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BackgroundDynamic hyperpolarized (HP)-13C MRI has enabled real-time, non-invasive assessment of Warburg-related metabolic dysregulation in glioma using a [1-13C]pyruvate tracer that undergoes conversion to [1-13C]lactate and [13C]bicarbonate. Using a multi-parametric 1H/HP-13C imaging approach, we investigated dynamic and steady-state metabolism, together with physiological parameters, in high-grade gliomas to characterize active tumor.MethodsMulti-parametric 1H/HP-13C MRI data were acquired from fifteen patients with progressive/treatment-naïve glioblastoma [prog/TN GBM, IDH-wildtype (n = 11)], progressive astrocytoma, IDH-mutant, grade 4 (G4AIDH+, n = 2) and GBM manifesting treatment effects (n = 2). Voxel-wise regional analysis of the cohort with prog/TN GBM assessed imaging heterogeneity across contrast-enhancing/non-enhancing lesions (CEL/NEL) and normal-appearing white matter (NAWM) using a mixed effects model. To enable cross-nucleus parameter association, normalized perfusion, diffusion, and dynamic/steady-state (HP-13C/spectroscopic) metabolic data were collectively examined at the 13C resolution. Prog/TN GBM were similarly compared against progressive G4AIDH+ and treatment effects.ResultsRegional analysis of Prog/TN GBM metabolism revealed statistically significant heterogeneity in 1H choline-to-N-acetylaspartate index (CNI)max, [1-13C]lactate, modified [1-13C]lactate-to-[1-13C]pyruvate ratio (CELval > NELval > NAWMval); [1-13C]lactate-to-[13C]bicarbonate ratio (CELval > NELval/NAWMval); and 1H-lactate (CELval/NELval > NAWMundetected). Significant associations were found between normalized perfusion (cerebral blood volume, nCBV; peak height, nPH) and levels of [1-13C]pyruvate and [1-13C]lactate, as well as between CNImax and levels of [1-13C]pyruvate, [1-13C]lactate and modified ratio. GBM, by comparison to G4AIDH+, displayed lower perfusion %-recovery and modeled rate constants for [1-13C]pyruvate-to-[1-13C]lactate conversion (kPL), and higher 1H-lactate and [1-13C]pyruvate levels, while having higher nCBV, %-recovery, kPL, [1-13C]pyruvate-to-[1-13C]lactate and modified ratios relative to treatment effects.ConclusionsGBM consistently displayed aberrant, Warburg-related metabolism and regional heterogeneity detectable by novel HP-13C/1H imaging techniques.

BackgroundDiagnostic classification of diffuse gliomas now requires an assessment of molecular features, often including IDH-mutation and 1p19q-codeletion status. Because genetic testing requires an invasive process, an alternative noninvasive approach is attractive, particularly if resection is not recommended. The goal of this study was to evaluate the effects of training strategy and incorporation of biologically relevant images on predicting genetic subtypes with deep learning.MethodsOur dataset consisted of 384 patients with newly diagnosed gliomas who underwent preoperative MRI with standard anatomical and diffusion-weighted imaging, and 147 patients from an external cohort with anatomical imaging. Using tissue samples acquired during surgery, each glioma was classified into IDH-wildtype (IDHwt), IDH-mutant/1p19q-noncodeleted (IDHmut-intact), and IDH-mutant/1p19q-codeleted (IDHmut-codel) subgroups. After optimizing training parameters, top performing convolutional neural network (CNN) classifiers were trained, validated, and tested using combinations of anatomical and diffusion MRI with either a 3-class or tiered structure. Generalization to an external cohort was assessed using anatomical imaging models.ResultsThe best model used a 3-class CNN containing diffusion-weighted imaging as an input, achieving 85.7% (95% CI: [77.1, 100]) overall test accuracy and correctly classifying 95.2%, 88.9%, 60.0% of the IDHwt, IDHmut-intact, and IDHmut-codel tumors. In general, 3-class models outperformed tiered approaches by 13.5%-17.5%, and models that included diffusion-weighted imaging were 5%-8.8% more accurate than those that used only anatomical imaging.ConclusionTraining a classifier to predict both IDH-mutation and 1p19q-codeletion status outperformed a tiered structure that first predicted IDH-mutation, then 1p19q-codeletion. Including apparent diffusion coefficient (ADC), a surrogate marker of cellularity, more accurately captured differences between subgroups.

