Estimation of the onset time of cerebral ischemia using T1rho and T2 MRI in rats.

BACKGROUND AND PURPOSE: Time of ischemia onset is the most critical factor for patient selection for available drug treatment strategies. The purpose of this study was to evaluate the abilities of the absolute longitudinal rotating frame (T(1ρ)) and transverse (T(2)) MR relaxation times to estimate the onset time of ischemia in rats. METHODS: Permanent middle cerebral artery occlusion in rats was used to induce focal cerebral ischemia and animals were imaged with multiparametric MRI at several time points up to 7 hours postischemia. Ischemic parenchyma was defined as tissue with apparent diffusion coefficient of water <70% from that in the contralateral nonischemic brain. RESULTS: The difference in the absolute T(1ρ) and T(2) between ischemic and contralateral nonischemic striatum increased linearly within the first 6 hours of middle cerebral artery occlusion. The slopes for T(1ρ) and T(2) fits for both tissue types were similar; however, the time offsets were significantly longer for both MR parameters in the cortex than in the striatum. CONCLUSIONS: T(1ρ) and T(2) MRI provide estimates for the onset time of cerebral ischemia requiring regional calibration curves from ischemic brain. Assuming that patients with suspected ischemic stroke are scanned by MRI within this timeframe, these MRI techniques may constitute unbiased tools for stroke onset time evaluation potentially aiding the decision-making for drug treatment strategies.

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.

Magnetic Resonance Imaging Protocol for Stroke Onset Time Estimation in Permanent Cerebral Ischemia.

MRI provides a sensitive and specific imaging tool to detect acute ischemic stroke by means of a reduced diffusion coefficient of brain water. In a rat model of ischemic stroke, differences in quantitative T1 and T2 MRI relaxation times (qT1 and qT2) between the ischemic lesion (delineated by low diffusion) and the contralateral non-ischemic hemisphere increase with time from stroke onset. The time dependency of MRI relaxation time differences is heuristically described by a linear function and thus provides a simple estimate of stroke onset time. Additionally, the volumes of abnormal qT1 and qT2 within the ischemic lesion increase linearly with time providing a complementary method for stroke timing. A (semi)automated computer routine based on the quantified diffusion coefficient is presented to delineate acute ischemic stroke tissue in rat ischemia. This routine also determines hemispheric differences in qT1 and qT2 relaxation times and the location and volume of abnormal qT1 and qT2 voxels within the lesion. Uncertainties associated with onset time estimates of qT1 and qT2 MRI data vary from ± 25 min to ± 47 min for the first 5 hours of stroke. The most accurate onset time estimates can be obtained by quantifying the volume of overlapping abnormal qT1 and qT2 lesion volumes, termed 'Voverlap' (± 25 min) or by quantifying hemispheric differences in qT2 relaxation times only (± 28 min). Overall, qT2 derived parameters outperform those from qT1. The current MRI protocol is tested in the hyperacute phase of a permanent focal ischemia model, which may not be applicable to transient focal brain ischemia.

A Magnetic Resonance Imaging Protocol for Stroke Onset Time Estimation in Permanent Cerebral Ischemia.

MRI provides a sensitive and specific imaging tool to detect acute ischemic stroke by means of a reduced diffusion coefficient of brain water. In a rat model of ischemic stroke, differences in quantitative T1 and T2 MRI relaxation times (qT1 and qT2) between the ischemic lesion (delineated by low diffusion) and the contralateral non-ischemic hemisphere increase with time from stroke onset. The time dependency of MRI relaxation time differences is heuristically described by a linear function and thus provides a simple estimate of stroke onset time. Additionally, the volumes of abnormal qT1 and qT2 within the ischemic lesion increase linearly with time providing a complementary method for stroke timing. A (semi)automated computer routine based on the quantified diffusion coefficient is presented to delineate acute ischemic stroke tissue in rat ischemia. This routine also determines hemispheric differences in qT1 and qT2 relaxation times and the location and volume of abnormal qT1 and qT2 voxels within the lesion. Uncertainties associated with onset time estimates of qT1 and qT2 MRI data vary from ± 25 min to ± 47 min for the first 5 hours of stroke. The most accurate onset time estimates can be obtained by quantifying the volume of overlapping abnormal qT1 and qT2 lesion volumes, termed 'Voverlap' (± 25 min) or by quantifying hemispheric differences in qT2 relaxation times only (± 28 min). Overall, qT2 derived parameters outperform those from qT1. The current MRI protocol is tested in the hyperacute phase of a permanent focal ischemia model, which may not be applicable to transient focal brain ischemia.

Stroke Onset Time Determination Using MRI Relaxation Times without Non-Ischaemic Reference in A Rat Stroke Model.

