Lesion Mismatch Research Articles

Oxygen Challenge Imaging Reveals Differences in Metabolic Activity Between Kurtosis Lesion and Diffusion/Kurtosis Lesion Mismatch in a Rodent Model of Acute Stroke.

Accurate identification of potentially salvageable tissues is critical for improving acute stroke treatment. A previous study showed that the kurtosis lesion exhibited insignificant response after prompt reperfusion treatment, while the diffusion/kurtosis lesion mismatch could recover after reperfusion. We hypothesized that these 2 regions are in different metabolic states. Transient oxygen challenge (OC) is a procedure that uses oxygen as a metabolic bio-tracer and has been performed to explore metabolic activity in tissues. We combined OC with multiparameter magnetic resonance imaging (including diffusion kurtosis imaging and T2* mapping sequences) to study metabolic activity in the ischemic brain of Sprague Dawley rats. Oxygen challenge image analysis revealed changes in T2* values, most significantly in the mean diffusivity (MD)/mean kurtosis (MK) lesion mismatch (22.3 ± 1.6%) and least significantly in the MK lesions (6.6 ± 0.6%). The MD images acquired within 138 ± 9 minutes after ischemia showed a larger ischemic lesion (45.5 ± 3.0% of the total area) than the MK images (33.2 ± 4.2% of the total area). The change rate of the MK value (53.0 ± 4.4%) was higher than that of the MD value (37.5 ± 3.2%). The present study shows that MK lesion and MD/MK lesion mismatch exhibited different metabolic activity states. The MK lesion presented metabolic-related values close to the ischemic core, while at least part of the MD/MK mismatch area was comparable with ischemic penumbra metabolic activity. These findings are important to support image-guided individualized stroke therapies.

Tissue perfusion of the kurtosis/diffusion mismatch differs from the central core and peripheral regions in acute cerebral infarction patients.

Despite its wide adoption in stroke imaging, the diffusion-weighted imaging (DWI) lesion is heterogeneous. The emerging diffusion kurtosis imaging (DKI) has been postulated to resolve the graded DWI lesion. To determine the perfusion characteristics of the central infarction core, kurtosis/diffusion mismatch, and peripheral regions. Patients with acute ischemic stroke underwent DWI, DKI, and perfusion-weighted imaging (PWI) scans. The patients were divided into mean kurtosis (MK)/mean diffusivity (MD) match and mismatch groups. Perfusion parameters were measured in the MK/MD lesion and peripheral areas in the MK/MD match group. We also analyzed perfusion status in the MK/MD lesion mismatch area for the mismatch group. A total of 40 eligible patients (24 MK/MD match and 16 MK/MD mismatch) were enrolled in the final data analysis. The MTT and TTP progressively decreased, while the cerebral blood flow (CBF) and cerebral blood volume (CBV) increased from the central to peripheral areas. In addition, CBF in the MK/MD mismatch region was significantly higher than that in the central region (P < 0.05), but similar to the peripheral region. Furthermore, CBV in the MK/MD mismatch region did not differ significantly from that of the central region, but both were significantly lower than that of the peripheral area (P < 0.05). The MK/MD mismatch region had blood flow similar to the peripheral region but with a reduced blood volume, indicating that it was less ischemic from the infarction core, albeit insufficient collateral circulation.

