Purpose: Overexpression and activation of matrix metalloproteinase-13 (MMP-13) within atheroma increases susceptibility to plaque rupture, a major cause of severe cardiovascular complications. In comparison to pan-MMP targeting [ 18 F]BR-351, we evaluated the potential for [ 18 F]FMBP, a selective PET radiotracer for MMP-13, to detect extracellular matrix (ECM) remodeling in vascular plaques possessing markers of inflammation.Procedures: [ 18 F]FMBP and [ 18 F]BR-351 were initially assessed in vitro by incubation with en face aortae from 8 month-old atherogenic ApoE -/mice. Ex vivo biodistributions, plasma metabolite analyses, and ex vivo autoradiography were analogously performed 30 minutes after intravenous radiotracer administration in age-matched C57Bl/6 and ApoE -/mice under baseline or homologous blocking conditions. En face aortae were subsequently stained with Oil Red O (ORO), sectioned, and subject to immunofluorescence staining for Mac-2 and MMP-13.Results: High-resolution autoradiographic image analysis demonstrated target specificity and regional concordance to lipid-rich lesions. Biodistribution studies revealed hepatobiliary excretion, low accumulation of radioactivity in non-excretory organs, and few differences between strains and conditions in non-target organs. Plasma metabolite analyses uncovered that [ 18 F]FMBP exhibited excellent in vivo stability (≥74% intact) while [ 18 F]BR-351 was extensively metabolized (≤37% intact). Ex vivo autoradiography and histology of en face aortae revealed that [ 18 F]FMBP, relative to [ 18 F]BR-351, exhibited 2.9-fold greater lesion uptake, substantial specific binding (68%), and improved sensitivity to atherosclerotic tissue (2.9-fold vs 2.1-fold). Immunofluorescent staining of aortic en face cross-sections demonstrated elevated Mac-2 and MMP-13 positive areas within atherosclerotic lesions identified by [ 18 F]FMBP ex vivo autoradiography.Conclusions: While both radiotracers successfully identified atherosclerotic plaques, [ 18 F]FMBP showed superior specificity and sensitivity for lesions possessing features of destructive plaque 3 remodeling. The detection of ECM remodeling by selective targeting of MMP-13 may enable characterization of high-risk atherosclerosis featuring elevated collagenase activity.
Following the development of magnetic resonance imaging (MRI) methods to assay the integrity of catecholamine nuclei, including the locus coeruleus (LC), there has been an effort to develop automated methods that can accurately segment this small structure in an automated manner to promote its widespread use and overcome limitations of manual segmentation. Here we characterize an automated LC segmentation approach (referred to as the funnel‐tip [FT] method) in healthy individuals and individuals with LC degeneration in the context of Alzheimer's disease (AD, confirmed with tau‐PET imaging using [18F]MK6240). The first sample included n = 190 individuals across the AD spectrum from cognitively normal to moderate AD. LC signal assayed with FT segmentation showed excellent agreement with manual segmentation (intraclass correlation coefficient [ICC] = 0.91). Compared to other methods, the FT method showed numerically higher correlation to AD status (defined by presence of tau: Cohen's d = 0.64) and AD severity (Braak stage: Pearson R = −.35, cognitive function: R = .25). In a separate sample of n = 12 control participants, the FT method showed excellent scan–rescan reliability (ICC = 0.82). In another sample of n = 30 control participants, we found that the structure of the LC defined by FT segmentation approximated its expected shape as a contiguous line: <5% of LC voxels strayed >1 voxel (0.69 mm) from this line. The FT LC segmentation shows high agreement with manual segmentation and captures LC degeneration in AD. This practical method may facilitate larger research studies of the human LC‐norepinephrine system and has potential to support future use of neuromelanin‐sensitive MRI as a clinical biomarker.
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