A. G. Sorensen

Pseudoprogression and Pseudoresponse: Imaging Challenges in the Assessment of Posttreatment Glioma

The current standard of care for newly diagnosed cases of high-grade glioma is surgical resection followed by RT with concurrent chemotherapy. The most widely used criteria for assessing treatment response are based on a 2D measurement of the enhancing area on MR imaging known as the Macdonald Criteria. Recently, nontumoral increases (pseudoprogression) and decreases (pseudoresponse) in enhancement have been found, and these can confuse outcome evaluation. Here we review pseudoprogression and pseudoresponse and describe how better understanding of these phenomena can aid interpretation.

Increased survival of glioblastoma patients who respond to antiangiogenic therapy with elevated blood perfusion.

The abnormal vasculature of the tumor microenvironment supports progression and resistance to treatment. Judicious application of antiangiogenic therapy may normalize the structure and function of the tumor vasculature, promoting improved blood perfusion. However, direct clinical evidence is lacking for improvements in blood perfusion after antiangiogenic therapy. In this study, we used MRI to assess tumor blood perfusion in 30 recurrent glioblastoma patients who were undergoing treatment with cediranib, a pan-VEGF receptor tyrosine kinase inhibitor. Tumor blood perfusion increased durably for more than 1 month in 7 of 30 patients, in whom it was associated with longer survival. Together, our findings offer direct clinical evidence in support of the hypothesis that vascular normalization can increase tumor perfusion and help improve patient survival.

Neuroanatomic correlates of stroke-related myocardial injury

Background: Myocardial injury can occur after ischemic stroke in the absence of primary cardiac causes. The neuroanatomic basis of stroke-related myocardial injury is not well understood. Objective: To identify regions of brain infarction associated with myocardial injury using a method free of the bias of an a priori hypothesis as to any specific location. Methods: Of 738 consecutive patients with acute ischemic stroke, the authors identified 50 patients in whom serum cardiac troponin T (cTnT) elevation occurred in the absence of any apparent cause within 3 days of symptom onset. Fifty randomly selected, age- and sex-matched patients with ischemic stroke without cTnT elevation served as controls. Diffusion-weighted images with outlines of infarction were co-registered to a template, averaged, and then subtracted to find voxels that differed between the two groups. Voxel-wise p values were determined using a nonparametric permutation test to identify specific regions of infarction that were associated with cTnT elevation. Results: The study groups were well balanced with respect to stroke risk factors, history of coronary artery disease, infarction volume, and frequency of right and left middle cerebral artery territory involvement. Brain regions that were a priori associated with cTnT elevation included the right posterior, superior, and medial insula and the right inferior parietal lobule. Among patients with right middle cerebral artery infarction, the insular cluster was involved in 88% of patients with and 33% without cTnT elevation (odds ratio: 15.00; 95% CI: 2.65 to 84.79). Conclusions: Infarctions in specific brain regions including the right insula are associated with elevated serum cardiac troponin T level indicative of myocardial injury.

Severity of leukoaraiosis correlates with clinical outcome after ischemic stroke

Background: Leukoaraiosis (LA) is closely associated with aging, a major determinant of clinical outcome after ischemic stroke. In this study we sought to identify whether LA, independent of advancing age, affects outcome after acute ischemic stroke. Methods: LA volume was quantified in 240 patients with ischemic stroke and MRI within 24 hours of symptom onset. We explored the relationship between LA volume at admission and clinical outcome at 6 months, as assessed by the modified Rankin Scale (mRS). An ordinal logistic regression model was developed to analyze the independent effect of LA volume on clinical outcome. Results: Bivariate analyses showed a significant correlation between LA volume and mRS at 6 months (r = 0.19, p = 0.003). Mean mRS was 1.7 ± 1.8 among those in the lowest (≤1.2 mL) and 2.5 ± 1.9 in the highest (>9.9 mL) quartiles of LA volume (p = 0.01). The unfavorable prognostic effect of LA volume on clinical outcome was retained in the multivariable model (p = 0.002), which included age, gender, stroke risk factors (hypertension, diabetes mellitus, atrial fibrillation), previous history of brain infarction, admission plasma glucose level, admission NIH Stroke Scale score, IV rtPA treatment, and acute infarct volume on MRI as covariates. Conclusions: The volume of leukoaraiosis is a predictor of clinical outcome after ischemic stroke and this relationship persists after adjustment for important prognostic factors including age, initial stroke severity, and infarct volume.

White matter hyperintensity volume is increased in small vessel stroke subtypes.

