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Neuroinflammation as a Therapeutic Target in Heart Failure-Related Cognitive Decline: A Feasibility PET Study

Award Number: R21AG102953
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/05/2026
PERIOD OF PERFORMANCE END DATE: 07/31/2028

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Neuroinflammation as a Therapeutic Target in Heart Failure-Related Cognitive Decline: A Feasibility PET Study - PROJECT SUMMARY Heart failure accelerates cognitive decline in 6.7 million Americans, with 40% of patients experiencing cognitive impairment that worsens treatment outcomes and survival. Despite this critical health burden, the biological mechanisms linking heart failure to cognitive decline remain poorly understood, preventing development of targeted interventions. Recent evidence suggests that neuroinflammation, particularly microglial activation in the brain, plays a central role in heart failure-related cognitive decline. Sacubitril-valsartan, a combined angiotensin receptor blocker and neprilysin inhibitor with incremental anti-inflammatory properties, has been associated with >30% lower rates of cognitive decline compared to standard renin-angiotensin system inhibitors in heart failure patients, but the mechanistic basis for this cognitive protection remains unknown. The long-term objective is to establish neuroinflammation as a therapeutic target for preventing vascular contributions to cognitive impairment and dementia in cardiovascular disease. This feasibility study will demonstrate the capability to quantify treatment-induced changes in brain neuroinflammation using the novel positron emission tomography (PET) radioligand [11C]PS13, which selectively targets cyclooxygenase-1 in activated microglia. The working hypothesis for future studies is that sacubitril-valsartan reduces microglial- driven neuroinflammation in heart failure patients, correlating with improved cognitive performance. The study will examine 12 patients ages 50-75 with heart failure and reduced ejection fraction and possible mild cognitive impairment through comprehensive brain PET imaging and cognitive assessment at baseline and 12 weeks after sacubitril-valsartan initiation. Aim 1 will establish the feasibility of detecting neuroinflammation changes by measuring global brain [11C]PS13 binding using gold-standard quantitative methods with arterial blood sampling and kinetic modeling. Aim 2 will demonstrate the ability to assess cognitive-neuroinflammation associations using comprehensive cognitive measures, controlling for cardiac function improvements through circulating N-terminal pro-B-type natriuretic peptide levels and brain perfusion improvements through PET imaging. Blood samples will be collected and stored for potential future biomarker analyses. This feasibility study will demonstrate the capability to assess neuroinflammation changes in response to cardiovascular therapy, providing methodological foundation for investigating brain-heart connections in vascular cognitive impairment. We expect ≥75% of participants (≥9 of 12) to complete the full protocol, with successful sacubitril- valsartan titration. This research will establish the infrastructure and generate the preliminary data for an R01 application proposing a clinical trial comparing sacubitril-valsartan vs. conventional renin-angiotensin system inhibitors with serial neuroimaging and cognitive endpoints. Examining neuroinflammation as a therapeutic target has the potential to advance treatment strategies for the millions of Americans at the intersection of cardiovascular disease and dementia.


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 = $436,001 )
2026	2026	THE RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK	W5510 FRANKS MELVILLE MEMORIAL LIBRARY	STONY BROOK	NY	11794	SUFFOLK	USA	Aging Research	000	1	8/4/2026	NEW	$436,001
														Subtotal = $436,001

Grand Total All Awards = $436,001

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Neuroinflammation as a Therapeutic Target in Heart Failure-Related Cognitive Decline: A Feasibility PET Study

Award Number: R21AG102953

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/05/2026

PERIOD OF PERFORMANCE END DATE: 07/31/2028

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