[11C]PS13 PET Imaging of Neuroinflammation in Heart Failure With Reduced Ejection Fraction (NEURO-HF)
Neuroinflammation as a Therapeutic Target in Heart Failure-Related Cognitive Decline: A Feasibility PET Study
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.
Descripción general del estudio
Estado
Condiciones
Intervención / Tratamiento
Descripción detallada
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.
Tipo de estudio
Inscripción (Estimado)
Fase
- Fase 1
Contactos y Ubicaciones
Estudio Contacto
- Nombre: Andreas Kalogeropoulos, MD MPH PhD
- Número de teléfono: 404-512-4463
- Correo electrónico: Andreas.Kalogeropoulos@stonybrookmedicine.edu
Copia de seguridad de contactos de estudio
- Nombre: Min-Jeong Kim, MD PhD
- Número de teléfono: 631-638-3154
- Correo electrónico: MinJeong.Kim@stonybrookmedicine.edu
Ubicaciones de estudio
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New York
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Stony Brook, New York, Estados Unidos, 11794
- Stony Brook University Medical Center
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Contacto:
- Andreas Kalogeropoulos, MD MPH PhD
- Número de teléfono: 404-512-4463
- Correo electrónico: Andreas.Kalogeropoulos@stonybrookmedicine.edu
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Contacto:
- Min-Jeong Kim, MD PhD
- Correo electrónico: MinJeong.Kim@stonybrookmedicine.edu
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Criterios de participación
Criterio de elegibilidad
Edades elegibles para estudiar
Acepta Voluntarios Saludables
Géneros elegibles para el estudio
Descripción
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)
Plan de estudios
¿Cómo está diseñado el estudio?
Detalles de diseño
- Propósito principal: Tratamiento
- Asignación: N / A
- Modelo Intervencionista: Asignación de un solo grupo
- Enmascaramiento: Ninguno (etiqueta abierta)
Armas e Intervenciones
Grupo de participantes/brazo |
Intervención / Tratamiento |
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Experimental: HFrEF with Mild Cognitive Impairment - Sacubitril-Valsartan Initiators
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. |
[11C]PS13 is an investigational positron emission tomography (PET) radioligand targeting cyclooxygenase-1 (COX-1), an enzyme primarily localized in microglia involved in neuroinflammation. Synthesized on the day of each scan at the Stony Brook BAHL cGMP or FERM facility, administered as a single intravenous bolus (up to 20 mCi) per PET visit. Administered under FDA IND 177118 (21 CFR Part 312). Not FDA-approved; experimental. Angiotensin receptor-neprilysin inhibitor (ARNI) initiated by the participant's treating cardiologist per ACC/AHA/HFSA guideline-directed medical therapy for HFrEF. The dose, titration, and monitoring of sacubitril-valsartan are entirely at the discretion of the treating cardiologist and are not research procedures. The timing of the follow-up PET scan (~12 weeks post-initiation) is aligned with expected clinical stabilization on the drug. |
¿Qué mide el estudio?