BackgroundMonitoring lower-grade gliomas (LrGGs) for disease progression is made difficult by the limits of anatomical MRI to distinguish treatment related tissue changes from tumor progression. MR spectroscopic imaging (MRSI) offers additional metabolic information that can help address these challenges. The goal of this study was to compare longitudinal changes in multiparametric MRI, including diffusion weighted imaging, perfusion imaging, and 3D MRSI, for LrGG patients who progressed at the final time-point and those who remained clinically stable.MethodsForty-one patients with LrGG who were clinically stable were longitudinally assessed for progression. Changes in anatomical, diffusion, perfusion and MRSI data were acquired and compared between patients who remained clinically stable and those who progressed.ResultsThirty-one patients remained stable, and 10 patients progressed. Over the study period, progressed patients had a significantly greater increase in normalized choline, choline-to-N-acetylaspartic acid index (CNI), normalized creatine, and creatine-to-N-acetylaspartic acid index (CRNI), than stable patients. CRNI was significantly associated with progression status and WHO type. Progressed astrocytoma patients had greater increases in CRNI than stable astrocytoma patients.ConclusionsLrGG patients in surveillance with tumors that progressed had significantly increasing choline and creatine metabolite signals on MRSI, with a trend of increasing T2 FLAIR volumes, compared to LrGG patients who remained stable. These data show that MRSI can be used in conjunction with anatomical imaging studies to gain a clearer picture of LrGG progression, especially in the setting of clinical ambiguity.

BackgroundCognitive impairment and cerebral microbleeds (CMBs) are long-term side-effects of cranial radiation therapy (RT). Previously we showed that memory function is disrupted in young patients and that the rate of cognitive decline correlates with CMB development. However, vascular injury alone cannot explain RT-induced cognitive decline. Here we use resting-state functional MRI (rsfMRI) to further investigate the complex mechanisms underlying memory impairment after RT.MethodsNineteen young patients previously treated with or without focal or whole-brain RT for a brain tumor underwent cognitive testing followed by 7T rsfMRI and susceptibility-weighted imaging for CMB detection. Global brain modularity and efficiency, and rsfMRI signal variability within the dorsal attention, salience, and frontoparietal networks were computed. We evaluated whether MR metrics could distinguish age- and sex-matched controls (N = 19) from patients and differentiate patients based on RT exposure and aggressiveness. We also related MR metrics with memory performance, CMB burden, and risk factors for cognitive decline after RT.ResultsCompared to controls, patients exhibited widespread hyperconnectivity, similar modularity, and significantly increased efficiency (p < 0.001) and network variability (p < 0.001). The most abnormal values were detected in patients treated with high dose whole-brain RT, having supratentorial tumors, and who did not undergo RT but had hydrocephalus. MR metrics and memory performance were correlated (R = 0.34-0.53), though MR metrics were more strongly related to risk factors for cognitive worsening and CMB burden with evidence of functional recovery.ConclusionsMR metrics describing brain connectivity and variability represent promising candidate imaging biomarkers for monitoring of long-term cognitive side-effects after RT.