BACKGROUND: Objective timing of stroke in emergency departments is expected to improve patient stratification. Magnetic resonance imaging (MRI) relaxations times, T2 and T1ρ , in abnormal diffusion delineated ischaemic tissue were used as proxies of stroke time in a rat model. METHODS: Both 'non-ischaemic reference'-dependent and -independent estimators were generated. Apparent diffusion coefficient (ADC), T2 and T1ρ , were sequentially quantified for up to 6 hours of stroke in rats (n = 8) at 4.7T. The ischaemic lesion was identified as a contiguous collection of voxels with low ADC. T2 and T1ρ in the ischaemic lesion and in the contralateral non-ischaemic brain tissue were determined. Differences in mean MRI relaxation times between ischaemic and non-ischaemic volumes were used to create reference-dependent estimator. For the reference-independent procedure, only the parameters associated with log-logistic fits to the T2 and T1ρ distributions within the ADC-delineated lesions were used for the onset time estimation. RESULT: The reference-independent estimators from T2 and T1ρ data provided stroke onset time with precisions of ±32 and ±27 minutes, respectively. The reference-dependent estimators yielded respective precisions of ±47 and ±54 minutes. CONCLUSIONS: A 'non-ischaemic anatomical reference'-independent estimator for stroke onset time from relaxometric MRI data is shown to yield greater timing precision than previously obtained through reference-dependent procedures.

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

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 (V(Overlap)) increased with time post-middle cerebral artery occlusion allowing stroke onset time to be estimated. V(Overlap) 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.

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 T2 This is motivated by the sensitivity of the ADC to the location of cerebral ischaemia and T2 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 T2, 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.

Timing the ischaemic stroke by 1H-MRI: improved accuracy using absolute relaxation times over signal intensities.

One in four ischaemic stroke patients are ineligible for thrombolytic treatment due to unknown onset time. Quantification of absolute MR relaxation times and signal intensities are potential methods for estimating stroke duration. We compared the accuracy of these approaches and determined whether changes in relaxation times and signal intensities identify the same ischaemic tissue as diffusion MRI. Seven Wistar rats underwent permanent middle cerebral artery occlusion to induce focal ischaemia and were scanned at six time points. The trace of the diffusion tensor (DAV), T1ρ and T2 were acquired at 4.7 T. Results show relaxation times, and signal intensities of the MR relaxation parameters increase linearly with ischaemia duration (P<0.001). Using T1ρ and T2 relaxation times, an estimate of 4.5 h after occlusion has an uncertainty of ± 12 and ± 35 min, respectively, compared with over 50 min for signal intensities. In addition, we present a pixel-by-pixel method that simultaneously estimates stroke onset time and identifies potentially irreversible ischaemic tissue using absolute relaxation times. This method demonstrates signal intensity changes during ischaemia display an ambiguous pattern and highlights the possibility that diffusion MRI overestimates the true extent of irreversible ischaemia. In conclusion, quantification of absolute relaxation times at a single time point enables a more accurate estimation of stroke duration than signal intensities and provides more information about tissue status in ischaemia.

Relaxation along a fictitious field (RAFF) and Z-spectroscopy using alternating-phase irradiation (ZAPI) in permanent focal cerebral ischemia in rat.

Cerebral ischemia alters the molecular dynamics and content of water in brain tissue, which is reflected in NMR relaxation, diffusion and magnetization transfer (MT) parameters. In this study, the behavior of two new MRI contrasts, Relaxation Along a Fictitious Field (RAFF) and Z-spectroscopy using Alternating-Phase Irradiation (ZAPI), were quantified together with conventional relaxation parameters (T1, T2 and T1ρ) and MT ratios in acute cerebral ischemia in rat. The right middle cerebral artery was permanently occluded and quantitative MRI data was acquired sequentially for the above parameters for up to 6 hours. The following conclusions were drawn: 1) Time-dependent changes in RAFF and T1ρ relaxation are not coupled to those in MT. 2) RAFF relaxation evolves more like transverse, rather than longitudinal relaxation. 3) MT measured with ZAPI is less sensitive to ischemia than conventional MT. 4) ZAPI data suggest alterations in the T2 distribution of macromolecules in acute cerebral ischemia. It was shown that both RAFF and ZAPI provide complementary MRI information from acute ischemic brain tissue. The presented multiparametric MRI data may aid in the assessment of brain tissue status early in ischemic stroke.

Anatomical and functional assessment of brown adipose tissue by magnetic resonance imaging.