Reduced Ischemic Lesion Growth with Heparin in Acute Ischemic Stroke

Objective: The role of heparin in acute ischemic stroke is controversial. We investigated the effect of heparin on ischemic lesion growth. Methods: Data were analyzed on nonthrombolyzed ischemic stroke patients in whom diffusion-weighted imaging (DWI)/perfusion-weighted imaging (PWI) MRI was performed less than 12 hours of last known well and showed a PWI-DWI lesion mismatch, and who underwent follow-up neuroimaging at least 4 days after admission. Lesion growth was assessed by (1) absolute lesion growth and (2) percentage mismatch lost (PML). Univariate and multivariate regression analysis, and propensity score matching, were used to determine the effects of heparin on ischemic lesion growth. Results: Of the 113 patients meeting study criteria, 59 received heparin within 24 hours. Heparin use was associated with ∼5-fold reductions in PML (3.5% versus 19.2%, P = .002) and absolute lesion growth (4.7 versus 20.5 mL, P = .009). In multivariate regression models, heparin independently predicted reduced PML (P = .04) and absolute lesion growth (P = .04) in the entire cohort, and in multiple subgroups (patients with and without proximal artery occlusion; DWI volume greater than 5 mL; cardio-embolic mechanism; DEFUSE-3 target mismatch). In propensity score matching analysis where patients were matched by admission NIHSS, DWI volume and proximal artery occlusion, heparin remained an independent predictor of PML (P = .048) and tended to predict absolute lesion growth (P = .06). Heparin treatment did not predict functional outcome at discharge or 90 days. Conclusion: Early heparin treatment in acute ischemic stroke patients with PWI-DWI mismatch attenuates ischemic lesion growth. Clinical trials with careful patient selection are warranted to investigate the potential ischemic protective effects of heparin.

Mapping tissue pH in an experimental model of acute stroke – Determination of graded regional tissue pH changes with non-invasive quantitative amide proton transfer MRI

pH-weighted amide proton transfer (APT) MRI is sensitive to tissue pH change during acute ischemia, complementing conventional perfusion and diffusion stroke imaging. However, the currently used pH-weighted magnetization transfer (MT) ratio asymmetry (MTRasym) analysis is of limited pH specificity. To overcome this, MT and relaxation normalized APT (MRAPT) analysis has been developed that to homogenize the background signal, thus providing highly pH conspicuous measurement. Our study aimed to calibrate MRAPT MRI toward absolute tissue pH mapping and determine regional pH changes during acute stroke. Using middle cerebral artery occlusion (MCAO) rats, we performed lactate MR spectroscopy and multi-parametric MRI. MRAPT MRI was calibrated against a region of interest (ROI)-based pH spectroscopy measurement (R2 = 0.70, P < 0.001), showing noticeably higher correlation coefficient than the simplistic MTRasym index. Capitalizing on this, we mapped brain tissue pH and semi-automatically segmented pH lesion, in addition to routine perfusion and diffusion lesions. Tissue pH from regions of the contralateral normal, perfusion/diffusion lesion mismatch and diffusion lesion was found to be 7.03 ± 0.04, 6.84 ± 0.10, 6.52 ± 0.19, respectively. Most importantly, we delineated the heterogeneous perfusion/diffusion lesion mismatch into perfusion/pH and pH/diffusion lesion mismatches, with their pH being 7.01 ± 0.04 and 6.71 ± 0.12, respectively (P < 0.05). To summarize, our study calibrated pH-sensitive MRAPT MRI toward absolute tissue pH mapping, semi-automatically segmented and determined graded tissue pH changes in ischemic tissue and demonstrated its feasibility for refined demarcation of heterogeneous metabolic disruption following acute stroke.

Elevated brain oxygen extraction fraction measured by MRI susceptibility relates to perfusion status in acute ischemic stroke

Recent clinical trials of new revascularization therapies in acute ischemic stroke have highlighted the importance of physiological imaging to identify optimal treatments for patients. Oxygen extraction fraction (OEF) is a hallmark of at-risk tissue in stroke, and can be quantified from the susceptibility effect of deoxyhemoglobin molecules in venous blood on MRI phase scans. We measured OEF within cerebral veins using advanced quantitative susceptibility mapping (QSM) MRI reconstructions in 20 acute stroke patients. Absolute OEF was elevated in the affected (29.3 ± 3.4%) versus the contralateral hemisphere (25.5 ± 3.1%) of patients with large diffusion–perfusion lesion mismatch (P = 0.032). In these patients, OEF negatively correlated with relative CBF measured by dynamic susceptibility contrast MRI (P = 0.004), suggesting compensation for reduced flow. Patients with perfusion–diffusion match or no hypo-perfusion showed less OEF difference between hemispheres. Nine patients received longitudinal assessment and showed OEF ratio (affected to contralateral) of 1.2 ± 0.1 at baseline that normalized (decreased) to 1.0 ± 0.1 at follow-up three days later (P = 0.03). Our feasibility study demonstrates that QSM MRI can non-invasively quantify OEF in stroke patients, relates to perfusion status, and is sensitive to OEF changes over time. Clinical trial registration: Longitudinal MRI examinations of patients with brain ischemia and blood brain barrier permeability; clinicaltrials.org: NCT02077582

