Neurodevelopmental brain reserve in behavioural variant Frontotemporal Dementia

Background: Behavioural variant Frontotemporal Dementia (bvFTD) is an early-onset dementia characterised by early anterior cingulate (AC) neuropathological insult. The AC exhibits high morphological heterogeneity, which may be classified according to the presence of a paracingulate sulcus (PCS), a tertiary sulcus that, when present, develops during the third gestational trimester and thereafter remains stable throughout life.
Aim: This thesis examines the role of the PCS in bvFTD, focusing on its prevalence and disease-specific associations with age at onset (AAO), disease progression, and survival. Furthermore, it aims to explore the impact of PCS presence on cerebral
structural and functional connectivity.
Results: Hemispheric PCS frequencies in both sporadic and genetic bvFTD were similar to those of healthy individuals. Presence of a right PCS was associated with a later AAO, an accelerated rate of disease progression and reduced survival following AAO in sporadic bvFTD. In genetic bvFTD, possession of a right PCS was associated with a later AAO in GRN but not C9orf72 or MAPT mutation carriers. In a sub-group of GRN mutation carriers accelerated early disease progression after AAO was observed in individuals possessing a right PCS. In healthy individuals, we identified an association between left PCS presence and altered structural and functional connectivity.
Conclusion: Whilst PCS presence is not a risk factor for the development of bvFTD, this thesis provides evidence that right PCS presence modifies disease expression, progression, and survival in this disease. As such, within the reserve framework, right PCS presence represents the first proxy of brain reserve in frontotemporal dementia. These findings establish a novel association between intrauterine neurodevelopment and the expression of a neurodegenerative disease – an insight with potential implications for future clinical trials in bvFTD. Finally, this thesis describes a novel link between structure and function and provides a plausible explanation of how cognitive advantages associated with paracingulate sulcal presence may be mediated by a highly connected local functional network reliant on short association fibres.