Medidas de resultado primarias
Medida de resultado |
Medida Descripción |
Periodo de tiempo |
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Change in [11C]PS13 Total Distribution Volume (VT) in Global Gray Matter
Periodo de tiempo: Baseline (Visit 2, prior to sacubitril-valsartan initiation) and approximately 12 weeks after initiation (Visit 4)
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Change in regional [11C]PS13 total distribution volume (VT, mL/cm³), a quantitative index of COX-1 binding (microglial density), in global cortical gray matter. VT will be calculated using two-tissue compartmental modeling with an arterial blood input function (arterial plasma concentration corrected for radiometabolites). A reduction in VT at follow-up relative to baseline is hypothesized to reflect sacubitril-valsartan-mediated attenuation of microglial neuroinflammation. |
Baseline (Visit 2, prior to sacubitril-valsartan initiation) and approximately 12 weeks after initiation (Visit 4)
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Medidas de resultado secundarias
Medida de resultado |
Medida Descripción |
Periodo de tiempo |
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Feasibility: [11C]PS13 PET Scan Completion Rate
Periodo de tiempo: Through study completion, approximately 16 weeks per participant
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Proportion of enrolled participants who successfully complete both PET scan visits with adequate image quality for quantitative analysis. Arterial line success rate and reasons for scan non-completion will be documented. A completion rate of ≥80% will be considered evidence of feasibility in this cardiac population. |
Through study completion, approximately 16 weeks per participant
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Change in Regional [11C]PS13 VT in Specific Brain Regions of Interest
Periodo de tiempo: Baseline (Visit 2) and ~12 weeks (Visit 4)
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Change in [11C]PS13 VT in pre-specified regions of interest including frontal cortex, temporal cortex, hippocampus, parietal cortex, occipital cortex, cingulate cortex, and thalamus, evaluated using PET-MRI co-registration and Logan graphical analysis. Regional analysis will explore the spatial pattern of neuroinflammation in HFrEF and its response to sacubitril-valsartan. |
Baseline (Visit 2) and ~12 weeks (Visit 4)
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Change in Neurocognitive Performance (Composite Battery)
Periodo de tiempo: Baseline (Visit 1) and ~12 weeks (Visit 4)
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Change in performance on the standardized neurocognitive battery instruments administered at both baseline (Visit 1) and follow-up (Visit 4): Montreal Cognitive Assessment (MoCA; global cognition), Digit Symbol Substitution Test (DSST; processing speed), Trail Making Test Parts A and B (TMT-A/B; processing speed and executive function), Free and Cued Selective Reminding Test immediate and delayed recall (FCSRT; episodic memory), and Geriatric Depression Scale-15 item version (GDS-15; depression symptoms). The battery takes approximately 45-60 minutes to administer. Spearman correlations between ΔVTPET and changes in individual test scores will be explored as exploratory analyses. |
Baseline (Visit 1) and ~12 weeks (Visit 4)
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Arterial Blood Input Function Quality and Radiometabolite Profile
Periodo de tiempo: Baseline (Visit 2) and ~12 weeks (Visit 4)
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Characterization of the [11C]PS13 arterial plasma input function and radiometabolite-corrected curves in HFrEF patients at both time points. This will inform whether the pharmacokinetic profile of [11C]PS13 in HFrEF patients is comparable to prior neurological cohorts, a key methodological feasibility outcome. |
Baseline (Visit 2) and ~12 weeks (Visit 4)
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Change in Instrumental Activities of Daily Living (IADL / Lawton-Brody Scale)
Periodo de tiempo: Baseline (Visit 2) and ~12 weeks (Visit 4)
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Characterization of the [11C]PS13 arterial plasma input function and radiometabolite-corrected curves in HFrEF patients at both time points. This will inform whether the pharmacokinetic profile of [11C]PS13 in HFrEF patients is comparable to prior neurological cohorts, a key methodological feasibility outcome. |
Baseline (Visit 2) and ~12 weeks (Visit 4)
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Colaboradores e Investigadores
Patrocinador
Publicaciones y enlaces útiles
Publicaciones Generales
- Ghazanfari N, Liow JS, Kim MJ, Cureton R, Lee A, Knoer C, Jenkins M, Hong J, Santamaria JAM, Shetty HU, Galassi A, Wighton P, Norgaard M, Greve DN, Zoghbi SS, Pike VW, Innis RB, Zanotti-Fregonara P. [11C]PS13 Demonstrates Pharmacologically Selective and Substantial Binding to Cyclooxygenase-1 in the Human Brain. J Nucl Med. 2025 Jan 3;66(1):117-122. doi: 10.2967/jnumed.124.267928.
