Pathology-guided biofluid biomarker strategies for classification and progression of frontotemporal lobar degeneration (FTLD) - Project Abstract Frontotemporal lobar degeneration (FTLD) is a family of neurodegenerative proteinopathies with no treatment to cure or slow disease progression. Clinical trials for FTLD are hamstrung by the limited biomarkers in cerebrospinal fluid (CSF) or plasma for screening or prognosis of FTLD, due in part to the extensive clinical and pathological heterogeneity in FTLD. There are no in vivo biomarkers to classify the two major pathological forms of FTLD: FTLD due to tau (FTLD-tau) or TAR DNA-binding protein of 43 kDa (TDP-43; FTLD-TDP). Both FTLD-tau and FTLD-TDP can be sporadic or due to pathogenic mutations, and both subtypes are associated with several cognitive and motor syndromes which cannot reliably indicate underlying pathology. This heterogeneity, combined with the lack of FTLD biomarkers, means a biological study of the full spectrum of FTLD requires autopsy-confirmation, but these data are very rare. We propose a pathologically-grounded study of biofluid biomarkers in autopsy- and genetically-confirmed FTLD-tau and FTLD-TDP. Our clinical translational goal is to develop multi-analyte algorithms for screening and prognosis of FTLD. We leverage the unique FTLD cohort at University of Pennsylvania composed of >200 pathology-confirmed FTLD-tau and FTLD-TDP with banked CSF and plasma, as well as antemortem genetic, clinical, demographic, and neuroimaging data. We compare biomarkers in FTLD to healthy controls and autopsy- confirmed Alzheimer's disease (AD), a related proteinopathy. In lieu of FTLD-specific biomarkers, we test biofluid markers of disease processes central to FTLD pathogenesis: neurodegeneration (e.g., neurofilament light chain, total tau), neuroinflammation (e.g., glial fibrillary acidic protein, chitinase-3-like protein 1), and synaptic dysfunction (e.g., neuronal pentraxin-2, neurogranin). Advantages are that these biomarkers are analytically validated, can be precisely measured in CSF and plasma using high-sensitivity immunoassays, and preliminary data indicate their high potential to inform and track FTLD biology. Our study would be first to combine these biomarkers in autopsy-confirmed FTLD, to test their association with neuropathology, and to test changes over disease course. Findings will advance our understanding of FTLD biology and how pathogenesis differs across tau and TDP-43 molecular forms, and will expand the diagnostic and prognostic FTLD biomarker toolkit. Aim 1: Pathologically validate biomarkers in FTLD subtypes using autopsy and digital-histopathology data, compared to AD and controls. Test hypothesized direct and indirect effects with FTLD pathophysiology. Aim 2: Map the pathogenic disease cascades in FTLD subtypes by tracking the natural history of biomarker dynamics; use disease progression modeling to sequence biomarker abnormalities in FTLD. Aim 3: Develop multi-analyte algorithms to provide a differential diagnosis (FTLD vs. AD and controls, FTLD-tau vs. FTLD-TDP) and to estimate prognosis in FTLD; we ensure that our algorithms will generalize by verifying accuracy in an independent replication sample, using data from the multi-site ALLFTD consortium.