JOURNAL CLUB: Evaluation of Diffusion Kurtosis Imaging of Stroke Lesion With Hemodynamic and Metabolic MRI in a Rodent Model of Acute Stroke

Diffusion kurtosis imaging (DKI) has emerged as a new acute stroke imaging approach, augmenting routine DWI. Although it has been shown that a diffusion lesion without kurtosis abnormality is more likely to recover after reperfusion, whereas a kurtosis lesion shows poor response, little is known about the underlying pathophysiologic profile of the kurtosis lesion versus the kurtosis lesion-diffusion lesion mismatch. We performed multiparametric MRI, including arterial spin labeling, pH-sensitive amide proton transfer, and DKI, in a rodent model of acute stroke caused by embolic middle cerebral artery occlusion. Diffusion and kurtosis lesions were semiautomatically segmented, and multiparametric MRI indexes were compared among the kurtosis lesion, diffusion lesion, kurtosis lesion-diffusion lesion mismatch, and the contralateral normal tissue area. We confirmed a significant difference between diffusion lesion and kurtosis lesion volumes (mean [± SD] volume, 151 ± 65 vs 125 ± 47 mm3; p < 0.05). Although ischemic lesions have significantly reduced cerebral blood flow compared with contralateral normal tissue, we did not find a significant difference in cerebral blood flow between the kurtosis lesion and the kurtosis lesion-diffusion lesion mismatch (mean cerebral blood flow, 0.53 ± 0.10 vs 0.47 ± 0.14 mL/g of tissue per minute; p > 0.05). Of importance, the pH of the kurtosis lesion was significantly lower than that of the lesion mismatch (mean pH, 6.81 ± 0.08 vs 6.89 ± 0.09; p < 0.01). The present study confirms that DKI provides an expedient approach for refining the heterogeneous DWI lesion that is associated with graded metabolic derangement, which is promising for improving the infarction core definition and ultimately helping to guide stroke treatment.

Abstract TP47: Prediction of Stroke Outcome With Immediate Post-Thrombolysis Magnetic Resonance Imaging

Background: Early recanalization and adequate collateral blood flow are strong surrogates for functional recovery in endovascular stroke treatment. We sought to evaluate the prognostic value of immediate post-thrombolysis magnetic resonance imaging (MRI). Methods: Consecutive patients with acute ischemic stroke who underwent endovascular treatment were enrolled. We measured diffusion-weighted MRI (DWI) and perfusion-weighted MRI (PWI) lesion volume, mismatch ratio, and DWI and PWI lesion volume change before and immediate after treatment. Outcome was measured with modified Rankin Scale (mRS) at 90 days, early neurological improvement (NIHSS ≥ 8) within 7 days, and any intracerebral hemorrhage. Multivariate analysis and c -statistics were used to identify prognostic value of MR parameters. Results: A total of 65 patients with a complete pre- and post-thrombolysis MRI were included. Mean age was 65±18 years, median baseline NIHSS score was 14, and median time from symptom onset to endovascular treatment was 192 minutes. Median time from endovascular treatment to post-treatment MRI was 20 minutes. After control of initial stroke severity and complete recanalization on angiography, post-thrombolysis PWI lesion volume remained an independent predictor of favorable outcome ( p = 0.017, odds ratio [OR] = 0.970, 95% confidence interval [CI] = 0.946-0.995), and early neurological improvement ( p = 0.014, OR = 0.957, 95% CI = 0.923-0.991), whereas DWI lesion volume, mismatch ratio, and DWI and PWI lesion volume changes did not show statistical significance. None of the measured variables predicts intracerebral hemorrhage. Post-thrombolysis PWI lesion volume revealed area under the curve of 0.821 (p &lt; 0.001, 95% CI = 0.722-0.920) for favorable outcome and 0.878 (p &lt; 0.001, 95% CI = 0.799-0.957) for early neurological improvement. Conclusions: Perfusion lesion volume on immediate post-thrombolysis MRI more accurately predicts functional recovery and early neurological improvement than pre-treatment DWI and PWI parameters.

