PhD defence L. (Lucia) Giannini

Below is a brief summary of the dissertation

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 improving the diagnosis of FTD 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. However, even within the same neuropathology, we observe heterogeneous pathological profiles, such as in tau pathology associated with MAPT genetic variants. Moreover, we find evidence of iron accumulation, associated with inflammation in the brain, in two different genetic subtypes of FTD (with variants in the MAPT and C9orf72 genes), and we uncover a dysfunction of the brain vasculature as a core disease mechanism in TDP-43 pathology, associated with genetic variants in the GRN gene. Finally, we study blood biomarkers suggestive of neuronal loss. We find that the protein neurofilament light chain (in short NfL) is helpful to diagnose the early stage of genetic FTD, and we identify altered methylation of cell-free DNA as a potential marker of neuronal death before the onset of symptoms.