Bridging the clinicopathological gap in the frontotemporal dementia spectrum

Frontotemporal dementia (FTD) is a currently incurable neurodegenerative disease comprising a spectrum of clinical syndromes and underlying neuropathologies. Each neuropathology is characterized by the accumulation of a specific protein (tau, TDP-43) in the brain, which cannot be easily detected during life nor predicted by clinical syndromes, hampering proper disease diagnosis. This thesis contributes to bridging this diagnostic gap by studying brain tissue from patients with FTD who underwent autopsy, and blood biomarkers in families carrying genetic variants associated with FTD. First, through pathological studies, we find that the two main underlying neuropathologies, TDP-43 and tau, show a different regional distribution in the brains of patients with FTD. Next, in a specific subtype of tau pathology, that associated with MAPT genetic variants, we observe a strongly heterogeneous pathological profile, in part explained by the biochemical structure of tau aggregates. Moreover, we find evidence of iron accumulation, associated with neuroinflammation, in two different subtypes of FTD (with MAPT and C9orf72 genetic variants), and we uncover neurovascular dysfunction as a core disease mechanism in TDP-43 pathology associated with GRN genetic variants. Finally, we study blood biomarkers suggestive of brain neurodegeneration. We find that the protein neurofilament light chain (in short, NfL) is helpful to diagnose the early (prodromal) stage of genetic FTD, and we identify altered methylation of cell-free DNA as a potential presymptomatic marker of neuronal death.