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Ex Vivo Imaging of the Aging Brain to Discover Morphology/Pathology Associations

Award Number: R01AG056014
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/15/2023
PERIOD OF PERFORMANCE END DATE: 03/31/2028

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Ex Vivo Imaging of the Aging Brain to Discover Morphology/Pathology Associations - Alzheimer's disease (AD) is associated with surprisingly high degree of pathologic heterogeneity. In most individuals diagnosed with AD at autopsy, the brain not only harbors the β-amyloid and tau pathologies that are the hallmarks of AD, but also one or more co-pathologies, including TDP-43, α-synuclein, non-AD tauopathy, and cerebral small vessel disease (SVD). The primary AD pathologies and co-pathologies all contribute to neurodegeneration in AD, but their relative contribution in different brain regions and the degree in which co- pathologies modulate the progression of primary pathologies is not well understood. It is widely recognized that it is important for clinical trials in AD to account for these additional drivers of neurodegeneration, but there is a lack of in vivo biomarkers that can reliably detect and quantify co-pathology. Pathologic heterogeneity may help explain why AD treatments targeting a single pathological mechanism have been largely ineffective. This project seeks to address this limitation by using ex vivo human brain MRI to characterize the contributions of primary AD pathologies and co-pathologies to neuronal loss and cortical thinning in AD. The project leverages a prospective dataset from 100-120 autopsies conducted at the University of Pennsylvania AD Research Center that will include high-resolution 7 Tesla MRI of intact brain hemispheres with co-registered histology at selected gray matter locations and around white matter lesions. Moreover, the temporal lobe, part of the brain where earliest and most severe AD-related neurodegeneration occurs, will be scanned at 9.4 Tesla, and undergo serial histological imaging, allowing three-dimensional mapping of tau pathology (tangles, threads, etc.) and neuronal density across the entire temporal lobe. This unique ex vivo imaging dataset will represent a convergence of structural and pathological imaging data in the same 3D space, allowing a broad range of studies analyzing trajectories of pathology deposition and pathology-neurodegeneration relationships. The specific aims of the proposal are as follows. Aim 1 is to develop deep learning-based image analysis techniques for 7 Tesla whole- hemisphere MRI, which are currently lacking, including segmentation of cortical gray matter, white matter lesions, normal-appearing white matter, and subcortical structures; groupwise registration to both ex vivo and in vivo MRI templates; and extraction of both MRI-based and histological features to characterize white matter lesions associated with SVD. Aim 2 is to analyze the complete 100-120 specimen dataset to characterize the distribution of tau pathology, neuronal loss, and cortical thinning both in the temporal lobe and in the whole brain and to describe the impact of co-pathologies on these distributions and on the relationships between them. Aim 3 is to leverage pathology-specific “signatures” extracted from analyzing this ex vivo dataset to improve the sensitivity of in vivo biomarkers for inferring the presence of co-pathology and tracking disease progression.


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 = $680,099 )
2026	2026	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Aging Research	000	7	4/8/2026	EXTENSION WITH OR WITHOUT FUNDS	$576,255
2026	2026	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Aging Research	001	7	4/29/2026	SUPPLEMENT FOR EXPANSION	$103,844
														Subtotal = $680,099

Issue Date FY: 2024 ( Subtotal = -$368,015 )
2024	2021	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Aging Research	000	5	12/13/2023	NON-COMPETING CONTINUATION	-$368,015
														Subtotal = -$368,015

Issue Date FY: 2023 ( Subtotal = $0 )
2023	2021	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Aging Research	000	5	4/20/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2021 ( Subtotal = $682,315 )
2021	2021	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Aging Research	000	5	4/9/2021	NON-COMPETING CONTINUATION	$682,315
														Subtotal = $682,315

Issue Date FY: 2020 ( Subtotal = $698,415 )
2020	2020	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Aging Research	000	4	4/13/2020	NON-COMPETING CONTINUATION	$698,415
														Subtotal = $698,415

Issue Date FY: 2019 ( Subtotal = $905,275 )
2019	2019	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Aging Research	000	3	5/9/2019	NON-COMPETING CONTINUATION	$724,225
2019	2019	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Aging Research	001	3	5/13/2019	SUPPLEMENT FOR EXPANSION	$181,050
														Subtotal = $905,275

Issue Date FY: 2018 ( Subtotal = $740,325 )
2018	2018	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Aging Research	000	2	4/23/2018	NON-COMPETING CONTINUATION	$740,325
														Subtotal = $740,325

Issue Date FY: 2017 ( Subtotal = $772,049 )
2017	2017	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Aging Research	002	1	7/19/2017	NEW	$0
2017	2017	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Aging Research	001	1	5/29/2017	NEW	$136,225
2017	2017	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Aging Research	000	1	4/30/2017	NEW	$635,824
2017	2017	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Aging Research	003	1	7/27/2017	NEW	$0
														Subtotal = $772,049

Grand Total All Awards = $4,110,463

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Ex Vivo Imaging of the Aging Brain to Discover Morphology/Pathology Associations

Award Number: R01AG056014

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 04/15/2023

PERIOD OF PERFORMANCE END DATE: 03/31/2028

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