BackgroundReal-time metabolic conversion of intravenously-injected hyperpolarized [1-13C]pyruvate to [1-13C]lactate and [13C]bicarbonate in the brain can be measured using dynamic hyperpolarized carbon-13 (HP-13C) MRI. However, voxel-wise evaluation of metabolism in patients with glioma is challenged by the limited signal-to-noise ratio (SNR) of downstream 13C metabolites, especially within lesions. The purpose of this study was to evaluate the ability of higher-order singular value decomposition (HOSVD) denoising methods to enhance dynamic HP [1-13C]pyruvate MRI data acquired from patients with glioma.MethodsDynamic HP-13C MRI were acquired from 14 patients with glioma. The effects of two HOSVD denoising techniques, tensor rank truncation-image enhancement (TRI) and global-local HOSVD (GL-HOSVD), on the SNR and kinetic modeling were analyzed in [1-13C]lactate data with simulated noise that matched the levels of [13C]bicarbonate signals. Both methods were then evaluated in patient data based on their ability to improve [1-13C]pyruvate, [1-13C]lactate and [13C]bicarbonate SNR. The effects of denoising on voxel-wise kinetic modeling of kPL and kPB was also evaluated. The number of voxels with reliable kinetic modeling of pyruvate-to-lactate (kPL) and pyruvate-to-bicarbonate (kPB) conversion rates within regions of interest (ROIs) before and after denoising was then compared.ResultsBoth denoising methods improved metabolite SNR and regional signal coverage. In patient data, the average increase in peak dynamic metabolite SNR was 2-fold using TRI and 4-5 folds using GL-HOSVD denoising compared to acquired data. Denoising reduced kPL modeling errors from a native average of 23% to 16% (TRI) and 15% (GL-HOSVD); and kPB error from 42% to 34% (TRI) and 37% (GL-HOSVD) (values were averaged voxelwise over all datasets). In contrast-enhancing lesions, the average number of voxels demonstrating within-tolerance kPL modeling error relative to the total voxels increased from 48% in the original data to 84% (TRI) and 90% (GL-HOSVD), while the number of voxels showing within-tolerance kPB modeling error increased from 0% to 15% (TRI) and 8% (GL-HOSVD).ConclusionPost-processing denoising methods significantly improved the SNR of dynamic HP-13C imaging data, resulting in a greater number of voxels satisfying minimum SNR criteria and maximum kinetic modeling errors in tumor lesions. This enhancement can aid in the voxel-wise analysis of HP-13C data and thereby improve monitoring of metabolic changes in patients with glioma following treatment.

BackgroundNeurocognitive deficits in pediatric cancer survivors occur frequently; however, individual outcomes are unpredictable. We investigate clinical, genetic, and imaging predictors of neurocognition in pediatric cancer survivors, with a focus on survivors of central nervous system (CNS) tumors exposed to radiation.MethodsOne hundred eighteen patients with benign or malignant cancers (median diagnosis age: 7; 32% embryonal CNS tumors) were selected from an existing multi-institutional cohort (RadART Pro) if they had: 1) neurocognitive evaluation; 2) available DNA; 3) standard imaging. Utilizing RadART Pro, we collected clinical history, genomic sequencing, CNS imaging, and neurocognitive outcomes. We performed single nucleotide polymorphism (SNP) genotyping for candidate genes associated with neurocognition: COMT, BDNF, KIBRA, APOE, KLOTHO. Longitudinal neurocognitive testing were performed using validated computer-based CogState batteries. The imaging cohort was made of patients with available iron-sensitive (n = 28) and/or T2 FLAIR (n = 41) sequences. Cerebral microbleeds (CMB) were identified using a semi-automated algorithm. Volume of T2 FLAIR white matter lesions (WML) was measured using an automated method based on a convolutional neural network. Summary statistics were performed for patient characteristics, neurocognitive assessments, and imaging. Linear mixed effects and hierarchical models assessed patient characteristics and SNP relationship with neurocognition over time. Nested case-control analysis was performed to compare candidate gene carriers to non-carriers.ResultsCMB presence at baseline correlated with worse performance in 3 of 7 domains, including executive function. Higher baseline WML volumes correlated with worse performance in executive function and verbal learning. No candidate gene reliably predicted neurocognitive outcomes; however, APOE ϵ4 carriers trended toward worse neurocognitive function over time compared to other candidate genes and carried the highest odds of low neurocognitive performance across all domains (odds ratio 2.85, P=0.002). Hydrocephalus and seizures at diagnosis were the clinical characteristics most frequently associated with worse performance in neurocognitive domains (5 of 7 domains). Overall, executive function and verbal learning were the most frequently negatively impacted neurocognitive domains.ConclusionPresence of CMB, APOE ϵ4 carrier status, hydrocephalus, and seizures correlate with worse neurocognitive outcomes in pediatric cancer survivors, enriched with CNS tumors exposed to radiation. Ongoing research is underway to verify trends in larger cohorts.