- Kim MJ, Lee JH, Juarez Anaya F, Hong J, Miller W, Telu S, Singh P, Cortes MY, Henry K, Tye GL, Frankland MP, Montero Santamaria JA, Liow JS, Zoghbi SS, Fujita M, Pike VW, Innis RB. First-in-human evaluation of [11C]PS13, a novel PET radioligand, to quantify cyclooxygenase-1 in the brain. Eur J Nucl Med Mol Imaging. 2020 Dec;47(13):3143-3151. doi: 10.1007/s00259-020-04855-2. Epub 2020 May 12.
- Grewal PK, Abboud A, Myserlis EP, Goldschmidt ME, Butler J, Skopicki HA, Kalogeropoulos AP. Sacubitril/Valsartan and Cognitive Outcomes in Heart Failure With Reduced Ejection Fraction. JACC Adv. 2023 Jun 7;2(4):100372. doi: 10.1016/j.jacadv.2023.100372. eCollection 2023 Jun.
Fechas de registro del estudio
Fechas importantes del estudio
Inicio del estudio (Estimado)
Finalización primaria (Estimado)
Finalización del estudio (Estimado)
Fechas de registro del estudio
Enviado por primera vez
Primero enviado que cumplió con los criterios de control de calidad
Publicado por primera vez (Actual)
Actualizaciones de registros de estudio
Última actualización publicada (Actual)
Última actualización enviada que cumplió con los criterios de control de calidad
Última verificación
Más información
Términos relacionados con este estudio
Palabras clave
Términos MeSH relevantes adicionales
- Enfermedades Cerebrales
- Enfermedades del Sistema Nervioso Central
- Enfermedades del Sistema Nervioso
- Enfermedades cardiovasculares
- Desordenes mentales
- Procesos Patológicos
- Enfermedades cardíacas
- Trastornos neurocognitivos
- Inflamación
- Trastornos cognitivos
- Condiciones Patológicas, Signos y Síntomas
- Enfermedades Neuroinflamatorias
- Insuficiencia cardiaca
- Disfunción congnitiva
- Demencia
- Encefalitis
- 11C-PS13
- Sacubitril y Valsartan Combinación de fármacos de hidrato de sodio
Otros números de identificación del estudio
- IRB2026-00185
- R21AG102953 (Subvención/contrato del NIH de EE. UU.)
- 26RIRA1639136 (Otro número de subvención/financiamiento: American Heart Association)
Plan de datos de participantes individuales (IPD)
¿Planea compartir datos de participantes individuales (IPD)?
Descripción del plan IPD
De-identified participant-level brain PET imaging data ([11C]PS13), structural MRI data (MP-RAGE, T2-FLAIR), cognitive assessment scores (MoCA, DSST, TMT-A/B, FCSRT), and associated clinical metadata (demographics, HF characteristics, NT-proBNP) will be shared. Data will be formatted in Brain Imaging Data Structure (BIDS) standard per Knudsen et al. (J Cereb Blood Flow Metab 2020). Plasma biospecimens will be transferred to NCRAD after 5 years. Analytic code and the statistical analysis plan will also be shared.
Marco de tiempo para compartir IPD
De-identified imaging data, cognitive scores, and clinical metadata will be made available no later than the time of the primary associated publication, or at the end of the study performance period, whichever comes first. Supporting documents (SAP, ICF, analytic code) will be shared simultaneously. All shared data will remain available indefinitely with no end date.
Criterios de acceso compartido de IPD
Qualified researchers may request access to de-identified brain PET and MRI images, cognitive assessment scores, and clinical metadata via OpenNeuro PET Archive (openneuro.org). Access is initially granted through the repository review process. After an optional 36-month grace period from initial deposit, data will be released under a Creative Commons CC0 license for unrestricted reuse. Facial features will be removed from structural MRI prior to upload.
Tipo de información de apoyo para compartir IPD
- PROTOCOLO DE ESTUDIO
- SAVIA
- CIF
- CÓDIGO_ANALÍTICO
- RSC
Información sobre medicamentos y dispositivos, documentos del estudio
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