Clinicopathologic correlates of cognitive impairment in amyotrophic lateral sclerosis and frontotemporal dementia spectrum disorders (ALS-FTD)

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PROJECT SUMMARY Amyotrophic lateral sclerosis and frontotemporal dementia (ALS-FTD) is a neurodegenerative disorder with clinical presentations ranging from progressive paralysis to cognitive impairment. FTD is the second most common cause of dementia in people under the age of 65 and accounts for 25% of cases of dementia in people over 65 years of age. Approximately 15% of ALS-FTD patients initially presenting with motor symptoms also receive a diagnosis of dementia, but a majority of ALS-FTD patients demonstrate some level of cognitive impairment over the course of disease. Identifying molecular pathways that contribute to the development of cognitive deficits in ALS-FTD has thus far been limited by the quality of clinical information and postmortem tissue preservation as well as available technologies. Our collaborators at the University of Edinburgh have assembled a cohort of non-demented ALS-FTD patients with detailed cognitive profiling and high quality postmortem tissue preservation for molecular studies. Novel highly multiplexed protein imaging and spatially resolved transcriptomics methods have made it possible to quantify cell type composition and gene expression in situ in postmortem tissue sections. These experimental advances have the potential to elucidate molecular mechanisms that are associated with cognitive dysfunction in ALS-FTD. This proposal seeks to understand how TDP-43 pathology and local changes in the tissue microenvironment contribute to cognitive impairment in patients with ALS-FTD. By integrating multiplexed imaging and spatial transcriptomics data, I will quantify cell type proportions (Aim 1) and perturbations in gene expression (Aim 2) proximal to TDP-43 pathology in postmortem tissues from this cohort of ALS-FTD patients with detailed clinical and neuropathological characterization. By comparing these features in patients with and without cognitive dysfunction, I will identify molecular pathways that may contribute to or protect against cognitive impairment in ALS-FTD. This multimodal approach can be applied to study clinicopathologic correlates of other proteinopathies. My fellowship proposal also outlines a rigorous training plan focused on developing the intellectual and professional skills required for a successful career as a physician scientist: 1) designing rigorous, well- controlled and well-powered studies, 2) effective science communication through oral presentations, manuscript writing and grant writing, 3) cutting-edge experimental and computational genomics methods, 4) mentorship of trainees and collaboration with scientists from other disciplines, and 5) placing research in a clinical context. As a predoctoral trainee, I will benefit from the mentorship of Dr. Hemali Phatnani and Dr. Tom Maniatis, the expertise of our neuropathology, engineering, and computational collaborators, and the collaborative and supportive training environments at the New York Genome Center and the Columbia University Irving Medical Center.