PurposeAlthough radiation therapy (RT) is a common treatment for pediatric brain tumors, it is associated with detrimental long-term effects such as impaired cognition, vascular injury, and increased stroke risk. This study aimed to develop metrics that describe vascular injury and relate them to the presence of cerebral microbleeds (CMBs) and cognitive performance scores.MethodsTwenty-five young adult survivors of pediatric brain tumors treated with either whole-brain (n = 12), whole-ventricular (n = 7), or no RT (n = 6) underwent 7T MRI and neurocognitive testing. Simultaneously acquired MR angiography and susceptibility-weighted images were used to segment CMBs and vessels and quantify their radii and volume.ResultsPatients treated with whole-brain RT had significantly lower arterial volumes (p = 0.003) and a higher proportion of smaller vessels (p = 0.003) compared to the whole-ventricular RT and non-irradiated control patients. Normalized arterial volume decreased with increasing CMB count (R = - 0.66, p = 0.003), and decreasing trends were observed with time since RT and at longitudinal follow-up. Global cognition and verbal memory significantly decreased with smaller normalized arterial volume (p ≤ 0.05).ConclusionsArterial volume is reduced with increasing CMB presence and is influenced by the total brain volume exposed to radiation. This work highlights the potential use of vascular-derived metrics as non-invasive markers of treatment-induced injury and cognitive impairment in pediatric brain tumor patients.

BackgroundRadiation therapy (RT) is essential to the management of many brain tumors, but has been known to lead to cognitive decline and vascular injury in the form of cerebral microbleeds (CMBs).PurposeIn a subset of children, adolescents, and young adults recruited from a larger trial investigating arteriopathy and stroke risk after RT, we evaluated the prevalence of CMBs after RT, examined risk factors for CMBs and cognitive impairment, and related their longitudinal development to cognitive performance changes.MethodsTwenty-five patients (mean 17 years, range: 10-25 years) underwent 7-Tesla MRI and cognitive assessment. Nineteen patients were treated with whole-brain or focal RT 1-month to 20-years prior, while 6 non-irradiated patients with posterior-fossa tumors served as controls. CMBs were detected on 7T susceptibility-weighted imaging (SWI) using semi-automated software, a first use in this population.ResultsCMB detection sensitivity with 7T SWI was higher than previously reported at lower field strengths, with one or more CMBs detected in 100% of patients treated with RT at least 1-year prior. CMBs were localized to dose-targeted brain volumes with risk factors including whole-brain RT (p = 0.05), a higher RT dose (p = 0.01), increasing time since RT (p = 0.03), and younger age during RT (p = 0.01). Apart from RT dose, these factors were associated with impaired memory performance. Follow-up data in a subset of patients revealed a proportional increase in CMB count with worsening verbal memory performance (r = -0.85, p = 0.03).ConclusionsTreatment with RT during youth is associated with the chronic development of CMBs that evolve with memory impairment over time.

ObjectivesTreatment-induced lesions represent a great challenge in neuro-oncology. The aims of this study were (i) to characterize treatment induced lesions in glioblastoma patients treated with chemoradiotherapy and heat-shock protein (HSP) vaccine and (ii) to evaluate the diagnostic accuracy of diffusion weighted imaging for differentiation between treatment-induced lesions and tumor progression.MethodsTwenty-seven patients with newly diagnosed glioblastoma treated with HSP vaccine and chemoradiotherapy were included. Serial magnetic resonance imaging evaluation was performed to detect treatment-induced lesions and assess their growth. Quantitative analysis of the apparent diffusion coefficient (ADC) was performed to discriminate treatment-induced lesions from tumor progression. Mann-Whitney U-test and receiver operating characteristic (ROC) curves were used for analysis.ResultsThirty-three percent of patients developed treatment-induced lesions. Five treatment-related lesions appeared between end of radiotherapy and the first vaccine administration; 4 lesions within the first 4 months from vaccine initiation and 1 at 3.5 years. Three patients with pathology proven treatment-induced lesions showed a biphasic growth pattern progressed shortly after. ADC ratio between the peripheral enhancing rim and central necrosis showed an accuracy of 0.84 (95% CI 0.63-1) for differentiation between progression and treatment-induced lesions.ConclusionOur findings do not support the iRANO recommendation of a 6-month time window in which progressive disease should not be declared after immunotherapy initiation. A biphasic growth pattern of pathologically proven treatment-induced lesions was associated with a dismal prognosis. The presence of lower ADC values in the central necrotic portion of the lesions compared to the enhancing rim shows high specificity for detection of treatment-induced lesions.

