Determining Stroke Onset Time Using Quantitative MRI: High Accuracy, Sensitivity and Specificity Obtained from Magnetic Resonance Relaxation Times

Many ischaemic stroke patients are ineligible for thrombolytic therapy due to unknown onset time. Quantitative MRI (qMRI) is a potential surrogate for stroke timing. Rats were subjected to permanent middle cerebral artery occlusion and qMRI parameters including hemispheric differences in apparent diffusion coefficient, T2-weighted signal intensities, T1 and T2 relaxation times (qT1, qT2) and f1, f2 and Voverlap were measured at hourly intervals at 4.7 or 9.4 T. Accuracy and sensitivity for identifying strokes scanned within and beyond 3 h of onset was determined. Accuracy for Voverlap, f2 and qT2 (>90%) was significantly higher than other parameters. At a specificity of 1, sensitivity was highest for Voverlap (0.90) and f2 (0.80), indicating promise of these qMRI indices in the clinical assessment of stroke onset time

A spatiotemporal theory for MRI T2 relaxation time and apparent diffusion coefficient in the brain during acute ischaemia:Application and validation in a rat acute stroke model

The objective of this study is to present a mathematical model which can describe the spatiotemporal progression of cerebral ischaemia and predict magnetic resonance observables including the apparent diffusion coefficient (ADC) of water and transverse relaxation time T(2). This is motivated by the sensitivity of the ADC to the location of cerebral ischaemia and T(2) to its time-course, and that it has thus far proven challenging to relate observations of changes in these MR parameters to stroke timing, which is of considerable importance in making treatment choices in clinics. Our mathematical model, called the cytotoxic oedema/dissociation (CED) model, is based on the transit of water from the extra- to the intra-cellular environment (cytotoxic oedema) and concomitant degradation of supramacromolecular and macromolecular structures (such as microtubules and the cytoskeleton). It explains experimental observations of ADC and T(2), as well as identifying the rate of spread of effects of ischaemia through a tissue as a dominant system parameter. The model brings the direct extraction of the timing of ischaemic stroke from quantitative MRI closer to reality, as well as providing insight on ischaemia pathology by imaging in general. We anticipate that this may improve patient access to thrombolytic treatment as a future application

Stroke onset time estimation from multispectral quantitative magnetic resonance imaging in a rat model of focal permanent cerebral ischaemia

Background Quantitative T2 relaxation magnetic resonance imaging allows estimation of stroke onset time. Aims We aimed to examine the accuracy of quantitative T1 and quantitative T2 relaxation times alone and in combination to provide estimates of stroke onset time in a rat model of permanent focal cerebral ischemia and map the spatial distribution of elevated quantitative T1 and quantitative T2 to assess tissue status. Methods Permanent middle cerebral artery occlusion was induced in Wistar rats. Animals were scanned at 9.4T for quantitative T1, quantitative T2, and Trace of Diffusion Tensor (Dav) up to 4 h post-middle cerebral artery occlusion. Time courses of differentials of quantitative T1 and quantitative T2 in ischemic and non-ischemic contralateral brain tissue (ΔT1, ΔT2) and volumes of tissue with elevated T1 and T2 relaxation times ( f1, f2) were determined. TTC staining was used to highlight permanent ischemic damage. Results ΔT1, ΔT2, f1, f2, and the volume of tissue with both elevated quantitative T1 and quantitative T2 (VOverlap) increased with time post-middle cerebral artery occlusion allowing stroke onset time to be estimated. VOverlap provided the most accurate estimate with an uncertainty of ±25 min. At all times-points regions with elevated relaxation times were smaller than areas with Dav defined ischemia. Conclusions Stroke onset time can be determined by quantitative T1 and quantitative T2 relaxation times and tissue volumes. Combining quantitative T1 and quantitative T2 provides the most accurate estimate and potentially identifies irreversibly damaged brain tissue. </jats:sec

Progressive Volume Loss and White Matter Degeneration in Cstb-Deficient Mice: A Diffusion Tensor and Longitudinal Volumetry MRI Study

Peer reviewe

Early Maternal Alcohol Consumption Alters Hippocampal DNA Methylation, Gene Expression and Volume in a Mouse Model

The adverse effects of alcohol consumption during pregnancy are known, but the molecular events that lead to the phenotypic characteristics are unclear. To unravel the molecular mechanisms, we have used a mouse model of gestational ethanol exposure, which is based on maternal ad libitum ingestion of 10% (v/v) ethanol for the first 8 days of gestation (GD 0.5-8.5). Early neurulation takes place by the end of this period, which is equivalent to the developmental stage early in the fourth week post-fertilization in human. During this exposure period, dynamic epigenetic reprogramming takes place and the embryo is vulnerable to the effects of environmental factors. Thus, we hypothesize that early ethanol exposure disrupts the epigenetic reprogramming of the embryo, which leads to alterations in gene regulation and life-long changes in brain structure and function. Genome-wide analysis of gene expression in the mouse hippocampus revealed altered expression of 23 genes and three miRNAs in ethanol-exposed, adolescent offspring at postnatal day (P) 28. We confirmed this result by using two other tissues, where three candidate genes are known to express actively. Interestingly, we found a similar trend of upregulated gene expression in bone marrow and main olfactory epithelium. In addition, we observed altered DNA methylation in the CpG islands upstream of the candidate genes in the hippocampus. Our MRI study revealed asymmetry of brain structures in ethanol-exposed adult offspring (P60): we detected ethanol-induced enlargement of the left hippocampus and decreased volume of the left olfactory bulb. Our study indicates that ethanol exposure in early gestation can cause changes in DNA methylation, gene expression, and brain structure of offspring. Furthermore, the results support our hypothesis of early epigenetic origin of alcohol-induced disorders: changes in gene regulation may have already taken place in embryonic stem cells and therefore can be seen in different tissue types later in life.Peer reviewe

Determining T2 relaxation time and stroke onset relationship in ischaemic stroke within apparent diffusion coefficient-defined lesions. A user-independent method for quantifying the impact of stroke in the human brain

Background and objective:In hyperacute ischaemic stroke, T2 of cerebral water increases with time. Quantifying this change may be informative of the extent of tissue damage and onset time. Our objective was to develop a user-unbiased method to measure the effect of cerebral ischaemia on T2 to study stroke onset time-dependency in human acute stroke lesions. Methods:Six rats were subjected to permanent middle cerebral occlusion to induce focal ischaemia, and a consecutive cohort of acute stroke patients (n=38) were recruited within 9 hours from symptom onset. T1-weighted structural, T2 relaxometry, and diffusion MRI for apparent diffusion coefficient (ADC) were acquired. Ischaemic lesions were defined as regions of lowered ADC. The median T2 difference (ΔT2) between lesion and contralateral non-ischaemic control region was determined by the newly-developed spherical reference method, and data compared to that obtained by the mirror reference method. Linear regressions and receiver operating characteristics (ROC) were compared between the two methods. Results:ΔT2 increases linearly in rat brain ischaemia by 1.9 ± 0.8 ms/h during the first 6 hours, as determined by the spherical reference method. In patients, ΔT2 linearly increases by 1.6 ± 1.4 and 1.9 ± 0.9 ms/h in the lesion, as determined by the mirror reference and spherical reference method, respectively. ROC analyses produced areas under the curve of 0.83 and 0.71 for the spherical and mirror reference methods, respectively. Conclusions:Data from the spherical reference method showed that the median T2 increase in the ischaemic lesion is correlated with stroke onset time in a rat as well as in a human patient cohort, opening the possibility of using the approach as a timing tool in clinics.</p