Project 2

Mayo Clinic Rochester, Rochester MN

Investigators

Linked publications & trials

Abstract

ABSTRACT – ALLFTD2: PROJECT 2 Approximately 70% of FTLD cases are sporadic (s-FTLD) and have no clear genetic or other identifiable cause. Like familial FTLD (f-FTLD), s-FTLD is uniformly fatal and there are no approved treatments. The most common s-FTLD syndrome is sporadic behavioral variant frontotemporal dementia (s-bvFTD), accounting for at least half of all FTLD cases (including familial). Over the past five years, numerous disease-modifying drug development programs have begun for f-FTLD, but none in s-bvFTD. This is because the underlying pathology and biological mechanisms of disease are currently unknowable in most s-bvFTD patients during life. Moreover, the limited tools to measure clinical features of disease and biomarkers outside expert tertiary referral centers leads to delayed diagnosis, often past the stage where many disease-modifying strategies would be predicted to be effective. This further complicates biomarker development and clinical trials due to the difficulty in obtaining high- quality longitudinal data at quarterly intervals that would be examined in 12-18 month trials because travel to research centers is a major barrier to data collection. The overall goal of this renewal project is to advance the ability to conduct precision s-bvFTD and other s-FTLD clinical trials, by building molecular pathology-specific disease progression models and more efficient assessment tools, leveraging advances that were made in f- FTLD during the current ALLFTD cycle. During the current ALLFTD cycle we built Bayesian disease progression models of the changes in biomarkers and clinical outcomes from presymptomatic through fully symptomatic disease in f-FTLD-TDP (C9orf72 or GRN) and f-FTLD-tau (MAPT). We also developed and validated a mobile smartphone app (mApp) and identified new candidate fluid biomarkers for FTLD-tau and -TDP in CSF and plasma using novel unbiased proteomic techniques. For this proposed project, we will leverage these advances, as well as new plasma extracellular vesicle (EV) biomarker measures to enable precision s-bvFTD trials. This research project will develop fluid biomarkers for diagnosis and prediction in s-FTLD pathologic subtypes and develop remotely collected digital assessments tailored for use in symptomatic s-FTLD syndromes. Importantly, the project will also build s-bvFTD±ALS disease progression models (DPMs) from more frequently collected data, informed by f-FTLD DPMs that will be critical for future biomarker discovery and improving early diagnosis. By accomplishing these goals, we will have a new set of tools to diagnose and monitor s-FTLD patients that will be useful both for clinical care and decentralized clinical trials that will be more feasible for the rare and geographically dispersed populations who are recruited for s-FTLD clinical trials.