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Protein Aggregation and Neurotransmitter Deficits in Parkinson Disease

Award Number: R01NS097799
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: 08/01/2016
PERIOD OF PERFORMANCE END DATE: 11/30/2027

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Protein Aggregation and Neurotransmitter Deficits in Parkinson Disease - Abstract People with Parkinson disease (PD) frequently develop dementia, which is associated with neocortical deposition of alpha-synuclein (α-syn) in Lewy bodies and referred to as Lewy body dementia (LBD), an Alzheimer’s Disease Related Dementia (ADRD). In addition, neuronal loss and deposition of aggregated α-syn also occurs in multiple subcortical nuclei including substantia nigra (dopaminergic), nucleus basalis of Meynert (cholinergic), locus coeruleus (noradrenergic) and dorsal raphe nuclei (serotonergic). Accumulation of α-syn likely contributes to degeneration of cortical neurons, which may also be affected by widespread Aβ accumulation that occurs in approximately 55% of PD with dementia cases and widespread tau accumulation in fewer cases. However, the affected subcortical nuclei project rostrally to thalamic, striatal, limbic and neocortical regions, and the loss of innervation from these nuclei also may contribute to cognitive impairment in PD. We developed postmortem tissue analysis methods to quantify pathologic accumulation of α-syn, Aβ and tau, neuronal degeneration marked by loss of synaptic terminals, and loss of innervating projections from dopaminergic, serotonergic, noradrenergic and cholinergic subcortical neurons. In this project we will collect autopsies from a longitudinal study of PD participants that measures cognition, neurobehavioral function and gait. We will sample cerebellar, basal ganglia, limbic and neocortical regions from frozen brain tissue for each autopsy case and analyze the tissue with the following goals: 1) Determine the relationship between α-syn, Aβ and tau accumulation, neuronal degeneration, and loss of subcortical projections. 2) Determine whether pathologic protein accumulation, neuronal degeneration and loss of projections from subcortical nuclei relate to global cognition and specific cognitive phenotypes, including impaired attention, memory, visuospatial and executive function. Defining the pathologic substrates for cognitive impairment in PD will provide further guidance for therapeutic targets, biomarkers, and outcome measures for therapeutic trials in PD.


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 = $712,576 )
2026	2026	WASHINGTON UNIVERSITY, THE	1 BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	9	4/24/2026	NON-COMPETING CONTINUATION	$712,576
2026	2024	WASHINGTON UNIVERSITY, THE	1 BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	8	2/25/2026	NON-COMPETING CONTINUATION	$0
														Subtotal = $712,576

Issue Date FY: 2025 ( Subtotal = $0 )
2025	2024	WASHINGTON UNIVERSITY, THE	1 BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	8	8/7/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $860,301 )
2024	2024	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63110	SAINT LOUIS CITY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	8	7/1/2024	NON-COMPETING CONTINUATION	$712,576
2024	2024	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63110	SAINT LOUIS CITY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	003	8	8/9/2024	NON-COMPETING CONTINUATION	$0
2024	2024	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63110	SAINT LOUIS CITY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	8	8/8/2024	SUPPLEMENT FOR EXPANSION	$147,725
2024	2020	WASHINGTON UNIVERSITY, THE	1 BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	10/18/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $860,301

Issue Date FY: 2023 ( Subtotal = $712,576 )
2023	2023	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	7	7/7/2023	NON-COMPETING CONTINUATION	$712,576
														Subtotal = $712,576

Issue Date FY: 2022 ( Subtotal = $742,741 )
2022	2022	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	6	6/30/2022	COMPETING CONTINUATION	$742,741
														Subtotal = $742,741

Issue Date FY: 2020 ( Subtotal = $506,507 )
2020	2020	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	6/22/2020	NON-COMPETING CONTINUATION	$506,507
														Subtotal = $506,507

Issue Date FY: 2019 ( Subtotal = $511,540 )
2019	2019	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	5/9/2019	NON-COMPETING CONTINUATION	$511,540
														Subtotal = $511,540

Issue Date FY: 2018 ( Subtotal = $511,540 )
2018	2018	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	3	6/8/2018	NON-COMPETING CONTINUATION	$0
2018	2018	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	5/4/2018	NON-COMPETING CONTINUATION	$511,540
														Subtotal = $511,540

Issue Date FY: 2017 ( Subtotal = $511,540 )
2017	2017	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	2	6/16/2017	NON-COMPETING CONTINUATION	$51,154
2017	2017	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	4/20/2017	NON-COMPETING CONTINUATION	$460,386
														Subtotal = $511,540

Issue Date FY: 2016 ( Subtotal = $620,045 )
2016	2016	WASHINGTON UNIVERSITY	CAMPUS BOX 1034	SAINT LOUIS	MO	63112	SAINT LOUIS CITY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	7/22/2016	NEW	$511,540
2016	2016	WASHINGTON UNIVERSITY	CAMPUS BOX 1034	SAINT LOUIS	MO	63112	SAINT LOUIS CITY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	1	9/8/2016	NEW	$108,505
														Subtotal = $620,045

Grand Total All Awards = $5,689,366

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Protein Aggregation and Neurotransmitter Deficits in Parkinson Disease

Award Number: R01NS097799

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: 08/01/2016

PERIOD OF PERFORMANCE END DATE: 11/30/2027

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