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

INTRODUCTIONIntrinsic 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. METHODSWe analyzed task-free fMRI and structural MRI data in 36 asymptomatic (aSxC9), 17 prodromal (proC9), and 29 symptomatic (SxC9) carriers, and 107 healthy controls (HC). 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. RESULTSDespite lacking detectable gray matter decline, 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. DISCUSSIONC9orf72 expansion carriers demonstrate stage-specific network connectivity changes. Highlights- Stage-specific longitudinal connectivity changes were detected in C9orf72. - Compared to controls, each C9orf72 cohort lacked detectable gray matter decline. - For aSxC9, connectivity network changes correlated with baseline NfL. - Connectivity/GM changes in proC9 and SxC9 correlate with NfL and symptom severity. Research in ContextSystematic review: The authors conducted a systematic review using major databases (e.g., PubMed and Google Scholar). While cross-sectional studies have investigated functional connectivity patterns in C9orf72 expansion carriers (C9orf72), longitudinal studies are scarce. Notably, no study has examined longitudinal functional connectivity changes during the prodromal stage, a critical transition stage from the asymptomatic to symptomatic phases, which was included in this study. Interpretation: Leveraging a large longitudinal neuroimaging cohort of C9orf72, we comprehensively characterized stage-specific connectivity changes in asymptomatic, prodromal and symptomatic carriers. Associations between longitudinal connectivity, and neurodegeneration and symptom severity highlight the potential of task-free fMRI for tracking disease progression during each clinical stage. Future directions: This study lays important groundwork for tracking disease progression as early as the asymptomatic stage. Future research should establish phenotype- and stage-specific connectivity trajectories in carriers who convert to advanced stages or develop distinct C9orf72-associated syndromes.