Magnetic Resonance Imaging Lesion Volume Research Articles

Exploring the neuroprotective effects of montelukast on brain inflammation and metabolism in a rat model of quinolinic acid-induced striatal neurotoxicity

BackgroundOne intrastriatal administration of quinolinic acid (QA) in rats induces a lesion with features resembling those observed in Huntington’s disease. Our aim is to evaluate the effects of the cysteinyl leukotriene receptor antagonist montelukast (MLK), which exhibited neuroprotection in different preclinical models of neurodegeneration, on QA-induced neuroinflammation and regional metabolic functions.MethodsThe right and left striatum of Sprague Dawley and athymic nude rats were injected with QA and vehicle (VEH), respectively. Starting from the day before QA injection, animals were treated with 1 or 10 mg/kg of MLK or VEH for 14 days. At 14 and 30 days post-lesion, animals were monitored with magnetic resonance imaging (MRI) and positron emission tomography (PET) using [18F]-VC701, a translocator protein (TSPO)-specific radiotracer. Striatal neuroinflammatory response was measured post-mortem in rats treated with 1 mg/kg of MLK by immunofluorescence. Rats treated with 10 mg/kg of MLK also underwent a [18F]-FDG PET study at baseline and 4 months after lesion. [18F]-FDG PET data were then used to assess metabolic connectivity between brain regions by applying a covariance analysis method.ResultsMLK treatment was not able to reduce the QA-induced increase in striatal TSPO PET signal and MRI lesion volume, where we only detected a trend towards reduction in animals treated with 10 mg/kg of MLK. Post-mortem immunofluorescence analysis revealed that MLK attenuated the increase in striatal markers of astrogliosis and activated microglia in the lesioned hemisphere. We also found a significant increase in a marker of anti-inflammatory activity (MannR) and a trend towards reduction in a marker of pro-inflammatory activity (iNOS) in the lesioned striatum of MLK—compared to VEH-treated rats. [18F]-FDG uptake was significantly reduced in the striatum and ipsilesional cortical regions of VEH-treated rats at 4 months after lesion. MLK administration preserved glucose metabolism in these cortical regions, but not in the striatum. Finally, MLK was able to counteract changes in metabolic connectivity and measures of network topology induced by QA, in both lesioned and non-lesioned hemispheres.ConclusionsOverall, MLK treatment produced a significant neuroprotective effect by reducing neuroinflammation assessed by immunofluorescence and preserving regional brain metabolism and metabolic connectivity from QA-induced neurotoxicity in cortical and subcortical regions.

Performance on the Rey-Osterrieth complex figure test and the correlation with the magnetic resonance imaging brain lesion volume in multi-infract versus small vessel disease dementia

Background/Aim. Regarding several cognitive domains, including visuospatial and visuoconstructional abilities, little is known about the differences between vascular dementia (VaD) subtypes, even in the most common sub-types, such as multi-infarct dementia (MID) and subcortical ischemic small vessel disease dementia (SSVD). This paper aimed to identify the differences between the performances on the Rey-Osterrieth Complex Figure (ROCF) test in MID and SSVD and correlate the ROCF scores in both groups with magnetic resonance imaging (MRI) ischemic lesion load. Methods. Sixty VaD patients with matching severity of dementia, age, and education were included in this study: 32 with SSVD and 28 with MID ac-cording to the NINDS-AIREN (National Institute of Neuro-logical Disorders and Stroke and Association Internationale pour la Recherch? et l'Enseignement en Neurosciences) neuroradiological criteria. A quantitative scoring system was performed. ROCF was given to all subjects in three test conditions: copy, immediate recall after 3 minutes, and delayed recall after 45 min. Magnetic resonance imaging (MRI) of the is-chemic brain volumes of anterior and posterior lesions, left and right hemispheric lesions, left and right-sided basal ganglia lesions, and total lesion load (TLL) were calculated in both groups. Results. The MID group was more impaired than SSVD on ROCF copy (p = 0.008), immediate recall (p= 0.005) and delayed recall (p = 0.001). There were significant correlations between ROCF copy score and the TLL (p < 0.05) and posterior brain lesion volume (p< 0.05) in the MID group. Conclusion. The importance of visuospatial, visuoconstructional deficit and impairment of visual memory is disregarded in VaD subtypes. These impairments are more severe in MID than SSVD and the deficit of ROCF copying in MID patients correlates with posterior and total MRI lesion volume.

