Clinicopathological associations in frontotemporal dementia

The clinicopathological heterogeneity of frontotemporal dementia (FTD) currently precludes an accurate diagnosis, which in turn impacts the identification of biomarkers for targeted therapeutics. Revised diagnostic criteria now recognise four clinical phenotypes, including the behavioural variant FTD, and three primary progressive aphasia variants (semantic, non-fluent and logopenic). Frontotemporal lobar degeneration (FTLD) encompasses the major pathological substrates of these clinical syndromes, although a one to one clinicopathological match is rare. This issue is further compounded by the presence of alternate pathological as well as clinical syndromes such as Alzheimer’s disease (AD), which contaminate the clinical and pathological cohorts of FTD/FTLD. In this thesis, a large cohort of neuropathologically-ascertained FTD cases was assessed from a clinically relevant standpoint in order to understand the aspects that contribute to this heterogeneity and subsequently simplify the complicated picture of this spectrum of diseases. The background of FTD and associated disorders is covered in Chapter 1, followed by the general experimental design used (Chapter 2). Chapter 3 validated the updated clinical diagnostic criteria for the four variants of FTD, and Chapter 4 followed on from these findings to identify discriminatory features between these syndromes as well as those with clinical FTD but atypical pathology (AD). Chapter 5 identified clearly separable clinicopathological entities and assessed the presence of a clinical continuums within the major pathological FTLD groups, tau and TDP. The results of Chapter 6 found a set of further clinical features that assist in discriminating FTD mimics; vascular risk factors identify pathological AD in clinical FTD cohorts and family history and genetic factors assist in anticipating pathological FTLD in clinical AD cohorts.The detailed analysis of the clinical and pathological heterogeneity that underlies the FTD spectrum of diseases studied in this thesis will facilitate early and accurate diagnoses. Furthermore, the novel approach in clinicopathological assessments of this disease, clarify the complex pathological basis of this disease and will be beneficial for directing future biomarker studies for therapeutics