Objective: White matter hyperintensity (WMH) may be a marker of an underlying cerebral microangiopathy. Therefore, we hypothesized that WMH would be most severe in patients with lacunar stroke and intracerebral hemorrhage (ICH), 2 types of stroke in which cerebral small vessel (SV) changes are pathophysiologically relevant. Methods: We determined WMH volume (WMHV) in cohorts of prospectively ascertained patients with acute ischemic stroke (AIS) (Massachusetts General Hospital [MGH], n = 628, and the Ischemic Stroke Genetics Study [ISGS], n = 263) and ICH (MGH, n = 122). Results: Median WMHV was 7.5 cm3 (interquartile range 3.4–14.7 cm3) in the MGH AIS cohort (mean age 65 ± 15 years). MGH patients with larger WMHV were more likely to have lacunar stroke compared with cardioembolic (odds ratio [OR] = 1.87 per SD normally transformed WMHV), large artery (OR = 2.25), undetermined (OR = 1.87), or other (OR = 1.85) stroke subtypes (p < 0.03). These associations were replicated in the ISGS cohort (p = 0.03). In a separate analysis, greater WMHV was seen in ICH compared with lacunar stroke (OR = 1.2, p < 0.02) and in ICH compared with all ischemic stroke subtypes combined (OR = 1.34, p < 0.007). Conclusions: Greater WMH burden was associated with SV stroke compared with other ischemic stroke subtypes and, even more strongly, with ICH. These data, from 2 independent samples, support the model that increasing WMHV is a marker of more severe cerebral SV disease and provide further evidence for links between the biology of WMH and SV stroke.

QUantitative Imaging of eXtraction of oxygen and TIssue consumption (QUIXOTIC) using venular-targeted velocity-selective spin labeling.

While oxygen extraction fraction (OEF) and cerebral metabolic rate of oxygen (CMRO2) are fundamental parameters of brain health and function, a robust MRI‐based mapping of OEF and CMRO2 amenable to functional MRI (fMRI) has not been established. To address this issue, a novel method called QUantitative Imaging of eXtraction of Oxygen and TIssue Consumption, or QUIXOTIC, is introduced. The key innovation in QUIXOTIC is the use of velocity‐selective spin labeling to isolate MR signal exclusively from postcapillary venular blood on a voxel‐by‐voxel basis. Measuring the T2 of this venular‐targeted blood allows calibration to venular oxygen saturation (Yv) via theoretical and experimental T2 versus blood oxygen saturation relationships. Yv is converted to OEF, and baseline CMRO2 is subsequently estimated from OEF and additional cerebral blood flow and hematocrit measurements. Theory behind the QUIXOTIC technique is presented, and implications of cutoff velocity (VCUTOFF) and outflow time parameters are discussed. Cortical gray matter values obtained with QUIXOTIC in 10 healthy volunteers are Yv = 0.73 ± 0.02, OEF = 0.26 ± 0.02, and CMRO2 = 125 ± 15 μmol/100 g min. Results are compared to global measures obtained with the T2 relaxation under spin tagging (TRUST) technique. The preliminary data presented suggest that QUIXOTIC will be useful for mapping Yv, OEF, and CMRO2, in both clinical and functional MRI settings. Magn Reson Med, 2011.

Diffusion-weighted MRI in diffuse axonal injury of the brain

Abstract. The goal of this study was to identify and describe the different types and patterns of tissue injury which are encountered by diffusion-weighted imaging (DWI) in diffuse axonal injury (DAI) of the brain. The DWI data sets of 98 patients who suffered from a closed-head injury were retrospectively evaluated. Medical records were reviewed to rule out pre-existing neurological diseases. Lesions were studied for their DWI signal characteristics and lesion size or extension. Traumatic lesions were classified into three categories depending on their signal characteristica on DWI and apparent diffusion coefficient (ADC) maps: type 1, DWI- and ADC-hyperintense most likely representing lesions with vasogenic edema; type 2, DWI-hyperintense, ADC-hypointense indicating cytotoxic edema; type 3, central hemorrhagic lesion surrounded by an area of increased diffusion. According to the size and extent of lesions, injury was classified into three groups: group A, focal injury; group B, regional/confluent injury; and group C, extensive/diffuse injury. Our study showed that diffusion-weighted imaging differentiates between lesions with decreased and increased diffusion in patients with DAI. Different degrees of tissue injury extent were noticed. Future prospective studies should study if this additional information can be used as a predictor of injury reversibility, final outcome and prognosis.

