Modelling pathological spread through the structural connectome in the frontotemporal dementia clinical spectrum

The ability to predict the spreading of pathology in patients with frontotemporal dementia (FTD) is crucial for early diagnosis and targeted interventions. In this study, we examined the relationship between network vulnerability and longitudinal progression of atrophy in FTD patients, using the network diffusion model (NDM) of the spread of pathology. Thirty behavioural variant FTD (bvFTD), 13 semantic variant primary progressive aphasia (svPPA), 14 non-fluent variant primary progressive aphasia (nfvPPA) and 12 semantic behavioural variant FTD (sbvFTD) patients underwent longitudinal T1-weighted MRI. Fifty young controls (20-31 years of age) underwent multi-shell diffusion MRI scan. An NDM was developed to model progression of FTD pathology as a spreading process from a seed through the healthy structural connectome, using connectivity measures from fractional anisotropy and intracellular volume fraction in young controls. Four disease epicentres were initially identified from the peaks of atrophy of each FTD variant: left insula (bvFTD), left temporal pole (svPPA), right temporal pole (sbvFTD) and left supplementary motor area (nfvPPA). Pearson's correlations were calculated between NDM-predicted atrophy in young controls and the observed longitudinal atrophy in FTD patients over a follow-up period of 24 months. The NDM was then run for all 220 brain seeds to verify whether the four epicentres were among those that yielded the highest correlation. Using the NDM, predictive maps in young controls showed progression of pathology from the peaks of atrophy in svPPA, nfvPPA and sbvFTD over 24 months. svPPA exhibited early involvement of the left temporal and occipital lobes, progressing to extensive left hemisphere impairment. nfvPPA and sbvFTD spread in a similar manner bilaterally to frontal, sensorimotor and temporal regions, with sbvFTD additionally affecting the right hemisphere. Moreover, the NDM-predicted atrophy of each region was positively correlated with longitudinal real atrophy, with a greater effect in svPPA and sbvFTD. In bvFTD, the model starting from the left insula (the peak of atrophy) demonstrated a highly left-lateralized pattern, with pathology spreading to frontal, sensorimotor, temporal and basal ganglia regions, with minimal extension to the contralateral hemisphere by 24 months. However, unlike the atrophy peaks observed in the other three phenotypes, the left insula did not show the strongest correlation between the estimated and real atrophy. Instead, the bilateral superior frontal gyrus emerged as optimal seeds for modelling atrophy spread, showing the highest correlation ranking in both hemispheres. Overall, NDM applied on the intracellular volume fraction connectome yielded higher correlations relative to NDM applied on fractional anisotropy maps. The NDM implementation using the cross-sectional structural connectome is a valuable tool to predict patterns of atrophy and spreading of pathology in FTD clinical variants.