Neuroinflammation as a Therapeutic Target in Heart Failure-Related Cognitive Decline: A Feasibility PET Study
| Registry | NCT07856043, acronym NEURO-HF |
|---|---|
| Status | Not yet recruiting |
| Phase | Phase 1 |
| Study type | Interventional; na, single group, masking: none, treatment |
| Enrollment | 18 (Estimated) |
| Sponsor | Stony Brook University (Other); collaborators: American Heart Association, National Institute on Aging (NIA) |
| Conditions | Heart Failure With Reduced Ejection Fraction, Cognitive Impairment, Mild, Neuroinflammation, Vascular Contributions to Cognitive Impairment and Dementia (VCID) |
| Interventions | [11C]PS13: [carbon-11]PS13; COX-1 PET radioligand, Sacubitril-Valsartan (Drug) |
| Dates | start 2026-10-01 (estimated), primary completion 2028-06-30 (estimated), completion 2028-12-31 (estimated), first posted 2026-10-02, last updated 2026-10-02 |
| Locations | 1 site in United States |
Related Papers Related Patents Related Grants Related Experts
All trials for Heart Failure With Reduced Ejection Fraction All trials for Cognitive Impairment, Mild All trials of [11C]PS13: [carbon-11]PS13; COX-1 PET radioligand All trials of Sacubitril-Valsartan
Heart failure reduces the amount of blood the heart pumps, which can lead to memory and thinking problems in many patients. One possible reason is that heart failure triggers brain inflammation, a process in which certain brain immune cells (called microglia) become overactive. A heart failure medication called sacubitril-valsartan has been shown to reduce the risk of developing dementia, but it is not known whether this is because it reduces brain inflammation. This study uses a new experimental brain scan drug called \[11C\]PS13 (PS13) to measure brain inflammation directly and non-invasively, using a technique called positron emission tomography (PET). PS13 sticks to a molecule called COX-1, which is found mainly in brain immune cells (microglia). By measuring how much PS13 accumulates in the brain, researchers can estimate how much brain inflammation is present. In this pilot study, 18 patients with heart failure and mild memory or thinking problems who are being started on sacubitril-valsartan by their cardiologist (as standard clinical care) will undergo two brain PET scans: one before starting sacubitril-valsartan, and one approximately 12 weeks after. The study will also assess memory, thinking, daily function, mood, and social well-being using standard questionnaires. The study will test whether sacubitril-valsartan is associated with measurable changes in brain inflammation, and whether this type of imaging is feasible in heart failure patients. The study is funded by the American Heart Association and the National Institute on Aging, and an independent Data and Safety Monitoring Board oversees participant safety. The results will be used to design a larger study.
Heart failure with reduced ejection fraction (HFrEF) affects \~6.7 million Americans and is a powerful independent risk factor for accelerated cognitive decline and dementia, playing a major role in vascular contributions to cognitive impairment and dementia (VCID). Neuroinflammation, and particularly microglial activation, is a leading mechanistic hypothesis for HFrEF-associated cognitive decline, driven by chronic cerebral hypoperfusion and systemic inflammatory signaling. However, direct in vivo evidence of neuroinflammation in living HFrEF patients is lacking. Sacubitril-valsartan (an angiotensin receptor-neprilysin inhibitor \[ARNI\]) is guideline-directed first-line therapy for HFrEF. Beyond established cardiovascular benefits, epidemiological data demonstrate a >30% reduction in incident dementia and cognitive decline with sacubitril-valsartan vs. standard renin-angiotensin inhibitors over 3 years, suggesting neuroprotective properties. These may be mechanistically linked to anti-inflammatory actions via natriuretic peptide signaling and neprilysin-mediated peptide degradation, a hypothesis that has not yet ben=en testedhas not yet been tested in the living human brain. \[11C\]PS13 is a novel PET radioligand developed at Stony Brook University targeting cyclooxygenase-1 (COX-1), a microglial-specific marker of neuroinflammatory activity.is a novel PET radioligand, co-developed by study co-investigator Dr. Min-Jeong Kim, that selectively targets cyclooxygenase-1 (COX-1), which is primarily localized in microglia and serves as a biomarker of microglial density and neuroinflammatory activity. \[11C\]PS13 has demonstrated excellent selectivity and signal-to-noise in non-human primates and healthy humans (Kim et al., J Nucl Med 2018; Kim et al., Eur J Nucl Med Mol Imaging 2020), and elevated binding in Alzheimer's disease and dementia with Lewy bodies compared to controls.and increased binding in Alzheimer's disease compared with age-matched healthy controls; work in dementia with Lewy bodies is ongoing. The present study extends \[11C\]PS13 PET to patients with HFrEF to: (1) establish feasibility of this neuroimaging approach in a cardiac population; (2) characterize baseline brain microglial density (COX-1 expression) in HFrEF patients with mild cognitive impairment; and (3) generate preliminary effect size data for changes in neuroinflammation after sacubitril-valsartan initiation. In addition to PET imaging, participants will undergo a comprehensive neurocognitive assessment at baseline and follow-up, including evaluation of global cognition, processing speed, executive function, free recall, depression, loneliness, social isolation, social network, and instrumental activities of daily living. This AHA-funded pilot will provide the foundational data for a more definitive mechanistic study.The study will enroll 18 participants under a single protocol (6 supported by the American Heart Association and 12 by the National Institute on Aging, R21AG102953), with data pooled for analysis. \[11C\]PS13 is administered under FDA IND 177118, and an independent, NIA-appointed Data and Safety Monitoring Board oversees participant safety, data quality, and study progress. This pilot will provide the foundational data for a more definitive mechanistic study.
