Putative mitochondrial components of frontotemporal lobar degeneration: topological correlations between...

Frontotemporal lobar degeneration encompasses a spectrum of clinically, radiologically, and molecularly heterogeneous conditions. Clinical phenotypes are defined based on predominant neuropsychological manifestations and the selective involvement of specific brain regions determines the core symptoms, disability profiles, and care needs. While the unique anatomical patterns of cortical and subcortical degeneration along the FTLD/FTD spectrum are well recognised, the molecular basis of this selective vulnerability remains unclear.

A large prospective neuroimaging study has been undertaken to explore topological associations between phenotype-specific atrophy patterns and physiological mitochondrial density along the FTLD/FTD spectrum. Patients with behavioural variant FTD (bvFTD), nonfluent variant primary progressive aphasia (nfvPPA), semantic variant primary progressive aphasia (svPPA), C9orf72-positive ALS-FTD, C9orf72-negative ALS-FTD, and a cohort of healthy controls (HC) were included. FTD phenotypes were first contrasted to healthy controls and the resulting voxelwise maps were correlated to physiological mitochondrial density maps.

We have identified voxelwise associations between atrophic change and physiological mitochondrial density. The resulting correlation coefficients over the entire GM mask revealed weak topological associations with r = 0.217 in C9NEG ALS-FTD, r = 0.251 in C9POS ALS-FTD, r = 0.213 in bvFTD, r = 0.182 in nfvPPA, and r = 0.292 in svPPA at p _FWE < 0.001. Our region-of-interest analyses revealed moderate-to-strong regional associations between mitochondrial density and focal degenerative change with r values above 0.65 in multiple brain regions in all five FTD subgroups. Brain regions exhibiting the most significant associations between volume loss and mitochondrial density in each FTD subgroup are the very regions that define the core clinical manifestations of the given phenotype.

Cortical and subcortical brain regions with high physiological mitochondrial density are particularly vulnerable to neurodegenerative change in FTD. While these anatomical associations do not indicate direct causation, mitochondrial metabolism may represent an important component in the cascade of focal degeneration.