Methylene Blue Attenuates Significant Shifts in the Gut Microbiome Following Traumatic Brain Injury in Rodents

Abstract INTRODUCTION Recent advances in DNA sequencing technology have elucidated the role that the gut microbiome (GM) plays in health and disease. There remains, however, a paucity of data on GM’s role following a traumatic brain injury (TBI). While in Vivo studies have revealed neuroprotective effects of methylene blue (MB), we hypothesized that TBI would cause significant shifts in the GM that may be attenuated using MB. METHODS Male rats underwent craniotomy and were randomized to sham (n = 6), mild TBI (1 mm; n = 10), or moderate (2 mm; n = 6) TBI induced via a pneumatic impactor, as previously described. Rats were also assigned to receive either 1 mg/kg MB or vehicle/no treatment (NT). Stool was collected for 16S rRNA sequencing preinjury, as well as 1, 3, and 7 d postinjury. Magnetic resonance imaging (MRI) was performed on a subset of animals in each group. Illumina MiSeq sequencing was performed, and MB analysis was conducted using the Qiime2 standard pipeline to determine the beta-diversity significance using PERMANOVA. RESULTS In the absence of treatment, moderate (but not mild) TBI induced a significant shift in beta-diversity by day 3 (P = .029), which became increasingly pronounced by day 7 (P = .006). Treatment with MB reversed this shift, as these animals were not different from sham on day 7 (P = .06). A significant increase in the phylum Bacteroidetes was noted after moderate TBI (P = .009), which was attenuated with MB. Although alpha-diversity was not significantly altered after TBI, the MRI lesion volume positively correlated with Faith alpha-diversity (R2 = 0.82; P = .013). CONCLUSION After moderate TBI, the GM represented a unique community compared to sham controls. The significant shift in GM beta-diversity was attenuated with the administration of MB in this in Vivo rodent model. This research may have clinical implications in the context of normalizing aberrations in the gut-brain axis following TBI.

Big Data Approaches to Phenotyping Acute Ischemic Stroke Using Automated Lesion Segmentation of Multi-Center Magnetic Resonance Imaging Data.

Background and Purpose- We evaluated deep learning algorithms' segmentation of acute ischemic lesions on heterogeneous multi-center clinical diffusion-weighted magnetic resonance imaging (MRI) data sets and explored the potential role of this tool for phenotyping acute ischemic stroke. Methods- Ischemic stroke data sets from the MRI-GENIE (MRI-Genetics Interface Exploration) repository consisting of 12 international genetic research centers were retrospectively analyzed using an automated deep learning segmentation algorithm consisting of an ensemble of 3-dimensional convolutional neural networks. Three ensembles were trained using data from the following: (1) 267 patients from an independent single-center cohort, (2) 267 patients from MRI-GENIE, and (3) mixture of (1) and (2). The algorithms' performances were compared against manual outlines from a separate 383 patient subset from MRI-GENIE. Univariable and multivariable logistic regression with respect to demographics, stroke subtypes, and vascular risk factors were performed to identify phenotypes associated with large acute diffusion-weighted MRI volumes and greater stroke severity in 2770 MRI-GENIE patients. Stroke topography was investigated. Results- The ensemble consisting of a mixture of MRI-GENIE and single-center convolutional neural networks performed best. Subset analysis comparing automated and manual lesion volumes in 383 patients found excellent correlation (ρ=0.92; P<0.0001). Median (interquartile range) diffusion-weighted MRI lesion volumes from 2770 patients were 3.7 cm3 (0.9-16.6 cm3). Patients with small artery occlusion stroke subtype had smaller lesion volumes ( P<0.0001) and different topography compared with other stroke subtypes. Conclusions- Automated accurate clinical diffusion-weighted MRI lesion segmentation using deep learning algorithms trained with multi-center and diverse data is feasible. Both lesion volume and topography can provide insight into stroke subtypes with sufficient sample size from big heterogeneous multi-center clinical imaging phenotype data sets.

