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

INTRODUCTION Intrinsic functional connectivity network abnormalities in C9orf72 hexanucleotide repeat expansion carriers emerge during the asymptomatic phase, yet longitudinal studies remain limited. We examined cross‐sectional abnormalities and longitudinal connectivity changes across clinical stages. METHODS We analyzed task‐free functional magnetic resonance imaging (fMRI) and structural MRI data in 36 asymptomatic (aSxC9), 17 prodromal (proC9), and 29 symptomatic (SxC9) carriers, and 107 healthy controls (HCs). Functional networks previously found altered in C9orf72 , including salience, sensorimotor, default mode, and medial pulvinar thalamic networks, were examined. Associations between longitudinal connectivity and gray matter decline with baseline neurofilament light chain (NfL) concentrations and symptom severity were assessed. RESULTS aSxC9 and SxC9 showed longitudinal connectivity changes within specific networks. In aSxC9, connectivity changes correlated with baseline NfL. In proC9 and SxC9, changes in connectivity and gray matter were associated with baseline NfL and symptom severity. DISCUSSION C9orf72 expansion carriers demonstrate stage‐specific network connectivity changes.