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The role of astrogliosis in aging and the pathological and clinical progression of Alzheimer's Disease

Award Number: P01AG025204
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 12/01/2004
PERIOD OF PERFORMANCE END DATE: 04/30/2028

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The role of astrogliosis in aging and the pathological and clinical progression of Alzheimer's Disease - Overall Summary/Abstract Our research focuses on understanding the pathophysiological mechanisms that lead individuals to develop dementia, especially Alzheimer’s disease (AD). Our findings, as well as those from others, indicate that there is a complex interaction of clinical and subclinical cerebral and systemic factors during the pre-clinical phases of AD, some which convey vulnerability and some which convey resilience. The use of state-of-the-art technology is gradually providing us with better knowledge of the sequence of events and the role played by each risk factor. There is agreement among researchers that inflammation plays a critical role in the AD pathophysiological process, as noted in multiple pathological studies but examining inflammation in vivo has been challenging. To address these issues, we propose to characterize a new PET tracer, SMBT-1, that has high binding affinity for MAO-B, a proxy of astrogliosis. Astrogliosis is involved in Aβ deposition and alterations in cerebral blood flow and blood brain barrier integrity. One critical remaining question is the temporal relationship of astrogliosis to amyloid deposition, is astrogliosis reactive to Aβ deposition or does astrogliosis represent an additional “hit” exacerbating the effects of amyloid and tau pathology. The present PPG proposes to explore across 4 projects, the relationship of astrogliosis to AD pathology and risk factors using a combination of state-of-the-art neuroimaging, clinical, blood biomarker (and neuropathological tools. We propose to assemble a cohort of 300 participants age 55 and older who will complete annual neuropsychological, clinical, and blood examinations on all participants. At 24 and 48 months follow up evaluation will also include repeat PET and MRI scans to identify abnormalities and/or changes in Aβ and tau deposition, astrogliosis, brain structure and function to determine severity and progression of AD pathology, astrogliosis and cerebrovascular disease (CVD). Utilizing this cohort, Project 1 will focus on the hypothesis that astrogliosis augments, either directly or independently, the effects of Aβ and tau pathology as well as the effects of CVD on neurodegeneration (MRI) and cognition. In Project 2, we will explore the hypothesis that astrogliosis mediates the association between health risk factors (cardiovascular risk factors and sleep) and amyloid and tau pathology. Project-3 will utilize novel 7T MRI to assess the role of brain fluid dynamics in the pathway between astrogliosis and AD pathology. Finally, Project 4 will use the existing ADRC and PPG banked brains to characterize regional differences in SMBT-1 autoradiography and in vitro binding in relation to fine-grained immunohistochemical and biochemical analyses of MAO-B/GFAP astrogliosis, amyloid and tau pathology, vascular pathology, and synaptic markers in AD and non-AD autopsy brains, and it will ultimately characterize SMBT-1 PET in relation to neuropathology in postmortem brains from PPG participants who come to autopsy.


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 = $6,626,476 )
2026	2026	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Aging Research	000	19	3/30/2026	NON-COMPETING CONTINUATION	$6,626,476
														Subtotal = $6,626,476

Issue Date FY: 2025 ( Subtotal = $0 )
2025	2024	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Aging Research	000	18	4/9/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $6,703,737 )
2024	2024	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Aging Research	000	18	4/24/2024	NON-COMPETING CONTINUATION	$6,703,737
														Subtotal = $6,703,737

Issue Date FY: 2023 ( Subtotal = $6,932,984 )
2023	2023	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Aging Research	003	17	5/31/2023	NON-COMPETING CONTINUATION	$6,932,984
2023	2022	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Aging Research	002	16	5/2/2023	COMPETING CONTINUATION	$0
2023	2022	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Aging Research	001	16	4/10/2023	COMPETING CONTINUATION	$638,956
2023	2020	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Aging Research	000	15	4/10/2023	NON-COMPETING CONTINUATION	-$638,956
														Subtotal = $6,932,984