Brown adipose tissue (BAT) is the primary tissue responsible for nonshivering thermogenesis in mammals. The amount of BAT and its level of activation help regulate the utilization of excessive calories for thermogenesis as opposed to storage in white adipose tissue (WAT) which would lead to weight gain. Over the past several years, BAT activity in vivo has been primarily assessed by positron emission tomography-computed tomography (PET-CT) scan using 2-[18F]-fluoro-2-deoxy-D-glucose (18F-FDG) to measure glucose utilization associated with BAT mitochondrial respiration. In this study, we demonstrate the feasibility of mapping and estimating BAT volume and metabolic function in vivo in rats at a 9.4T magnetic resonance imaging (MRI) scanner using sequences available from clinical MR scanners. Based on the morphological characteristics of BAT, we measured the volume distribution of BAT with MRI sequences that have strong fat-water contrast. We also investigated BAT volume by utilizing spin-echo MRI sequences. The in vivo MRI-estimated BAT volumes were correlated with direct measurement of BAT mass from dissected samples. Using MRI, we also were able to map hemodynamic responses to changes in BAT metabolism induced pharmacologically by ß3-adrenergic receptor agonist, CL-316,243 and compare this to BAT activity in response to CL-316,243 assessed by PET 18F-FDG. In conclusion, we demonstrate the feasibility of measuring BAT volume and function in vivo using routine MRI sequences. The MRI measurement of BAT volume is consistent with quantitative measurement of the tissue ex vivo.

Correlating tissue outcome with quantitative multiparametric MRI of acute cerebral ischemia in rats.

Predicting tissue outcome remains a challenge for stroke magnetic resonance imaging (MRI). In this study, we have acquired multiparametric MRI data sets (including absolute T(1), T(2), diffusion, T(1rho) using continuous wave and adiabatic pulse approaches, cerebral blood flow (CBF), and amide proton transfer ratio (APTR) images) during and after 65 mins of middle cerebral artery occlusion (MCAo) in rats. The MRI scans were repeated 24 h after MCAo, when the animals were killed for quantitative histology. Magnetic resonance imaging parameters acquired at three acute time points were correlated with regionally matching cell count at 24 h. The results emphasize differences in the temporal profile of individual MRI contrasts during MCAo and especially during early reperfusion, and suggest that complementary information from CBF and tissue damage can be obtained with appropriate MRI contrasts. The data show that by using three to four MRI parameters, sensitive to both hemodynamic changes and different aspects of parenchymal changes, the fate of the tissue can be predicted with increased correlation compared with single-parameter techniques. Combined multiparametric MRI data and multiparametric analysis may provide an excellent tool for preclinical testing of new treatments and also has the potential to facilitate decision-making in the management of acute stroke patients.

Quantitative assessment of water pools by T 1 rho and T 2 rho MRI in acute cerebral ischemia of the rat.

The rotating frame longitudinal relaxation magnetic resonance imaging (MRI) contrast, T(1 rho), obtained with on-resonance continuous wave (CW) spin-lock field is a sensitive indicator of tissue changes associated with hyperacute stroke. Here, the rotating frame relaxation concept was extended by acquiring both T(1 rho) and transverse rotating frame (T(2 rho)) MRI data using both CW and adiabatic hyperbolic secant (HSn; n=1, 4, or 8) pulses in a rat stroke model of middle cerebral artery occlusion. The results show differences in the sensitivity of spin-lock T(1 rho) and T(2 rho) MRI to detect hyperacute ischemia. The most sensitive techniques were CW-T(1 rho) and T(1 rho) using HS4 or HS8 pulses. Fitting a two-pool exchange model to the T(1 rho) and T(2 rho) MRI data acquired from the infarcting brain indicated time-dependent increase in free water fraction, decrease in the correlation time of water fraction associated with macromolecules, and increase in the exchange correlation time. These findings are consistent with known pathology in acute stroke, including vasogenic edema, destructive processes, and tissue acidification. Our results show that the sensitivity of the spin-lock MRI contrast in vivo can be modified using different spin-lock preparation blocks, and that physicochemical models of the rotating frame relaxation may provide insight into progression of ischemia in vivo.

Proton transfer ratio, lactate, and intracellular pH in acute cerebral ischemia.

The amide proton transfer ratio (APTR) from the asymmetry of the Z-spectrum was determined in rat brain tissue during and after unilateral middle cerebral artery occlusion (MCAo). Cerebral lactate (Lac) as determined by (1)H NMR spectroscopy, water diffusion, and T(1rho) were quantified as well. Lac concentrations were used to estimate intracellular pH (pH(i)) in the brain during the MCA occlusion. A decrease in APTR during occlusion indicated acidification from 7.1 to 6.79 +/- 0.19 (a drop by 0.3 +/- 0.2 pH units), whereas pH(i) computed from Lac concentration was 6.3 +/- 0.2 (a drop by 0.8 +/- 0.2 pH units). Despite the disagreement between the two methods in terms of the size of the change in the absolute pH(i) during ischemia, DeltaAPTR and pH(i) (and Lac concentration) displayed a strong correlation during the MCAo. Diffusion and T(1rho) indicated cytotoxic edema following MCA occlusion; however, APTR returned slowly toward the values determined in the contralateral hemisphere post-ischemia. These data argue that the APTR during ischemia is affected not only by pH(i) but by other physicochemical factors as well, and indicates different aspects of pathology in the post-ischemic brain compared to those that influence water diffusion and T(1rho).