A neuropathological approach to the selective vulnerability of frontotemporal dementia.

Frontotemporal dementia (FTD) is a rare neurodegenerative disorder typically emerging between ages 40 and 65, characterized by significant clinical and pathological diversity. Both sporadic and familial forms exist, with specific genetic mutations predisposing individuals to distinct pathologies. Presently, symptomatic management remains the only available care as there's no curative therapy for FTD. Clinically, FTD often manifests with social cognitive decline, including personality and behavioural changes, alongside speech impairments, word-finding difficulties, and surface dyslexia. Neuropsychiatric symptoms such as psychosis, depression, and hallucinations are also common, especially in the behavioural variant of the disease. Pathologically, FTD is marked by degeneration in the frontal and temporal cerebral lobes, termed frontotemporal lobar degeneration (FTLD). Different protein aggregations in the brain, including phosphorylated TDP-43, tau, or FUS, define various subtypes of FTLD. Major genetic mutations associated with FTD include C9orf72, GRN, and MAPT. Neuroimaging studies offer insights into brain degeneration patterns in FTD, yet predicting underlying pathologies based on clinical presentation remains challenging. Recent recognition of neuropsychiatric symptoms as early FTD indicators prompts further investigation into their correlation with underlying pathology. At the cellular level, von Economo neurons (VENs) and GABRQ-expressing pyramidal neurons are implicated in FTD's behavioural changes. Research suggests selective vulnerability of these neurons, particularly in the anterior cingulate cortex (ACC), though correlations with specific FTD subtypes remain unclear. This thesis investigates the relationship between clinical symptoms and region-specific pathology in FTD, finding potential indicators for distinguishing underlying pathologies. Additionally, it explores the correlation between neuropsychiatric symptoms and brain pathology, revealing associations suggesting broader roles for certain proteins beyond primary pathology. Further examination of VENs and GABRQ-expressing neurons in different FTD subtypes demonstrates their involvement in modulating behaviour, particularly in FTD cases with TDP-43 and FUS pathology. These findings underscore the potential diagnostic and therapeutic implications of understanding these neuronal populations in FTD. Investigations into cellular mechanisms activated in vulnerable neurons suggest responses aimed at restoring protein homeostasis, namely UPR and GVD markers, particularly in cases with dipeptide pathology. This research offers insights into potential diagnostic markers and therapeutic targets for FTD. Overall the results of this thesis support the growing evidence for the inclusion of the neuropsychiatric symptoms, hallucinations, mania and delusions to be included in the standardised diagnostic criteria for FTD. Including these key symptoms would not only improve clinical diagnostic accuracy but could also provide an opportunity to diagnose patients earlier in their disease course and in turn provide the correct care, support and future medication. In addition, we have established that VENs are part of a larger neuronal population which provides more opportunity for research. This thesis strengthens the hypothesis that the GABRQ-expressing pyramidal neurons and VENs are involved in modulating behaviour in FTD patients with TDP-43 and FUS pathology. This, together with biomarker studies, could provide a potential means of distinguishing bvFTD patients with tau pathology from those with TDP-43 or FUS pathology in clinics.