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Integrating spatial multi-omics and clinical covariates to identify mechanisms of disease in ALS-FTD

Award Number: R01NS118183
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/15/2020
PERIOD OF PERFORMANCE END DATE: 01/31/2031

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Integrating spatial multi-omics and clinical covariates to identify mechanisms of disease in ALS-FTD - PROJECT SUMMARY Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are progressive neurodegenerative diseases that, despite having distinct clinical presentations, exist on a continuum known as the Amyotrophic Lateral Sclerosis-Frontotemporal spectrum disorders (ALS-FTSD). Up to 50% of ALS patients experience cognitive or behavioral symptoms, with about 15% meeting criteria for FTD. Affected cognitive domains vary between individuals, ranging from language (spelling and word finding), fluency, executive function (decision making and problem solving), and behavior (apathy and disinhibition). The pathological mechanisms underlying this heterogeneity in clinical presentation are not yet known. Our initial aims were to link defined molecular, cellular, and pathological features to specific cognitive deficits on the ALS-FTSD spectrum. We found region- specific differential gene expression patterns linked to domain-specific clinical impairment; Brodmann Area (BA) 44 and 46 showed distinct changes, with patients exhibiting language dysfunction differing from those with executive dysfunction and distinct vulnerable subpopulations found in each. We additionally found that patients with cognitive impairment were more likely to display signatures of gliosis, and that this enrichment of glial dysfunction, and the types of glia involved, was similarly region dependent. It remains unclear, however, whether the clinical phenotypes observed in ALS stem from a shared root mechanism or instead emerge from brain region-dependent interactions of distinct cellular, molecular, neuropathological, and genetic factors. Further, although TDP-43 proteinopathy is a defining pathological hallmark of ALS-FTSD, the presence of pathognomonic TDP-43 inclusions alone was insufficient to explain the differences in gene expression that we found. Accordingly, the long-term goals of this work are the following: 1) to define the region and clinical phenotype-specific neuron- glia interactions; 2) to elucidate the contribution of genotype to molecular pathology; and 3) to determine how abnormalities in TDP-43 function and localization map onto cognitive impairment in affected individuals. To define the molecular and cellular events underpinning disease heterogeneity we will leverage cutting-edge spatial transcriptomics (ST) and multiplexed protein imaging technologies to simultaneously profile RNA dysregulation, TDP-43 pathology, and cellular pathology in a clinicopathologically stratified ALS-FTSD cohort that includes both sporadic ALS cases and cases with mutations in known ALS-associated genes. By integrating advanced spatial transcriptomics and multiplexed imaging technologies, this work will provide insights into the cellular and molecular drivers of cognitive impairment in ALS-FTSD. Understanding how region-specific neuronal and glial interactions contribute to disease progression and clarifying the role of TDP-43 dysfunction in distinct brain regions will be critical in developing targeted therapeutic interventions.


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: 2026 ( Subtotal = $712,015 )
2026	2026	NEW YORK GENOME CENTER, INC.	101 AVENUE OF THE AMERICAS FL 7	NEW YORK	NY	10013	NEW YORK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	6	2/3/2026	COMPETING CONTINUATION	$712,015
2026	2024	NEW YORK GENOME CENTER, INC.	101 AVENUE OF THE AMERICAS FL 7	NEW YORK	NY	10013	NEW YORK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	1/26/2026	NON-COMPETING CONTINUATION	$0
														Subtotal = $712,015

Issue Date FY: 2024 ( Subtotal = $751,277 )
2024	2024	NEW YORK GENOME CENTER, INC.	101 AVENUE OF THE AMERICAS FL 7	NEW YORK	NY	10013	NEW YORK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	5/1/2024	NON-COMPETING CONTINUATION	$751,277
														Subtotal = $751,277

Issue Date FY: 2023 ( Subtotal = $767,453 )
2023	2023	NEW YORK GENOME CENTER, INC.	101 AVE OF THE AMERICAS FL 7	NEW YORK	NY	10013	NEW YORK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	4/7/2023	NON-COMPETING CONTINUATION	$767,453
														Subtotal = $767,453

Issue Date FY: 2022 ( Subtotal = $787,330 )
2022	2022	NEW YORK GENOME CENTER, INC.	101 AVE OF THE AMERICAS FL 7	NEW YORK	NY	10013	NEW YORK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	3	4/1/2022	NON-COMPETING CONTINUATION	$787,330
2022	2021	NEW YORK GENOME CENTER, INC.	101 AVE OF THE AMERICAS	NEW YORK	NY	10013	NEW YORK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	10/27/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = $787,330

Issue Date FY: 2021 ( Subtotal = $802,118 )
2021	2021	NEW YORK GENOME CENTER, INC.	101 AVE OF THE AMERICAS	NEW YORK	NY	10013	NEW YORK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	3/26/2021	NON-COMPETING CONTINUATION	$802,118
														Subtotal = $802,118

Issue Date FY: 2020 ( Subtotal = $867,241 )
2020	2020	NEW YORK GENOME CENTER, INC.	101 AVE OF THE AMERICAS	NEW YORK	NY	10013	NEW YORK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	8/3/2020	NEW	$867,241
														Subtotal = $867,241

Grand Total All Awards = $4,687,434

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Integrating spatial multi-omics and clinical covariates to identify mechanisms of disease in ALS-FTD

Award Number: R01NS118183

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 08/15/2020

PERIOD OF PERFORMANCE END DATE: 01/31/2031

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