Multi-biomarker evaluation of 64Cu-FBP8 PET for imaging of brain fibrin in aging and neurodegeneration

This R01 resubmission is a 4-year methodology grant (PAR-25-332). The overarching goal is to assess the utility of 64Cu-fibrin-binding-probe-8 Positron Emission Tomography (or FBP8 PET) for the in vivo detection and quantification of pathological fibrin in brain, within a multi-biomarker framework. We will study Harvard Aging Brain Study 2 (HABS-2) participants who underwent amyloid (Aβ) and tau PET, Magnetic Resonance Imaging (MRI), APOE genotyping, and cognitive testing. This includes individuals with (+) and without (-) evidence of Aβ and/or tau load or cognitive impairment (MCI/AD). As reviewed by Badimon (2023), fibrinogen is a soluble plasma protein that is converted to an insoluble fibrin clot by the serine protease thrombin. After fibrinogen cleavage by thrombin, fibrin forms a mesh-like network that traps blood cells and other components to form a clot, preventing further bleeding and facilitating tissue repair. Vascular damage in AD allows for plasma protein extravasation into brain and there is literature evidence of fibrin and fibrinogen in AD brain, co-localizing with Aβ. Fibrin deposition has been reported to increase in AD brain, compared to healthy controls, and to correlate with the degree of Aβ pathology. There is also evidence that Lecanemab (FDA-approved anti-amyloid AD therapeutic) targets Aβ and overlaps with the fibrinogen binding site. Our preliminary data suggest an age-related increase in 64Cu-FBP8 PET uptake in healthy brain. We will evaluate the in vivo pharmacokinetics of FBP8 in cognitively unimpaired young and older control and MCI/AD HABS-2 participants using standard compartmental modeling approaches and identify a simplified method for routine quantification of fibrin load in brain (Aim 1). We hypothesize that a quantitative kinetic modeling approach will emerge as a reference standard that provides robust measures of fibrin load in the brain. To achieve this, we will evaluate model performance and in vivo parameters that include FBP8 metabolism in plasma and extent that FBP8 fibrin load measures depend on BBB leakage and/or blood flow (by measuring DCE MRI KTRANS and 15O-water PET K1-WATER respectively). Finally, we will evaluate how age, Aβ load, and tau load relate to FBP8 PET fibrin load (Aim 2). We hypothesize that there will be a significant relationship between FBP8 fibrin load and age, with an interaction between Aβ and/or tau PET load and age. The availability of a well characterized PET fibrin brain imaging agent that is feasible to apply in older adults and patients with AD could enable new possibilities for the study of in vivo relationships between BBB dysfunction, fibrinogenesis and fibrinolysis, and impact of these factors with AD therapeutic efficacy. This includes those who may be vulnerable to edema and/or microhemorrhages that result from Aβ- related imaging abnormalities (ARIAs), a major side effect of anti-amyloid therapies. Project Number: 1R01AG093756-01A1 | Fiscal Year: 2026 | NIH Institute/Center: National Institute on Aging (NIA) | Principal Investigator: Julie Price (+2 co-PIs) | Institution: MASSACHUSETTS GENERAL HOSPITAL, BOSTON, MA | Award Amount: $684,567 | Activity Code: R01 | Study Section: Special Emphasis Panel[ZRG1 AN-W (55)] View on NIH RePORTER: https://reporter.nih.gov/project-details/11299618