PH imaging reveals worsened tissue acidification in diffusion kurtosis lesion than the kurtosis/diffusion lesion mismatch in an animal model of acute stroke

Diffusion weighted imaging (DWI) has been commonly used in acute stroke examination, yet a portion of DWI lesion may be salvageable. Recently, it has been shown that diffusion kurtosis imaging (DKI) defines the most severely damaged DWI lesion that does not renormalize following early reperfusion. We postulated that the diffusion and kurtosis lesion mismatch experience heterogeneous hemodynamic and/or metabolic injury. We investigated tissue perfusion, pH, diffusion, kurtosis and relaxation from regions of the contralateral normal area, diffusion lesion, kurtosis lesion and their mismatch in an animal model of acute stroke. Our study revealed significant kurtosis and diffusion lesion volume mismatch (19.7 ± 10.7%, P < 0.01). Although there was no significant difference in perfusion and diffusion between the kurtosis lesion and kurtosis/diffusion lesion mismatch, we showed lower pH in the kurtosis lesion (pH = 6.64 ± 0.12) from that of the kurtosis/diffusion lesion mismatch (6.84 ± 0.11, P < 0.05). Moreover, pH in the kurtosis lesion and kurtosis/diffusion mismatch agreed well with literature values for regions of ischemic core and penumbra, respectively. Our work documented initial evidence that DKI may reveal the heterogeneous metabolic derangement within the commonly used DWI lesion.

CT-perfusion stroke imaging: a threshold free probabilistic approach to predict infarct volume compared to traditional ischemic thresholds

The aim was to evaluate a novel method of threshold-free prediction of brain infarct from computed tomography perfusion (CTP) imaging in comparison to conventional ischemic thresholds. In a multicenter cohort of 161 patients with acute large vessel occlusion who received endovascular therapy, brain infarction was predicted by CTP using (1) optimized parameter cut-off values determined by ROC curve analysis and (2) probabilistic logistic regression threshold-free analysis. Predicted infarct volumes and prediction errors based on four perfusion parameter maps were compared against observed infarcts. In 93 patients with successful recanalization, the mean observed infarct volume was 35.7 ± 61.9 ml (the reference for core infarct not savable by reperfusion). Optimal parameter thresholds predicted mean infarct volumes between 53.2 ± 44.4 and 125.0 ± 95.4 ml whereas threshold-free analysis predicted mean volumes between 35.9 ± 28.5 and 36.1 ± 29.0 ml. In 68 patients with persistent occlusion, the mean observed infarct volume was 113.4 ± 138.3 ml (the reference to define penumbral infarct savable by reperfusion). Predicted mean infarct volumes by parameter thresholds ranged from 91.4 ± 81.5 to 163.8 ± 135.7 ml, by threshold-free analysis from 113.2 ± 89.9 to 113.5 ± 89.0 ml. Threshold-free prediction of infarct volumes had a higher precision and lower patient-specific prediction error than conventional thresholding. Penumbra to core lesion mismatch estimate may therefore benefit from threshold-free CTP analysis.

PH-sensitive amide proton transfer effect dominates the magnetization transfer asymmetry contrast during acute ischemia-quantification of multipool contribution to in vivo CEST MRI.