BackgroundHyperpolarized carbon-13 (HP-13C) MRI is a non-invasive imaging technique for probing brain metabolism, which may improve clinical cancer surveillance. This work aimed to characterize the consistency of serial HP-13C imaging in patients undergoing treatment for brain tumors and determine whether there is evidence of aberrant metabolism in the tumor lesion compared to normal-appearing tissue.MethodsSerial dynamic HP [1-13C]pyruvate MRI was performed on 3 healthy volunteers (6 total examinations) and 5 patients (21 total examinations) with diffuse infiltrating glioma during their course of treatment, using a frequency-selective echo-planar imaging (EPI) sequence. HP-13C imaging at routine clinical timepoints overlapped treatment, including radiotherapy (RT), temozolomide (TMZ) chemotherapy, and anti-angiogenic/investigational agents. Apparent rate constants for [1-13C]pyruvate conversion to [1-13C]lactate (kPL) and [13C]bicarbonate (kPB) were simultaneously quantified based on an inputless kinetic model within normal-appearing white matter (NAWM) and anatomic lesions defined from 1H MRI. The inter/intra-subject consistency of kPL-NAWM and kPB-NAWM was measured in terms of the coefficient of variation (CV).ResultsWhen excluding scans following anti-angiogenic therapy, patient values of kPL-NAWM and kPB-NAWM were 0.020 s-1 ± 23.8% and 0.0058 s-1 ± 27.7% (mean ± CV) across 17 HP-13C MRIs, with intra-patient serial kPL-NAWM/kPB-NAWM CVs ranging 6.8-16.6%/10.6-40.7%. In 4/5 patients, these values (0.018 s-1 ± 13.4% and 0.0058 s-1 ± 24.4%; n = 13) were more similar to those from healthy volunteers (0.018 s-1 ± 5.0% and 0.0043 s-1 ± 12.6%; n = 6) (mean ± CV). The anti-angiogenic agent bevacizumab was associated with global elevations in apparent rate constants, with maximum kPL-NAWM in 2 patients reaching 0.047 ± 0.001 and 0.047 ± 0.003 s-1 (±model error). In 3 patients with progressive disease, anatomic lesions showed elevated kPL relative to kPL-NAWM of 0.024 ± 0.001 s-1 (±model error) in the absence of gadolinium enhancement, and 0.032 ± 0.008, 0.040 ± 0.003 and 0.041 ± 0.009 s-1 with gadolinium enhancement. The lesion kPB in patients was reduced to unquantifiable values compared to kPB-NAWM.ConclusionSerial measures of HP [1-13C]pyruvate metabolism displayed consistency in the NAWM of healthy volunteers and patients. Both kPL and kPB were globally elevated following bevacizumab treatment, while progressive disease demonstrated elevated kPL in gadolinium-enhancing and non-enhancing lesions. Larger prospective studies with homogeneous patient populations are planned to evaluate metabolic changes following treatment.

BackgroundAlthough radiation therapy (RT) contributes to survival benefit in many brain tumor patients, it has also been associated with long-term brain injury. Cerebral microbleeds (CMBs) represent an important manifestation of radiation-related injury.PurposeTo characterize the change in size and number of CMBs over time and to evaluate their relationship to white matter structural integrity as measured using diffusion MRI indices.Study typeLongitudinal, retrospective, human cohort.PopulationIn all, 113 brain tumor patients including patients treated with focal RT (n = 91, 80.5%) and a subset of nonirradiated controls (n = 22, 19.5%).Field strength/sequenceSingle and multiecho susceptibility-weighted imaging (SWI) and multiband, shell, and direction diffusion tensor imaging (DTI) at 7 T.AssessmentPatients were scanned either once or serially. CMBs were detected and quantified on SWI images using a semiautomated approach. Local and global fractional anisotropy (FA) were measured from DTI data for a subset of 35 patients.Statistical testsPotential risk factors for CMB development were determined by multivariate linear regression and using linear mixed-effect models. Longitudinal FA was quantitatively and qualitatively evaluated for trends.ResultsAll patients scanned at 1 or more years post-RT had CMBs. A history of multiple surgical resections was a risk factor for development of CMBs. The total number and volume of CMBs increased by 18% and 11% per year, respectively, although individual CMBs decreased in volume over time. Simultaneous to these microvascular changes, FA decreased by a median of 6.5% per year. While the majority of nonirradiated controls had no CMBs, four control patients presented with fewer than five CMBs.Data conclusionIdentifying patients who are at the greatest risk for CMB development, with its likely associated long-term cognitive impairment, is an important step towards developing and piloting preventative and/or rehabilitative measures for patients undergoing RT.Level of evidence3 Technical Efficacy: Stage 4 J. Magn. Reson. Imaging 2019;50:868-877.