A score to predict early risk of recurrence after ischemic stroke

Background: There is currently no instrument to stratify patients presenting with ischemic stroke according to early risk of recurrent stroke. We sought to develop a comprehensive prognostic score to predict 90-day risk of recurrent stroke. Methods: We analyzed data on 1,458 consecutive ischemic stroke patients using a Cox regression model with time to recurrent stroke as the response and clinical and imaging features typically available to physician at admission as covariates. The 90-day risk of recurrent stroke was calculated by summing up the number of independent predictors weighted by their corresponding β-coefficients. The resultant score was called recurrence risk estimator at 90 days or RRE-90 score (available at: http://www.nmr.mgh.harvard.edu/RRE-90/). Results: Sixty recurrent strokes (54 had baseline imaging) occurred during the follow-up period. The risk adjusted for time to follow-up was 6.0%. Predictors of recurrence included admission etiologic stroke subtype, prior history of TIA/stroke, and topography, age, and distribution of brain infarcts. The RRE-90 score demonstrated adequate calibration and good discrimination (area under the ROC curve [AUC] = 0.70–0.80), which was maintained when applied to a separate cohort of 433 patients (AUC = 0.70–0.76). The models performance was also maintained for predicting early (14-day) risk of recurrence (AUC = 0.80). Conclusions: The RRE-90 is a Web-based, easy-to-use prognostic score that integrates clinical and imaging information available in the acute setting to quantify early risk of recurrent stroke. The RRE-90 demonstrates good predictive performance, suggesting that, if validated externally, it has promise for use in creating individualized patient management algorithms and improving clinical practice in acute stroke care.

Early experience of translating pH-weighted MRI to image human subjects at 3 Tesla.

Background and Purpose— In acute stroke, mismatch between lesions seen on diffusion- (DWI) and perfusion-weighted (PWI) MRI has been used to identify ischemic tissue before irreversible damage. Nevertheless, the concept of PWI/DWI mismatch is oversimplified and the ischemic tissue metabolic status and outcome are often heterogeneous. Tissue pH, a well-regulated physiological index that alters on disrupted tissue metabolism, may provide a surrogate metabolic imaging marker that augments the DWI and PWI for penumbra imaging. Methods— pH-weighted MRI was obtained by probing the pH-dependent amide proton transfer between endogenous mobile proteins/peptides and tissue water. The technique was validated using animal stroke models, optimized for human use, and preliminarily tested for imaging healthy volunteers. Results— pH-weighted MRI is sensitive and specific to ischemic tissue acidosis. pH MRI can be optimized for clinical use, and a pilot human study showed it is feasible using a standard 3 Tesla MRI scanner. Conclusions— Ischemic acidosis can be imaged via an endogenous pH-weighted MRI technique, which complements conventional PWI and DWI for penumbra imaging. pH-weighted MRI has been optimized and appears feasible and practical in imaging human subjects. Additional study is necessary to elucidate the diagnostic use of pH MRI in stroke patients.

The Causative Classification of Stroke system: an international reliability and optimization study.

Background: Valid and reliable ischemic stroke subtype determination is crucial for well-powered multicenter studies. The Causative Classification of Stroke System (CCS, available at http://ccs.mgh.harvard.edu) is a computerized, evidence-based algorithm that provides both causative and phenotypic stroke subtypes in a rule-based manner. We determined whether CCS demonstrates high interrater reliability in order to be useful for international multicenter studies. Methods: Twenty members of the International Stroke Genetics Consortium from 13 centers in 8 countries, who were not involved in the design and development of the CCS, independently assessed the same 50 consecutive patients with acute ischemic stroke through reviews of abstracted case summaries. Agreement among ratings was measured by kappa statistic. Results: The κ value for causative classification was 0.80 (95% confidence interval [CI] 0.78–0.81) for the 5-subtype, 0.79 (95% CI 0.77–0.80) for the 8-subtype, and 0.70 (95% CI 0.69–0.71) for the 16-subtype CCS. Correction of a software-related factor that generated ambiguity improved agreement: κ = 0.81 (95% CI 0.79–0.82) for the 5-subtype, 0.79 (95% CI 0.77–0.80) for the 8-subtype, and 0.79 (95% CI 0.78–0.80) for the 16-subtype CCS. The κ value for phenotypic classification was 0.79 (95% CI 0.77–0.82) for supra-aortic large artery atherosclerosis, 0.95 (95% CI 0.93–0.98) for cardioembolism, 0.88 (95% CI 0.85–0.91) for small artery occlusion, and 0.79 (0.76–0.82) for other uncommon causes. Conclusions: CCS allows classification of stroke subtypes by multiple investigators with high reliability, supporting its potential for improving stroke classification in multicenter studies and ensuring accurate means of communication among different researchers, institutions, and eras.