Issue Date FY: 2022 ( Subtotal = $6,909,110 )
2022	2022	UNIVERSITY OF PITTSBURGH, THE	4200 5TH AVE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Aging Research	000	16	7/28/2022	COMPETING CONTINUATION	$6,909,110
2022	2022	UNIVERSITY OF PITTSBURGH, THE	4200 5TH AVE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Aging Research	001	16	8/16/2022	COMPETING CONTINUATION	$0
														Subtotal = $6,909,110

Issue Date FY: 2021 ( Subtotal = $0 )
2021	2020	UNIVERSITY OF PITTSBURGH THE	3520 FIFTH AVE	PITTSBURGH	PA	15213	ALLEGHENY	USA	Aging Research	001	15	2/15/2021	NON-COMPETING CONTINUATION	$0
2021	2020	UNIVERSITY OF PITTSBURGH THE	3520 FIFTH AVE	PITTSBURGH	PA	15213	ALLEGHENY	USA	Aging Research	000	15	1/29/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2020 ( Subtotal = $2,148,033 )
2020	2020	UNIVERSITY OF PITTSBURGH THE	3520 FIFTH AVE	PITTSBURGH	PA	15213	ALLEGHENY	USA	Aging Research	001	15	4/13/2020	NON-COMPETING CONTINUATION	$2,148,033
2020	2019	UNIVERSITY OF PITTSBURGH THE	3520 FIFTH AVE	PITTSBURGH	PA	15213	ALLEGHENY	USA	Aging Research	000	14	2/10/2020	NON-COMPETING CONTINUATION	$0
														Subtotal = $2,148,033

Issue Date FY: 2019 ( Subtotal = $2,345,119 )
2019	2019	UNIVERSITY OF PITTSBURGH THE	3520 FIFTH AVE	PITTSBURGH	PA	15213	ALLEGHENY	USA	Aging Research	001	14	5/9/2019	NON-COMPETING CONTINUATION	$2,188,440
2019	2019	UNIVERSITY OF PITTSBURGH THE	3520 FIFTH AVE	PITTSBURGH	PA	15213	ALLEGHENY	USA	Aging Research	002	14	9/24/2019	NON-COMPETING CONTINUATION	$0
2019	2019	UNIVERSITY OF PITTSBURGH THE	3520 FIFTH AVE	PITTSBURGH	PA	15213	ALLEGHENY	USA	Aging Research	000	13	1/22/2019	SUPPLEMENT FOR EXPANSION	$156,679
														Subtotal = $2,345,119

Issue Date FY: 2018 ( Subtotal = $1,995,282 )
2018	2018	UNIVERSITY OF PITTSBURGH THE	3520 FIFTH AVE	PITTSBURGH	PA	15213	ALLEGHENY	USA	Aging Research	000	13	4/27/2018	NON-COMPETING CONTINUATION	$1,995,282
														Subtotal = $1,995,282

Issue Date FY: 2017 ( Subtotal = $2,020,576 )
2017	2017	UNIVERSITY OF PITTSBURGH THE	3520 FIFTH AVE	PITTSBURGH	PA	15213	ALLEGHENY	USA	Aging Research	001	12	6/23/2017	NON-COMPETING CONTINUATION	$202,059
2017	2017	UNIVERSITY OF PITTSBURGH THE	3520 FIFTH AVE	PITTSBURGH	PA	15213	ALLEGHENY	USA	Aging Research	000	12	4/27/2017	NON-COMPETING CONTINUATION	$1,818,517
														Subtotal = $2,020,576

Issue Date FY: 2016 ( Subtotal = $1,998,101 )
2016	2016	UNIVERSITY OF PITTSBURGH	123 UNIVERSITY PLACE	PITTSBURGH	PA	15213	ALLEGHENY	USA	Aging Research	000	11	5/12/2016	COMPETING CONTINUATION	$1,998,101
														Subtotal = $1,998,101