BackgroundActivation of the phosphatidylinositol 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) pathway is common in patients with low-grade gliomas (LGGs), but agents that inhibit this pathway, including mTOR inhibitors, have not been studied in this population.MethodsFifty-eight patients with pathologic evidence of recurrence after they had initially been diagnosed with World Health Organization (WHO) grade II gliomas were enrolled into a prospective phase 2 clinical trial and received daily everolimus (RAD001) for 1 year or until progression. Tissue at the time of enrollment was analyzed for markers of PI3K/mTOR pathway activation. Thirty-eight patients underwent serial multiparametric magnetic resonance imaging, with the tumor volume and the perfusion metrics (the fractional blood volume [fBV] for capillary density and the transfer coefficient [Kps ] for vascular permeability) measured during treatment. The primary endpoint was progression-free survival at 6 months (PFS-6) in patients with WHO II disease at enrollment.ResultsFor patients with WHO II gliomas at enrollment, the PFS-6 rate was 84%, and this met the primary endpoint (P

BackgroundCranial irradiation is associated with long-term cognitive changes. Cerebral microbleeds (CMBs) have been identified on susceptibility-weighted MRI (SWI) in patients who have received prior cranial radiation, and serve as radiographic markers for microvascular injury thought to contribute to late cognitive decline. The relationship between CMB formation and radiation dose has not previously been quantified.MethodsSWI was performed on 13 patients with stable WHO grade III-IV gliomas between 2 and 4 years after chemoradiotherapy to 60 Gy. The median age at the time of treatment was 41 years (range 25 - 74 years). CMBs were identified as discrete foci of susceptibility on SWI that did not correspond to vessels. CMB density for low (45 Gy) dose regions was computed.ResultsTwelve of 13 patients exhibited CMBs. The number of CMBs was significantly higher for late (>3 years from treatment) compared to early (

BackgroundAlthough the contrast-enhancing (CE) lesion on T1-weighted MR images is widely used as a surrogate for glioblastoma (GBM), there are also non-enhancing regions of infiltrative tumor within the T2-weighted lesion, which elude radiologic detection. Because non-enhancing GBM (Enh-) challenges clinical patient management as latent disease, this study sought to characterize ex vivo metabolic profiles from Enh- and CE GBM (Enh+) samples, alongside histological and in vivo MR parameters, to assist in defining criteria for estimating total tumor burden.MethodsFifty-six patients with newly diagnosed GBM received a multi-parametric pre-surgical MR examination. Targets for obtaining image-guided tissue samples were defined based on in vivo parameters that were suspicious for tumor. The actual location from where tissue samples were obtained was recorded, and half of each sample was analyzed for histopathology while the other half was scanned using HR-MAS spectroscopy.ResultsThe Enh+ and Enh- tumor samples demonstrated comparable mitotic activity, but also significant heterogeneity in microvascular morphology. Ex vivo spectroscopic parameters indicated similar levels of total choline and N-acetylaspartate between these contrast-based radiographic subtypes of GBM, and characteristic differences in the levels of myo-inositol, creatine/phosphocreatine, and phosphoethanolamine. Analysis of in vivo parameters at the sample locations were consistent with histological and ex vivo metabolic data.ConclusionsThe similarity between ex vivo levels of choline and NAA, and between in vivo levels of choline, NAA and nADC in Enh+ and Enh- tumor, indicate that these parameters can be used in defining non-invasive metrics of total tumor burden for patients with GBM.