Lower Grade Gliomas: Relationships Between Metabolic and Structural Imaging with Grading and Molecular Factors

Positron emission tomography (PET) is a valuable tool for the characterization of brain tumors invivo. However, few studies have investigated the correlation between carbon-11-methionine (11C-METH) PET metrics and the clinical, radiological, histological, and molecular features of patients affected by lower grade gliomas (LGGs). The present observational study evaluated the relationships between 11C-METH PET metrics and structural magnetic resonance imaging (MRI) findings with the histomolecular biomarkers in patients with LGGs who were candidates for surgery. We enrolled 96 patients with pathologically proven LGG (51 men, 45 women; age 44.1 ± 13.7 years; 45 with grade II, 51 with grade III), who had been referred from March 2012 to January 2015 for tumor resection and had undergone preoperative 11C-METH PET. The semiquantitative metrics for 11C-METH PET included maximum standardized uptake value (SUVmax), SUV ratio to normal brain, and metabolic tumor burden (MTB). The PET semiquantitative metrics were analyzed and compared with the MRI features, histological diagnosis, isocitrate dehydrogenase-1/2 status, and 1p/19q codeletion. Histological grade was associated with SUVmax (P= 0.002), SUV ratio (P= 0.011), and MTB (P= 0.001), with grade III lesions showing higher values. Among the nonenhancing lesions on MRI, SUVmax (P= 0.001), SUV ratio (P= 0.003) and MTB (P < 0.001) were significantly different statistically for grade II versus grade III. The MRI lesion volume correlated poorly with MTB (r2= 0.13). The SUVmax and SUV ratio were greater (P < 0.05) in isocitrate dehydrogenase-1/2 wild-type lesions, and the SUV ratio was associated with the presence of the 1p19q codeletion. The 11C-METH PET metrics correlated significantly with histological grade and the molecular profile. Semiquantitative PET metrics can improve the preoperative evaluation of LGGs and thus support clinical decision-making.

Targets missed: predictors of MRI-targeted biopsy failing to accurately localize prostate cancer found on systematic biopsy

Magnetic resonance imaging (MRI)/ultrasound (US) fusion-guided biopsy has improved the ability to localize and detect prostate cancer (PCa) with efficiency surpassing systematic biopsy. Nevertheless, some patients have PCa missed using the MRI-targeted biopsy sampling alone. We aim to identify clinical and imaging parameters associated with cases where targeted biopsy did not detect PCa compared to systematic biopsy. We conducted a retrospective review of patients who underwent MRI/US fusion-guided biopsy in addition to concurrent systematic, extended-sextant biopsy between 2014 and 2017. For patients with PCa detected on systematic biopsy not properly localized by MRI/US fusion-guided biopsy, the sextant distance from MRI-targeted lesion to the cancer-positive sextant was calculated and parameters potentially predicting this targeting miss were evaluated. In all, 35/127 (27.6%) patients with single-session MRI/US fusion-guided biopsy plus standard biopsy finding PCa had lesions incorrectly localized. Of these, 15/35 (42.9%) were identified as possible fusion-software misregistrations. The remainder, 12/35 (34.3%), represented targeted biopsies one sextant away from the cancer focus and 8/35 (22.9%) targeted biopsies two sextants away from the cancer focus. Only 7/35 (20.0%) patients were determined to have clinically significant PCa, which represents 7/127 (5.5%) of the overall population. Lower MRI lesion volumes (p = 0.022), lesion density (p < 0.001), and PI-RADS scores (p < 0.001) were significantly associated with targeted biopsy missing PCa detected on systematic biopsy. Clinically significant PCa is rarely missed utilizing MRI/US fusion-guided biopsy. With the majority of missed tumors representing targeting misregistrations or cases of low-grade cancer in sextants immediately adjacent to MRI suspicious lesions. Lower MRI lesion volumes, lesion density, and PI-RADS are predictors of cases with targeted biopsies missing cancer, for which systematic sampling of the sextants containing MRI targets and adjacent sextants would most optimize PCa detection.

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.

478: Imaging before 24 weeks gestation can predict neonatal respiratory morbidity in pregnancies complicated by fetal lung masses

