Frontotemporal dementia (FTD) is a heterogeneous neurodegenerative disorder, comprising a spectrum of subtypes that are different on the clinical, genetic and pathological level. Clinically, symptoms typically present before the age of 65 and include behavioural and/or language disturbances, yet also motor problems frequently occur. FTD can be heritable, and 10-20% of the patients have an autosomal dominant form, which is most frequently caused by a mutation in granulin (GRN, also known as progranulin), in microtubule-associated protein tau (MAPT), or a repeat expansion in chromosome 9 open reading frame 72 (C9orf72). Pathological examination shows frontotemporal lobar degeneration (FTLD) with inclusions of either TAR DNA-binding protein 43 (FTLD-TDP), tau (FTLD-tau), or FET (fused in sarcoma, Ewing’s sarcoma and TAT-binding protein-associated factor 15).
Currently, major advances are being made to develop therapeutic interventions for FTD. However, the heterogeneity of this disorder hampers the diagnostic process, tracking of disease progression, and the appropriate selection of patients for clinical trials. Reliable biomarkers are therefore critically needed. This thesis investigated the utility of biomarkers in cerebrospinal fluid (CSF) and blood, so-called fluid biomarkers, across the entire FTD spectrum. The thesis has shown that NfL is a promising biomarker in CSF and in blood across the entire FTD spectrum, both in sporadic and genetic forms. NfL levels are higher in patients than controls and can thus be used to ascertain disease. Also, NfL could monitor disease severity and progression and predicts survival – valuable information for the individual patient – in most subtypes within the FTD spectrum, except for svPPA. To select patients on underlying proteinopathy, the p/t-tau ratio may be useful being decreased in FTLD-TDP versus FTLD-tau, but more discriminative markers are needed. Our CSF proteomics study in GRN mutations identified potential novel biomarkers and provides knowledge of the pathophysiology of GRN mutations. Lastly, for FTD caused by GRN mutations or C9orf72 repeat expansions, PGRN and poly(GP) respectively identify mutation carriers and are target engagement markers for clinical trials that are underway. Our results facilitate the implementation of these biomarkers for clinical or research purposes, and provide additional understanding of the pathophysiological process underlying FTD, opening new avenues towards treating FTD.