Non-invasive diagnostic biomarkers for estimating the onset time of permanent cerebral ischemia

The treatments for ischemic stroke can only be administered in a narrow time-window. However, the ischemia onset time is unknown in ~30% of stroke patients (wake-up strokes). The objective of this study was to determine whether MR spectra of ischemic brains might allow the precise estimation of cerebral ischemia onset time. We modeled ischemic stroke in male ICR-CD1 mice using a permanent middle cerebral artery filament occlusion model with laser Doppler control of the regional cerebral blood flow. Mice were then subjected to repeated MRS measurements of ipsilateral striatum at 14.1[thinsp]T. A striking initial increase in [gamma]-aminobutyric acid (GABA) and no increase in glutamine were observed. A steady decline was observed for taurine (Tau), N-acetyl-aspartate (NAA) and similarly for the sum of NAA+Tau+glutamate that mimicked an exponential function. The estimation of the time of onset of permanent ischemia within 6[thinsp]hours in a blinded experiment with mice showed an accuracy of 33[plusmn]10[thinsp]minutes. A plot of GABA, Tau, and neuronal marker concentrations against the ratio of acetate/NAA allowed precise separation of mice whose ischemia onset lay within arbitrarily chosen time-windows. We conclude that 1H-MRS has the potential to detect the clinically relevant time of onset of ischemic stroke.

High-resolution spatial mapping of changes in the neurochemical profile after focal ischemia in mice

Malte Alf, Rolf Gruetter, Hongxia Lei

After ischemic stroke, the ischemic damage to brain tissue evolves over time and with an uneven spatial distribution. Early irreversible changes occur in the ischemic core, whereas, in the penumbra, which receives more collateral blood flow, the damage is more mild and delayed. A better characterization of the penumbra, irreversibly damaged and healthy tissues is needed to understand the mechanisms involved in tissue death. MRSI is a powerful tool for this task if the scan time can be decreased whilst maintaining high sensitivity. Therefore, we made improvements to a H-1 MRSI protocol to study middle cerebral artery occlusion in mice. The spatial distribution of changes in the neurochemical profile was investigated, with an effective spatial resolution of 1.4 mu L, applying the protocol on a 14.1-T magnet. The acquired maps included the difficult-to-separate glutamate and glutamine resonances and, to our knowledge, the first mapping of metabolites gamma-aminobutyric acid and glutathione in vivo, within a metabolite measurement time of 45min. The maps were in excellent agreement with findings from single-voxel spectroscopy and offer spatial information at a scan time acceptable for most animal models. The metabolites measured differed with respect to the temporal evolution of their concentrations and the localization of these changes. Specifically, lactate and N-acetylaspartate concentration changes largely overlapped with the T-2-hyperintense region visualized with MRI, whereas changes in cholines and glutathione affected the entire middle cerebral artery territory. Glutamine maps showed elevated levels in the ischemic striatum until 8h after reperfusion, and until 24h in cortical tissue, indicating differences in excitotoxic effects and secondary energy failure in these tissue types. Copyright (C) 2011 John Wiley & Sons, Ltd.

Wiley-Blackwell2012

Treatment with Evasin-3 reduces atherosclerotic vulnerability for ischemic stroke, but not brain injury in mice

Jean-Christophe Copin, Luciano Dos Santos Aggum Capettini, Katia Galan, Danielle Gomes Passos Silva, Nikolaos Stergiopulos

Neutrophilic inflammation might have a pathophysiological role in both carotid plaque rupture and ischemic stroke injury. Here, we investigated the potential benefits of the CXC chemokine-binding protein Evasin-3, which potently inhibits chemokine bioactivity and related neutrophilic inflammation in two mouse models of carotid atherosclerosis and ischemic stroke, respectively. In the first model, the chronic treatment with Evasin-3 as compared with Vehicle (phosphate-buffered saline (PBS)) was investigated in apolipoprotein E-deficient mice implanted of a 'cast' carotid device. In the second model, acute Evasin-3 treatment (5 minutes after cerebral ischemia onset) was assessed in mice subjected to transient left middle cerebral artery occlusion. Although CXCL1 and CXCL2 were upregulated in both atherosclerotic plaques and infarcted brain, only CXCL1 was detectable in serum. In carotid atherosclerosis, treatment with Evasin-3 was associated with reduction in intraplaque neutrophil and matrix metalloproteinase-9 content and weak increase in collagen as compared with Vehicle. In ischemic stroke, treatment with Evasin-3 was associated with reduction in ischemic brain neutrophil infiltration and protective oxidants. No other effects in clinical and histological outcomes were observed. We concluded that Evasin-3 treatment was associated with reduction in neutrophilic inflammation in both mouse models. However, Evasin-3 administration after cerebral ischemia onset failed to improve poststroke outcomes. Journal of Cerebral Blood Flow & Metabolism (2013) 33, 490-498; doi:10.1038/jcbfm.2012.198; published online 19 December 2012

Nature Publishing Group2013

Metabolic fingerprints discriminating severity of acute ischemia using in vivo high-field H-1 magnetic resonance spectroscopy

Lara Buscemi Estefanell, Hongxia Lei

Despite the improving imaging techniques, it remains challenging to produce magnetic resonance (MR) imaging fingerprints depicting severity of acute ischemia. The aim of this study was to evaluate the potential of the overall high-field H-1 MR Spectroscopy (H-1-MRS) neurochemical profile as a metabolic signature for acute ischemia severity in rodent brains. We modeled global ischemia with one-stage 4-vessel-occlusion (4VO) in rats. Vascular structures were assessed immediately by magnetic resonance angiography. The neurochemical responses in the bilateral cortex were measured 1 h after stroke onset by H-1-MRS. Then we used Partial-Least-Squares discriminant analysis on the overall neurochemical profiles to seek metabolic signatures for ischemic severity subgroups. This approach was further tested on neurochemical profiles of mouse striatum 1 h after permanent middle cerebral artery occlusion, where vascular blood flow was monitored by laser Doppler. Magnetic resonance angiography identified successful 4VO from controls and incomplete global ischemia (e.g., 3VO). H-1-MR spectra of rat cortex after 4VO showed a specific metabolic pattern, distinct from that of respective controls and rats with 3VO. Partial-Least-Squares discriminant analysis on the overall neurochemical profiles revealed metabolic signatures of acute ischemia that may be extended to mice after permanent middle cerebral artery occlusion. Fingerprinting severity of acute ischemia using neurochemical information may improve MR diagnosis in stroke patients.

2020

High-resolution spatial mapping of changes in the neurochemical profile after focal ischemia in mice

Malte Alf, Rolf Gruetter, Hongxia Lei

Wiley-Blackwell2012