside 107 healthy controls (HC).
• Focused examination of functional networks previously identified as altered in C9orf72 carriers, including salience, sensorimotor, default mode, and medial pulvinar thalamic networks.
• Assessment of correlations between longitudinal connectivity and gray matter changes with baseline NfL and symptom severity.

Main Results:

• Longitudinal connectivity changes were observed in specific networks in asymptomatic (aSxC9) and symptomatic (SxC9) carriers, despite no detectable gray matter decline.
• In asymptomatic carriers (aSxC9), connectivity changes correlated with baseline NfL concentrations.
• In prodromal (proC9) and symptomatic (SxC9) carriers, alterations in connectivity and gray matter were associated with both baseline NfL and symptom severity.

Conclusions:

• C9orf72 expansion carriers exhibit stage-specific longitudinal changes in network connectivity.
• These findings highlight the potential of task-free fMRI for tracking disease progression from the asymptomatic stage onwards.
• Further research is needed to establish phenotype- and stage-specific connectivity trajectories in C9orf72 carriers.