Issue Date FY: 2014 ( Subtotal = $1,146,355 )
2014	2014	UNIVERSITY OF PITTSBURGH	FIFTH & BIGELOW BOULEVARD	PITTSBURGH	PA	15213	ALLEGHENY	USA	Aging Research	000	10	5/12/2014	NON-COMPETING CONTINUATION	$1,146,355
														Subtotal = $1,146,355

Issue Date FY: 2013 ( Subtotal = $1,295,247 )
2013	2013	UNIVERSITY OF PITTSBURGH	FIFTH & BIGELOW BOULEVARD	PITTSBURGH	PA	15213	ALLEGHENY	USA	Aging Research	000	9	5/29/2013	NON-COMPETING CONTINUATION	$1,295,247
														Subtotal = $1,295,247

Issue Date FY: 2012 ( Subtotal = $1,420,069 )
2012	2012	UNIVERSITY OF PITTSBURGH	FIFTH & BIGELOW BOULEVARD	PITTSBURGH	PA	15213	ALLEGHENY	USA	Aging Research	000	8	5/4/2012	NON-COMPETING CONTINUATION	$1,420,069
														Subtotal = $1,420,069

Issue Date FY: 2011 ( Subtotal = $1,482,584 )
2011	2011	UNIVERSITY OF PITTSBURGH	FIFTH & BIGELOW BOULEVARD	PITTSBURGH	PA	15213	ALLEGHENY	USA	Aging Research	000	7	6/10/2011	NON-COMPETING CONTINUATION	$1,482,584
														Subtotal = $1,482,584

Issue Date FY: 2010 ( Subtotal = $1,538,583 )
2010	2010	UNIVERSITY OF PITTSBURGH	FIFTH & BIGELOW BOULEVARD	PITTSBURGH	PA	15213	ALLEGHENY	USA	Aging Research	000	6	5/31/2010	COMPETING CONTINUATION	$1,538,583
														Subtotal = $1,538,583

Issue Date FY: 2009 ( Subtotal = $1,151,713 )
2009	2009	UNIVERSITY OF PITTSBURGH	FIFTH & BIGELOW BOULEVARD	PITTSBURGH	PA	15213	ALLEGHENY	USA	Aging Research	001	5	4/22/2009	NON-COMPETING CONTINUATION	$1,151,713
2009	2008	UNIVERSITY OF PITTSBURGH	FIFTH & BIGELOW BOULEVARD	PITTSBURGH	PA	15213	ALLEGHENY	USA	Aging Research	000	4	4/10/2009	SUPPLEMENT FOR EXPANSION	$0
														Subtotal = $1,151,713

Issue Date FY: 2008 ( Subtotal = $1,174,561 )
2008	2008	UNIVERSITY OF PITTSBURGH	FIFTH & BIGELOW BOULEVARD	PITTSBURGH	PA	15213	ALLEGHENY	USA	Aging Research	001	4	4/28/2008	SUPPLEMENT FOR EXPANSION	$142,645
2008	2008	UNIVERSITY OF PITTSBURGH	FIFTH & BIGELOW BOULEVARD	PITTSBURGH	PA	15213	ALLEGHENY	USA	Aging Research	000	4	4/24/2008	NON-COMPETING CONTINUATION	$1,031,916
2008	2008	UNIVERSITY OF PITTSBURGH	FIFTH & BIGELOW BOULEVARD	PITTSBURGH	PA	15213	ALLEGHENY	USA	Aging Research	001	3	12/28/2007	SUPPLEMENT FOR EXPANSION	$0
														Subtotal = $1,174,561

Issue Date FY: 2007 ( Subtotal = $1,085,718 )
2007	2007	UNIVERSITY OF PITTSBURGH	FIFTH & BIGELOW BOULEVARD	PITTSBURGH	PA	15213	ALLEGHENY	USA	Aging Research	000	3	5/11/2007	NON-COMPETING CONTINUATION	$1,085,718
														Subtotal = $1,085,718

Grand Total All Awards = $49,836,207

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The role of astrogliosis in aging and the pathological and clinical progression of Alzheimer's Disease

Award Number: P01AG025204

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 12/01/2004

PERIOD OF PERFORMANCE END DATE: 04/30/2028

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