| Arm | Type | Interventions | Description |
|---|---|---|---|
| HFrEF with Mild Cognitive Impairment - Sacubitril-Valsartan Initiators | Experimental | Drug: [11C]PS13: [carbon-11]PS13; COX-1 PET radioligand; Drug: Sacubitril-Valsartan | Patients with HFrEF (LVEF ≤40%) and mild cognitive impairment (MoCA 18-25) who are being initiated on sacubitril-valsartan per their cardiologist's clinical judgment. Participants undergo \[11C\]PS13 PET brain imaging with arterial blood sampling and brain MRI at baseline (prior to sacubitril-valsartan initiation) and at approximately 12 weeks after initiation. |
Sex: All, ages: 50 Years to 75 Years
Inclusion Criteria: * Age 50-75 years * Diagnosis of HFrEF (left ventricular ejection fraction ≤40% documented by echocardiography or cardiac imaging within the prior 12 months) * Montreal Cognitive Assessment (MoCA) score 18-25 (mild cognitive impairment) * Being initiated on sacubitril-valsartan per treating cardiologist's clinical judgment in accordance with current guideline-directed medical therapy for HFrEF * Clinically stable HF (NYHA functional Class I-III) at time of enrollment * Ability to provide written informed consent * Ability to lie flat for up to 90 minutes (required for PET scan acquisition) Exclusion Criteria: * Neurologic, psychiatric, or medical condition that may cause cognitive dysfunction or affect study data interpretation (e.g., major stroke, brain tumor, severe TBI, epilepsy, multiple sclerosis, schizophrenia, bipolar disorder) * Clinically unstable HF or acute decompensated heart failure within 4 weeks prior to enrollment * NYHA functional Class IV heart failure * Recent hospitalization for cardiovascular reasons within 4 weeks of enrollment * Severe pulmonary congestion or orthopnea precluding lying flat for \~90 minutes * Recent cardiac surgery within 3 months of enrollment * Implanted cardiac device (e.g., pacemaker, ICD, CRT-D) that is non-MRI-conditional, in the absence of an available clinical brain MRI from within the past 3 years * Other implanted device contraindicated for MRI (e.g., deep brain stimulator, cochlear implant, intracranial aneurysm clip) * Current drug or alcohol abuse or dependence * Recent research radiation exposure that combined with this study would exceed allowable limits as determined by the FDA * Inability to remain still on the scanner bed or body weight exceeding scanner maximum * Use of NSAIDs other than low-dose aspirin (≤100 mg/day) within 2 weeks prior to each \[11C\]PS13 PET scan * Pregnancy or breastfeeding * Severe renal impairment (eGFR <30 mL/min/1.73m²) or other condition that may affect radioligand clearance or biomarker interpretation * Active systemic inflammatory or autoimmune disease * Peripheral vascular disease or other condition precluding radial arterial catheter placement * Anticoagulation at therapeutic levels that would substantially increase the risk of arterial line placement (e.g., warfarin with INR >3.0, therapeutic heparin); patients on direct oral anticoagulants (DOACs) are assessed individually by the study physician * Whole blood or plasma donation within 8 weeks (56 days) before the first PET scan, or unwillingness to refrain from blood donation for the duration of study participation * Non-English speaking (the MoCA and the consent process require English-language comprehension)
| Facility | City | Country | Status |
|---|---|---|---|
| Stony Brook University Medical Center | Stony Brook, New York | United States |
NIH grants: R21AG102953