Neuroinflammation as a Therapeutic Target in Heart Failure-Related Cognitive Decline: A Feasibility PET Study
Description: Heart failure (HF) affects 6.7 million Americans and accelerates cognitive decline, playing a major role in vascular contributions to cognitive impairment and dementia (VCID). Cognitive impairment affects 40% of HF outpatients and significantly impacts self-care, treatment adherence, and outcomes. However, mechanisms underlying HF-related cognitive decline remain poorly understood, preventing development of therapeutic interventions. Among patients with HF and reduced ejection fraction (HFrEF), chronic neuroinflammation, particularly microglial activation, is considered a primary contributor to cognitive decline. This mechanism is supported by preclinical evidence, but clinical evidence is lacking, precluding development of neuroprotective strategies. We recently demonstrated that sacubitril-valsartan, a first-line HFrEF therapy, is associated with over 30% lower rates of cognitive decline and dementia compared to standard renin-angiotensin system inhibitors over 3 years of follow-up. Sacubitril offers incremental anti-inflammatory actions over standard therapies, which may underlie its neuroprotective effects, but mechanistic confirmation through direct neuroimaging is lacking. This pilot study will establish feasibility of using C-11-PS13 positron emission tomography (PET) imaging to detect treatment-induced neuroinflammation changes in HFrEF patients. C-11-PS13 is a novel PET radioligand that selectively targets cyclooxygenase-1 in microglia, providing direct quantification of neuroinflammation. We will enroll 6 patients age 50-75 with HFrEF and mild cognitive impairment (Montreal Cognitive Assessment score 18-25). Participants will undergo C-11-PS13 PET imaging with arterial blood sampling, brain MRI, and comprehensive cognitive testing at baseline and 12 weeks after sacubitril-valsartan initiation per clinical guidelines. The primary outcome is change in C-11-PS13 binding (reflecting microglial density) from baseline to follow-up. Secondary outcomes include exploratory correlations between neuroinflammation changes and cognitive performance. Primary feasibility outcomes include completion rates, imaging quality, and preliminary effect sizes. This pilot will provide first clinical evidence linking cardiovascular drug mechanisms to brain neuroinflammation in HFrEF, establish C-11-PS13 PET methodology in cardiac populations, and generate preliminary data for a definitive study investigating neuroinflammation as a therapeutic target in VCID.
Funder: American Heart Association
Amount: $99,900
Funding type: research
Funder scheme: Rapid Impact Research Award
Start date: 2026-04-01
End date: 2028-03-31
Investigators: Andreas Kalogeropoulos, Andreas Kalogeropoulos
Institution: The Research Foundation of SUNY- SUNY at Stony Brook
Funded outputs count: 0
Funder award ID: 26RIRA1639136
OpenAlex ID: G1981395071