Functional Connectivity Moderates the Impact of Synaptic Loss on Behaviour in Frontotemporal Lobar Degeneration Syndromes

AbstractBackgroundThere is growing evidence for early and extensive synaptic loss in frontotemporal lobar degeneration syndromes from in vivo and post‐mortem studies. We proposed that synaptic loss would affect behaviour, in relation to changes in functional connectivity.MethodWe recruited 29 participants with progressive supranuclear palsy, 16 participants with amyloid‐negative corticobasal syndrome, 8 participants with behavioural variant frontotemporal dementia and 24 similarly‐aged healthy volunteers. All participants underwent resting‐state functional 3T MRI and positron emission tomography with [11C]UCB‐J, that binds synaptic vesicle 2A. We compared the connectivity metrics of nodal weighted degree and voxelwise regional homogeneity with [11C]UCB‐J non‐displaceable binding potential (BPND), in associative and commonality analyses. We then used independent component analysis to extract [11C]UCB‐J BPND signal variance across participants, followed by derivation of participant‐specific scores of functional spatial covariance with the [11C]UCB‐J components. We applied model selection to assess whether connectivity scores would improve prediction of and moderate the effect of synaptic loss on clinical severity.ResultReduced [11C]UCB‐J BPND was associated with reduced connectivity, with synaptic density predicting both measures of connectivity over and above grey matter volume (Figure 1). The anatomical distribution of synaptic loss partially overlapped in PSP, bvFTD and CBS, but there were also disease‐specific effects (Figure 2). The effect of synaptic loss on functional connectivity was expressed local to the regions of severe synaptic loss, and in remote regions. Moreover, functional connectivity explained additional variance and moderated the relationship between synaptic density and clinical severity (Figure 3).ConclusionIn vivo synaptic loss is associated with reduced connectivity, and changes in behaviour, with implications for modelling disease pathogenesis and translational studies.