Frontotemporal degeneration (FTD) is an understudied clinical neurodegenerative condition even though it is the most common cause of dementia after Alzheimer?s disease (AD) in people <65 years old. The most common frontotemporal lobar degeneration (FTLD) pathology associated with FTD is TDP-43 proteinopathy known as FTLD-TDP. Although rare mutation carriers can be identified who have FTLD-TDP pathology during life, there are no known biomarkers for the vast majority of FTD patients with sporadic disease that can reliably distinguish patients with FTLD-TDP histopathology from those with FTLD-Tau pathology, nor from patients who present with clinical FTD but are atypical variants of pathological AD. This has resulted in major gaps in knowledge that severely limit our understanding of TDP-43-associated pathophysiology, significantly constrain the development of disease-modifying treatment trials, and severely impede designing clinical end-points to follow for prognosis and for treatment trials. It is thus necessary to collect data that help define the specific pathologic form of FTLD during life more accurately, and relate these data to imaging, biofluid biomarker, genetic and autopsy data studied in this PPG. Moreover, disease-modifying treatment trials require well- characterized natural histories of phenotypes related to FTLD-TDP in order to identify clinical markers indicating a beneficial treatment response. The Clinical Core will work with other cores and projects to improve our understanding of the TDP-related degeneration of multilevel neural networks examined in this Program Project Grant (PPG). To these ends, we will recruit patients with sporadic clinical FTD who have a high likelihood of having FTLD-TDP pathology such as semantic variant Primary Progressive Aphasia (svPPA), behavioral variant FTD (bvFTD) co-occurring with svPPA, PPA and bvFTD with co-occurring amyotrophic lateral sclerosis (ALS). We will also recruit symptomatic carriers of mutations associated with FTLD such as PGRN and C9orf72. We will assess these cases annually with a brief but comprehensive neuropsychological battery, recruit cases for imaging and biofluid studies, and recruit cases for autopsy. We propose four Specific Aims to achieve these goals.