To evaluate the utility of imaging before 24 weeks for predicting adverse neonatal respiratory morbidity in pregnancies with fetal lung masses. A retrospective analysis of pregnancies complicated by fetal lung masses between 2009 and 2016 at a single center was performed. Cases with ultrasound (US) and magnetic resonance imaging (MRI) performed before 24 weeks gestation were included. US and MRI measurements were used to calculate the congenital pulmonary airway malformation (CPAM) volume and CPAM volume ratio (CVR). Adverse neonatal respiratory outcome was defined as need for any of the following: intubation and mechanical ventilation at birth, surgery before discharge, or extracorporeal membrane oxygenation (ECMO). The sensitivity, specificity, positive and negative predictive value of both US and MRI were determined. ROC curves were calculated as well. 41 cases with initial US imaging performed at <24 weeks gestation were identified. Of those, 35 also had an initial MRI performed at before 24 weeks. 6 cases (15% of those with US <24 weeks) had an adverse respiratory outcome at birth (5 intubation and mechanical ventilation, 4 surgery before discharge, and 1 ECMO). Additionally, there was one case of intrauterine fetal demise, and one neonatal death which were excluded from the analysis. When analyzing all imaging parameters, the strongest predictors of adverse respiratory outcomes were lesion CVR by MRI ≥0.68 (79% specificity, 83% sensitivity, 45% positive predictive value, 96% negative predictive value) and volume by MRI ≥12.8 cm3 (79% specificity, 83% sensitivity, 45% positive predictive value, 96% negative predictive value). Whereas, CVR by US ≥0.31 (50% specificity, 100% sensitivity 24%, positive predictive value, 100% negative predictive value) and volume by US ≥11.8 cm3 (75% specificity, 80% sensitivity, 33% positive predictive value, 96% negative predictive value) were weaker predictors. MRI lesion volume had an AUC of 0.82 and MRI CVR had an AUC of 0.83. CVR and lesion volume by MRI calculated before 24 weeks gestational age were the strongest imaging predictors of adverse neonatal respiratory outcomes. MRI should be considered in cases of fetal lung masses in order to optimize delivery planning and multidisciplinary care coordination.View Large Image Figure ViewerDownload Hi-res image Download (PPT)

Effects of hyperoxia on 18F-fluoro-misonidazole brain uptake and tissue oxygen tension following middle cerebral artery occlusion in rodents: Pilot studies.

PurposeMapping brain hypoxia is a major goal for stroke diagnosis, pathophysiology and treatment monitoring. 18F-fluoro-misonidazole (FMISO) positron emission tomography (PET) is the gold standard hypoxia imaging method. Normobaric hyperoxia (NBO) is a promising therapy in acute stroke. In this pilot study, we tested the straightforward hypothesis that NBO would markedly reduce FMISO uptake in ischemic brain in Wistar and spontaneously hypertensive rats (SHRs), two rat strains with distinct vulnerability to brain ischemia, mimicking clinical heterogeneity.MethodsThirteen adult male rats were randomized to distal middle cerebral artery occlusion under either 30% O2 or 100% O2. FMISO was administered intravenously and PET data acquired dynamically for 3hrs, after which magnetic resonance imaging (MRI) and tetrazolium chloride (TTC) staining were carried out to map the ischemic lesion. Both FMISO tissue uptake at 2-3hrs and FMISO kinetic rate constants, determined based on previously published kinetic modelling, were obtained for the hypoxic area. In a separate group (n = 9), tissue oxygen partial pressure (PtO2) was measured in the ischemic tissue during both control and NBO conditions.ResultsAs expected, the FMISO PET, MRI and TTC lesion volumes were much larger in SHRs than Wistar rats in both the control and NBO conditions. NBO did not appear to substantially reduce FMISO lesion size, nor affect the FMISO kinetic rate constants in either strain. Likewise, MRI and TTC lesion volumes were unaffected. The parallel study showed the expected increases in ischemic cortex PtO2 under NBO, although these were small in some SHRs with very low baseline PtO2.ConclusionsDespite small samples, the apparent lack of marked effects of NBO on FMISO uptake suggests that in permanent ischemia the cellular mechanisms underlying FMISO trapping in hypoxic cells may be disjointed from PtO2. Better understanding of FMISO trapping processes will be important for future applications of FMISO imaging.

