Human Retinal Imaging Biomarkers for FTLD-Tau in Relation to FTLD-TDP and Nonamnestic AD

University Of Pennsylvania, Philadelphia PA

Investigators

Abstract

Project Summary/Abstract Frontotemporal degeneration (FTD) is a progressive neurodegenerative condition as common as Alzheimer’s Disease (AD) in those 65 and younger. There are no FDA approved medications for FTD, and development of therapies is severely limited by the absence of adequate biomarkers for the causative pathology. Most cases of FTD are caused by abnormalities related to the protein tau (FTLD-Tau) or the protein TAR DNA binding protein – 43 (FTLD-TDP). However, it can be difficult to determine prior to autopsy which patients have abnormalities from tau versus those with abnormalities from TDP-43. Furthermore, it can be difficult to distinguish prior to autopsy those patients with FTD from those with nonamnestic AD (naAD). Clinical trials testing therapies aimed at the underlying molecular causes of FTD are hindered by the problem of clinically distinguishing FTLD-Tau, FTLD-TDP, and naAD. For these reasons, there is an urgent need to develop biomarkers for FTD spectrum disorders as mechanism-based therapies emerge. Primarily using optical coherence tomography (OCT), the objective in this application is to evaluate retinal image abnormalities as biomarkers that can distinguish these proteinopathies and predict prognosis in the context of an interdisciplinary, deep endophenotyping approach. Based on preliminary cross-sectional and longitudinal studies in FTD patients and reports of inner retina thinning in AD and amyotrophic lateral sclerosis (a TDP-43 proteinopathy related to FTD), the overall hypothesis is that the underlying tau, TDP-43, or amyloid β neuropathology of a particular dementia may lead to specific abnormalities of the retina, an extension of neural tissue. OCT thus has potential as a rapid, low-cost, and non-invasive biomarker. The proposed aims are: 1A) To determine if retinal abnormalities, detected by OCT, are biomarkers distinguishing FTLD-Tau from both FTLD-TDP and naAD; 1B) To determine if retinal abnormalities, detected by OCT, predict clinical outcomes; 2) To determine if dementia relevant neuropathologies, as detected by histology and immunohistochemistry, are present in the retina of eyes at autopsy in our cohort of FTD and naAD patients. With rigorous methodology, the investigators will perform deep endophenotyping by ophthalmologists and neurologists, exclude confounding diseases, perform cross-sectional and longitudinal OCT image analyses with a validated OCT image segmentation algorithm, directly compare patient groups, and follow patients to autopsy of the brain and eyes. Developing retinal imaging as a biomarker distinguishing FTLD-Tau from FTLD-TDP and naAD would be a significant contribution because it would help resolve the current difficulty in properly enrolling FTD patients into clinical trials. This research is innovative as it represents a significant departure from the status quo by taking an interdisciplinary approach with careful phenotyping to determine if the retina is a biomarker for the underlying proteinopathy. This project will open new horizons for biomarker models including OCT, and it will advance the use of retinal imaging as a powerful biomarker for FTLD-Tau in relation to FTLD-TDP and naAD.