To determine the origins of in vivo magnetization transfer asymmetry contrast during acute ischemic stroke, particularly in the diffusion lesion, perfusion lesion, and their mismatch using a middle cerebral artery occlusion rat model of acute stroke. Adult male Wistar rats underwent multiparametric MRI of diffusion, perfusion, T1 , and amide proton transfer (APT) imaging at 4.7 T following a middle cerebral artery occlusion procedure. A multipool Lorentzian model, including the nuclear Overhauser effect, magnetization transfer, direct water saturation, amine and amide chemical exchange saturation transfer effects, was applied for Z-spectrum fitting to determine the sources of in vivo magnetization transfer asymmetry following acute stroke. We showed that changes in amine chemical exchange saturation transfer (2 ppm) and APT (3.5 ppm) effects, particularly the APT MRI effect, dominate the commonly used magnetization transfer asymmetry analysis and hence confer pH sensitivity to APT imaging of acute stroke. Also, the nuclear Overhauser effect and magnetization transfer show small changes that counteracted each other, contributing less than 0.3% to magnetization transfer asymmetry at 3.5 ppm. Moreover, we showed that diffusion lesion had worsened acidosis from perfusion/diffusion lesion mismatch (P < 0.05). The study complements recent in vivo quantitative chemical exchange saturation transfer work to shed light on the sensitivity and specificity of endogenous APT MRI to tissue acidosis. Magn Reson Med 79:1602-1608, 2018. © 2017 International Society for Magnetic Resonance in Medicine.

Validation of fast diffusion kurtosis MRI for imaging acute ischemia in a rodent model of stroke.

Diffusion-weighted imaging (DWI) captures ischemic tissue that is likely to infarct, and has become one of the most widely used acute stroke imaging techniques. Diffusion kurtosis imaging (DKI) has lately been postulated as a complementary MRI method to stratify the heterogeneously damaged DWI lesion. However, the conventional DKI acquisition time is relatively long, limiting its use in the acute stroke setting. Recently, a fast kurtosis mapping method has been demonstrated in fixed brains and control subjects. The fast DKI approach provides mean diffusion and kurtosis measurements under substantially reduced scan time, making it amenable to acute stroke imaging. Because it is not practical to obtain and compare different means of DKI to test whether the fast DKI method can reliably detect diffusion and kurtosis lesions in acute stroke patients, our study investigated its diagnostic value using an animal model of acute stroke, a critical step before fast DKI acquisition can be routinely applied in the acute stroke setting. We found significant correlation, per voxel, between the diffusion and kurtosis coefficients measured using the fast and conventional DKI protocols. In acute stroke rats, the two DKI methods yielded diffusion and kurtosis lesions that were in good agreement. Importantly, substantial kurtosis-diffusion lesion mismatch was observed using the conventional (26 ± 13%, P < 0.01) and fast DKI methods (23 ± 8%, P < 0.01). In addition, regression analysis showed that the kurtosis-diffusion lesion mismatches obtained using conventional and fast DKI methods were substantially correlated (R(2) = 0.57, P = 0.02). Our results confirmed that the recently proposed fast DKI method is capable of capturing heterogeneous diffusion and kurtosis lesions in acute ischemic stroke, and thus is suitable for translational applications in the acute stroke clinical setting.

Magnetic resonance imaging in acute ischemic stroke treatment.

Although intravenous administration of tissue plasminogen activator is the only proven treatment after acute ischemic stroke, there is always a concern of hemorrhagic risk after thrombolysis. Therefore, selection of patients with potential benefits in overcoming potential harms of thrombolysis is of great importance. Despite the practical issues in using magnetic resonance imaging (MRI) for acute stroke treatment, multimodal MRI can provide useful information for accurate diagnosis of stroke, evaluation of the risks and benefits of thrombolysis, and prediction of outcomes. For example, the high sensitivity and specificity of diffusion-weighted image (DWI) can help distinguish acute ischemic stroke from stroke-mimics. Additionally, the lesion mismatch between perfusion-weighted image (PWI) and DWI is thought to represent potential salvageable tissue by reperfusion therapy. However, the optimal threshold to discriminate between benign oligemic areas and the penumbra is still debatable. Signal changes of fluid-attenuated inversion recovery image within DWI lesions may be a surrogate marker for ischemic lesion age and might indicate risks of hemorrhage after thrombolysis. Clot sign on gradient echo image may reflect the nature of clot, and their location, length and morphology may provide predictive information on recanalization by reperfusion therapy. However, previous clinical trials which solely or mainly relied on perfusion-diffusion mismatch for patient selection, failed to show benefits of MRI-based thrombolysis. Therefore, understanding the clinical implication of various useful MRI findings and comprehensively incorporating those variables into therapeutic decision-making may be a more reasonable approach for expanding the indication of acute stroke thrombolysis.