Abstract 38: Brain CT Perfusion is Superior to Non-contrast CT Aspects in the Evaluation of Hyperacute Infarct Volume

Objective: To compare the predictive capacity to detect established infarct in acute anterior circulation stroke between the Alberta Stroke Program Early Computed Tomography Score (ASPECTS) on non-contrast computed tomography (CT) and CT perfusion. Methods: Fifty-nine acute anterior circulation ischemic stroke patients received brain non-contrast CT, CT perfusion and hyperacute magnetic resonance imaging (MRI) within 100 minutes from CT imaging. ASPECTS scores were calculated by 4 independent vascular neurologists, blinded from CT perfusion and MRI data. CT perfusion infarct core volumes were calculated by MIStar software. The accuracy of commonly used ASPECTS cut-off scores and a CT perfusion core volume of ≥ 70 mL to detect a hyperacute MRI diffusion lesion of ≥ 70 ml was evaluated. Results: Median ASPECTS score was 9 (IQR 7-10). Median CT perfusion core volume was 22 ml (IQR 10.4-71.9). Median MRI diffusion lesion volume was 24,5 ml (IQR 10-63.9). ASPECTS score of &lt; 6 had a sensitivity of 0.37, specificity of 0.95 and c-statistic of 0.66 to predict an acute MRI lesion ≥ 70 ml. In comparison, a CT perfusion core lesion of ≥ 70 ml had a sensitivity of 0.76, specificity of 0.98 and c-statistic of 0.92. The CT perfusion core lesion covered a median of 100% of the acute MRI lesion volume (IQR 86-100%). Conclusions: CT perfusion is superior to ASPECTS to predict hyperacute MRI lesion volume in ischemic stroke.

Lesion volume predicts prostate cancer risk and aggressiveness: validation of its value alone and matched with prostate imaging reporting and data system score

To demonstrate the association between magnetic resonance imaging (MRI) estimated lesion volume (LV), prostate cancer detection and tumour clinical significance, evaluating this variable alone and matched with Prostate Imaging Reporting and Data System version 2 (PI-RADS v2) score. We retrospectively analysed 157 consecutive patients, with at least one prior negative systematic prostatic biopsy, who underwent transperineal prostate MRI/ultrasonography fusion-targeted biopsy between January 2014 and February 2016. Suspicious lesions were delineated using a 'region of interest' and the system calculated prostate volume and LV. Patients were divided in groups considering LV (≤0.5, 0.5-1, ≥1 mL) and PI-RADS score (1-5). We considered clinically significant prostate cancer as all cancers with a Gleason score of ≥3 + 4 as suggested by PI-RADS v2. A direct comparison between MRI estimated LV (MRI LV) and histological tumour volume (HTV) was done in 23 patients who underwent radical prostatectomy during the study period. Differences between MRI LV and HTV were assessed using the paired sample t-test. MRI LV and HTV concordance was verified using a Bland-Altman plot. The chi-squared test and logistic and ordinal regression models were used to evaluate difference in frequencies. The MRI LV and PI-RADS score were associated both with prostate cancer detection (both P < 0.001) and with significant prostate cancer detection (P < 0.001 and P = 0.008, respectively). When the two variables were matched, increasing LV increased the risk within each PI-RADS group. Prostate cancer detection was 1.4-times higher for LVs of 0.5-1 mL and 1.8-times higher for LVs of ≥1 mL; significant prostate cancer detection was 2.6-times for LVs of 0.5-1 mL and 4-times for LVs of ≥1 mL. There was a positive correlation between MRI LV and HTV (r = 0.9876, P < 0.001). Finally, Bland-Altman analysis showed that MRI LV was underestimated by 4.2% compared to HTV. Study limitations include its monocentric and retrospective design and the limited cohort. This study demonstrates that PI-RADS score and the MRI LV, independently and in combination, are associated with prostate cancer detection and with tumour clinical significance.

Role of Acute Lesion Topography in Initial Ischemic Stroke Severity and Long-Term Functional Outcomes.

Acute infarct volume, often proposed as a biomarker for evaluating novel interventions for acute ischemic stroke, correlates only moderately with traditional clinical end points, such as the modified Rankin Scale. We hypothesized that the topography of acute stroke lesions on diffusion-weighted magnetic resonance imaging may provide further information with regard to presenting stroke severity and long-term functional outcomes. Data from a prospective stroke repository were limited to acute ischemic stroke subjects with magnetic resonance imaging completed within 48 hours from last known well, admission NIH Stroke Scale (NIHSS), and 3-to-6 months modified Rankin Scale scores. Using voxel-based lesion symptom mapping techniques, including age, sex, and diffusion-weighted magnetic resonance imaging lesion volume as covariates, statistical maps were calculated to determine the significance of lesion location for clinical outcome and admission stroke severity. Four hundred ninety subjects were analyzed. Acute stroke lesions in the left hemisphere were associated with more severe NIHSS at admission and poor modified Rankin Scale at 3 to 6 months. Specifically, injury to white matter (corona radiata, internal and external capsules, superior longitudinal fasciculus, and uncinate fasciculus), postcentral gyrus, putamen, and operculum were implicated in poor modified Rankin Scale. More severe NIHSS involved these regions, as well as the amygdala, caudate, pallidum, inferior frontal gyrus, insula, and precentral gyrus. Acute lesion topography provides important insights into anatomic correlates of admission stroke severity and poststroke outcomes. Future models that account for infarct location in addition to diffusion-weighted magnetic resonance imaging volume may improve stroke outcome prediction and identify patients likely to benefit from aggressive acute intervention and personalized rehabilitation strategies.

