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

Award Number: F30AG072766
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

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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.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2024 ( Subtotal = $52,694 )
2024	2024	THE TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK	630 W 168TH ST FL 4	NEW YORK	NY	10032	NEW YORK	USA	Aging Research	000	3	2/7/2024	NON-COMPETING CONTINUATION	$52,694
														Subtotal = $52,694

Issue Date FY: 2023 ( Subtotal = $52,694 )
2023	2023	TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK, THE	630 W 168TH ST FL 4	NEW YORK	NY	10032	NEW YORK	USA	Aging Research	000	2	2/10/2023	NON-COMPETING CONTINUATION	$52,694
														Subtotal = $52,694

Issue Date FY: 2022 ( Subtotal = $47,256 )
2022	2022	TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK, THE	630 W 168TH ST FL 4	NEW YORK	NY	10032	NEW YORK	USA	Aging Research	002	1	5/6/2022	NEW	$717
2022	2022	TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK, THE	630 W 168TH ST FL 4	NEW YORK	NY	10032	NEW YORK	USA	Aging Research	003	1	8/30/2022	NEW	-$1
2022	2022	TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK, THE	630 W 168TH ST FL 4	NEW YORK	NY	10032	NEW YORK	USA	Aging Research	001	1	1/20/2022	NEW	$0
2022	2022	TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK, THE	630 W 168TH ST FL 4	NEW YORK	NY	10032	NEW YORK	USA	Aging Research	000	1	1/20/2022	NEW	$46,540
														Subtotal = $47,256

Grand Total All Awards = $152,644

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

Award Number: F30AG072766

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

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