Identification of cholesteryl esters in human carotid atherosclerosis by ex vivo image-guided proton MRS

Abstract Cochlear implants include an electrode array (EA) which needs to be inserted into the cochlea. Insertion tests using artificial cochlear models (ACM) or ex vivo specimens are widely used methods during EA development to characterize EA design properties, including insertion forces. Measured forces are directly linked to the orientation of the cochlear lumen with respect to the insertion axis of the test bench. While desired insertion directions in ACM experiments can be predefined by design, specimens are individually shaped and the cochlear lumen is embedded invisibly. Therefore, a new method for accurate, individual specimen positioning is required. A key element of the proposed method is a customizable pose setting adapter (PSA) used to adjust the specimen’s fine positioning. After rigid fixation of the specimen to a holder featuring spherical registration markers and subsequent cone beam computed tomography the desired insertion direction is planned. The planned data is used to calculate the individual shape of the PSA. Finally, the PSA is 3D printed and mounted between force sensor and specimen holder to correctly align the specimen to the test bench’s insertion axis. All necessary hard- and software have been developed including the specimen holder, a software for registration and trajectory planning, and a custom Matlab script whose output drives a parametric CAD file of the PSA. Positioning accuracy was determined in a first trial using 10 virtual trajectories and was found to be 0.23 ± 0.12 mm and 0.38 ± 0.17°. The presented stereotactic positioning procedure enables high repeatability in future ex vivo insertion experiments due to accurate, image-guided control of the insertion direction.

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VEGF-targeted multispectral optoacoustic tomography and fluorescence molecular imaging in human carotid atherosclerotic plaques

10.21203/rs.3.rs-428529/v1 ◽

2021 ◽

Author(s):

Pieter J. Steinkamp ◽

Jasper Vonk ◽

Lydian A. Huisman ◽

Gert-Jan Meersma ◽

Gilles F.H. Diercks ◽

...

Keyword(s):

Molecular Imaging ◽

Carotid Artery ◽

Ex Vivo ◽

Carotid Plaques ◽

Symptomatic Carotid ◽

Optoacoustic Tomography ◽

Imaging Results ◽

Human Carotid ◽

Fluorescence Molecular Imaging

Abstract Background: Vulnerable atherosclerotic carotid plaques are prone to rupture resulting in ischemic strokes. Molecular imaging techniques have the potential to assess plaque vulnerability by visualizing molecular markers. Bevacizumab-800CW is a near-infrared fluorescent contrast agent antibody targeting vascular endothelial growth factor-A (VEGF-A). Here, we study if administration of bevacizumab-800CW is safe and can be visualized using multispectral optoacoustic tomography (MSOT) to evaluate atherosclerotic carotid plaques in vivo by visualizing intra-plaque neovascularization.Methods: Healthy volunteers were imaged with MSOT to determine the technical feasibility of human carotid imaging with MSOT. Patients with symptomatic carotid artery stenosis scheduled for carotid artery endarterectomy were intravenously administered with a bolus injection of 4.5 mg bevacizumab-800CW. Before and two days after tracer administration, in vivo non-invasive MSOT was performed. For validation, ex vivo fluorescence molecular imaging of the surgically removed plaque specimen was performed and correlated with histopathology.Results: Administration of 4.5 mg bevacizumab-800CW was safe in five patients. MSOT achieved accurate visualization of the carotid bifurcation area and assessment of the plaque in all five patients. Bevacizumab-800CW-resolved signal could not be detected with MSOT prior to surgery. However, ex vivo analysis of the carotid plaque showed accumulation of bevacizumab-800CW.Conclusions: These first-in-human MSOT and fluorescence molecular imaging results in carotid artery plaques suggest that bevacizumab is a potential tracer for imaging of vulnerable plaques. However, the microdose used here cannot be detected with MSOT. A subsequent phase I dose-finding study is needed to evaluate bevacizumab-800CW in higher doses as a useful optoacoustic imaging agent. Moreover, the development of dedicated optoacoustic contrast agents for signal attenuation of the targeting moiety is advisable for carotid atherosclerotic plaque assessment using MSOT.

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Amyloid-Targeting PET Tracer [18F]Flutemetamol Accumulates in Atherosclerotic Plaques

Molecules ◽

10.3390/molecules24061072 ◽

2019 ◽

Vol 24 (6) ◽

pp. 1072 ◽

Cited By ~ 2

Author(s):

Sanna Hellberg ◽

Johanna Silvola ◽

Heidi Liljenbäck ◽

Max Kiugel ◽

Olli Eskola ◽

...

Keyword(s):

Ex Vivo ◽

Mouse Strains ◽

Aortic Tissue ◽

Atherosclerotic Plaques ◽

Carotid Artery Plaque ◽

Pet Tracer ◽

Pet Ct ◽

Human Carotid

Atherosclerosis is characterized by the accumulation of oxidized lipids in the artery wall, which triggers an inflammatory response. Oxidized low-density lipoprotein (ox-LDL) presents amyloid-like structural properties, and different amyloid species have recently been recognized in atherosclerotic plaques. Therefore, we studied the uptake of the amyloid imaging agent [18F]Flutemetamol in atherosclerotic plaques. The binding of [18F]Flutemetamol to human carotid artery plaque was studied in vitro. In vivo uptake of the tracer was studied in hypercholesterolemic IGF-II/LDLR−/−ApoB100/100 mice and C57BL/6N controls. Tracer biodistribution was studied in vivo with PET/CT, and ex vivo by gamma counter and digital ex vivo autoradiography. The presence of amyloid, ox-LDL, and macrophages in the plaques was examined by immunohistochemistry. [18F]Flutemetamol showed specific accumulation in human carotid plaque, especially in areas positive for amyloid beta. The aortas of IGF-II/LDLR−/−ApoB100/100 mice showed large thioflavin-S-positive atherosclerotic plaques containing ox-LDL and macrophages. Autoradiography revealed 1.7-fold higher uptake in the plaques than in a lesion-free vessel wall, but no difference in aortic tissue uptake between mouse strains were observed in the in vivo PET/CT. In conclusion, [18F]Flutemetamol binds to amyloid-positive areas in human atherosclerotic plaques. Further studies are warranted to clarify the uptake mechanisms, and the potential of the tracer for in vivo imaging of atherosclerosis in patients.

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