Correlation of MRI sequences to assess progressive glioblastoma multiforme treated with bevacizumab

In the context of bevacizumab therapy for the treatment of progressive malignant gliomas, it is currently unclear how different magnetic resonance imaging (MRI) sequences correlate with each other over time. The objective of this study was to determine if a reliable and predictable relationship over time exists between post-gadolinium based contrast agent T1-weighted (T1+GBCA), T2-weighted, and FLAIR MRI in patients with progressive glioblastoma multiforme (GBM) receiving bevacizumab and chemotherapy. The MRI lesion volumes of 10 patients with progressive GBM that received bevacizumab plus chemotherapy were manually calculated by two independent reviewers. T2 and FLAIR volumes were analyzed by analysis of covariance (ANCOVA) as a function of T1+GBCA lesion enhancement volume, reviewer, and time interval between MRI acquisitions. Pearson product moment correlation (r) was used to compare pre and post treatment volumes for the group of 10 patients and for each individual patient over their treatment course. ANCOVA demonstrated a significant association between T1+GBCA and T2-weighted volumes (P=0.0006) and between T1+GBCA and FLAIR volumes (P<0.0001). These associations remained constant over time. The correlation between T1+GBCA and both T2-weighted and FLAIR volumes improved after bevacizumab treatment. Individual correlations between T1+GBCA and FLAIR were strong (r≥0.63) with one exception, while correlations between T1+GBCA and T2 were more variable (r=0.18-0.99). These findings suggest that FLAIR MRI should be evaluated in addition to T1+GBCA MRI when evaluating GBM responses.

Rodent Neonatal Bilateral Carotid Artery Occlusion with Hypoxia Mimics Human Hypoxic-Ischemic Injury

We report a new clinically relevant model of neonatal hypoxic-ischemic injury in a 10-day-old rat pup. Bilateral carotid artery occlusion and 8% hypoxia (1 to 15 mins, BCAO-H) was induced with varying degrees of injury (mild, moderate, severe), which was quantified using magnetic resonance imaging including diffusion-weighted and T2-weighted imaging at 24 h and 21/28 days. We developed a magnetic resonance imaging-based rat pup severity score and compared 3D ischemic injury volumes/rat pup severity score with histology and behavioral testing. At 24 h, hypoxic-ischemic injury was observed in 17/27 animals; long-term survival was 81%. Magnetic resonance imaging lesion volumes did not correlate with hypoxia duration but correlated with rat pup severity score, which was used to classify animals into mild (n=21), moderate (n=6), and severe (n=10) groups with average brain lesion volumes of 0.9%, 33.2%, and 56.3%, respectively. Histology confirmed lesion location and histologic scoring correlated with the rat pup severity score. We also found excellent correlation between injury severity and multiple behavioral tasks. Bilateral carotid artery occlusion and hypoxia in the P10 rat pup is an excellent model of neonatal hypoxic-ischemic injury because it induces diffuse global injury similar to the term infant. This model can produce graded injury severity, similar to that seen in human neonates, but manipulation with hypoxia duration is unpredictable.

Experimental intracerebral hematoma in the rat: Characterization by sequential magnetic resonance imaging, behavior, and histopathology. Effect of albumin therapy

