Functional Connectivity From Disease Epicenters in Frontotemporal Dementia

Background and objectives: MRI connectomics is an ideal tool to test a network-based model of pathological propagation from a disease epicenter in neurodegenerative disorders. Here, we used a novel graph-theory-based MRI paradigm to explore functional connectivity reorganization, discerning between direct and indirect connections from disease epicenters, and its relationship with neurodegeneration across clinical presentations of the frontotemporal dementia (FTD) spectrum, including behavioral variant of FTD (bvFTD), non-fluent (nfvPPA) and semantic variants of primary progressive aphasia (svPPA). Methods: In this observational, cross-sectional study, disease epicenters were defined as the peaks of atrophy of a cohort of patients with high confidence of FTLD pathology (Mayo Clinic). These were used as seed regions for stepwise functional connectivity (SFC) analyses in an independent (Milan) set of FTD patients, to assess connectivity in regions directly and indirectly connected to the epicenters. Correlations between SFC architecture in healthy conditions and atrophy patterns in FTD patients were also tested. Results: As defined by comparing the 42 Mayo Clinic patients with 15 controls, disease epicenters were the left anterior insula for bvFTD, left supplementary motor area for nfvPPA, and left inferior temporal gyrus (ITG) for svPPA. Compared with 94 age-matched controls, bvFTD (n=64) and nfvPPA patients (n=34) of the Milan cohort showed widespread decreased SFC in bilateral cortical regions with direct/indirect connections with epicenters, and increased SFC either in directly connected regions, physically close to the respective seed region, or in more distant cortical/cerebellar areas with indirect connections. Across all link-steps, svPPA (n=36) showed SFC decrease mostly within the temporal lobes, with co-occurrent SFC increase in cerebellar regions at indirect link-steps. Average stepwise topological distance from the left ITG in a reference group of 50 young healthy controls correlated with regional grey matter volume in svPPA, consistent with network-based degeneration. Discussion: Our findings demonstrate that each FTD syndrome is associated with a characteristic interplay of decreased and increased functional connectivity with the disease epicenter, affecting both direct and indirect connections. SFC revealed novel insights regarding the topology of functional disconnection across FTD syndromes, holding the promise to be used to model disease progression in future longitudinal studies.