Article

Tc-99-HYNIC-annexin VSPECT imaging of acute stroke and its response to neuroprotective therapy with anti-Fas ligand antibody

Stanford University, Palo Alto, California, United States
European journal of nuclear medicine and molecular imaging (Impact Factor: 5.22). 06/2006; 33(5):566-74. DOI: 10.1007/s00259-005-0046-6
Source: PubMed

ABSTRACT The first aim of the study was to determine whether (99m)Tc-HYNIC-annexin V, a marker of cellular stress and apoptosis, can detect ischemic injury in patients with acute stroke. Secondly, we wished to test radiolabeled annexin's ability to monitor therapy in a rodent model of focal ischemic injury.
SPECT imaging of patients was performed between 1 and 2 h after intravenous injection of 30 mCi (1,110 MBq) of tracer. Eight MFL4 (anti-FasL) antibody-treated (400 microg i.p. days 0 and 3) and 21 control adult male Sprague-Dawley rats underwent small animal SPECT imaging with 5-10 mCi (185-370 MBq) of tracer, 1 and 6 days after a 2-h intraluminal thread occlusion of the left middle cerebral artery.
Two patients with acute stroke had regions of multifocal annexin uptake that correlated with sites of restricted diffusion on MRI. Anti-FasL antibody treatment significantly reduced annexin uptake by 92% with a 60% decrease in the number of caspase-8 staining (apoptotic) neurons on day 1. On day 6, treated animals had an 80% reduction in tracer uptake with a 75% decrease in infarct size as compared with controls. Annexin uptake in controls and treated animals (day 6) linearly correlated with infarct size (r (2)=0.603, p=0.0036) and the number of TUNEL-positive (apoptotic) nuclei (r (2)=0.728, p=0.00084).
Annexin imaging shows foci of increased uptake at sites of ischemic injury in patients with acute stroke. Annexin imaging can assess the effects of therapy for ischemic cerebral injury in rats, suggesting its potential as a non-invasive indicator of drug efficacy in future clinical trials.

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    • "Tc-AnxV) has been used in the clinic to assess the efficacy of therapy in cancer patients, but also to detect apoptosis in acute myocardial infarction, rheumatoid arthritis, acute stroke and Alzheimer's dementia (Blankenberg et al., 2006; Lampl et al., 2006; Narula and Strauss, 2003; Rottey et al., 2006; Thimister et al., 2003). It should be noted that Annexin V imaging also shows physiologically normal apoptosis, for instance in the bone marrow, gastrointestinal mucosae and salivary glands (Kerr et al., 1972). "
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    ABSTRACT: Annexin V imaging is suggested to provide a good indication of cancer treatment efficacy. To study the accuracy of (99m)Tc-AnxV imaging, we monitored chemo-sensitive and chemo-resistant tumors in a mouse breast cancer model after treatment with docetaxel. Sensitive tumors showed a slight peak in (99m)Tc-AnxV uptake one day post-treatment, while uptake in resistant tumors remained constant. In contrast to immunohistochemical analysis, (99m)Tc-AnxV imaging could not be used to predict tumor response, due to large variation between animals.
    Applied radiation and isotopes: including data, instrumentation and methods for use in agriculture, industry and medicine 04/2011; 69(4):656-62. DOI:10.1016/j.apradiso.2010.12.012
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    • "Radiolabeled annexin A5 has already been used in animal and human studies of stroke without such a characterization (Blankenberg et al, 2006). Some of the images of these studies are indicative of unspecific signal from the choroid plexus, especially in the paper by Blankenberg et al (2006). The strong signal in the area of the ventricles detected with SPECT can be blood pool, as discussed in the paper or accumulation of the compound in the choroid plexus or both. "
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    ABSTRACT: To monitor stroke-induced brain damage and assess neuroprotective therapies, specific imaging of cell death after cerebral ischemia in a noninvasive manner is highly desirable. Annexin A5 has been suggested as a marker for imaging cell death under various disease conditions including stroke. In this study, C57BL6/N mice received middle cerebral artery occlusion (MCAO) and were injected intravenously with either active or inactive Cy5.5-annexin A5 48 hours after reperfusion. Some mice also received propidium iodide (PI), a cell integrity marker. Only in mice receiving active Cy5.5-annexin A5 were fluorescence intensities significantly higher over the hemisphere ipsilateral to MCAO than on the contralateral side. This was detected noninvasively and ex vivo 4 and 8 hours after injection. The majority of cells positive for fluorescent annexin A5 were also positive for PI and fragmented DNA as detected by terminal deoxynucleotidyl transferase-mediated 2'-deoxyuridine 5'-triphosphate-biotin nick end labeling (TUNEL) staining. This study demonstrates the high specificity of annexin A5 for visualization of cell death in a mouse model of stroke. To our knowledge, this is the first study to compare the distribution of injected active and inactive annexin A5, PI, and TUNEL staining. It provides important information on the experimental and potential clinical applications of annexin A5-based imaging agents in stroke.
    Journal of cerebral blood flow and metabolism: official journal of the International Society of Cerebral Blood Flow and Metabolism 01/2011; 31(5):1311-20. DOI:10.1038/jcbfm.2010.233
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    • "This is also consistent with prior reports (Rosenbaum et al. 2000; Qiu et al. 2002). Prior studies have suggested a detrimental effect of the Fas signaling pathway in experimental stroke, as treatment with Fas antibody or studying mice deficient in Fas led to less ischemic injury (Martin-Villalba et al. 1999; Martin-Villalba et al. 2001; Blankenberg et al. 2006), while overexpression of FasL led to increased apoptosis in a model of traumatic brain injury (Qiu et al. 2002). "
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    ABSTRACT: Protection by mild hypothermia has previously been associated with better mitochondrial preservation and suppression of the intrinsic apoptotic pathway. It is also known that the brain may undergo apoptotic death via extrinsic, or receptor-mediated pathways, such as that triggered by Fas/FasL. Male Sprague-Dawley rats subjected to 2 h middle cerebral artery occlusion with 2 h intraischemic mild hypothermia (33 degrees C) were assayed for Fas, FasL and caspase-8 expression. Ischemia increased Fas, but decreased FasL by approximately 50-60% at 6 and 24 h post-insult. Mild hypothermia significantly reduced expression of Fas and processed caspase-8 both by approximately 50%, but prevented ischemia-induced FasL decreases. Fractionation revealed that soluble/shed FasL (sFasL) was decreased by hypothermia, while membrane-bound FasL (mFasL) increased. To more directly assess the significance of the Fas/FasL pathway in ischemic stroke, primary neuron cultures were exposed to oxygen glucose deprivation. Since FasL is cleaved by matrix metalloproteinases (MMPs), and mild hypothermia decreases MMP expression, treatment with a pan-MMP inhibitor also decreased sFasL. Thus, mild hypothermia is associated with reduced Fas expression and caspase-8 activation. Hypothermia prevented total FasL decreases, and most of it remained membrane-bound. These findings reveal new observations regarding the effect of mild hypothermia on the Fas/FasL and MMP systems.
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