We characterized acute intracerebral hemorrhage (ICH) in the rat by sequential magnetic resonance imaging (MRI) and correlated MRI findings with neurobehavior and histopathology. In addition, we investigated whether albumin treatment would reduce ICH-induced brain injury. ICH was produced in rats by a double-injection method in which 45 μl of fresh arterial blood was injected into the right striatum. Susceptibility-weighted (SWI) and T2-weighted (T2WI) MRI was carried out on a 4.7T magnet at 0–1 h, 6 h, 24 h, 72 h, and 7 days after ICH. Animals were treated with either 25% human albumin, 1.25 g/kg, or saline vehicle i.v. at 90 min after ICH. Neurological status was evaluated before ICH and after treatment (at 4 h, 24 h, 48 h, 72 h, and 7 days). Brains were then perfusion-fixed, re-imaged on an 11.7T magnet, and studied by histopathology and immunochemistry. MRI revealed a consistent hematoma involving the striatum and overlying corpus callosum, with significant volume changes over time. Lesion volumes computed from T2WI images and by histopathology agreed closely with one another and were highly correlated ( p = 0.002). SWI lesion volumes were also highly correlated to histological volumes ( p < 0.001) but overestimated histological hematoma volume by ∼ 5-fold. Albumin treatment significantly improved neurological scores compared to saline at 72 h (3.8 ± 0.6 vs. 1.5 ± 0.7) and 7 days (3.8 ± 0.4 vs. 1.3 ± 0.5, respectively, p < 0.05), but did not affect histological or MRI lesion volumes. Taken together, sequential MRI plus histopathology provides a comprehensive characterization of experimental ICH. Albumin treatment improves neurological deficit after ICH but does not affect MRI or histological hematoma size.

Behavioral, Histological, and Ex Vivo Magnetic Resonance Imaging Assessment of Graded Contusion Spinal Cord Injury in Mice

This study characterized the Infinite Horizon (IH) Impactor for use in mouse models of contusion spinal cord injury (SCI), and investigated the feasibility and reliability of using magnetic resonance imaging (MRI) as a method to accurately measure lesion volume after mouse contusion SCI. Eight-week-old female C57Bl/6 mice received a mild (30 kilodyne), moderate (50 kilodyne), or severe (70 kilodyne) contusion injury at the T9 vertebral level. Uninjured control mice received a T9 laminectomy only. Functional recovery was assessed using the Basso, Beattie, Bresnahan (BBB) and Basso Mouse Scale (BMS) open-field locomotor rating scales. Next, 4% paraformaldehyde-perfused spinal cords were collected between the T6 and T12 spinal roots, and stored in phosphate-buffered saline (PBS) at 4 degrees C until MRI analysis. MRI lesion volumes were determined using T1-weighted images on a 7-Tesla MRI. Histology was performed on 20-microm polyester wax-embedded sections processed from the same spinal cords for stereological determination of fibronectin lesion volume and myelin basic protein spared white matter volume. Area of spared white matter at the epicenter was also analyzed. The results demonstrated that the IH Impactor produced precise, graded contusion SCI in mice. Lesion volumes were positively correlated with force of impact, and negatively correlated with spared white matter and functional recovery. Additionally, similar lesion volumes were detected using fibronectin staining and MRI analysis, although MRI may be more sensitive for milder injuries. These results give researchers more options in how to analyze spinal cord injuries in animal models.

Multi-modal characterisation of the neocortical clip model of focal cerebral ischaemia by MRI, behaviour and immunohistochemistry

The neocortical clip model of focal cerebral ischaemia has previously been used with success in neuroprotection studies. To further improve its translational qualities, we have characterised this model using a combination of serial Magnetic Resonance Imaging (MRI), neurological assessment, the bilateral asymmetry test (BAT) and immunohistochemistry. The right MCA was occluded in spontaneously hypertensive rats for 0, 60 and 120 min. MRI was performed pre-surgery, 1, 3 and 7 days post-surgery. Behavioural assessment was performed 2 days before and 3 and 7 days post-surgery whilst neurological deficits were monitored daily. Neuroimaging results showed that 0 min of MCA occlusion did not produce a lesion, whereas occlusion for 60 min produced a lesion that remained stable over time. Occlusion for 120 min caused a more severe lesion 1 day post-surgery, but decreased by 7 days. Behaviour, neurological scores and histological lesion volumes correlated strongly with MRI lesion volume. Immunohistochemistry revealed neuronal loss, astrogliosis and macrophage infiltration in lesioned cortices. The neocortical clip model produced ischaemic lesions that are restricted to cortical territories of the MCA. The duration of occlusion dictates lesion severity which may prove useful for probing therapeutic interventions at different stages of stroke progression. The correlation of MRI with two different behavioural measures and post-mortem histology strengthens the basis for MRI providing an in vivo surrogate marker for structural and behavioural deficits caused by a cortical stroke.

