[11C]PS13 PET Imaging of Neuroinflammation in Heart Failure With Reduced Ejection Fraction (NEURO-HF)

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.

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.

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.

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.

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.

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.

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.