J Clin Neurol.  2010 Mar;6(1):10-18. 10.3988/jcn.2010.6.1.10.

Will Molecular Optical Imaging Have Clinically Important Roles in Stroke Management, and How?

• Lee DK
• Nahrendorf M
• Schellingerhout D
• Kim DE

• KMID: 2135476
• DOI: http://doi.org/10.3988/jcn.2010.6.1.10

Abstract

Molecular imaging is a novel technology to visualize biological processes at the cellular and molecular levels, which is reshaping both biomedical research and clinical practice. By providing molecular information to supplement and augment conventional anatomy-based imaging, molecular imaging is expected to allow 1) the earlier detection of diseases, 2) precise evaluation of disease stages, and 3) both diagnostic and therapeutic monitoring of disease progression in a quantitative manner. In this brief review, we present our view on the prospects of molecular optical imaging in the field of stroke practice, focusing on the imaging vulnerability of atherosclerotic plaques, thrombolytic resistance, real-time cerebral perfusion, and penumbra.

Keyword

molecular imaging; stroke; optical imaging

MeSH Terms

Biological Processes
Disease Progression
Molecular Imaging
Optical Imaging
Perfusion
Plaque, Atherosclerotic
Stroke

Figure

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  Fig. 1 Duplex ultrasonography and angiography imaging provide structural information about carotid atherosclerosis. In the carotid sonograph (A), the atherosclerotic plaque is shown to have heterogeneous echodensity (blue arrows). The digital subtraction angiogram (B) shows significant atherosclerotic narrowing of the internal carotid artery. Current stroke practice relies heavily on the degree of carotid stenosis, as demonstrated by these anatomy-based structural imaging modalities. Adapted from Kim and Jeong87 with permission from the Korean Medical Association.

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  Fig. 2 Three-dimensional carotid positron-emission tomography and computed tomography angiography imaging. 18Fluoro-deoxyglucose uptake is elevated in the right carotid artery (blue arrow), reflecting increased metabolism due to heavy infiltration of inflammatory cells such as macrophages in the atherosclerotic plaque. Adapted from Kim and Jeong87 with permission from the Korean Medical Association. The numbers on the pseudo-color bar indicate standard uptake values.

• 

  Fig. 3 Protease-activatable near-infrared fluorescent (NIRF) imaging to allow the visualization of vulnerable plaques in the aorta of a mouse. In the areas positive for cathepsin K (CatK) immunohistochemical staining (A, ×20, red-colored regions), the fluorescence activation of the intravenously-injected imaging agent59 by the CatK cleavage activity is evident in NIRF microscopy imaging of cryosections of the aortic atheromata in an ApoEknock-out mouse fed on a Western diet (B, ×20); the co-localization is illustrated by the yellow arrowheads. Higher magnification (C, ×40) reveals the derangement of undulated elastic fibers (red arrow), suggesting matrix disorganization. A stable portion of the artery without CatK activity or elastin degradation is indicated by the blue arrow. Taken together, these results suggest that molecular optical imaging can reflect matrix-disorganizing protease activity, allowing identification of rupture-prone inflammatory plaques.

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  Fig. 4 Light imaging and protease-sensing molecular optical imaging to reflect the pro-atherosclerotic and anti-atherosclerotic effects of a high cholesterol diet and atorvastatin treatment, respectively. Eight-week-old ApoE knock-out mice were put on various diets: 1) a normal chow diet (left two panels), 2) a Western diet (center two panels), and 3) a Western diet with atorvastatin for 14 weeks (right two panels). The cathepsin B (CatB) NIRF imaging shows that the CatB-related signal is stronger in the mouse on a high cholesterol diet than in the mouse on a normal diet. In the animal on a Western diet with atorvastatin, the CatB-related signal is as low as that in the animal on a normal diet. Note that plaques that appear similar in the color photograph (of the animal on a Western diet) have different signal intensities in the CatB image (arrows and arrowheads). Adapted from Kim et al.88 with permission from the Korean Neurological Association. NIRF: near-infrared fluorescent.

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  Fig. 5 In vivo factor-XIII (FXIII) imaging to localize venous cerebral thrombi in a mouse. A mouse with cerebral venous th rombosis and a cranial window (inset) received a fluorescent imaging agent (A15) that could visualize the activity of the FXIII coagulation enzyme. Intravital microscopy imaging showed that the imaging agent initially remained intravascular, producing a cerebral angiogram (A). The NIRF signal subsequently decreased in all but thrombosed areas (B; image captured at 30 minutes after A15 injection). The representative H&E sections (C and D; acquired by cutting along the yellow and blue lines of B, respectively) of the superficial brain at the location of the frontal tip of the thrombus signal (black arrow in B) show the corresponding thrombus (yellow and blue arrows, respectively). In addition to the main body of the thrombus, a smaller thrombus in the adjacent vessel (asterisk in D) exhibits an FXIII-related NIRF signal (asterisk in B). Modified from Kim et al.70 with permission from the Korean Neurological Association. Scale bars: A, 1 mm; B, 150 µm. NIRF: near-infrared fluorescent.

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  Fig. 6 Potential role of molecular optical imaging to guide thrombolytic therapy in acute stroke patients. Currently there is no established clinical tool for characterizing the resistance of a thrombus to thrombolytic drugs. One of the key determinants of thrombolytic resistance is fibrin cross-linking resulting from the activity of FXIII. FXIII activity or the density of cross-linked fibrin mesh cannot be measured in vivo (A). One patient (who was later found to have had a highly cross-linked clot) had received a urokinase infusion in the setting of acute stroke. It took a long time to lyse the thrombus occluding (red circle in B) the left middle cerebral artery (MCA). This resistant thrombus was associated with not only delayed recanalization but also with high doses of thrombolytic drug delivered into MCA perforating arteries or collateral arteries (blue arrows in B and C). The patient exhibited post-thrombolysis hemorrhage in the basal ganglia and corona radiata (red arrow in D). In the near future, the thrombolytic resistance of a thrombus is likely to become measurable in vivo and in real time using a fluorescence-sensing fiber-optic catheter and molecular imaging probes to characterize the nature of the thrombus (E). This could be of great benefit in triaging patients to appropriate treatments (F and G).

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