Information from Lay-Language Summaries is Embargoed Until the Conclusion of the Scientific Presentation
250—Ischemia: Animal Models
Sunday, November 10, 2013, 1:00 pm - 5:00 pm
250.09: Non-invasive biomarkers estimate the time of onset of cerebral ischemia
Location: Halls B-H
">C. BERTHET1, L. XIN2, C. BENAKIS1, *R. GRUETTER2,3,4, L. HIRT1,4, H. LEI2,3; 1Dept. of Clin. Neurosciences, Ctr. Hospitalier Universitaire Vaudois, Lausanne, Switzerland; 2EPFL, Lausanne, Switzerland; 3Univ. of Geneva, Geneva, Switzerland; 4Univ. of Lausanne, Lausanne, Switzerland
Abstract Body: Thrombolysis, the only currently available treatment for ischemic stroke can be administered only in a narrow time window of 4.5 hours. A significant number of patients have an unknown time of onset as the stroke occurred during their sleep, which disqualifies them for thrombolysis. The objective of this study was to determine whether magnetic resonance spectra of the ischemic striatum could provide useful information for the estimation of the onset time of cerebral ischemia. We modeled ischemic stroke in male ICR CD1mice using a permanent middle cerebral artery filament occlusion model with laser Doppler control of the regional cerebral blood flow (<20% during ischemia). Mice were then measured by repeated magnetic resonance spectroscopy of the ipsilateral striatum in a 14.1T system. The acquired MR spectra were processed and quantified referencing to striatal water contents, as previously described for transient cerebral ischemia (Lei H et al. 2009, Berthet C et al. 2011) yielding metabolite concentrations. We observed different spectral patterns after permanent ischemia than after transient ischemia, with an initial striking increase in gamma-aminobutyric acid (GABA) and no increase in glutamine. We observed a mono-exponential decline (coefficient of determination, R2>0.90) of e.g. taurine (Tau), N-acetylaspartate (NAA) and the sum of Tau, NAA and glutamate (Glu, as in figure). Using these characteristic reductions, in a set of blinded measurements we were able to estimate the time of onset of permanent ischemia with an accuracy of approximately +/- 30 min (SDs). This is a novel approach, in mice, addressing the clinically highly relevant problem of determining the time of onset of ischemic stroke in stroke patients.
Lay Language Summary: Biomarkers to estimate the time of onset of cerebral ischemia Our study indicates that biochemical changes occurring in the rodent brain after stroke can be measured non-invasively in the live animal and allow estimating the time of stroke onset. This finding is important, as it will be extremely useful, if translated to a clinical setting, to propose appropriate treatment in patients in whom the stroke onset time is unknown, as for instance if the stroke occurs during their sleep. The most common type of stroke, ischemic stroke, results from the occlusion of a brain feeding artery, leading within minutes to hours to irreversible damage of the oxygen and glucose deprived brain tissue. Thrombolysis, the only currently available treatment for ischemic stroke consists of the intravenous injection of a blood clot dissolving agent. It is aimed at restoring blood flow to the brain and can be administered only in a narrow time window of 4.5 hours because of lack of efficacy and increased bleeding risk beyond this time-point. A significant number of patients, approximately one in five, have an unknown time of onset, which disqualifies them for thrombolysis. The objective of this study was to determine whether magnetic resonance spectroscopy, a method allowing non-invasive measurement of the concentration of different natural compounds in the brain, could provide useful information for the estimation of the onset time of cerebral ischemia. We modeled ischemic stroke in mice by inducing a permanent occlusion of the middle cerebral artery, a critically important artery supplying a large part of the cerebral hemisphere, commonly affected in human stroke. Mice were then subjected to repeated magnetic resonance spectroscopy measurements. Measurements were performed in the ischemic striatum, a deep brain structure lying in the territory of the middle cerebral artery and affected in this ischemia model. We observed different spectral patterns after permanent ischemia from those we previously described for transient ischemia resulting from transient occlusion of the middle cerebral artery. This allows us to distinguish tissue still deprived of blood supply from tissue with restored flow. We observed a specific pattern of decline of several metabolites such as taurine, N-acetylaspartate and to some extent the sum of taurine, N-acetylaspartate and glutamate. Using these decline curves we were able to estimate the time of onset of permanent ischemia in a set of mice, in a blinded experiment, with an accuracy of approximately +/- 30 min. This is a novel approach, addressing the highly relevant clinical problem of determining the time of onset of ischemic stroke, which should be translated to studies in patients.
Neuroscience 2013 (43rd annual meeting of the Society for Neuroscience)Exit