Early macrophage MRI of inflammatory lesions predicts lesion severity and disease development in relapsing EAE

Magnetic resonance imaging (MRI) is of great utility in diagnosis and monitoring of multiple sclerosis (MS). Axonal loss is considered the main cause of accumulating irreversible disability. MRI using ultrasmall-super-paramagnetic-iron-oxide (USPIO) nanoparticles is a new technique to disclose in vivo central nervous system (CNS) inflammatory lesions infiltrated by macrophages in experimental autoimmune encephalomyelitis (EAE). Here, we raised the question of whether USPIO-enhanced MRI could serve as a tool to predict disease severity. We investigated, in a relapsing EAE model with various degrees of disease severity, the interindividual differences at the beginning of CNS inflammation as revealed in vivo by MRI with USPIO in correlation to the severity of both acute and chronic tissue damage including axonal loss. At the onset of the disease, observation of MRI alterations with USPIO allowed assignment of animals into USPIO+ and USPIO− groups. In 54.5% of diseased rats, MRI with USPIO+ at first attack revealed signal abnormalities mainly localized in the brainstem and cerebellum. Although animals did not present any clinically significant differences during the first attack, USPIO+ rats presented significantly more important tissue alterations at the first attack (onset and initiated recovery phase) and, at the second attack, more severe clinical disease with axonal loss compared to USPIO− rats. MRI lesion load and volume at the first attack correlate significantly with inflammation, macrophage recruitment, demyelination, acute axonal damage and, at the second attack, extent of axonal loss. This new MRI application of in vivo monitoring of macrophage infiltration provides a new platform to investigate the severity of inflammatory demyelinating CNS diseases.

Greater MRI lesion volumes in elderly depressed subjects than in control subjects

Hyperintense lesions in both white matter and gray matter on T2-weighted magnetic resonance imaging (MRI) are associated with late-life depression. This large study examined differences in gray and white matter lesion volumes on brain MRI between 253 elderly depressed and 146 control subjects. White matter and gray matter lesion volumes were measured in each hemisphere using a semi-automated segmentation process and compared against depression status. Depressed subjects exhibited significantly greater total white matter (mean 7.22 ml) and gray matter (mean 0.30 ml) lesion volumes in both hemispheres than did control subjects (mean 4.87 ml in white matter and 0.18 ml in gray matter). This difference remained statistically significant even after controlling for confounders such as age, sex, race and reports of hypertension, diabetes and heart disease. Patients with late-life depression have larger white matter lesion and gray matter lesion volumes than do control subjects. Future research should combine similar volumetric techniques with methods of identifying the location of lesions specific to late-life depression.

A Pilot Study of Normobaric Oxygen Therapy in Acute Ischemic Stroke

Therapies that transiently prevent ischemic neuronal death can potentially extend therapeutic time windows for stroke thrombolysis. We conducted a pilot study to investigate the effects of high-flow oxygen in acute ischemic stroke. We randomized patients with acute stroke (<12 hours) and perfusion-diffusion "mismatch" on magnetic resonance imaging (MRI) to high-flow oxygen therapy via facemask for 8 hours (n=9) or room air (controls, n=7). Stroke scale scores and MRI scans were obtained at baseline, 4 hours, 24 hours, 1 week, and 3 months. Clinical deficits and MR abnormalities were compared between groups. Stroke scale scores were similar at baseline, tended to improve at 4 hours (during therapy) and 1 week, and significantly improved at 24 hours in hyperoxia-treated patients. There was no significant difference at 3 months. Mean (+/-SD) relative diffusion MRI lesion volumes were significantly reduced in hyperoxia-treated patients at 4 hours (87.8+/-22% versus 149.1+/-41%; P=0.004) but not subsequent time points. The percentage of MRI voxels improving from baseline "ischemic" to 4-hour "non-ischemic" values tended to be higher in hyperoxia-treated patients. Cerebral blood volume and blood flow within ischemic regions improved with hyperoxia. These "during-therapy" benefits occurred without arterial recanalization. By 24 hours, MRI showed reperfusion and asymptomatic petechial hemorrhages in 50% of hyperoxia-treated patients versus 17% of controls (P=0.6). High-flow oxygen therapy is associated with a transient improvement of clinical deficits and MRI abnormalities in select patients with acute ischemic stroke. Further studies are warranted to investigate the safety and efficacy of hyperoxia as a stroke therapy.