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Extracranial Carotid Atherosclerosis Contributions to Cognitive Impairment and Alzheimer's Disease Risk

Award Number: R01AG070987
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/15/2021
PERIOD OF PERFORMANCE END DATE: 05/31/2026

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Extracranial Carotid Atherosclerosis Contributions to Cognitive Impairment and Alzheimer's Disease Risk - PROJECT SUMMARY/ABSTRACT There is growing need to understand mechanisms and treatment options associated with vascular contributions to Alzheimer’s disease (AD) and other forms of dementia and cognitive dysfunction. Early brain changes associated with AD and other forms of cognitive dysfunction, such as white matter lesion (WML) burden, hypoperfusion and metabolic mismatch have vascular risk factors (hypertension, diabetes, aging and smoking). Such structural and functional brain changes are often considered secondary to intracranial cerebral small vessel disease. In contrast, our preliminary data indicate that extra-cranial carotid artery disease (ECAD) contributes to brain pathology and its treatment with carotid endarterectomy (CEA) (to surgically remove the plaque) decreases accumulation of WMLs and neurofibrillary tangles, increases structural connectivity, and most importantly, improves cognition. ECAD primarily signifies atherosclerosis of the carotid bifurcation, where plaque accumulation is uniquely prevalent compared to other cerebrovascular locations. Carotid arteries play a major role in brain physiology because they bring the majority of blood and nutrients to the brain. We hypothesize that mechanisms of ECAD contribution to Alzheimer’s disease and cognitive dysfunction are likely multifactorial and include embolic phenomena, decreased blood flow, and endothelial activation/inflammation. Interplay between these modifiable factors and non-modifiable risks (ie, age, sex and ApoE status) likely contribute to neurodegeneration that can lead to cognitive dysfunction. Our Aims 1 and 2 use cross-sectional studies to evaluate potential mechanisms of ECAD contribution to AD-related brain structure and function changes. Subject evaluation includes neurocognitive testing and quantification of MRI-defined structural parameters, WML accumulation, Alzheimer’s disease blood-based biomarkers, and systemic, cerebral and carotid markers of inflammation. Aim 3 employs a prospective, controlled cohort study evaluating the treatment of ECAD with CEA to determine which patients show improved cognitive function (responders) and what factors are drivers of this response. This project will define quantifiable measures of brain structural changes leading to neurodegeneration and cognitive dysfunction in subjects with ECAD. This should further build the impetus for clinical trials that change management of patients with ECAD. In addition, our study offers the exciting opportunity to reveal novel insights of early Alzheimer’s disease risk and specific mechanisms of vascular contributions. Understanding the unique contribution of ECAD to AD/cognitive dysfunction risk is particularly compelling because effective treatments exist for ECAD yet are not currently offered for the treatment/prevention of cognitive dysfunction.


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: 2025 ( Subtotal = $1,401,879 )
2025	2025	UNIVERSITY OF ARIZONA	845 N PARK AVE RM 538	TUCSON	AZ	85721	PIMA	USA	Aging Research	000	5	6/3/2025	NON-COMPETING CONTINUATION	$1,401,879
														Subtotal = $1,401,879

Issue Date FY: 2024 ( Subtotal = $1,665,258 )
2024	2024	UNIVERSITY OF ARIZONA	845 N PARK AVE RM 538	TUCSON	AZ	85721	PIMA	USA	Aging Research	002	4	8/27/2024	SUPPLEMENT FOR EXPANSION	$277,945
2024	2024	UNIVERSITY OF ARIZONA	845 N PARK AVE RM 538	TUCSON	AZ	85721	PIMA	USA	Aging Research	000	4	5/21/2024	NON-COMPETING CONTINUATION	$1,011,212
2024	2024	UNIVERSITY OF ARIZONA	845 N PARK AVE RM 538	TUCSON	AZ	85721	PIMA	USA	Aging Research	001	4	6/10/2024	NON-COMPETING CONTINUATION	$376,101
														Subtotal = $1,665,258

Issue Date FY: 2023 ( Subtotal = $1,543,799 )
2023	2023	UNIVERSITY OF ARIZONA	845 N PARK AVE RM 538	TUCSON	AZ	85721	PIMA	USA	Aging Research	001	3	8/16/2023	SUPPLEMENT FOR EXPANSION	$382,766
2023	2023	UNIVERSITY OF ARIZONA	845 N PARK AVE RM 538	TUCSON	AZ	85721	PIMA	USA	Aging Research	000	3	6/8/2023	NON-COMPETING CONTINUATION	$1,161,033
														Subtotal = $1,543,799

Issue Date FY: 2022 ( Subtotal = $1,019,526 )
2022	2022	UNIVERSITY OF ARIZONA	888 N EUCLID AVE RM 510	TUCSON	AZ	85719	PIMA	USA	Aging Research	000	2	5/26/2022	NON-COMPETING CONTINUATION	$1,019,526
														Subtotal = $1,019,526

Issue Date FY: 2021 ( Subtotal = $844,972 )
2021	2021	UNIVERSITY OF ARIZONA	888 N EUCLID AVE RM 510	TUCSON	AZ	85719	PIMA	USA	Aging Research	000	1	8/9/2021	NEW	$844,972
														Subtotal = $844,972

Grand Total All Awards = $6,475,434

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Extracranial Carotid Atherosclerosis Contributions to Cognitive Impairment and Alzheimer's Disease Risk

Award Number: R01AG070987

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/15/2021

PERIOD OF PERFORMANCE END DATE: 05/31/2026

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