PurposeDissolution dynamic nuclear polarization (DNP) enables the acquisition of 13 C magnetic resonance data with a high sensitivity. Recently, metabolically inactive hyperpolarized 13 C-labeled compounds have shown to be potentially useful for perfusion imaging. The purpose of this study was to validate hyperpolarized perfusion imaging methods by comparing with conventional gadolinium (Gd)-based perfusion MRI techniques and pathology.MethodsDynamic 13 C data using metabolically inactive hyperpolarized bis-1,1-(hydroxymethyl)-[1-13 C]cyclopropane-d8 (HMCP) were obtained from an orthotopic human glioblastoma (GBM) model for the characterization of tumor perfusion and compared with standard Gd-based dynamic susceptibility contrast (DSC) MRI data and immunohistochemical analysis from resected brains.ResultsDistinct HMCP perfusion characteristics were observed within the GBM tumors compared with contralateral normal brain tissue. The perfusion parameters obtained from the hyperpolarized HMCP data in tumor were strongly correlated with normalized peak height measured from the DSC images. The results from immunohistochemical analysis supported these findings by showing a high level of vascular staining for tumor that exhibited high levels of hyperpolarized HMCP signal.ConclusionThe results from this study have demonstrated that hyperpolarized HMCP data can be used as an indicator of tumor perfusion in an orthotopic xenograft model for GBM. Magn Reson Med 77:841-847, 2017. © 2016 International Society for Magnetic Resonance in Medicine.

BackgroundA specific form of small-vessel vasculopathy-cerebral microbleeds (CMBs)-has been linked to various types of dementia in adults. We assessed the incidence of CMBs and their association with neurocognitive function in pediatric brain tumor survivors.MethodsIn a multi-institutional cohort of 149 pediatric brain tumor patients who received cranial radiation therapy (CRT) between 1987 and 2014 at age

BackgroundRadiotherapy (RT) is an integral component in managing patients with glioma, but the damage it may cause to healthy brain tissue and quality of life is of concern. Susceptibility-weighted imaging (SWI) is highly sensitive to the detection of microbleeds that occur years after RT. This study's goals were to characterize the evolution of radiation-induced microbleeds in normal-appearing brain and determine whether the administration of an anti-angiogenic agent altered this process.MethodsSerial high-resolution SWI was acquired on 17 patients with high-grade glioma between 8 months and 4.5 years posttreatment with RT and adjuvant chemotherapy. Nine of these patients were also treated with the anti-angiogenic agent enzastaurin. Microbleeds were identified as discrete foci of susceptibility not corresponding to vessels, tumor, or postoperative infarct, and counted in normal-appearing brain. Analysis of covariance was performed to compare slopes of regression of individual patients' microbleed counts over time, Wilcoxon rank-sum tests examined significant differences in rates of microbleed formation between groups, and linear and quadratic mixed-effects models were employed.ResultsThe number of microbleeds increased with time for all patients, with initial onset occurring at 8-22 months. No microbleeds disappeared once formed. The average rate of microbleed formation significantly increased after 2 years post-RT (P < .001). Patients receiving anti-angiogenic therapy exhibited fewer microbleeds overall (P < .05) and a significant reduction in initial rate of microbleed appearance (P = .01).ConclusionsWe have demonstrated a dramatic increase in microbleed formation after 2 years post-RT that was decelerated by the concomitant administration of anti-angiogenic therapy, which may aid in determining brain regions susceptible to RT.

This review is focused on describing the use of magnetic resonance (MR) spectroscopy for metabolic imaging of brain tumors. We will first review the MR metabolic imaging findings generated from preclinical models, focusing primarily on in vivo studies, and will then describe the use of metabolic imaging in the clinical setting. We will address relatively well-established (1) H MRS approaches, as well as (31) P MRS, (13) C MRS and emerging hyperpolarized (13) C MRS methodologies, and will describe the use of metabolic imaging for understanding the basic biology of glioma as well as for improving the characterization and monitoring of brain tumors in the clinic.

BackgroundThe purpose of this study was to implement and evaluate the utility of a multi-echo sequence at 7 Tesla (T) for simultaneous time-of-flight (TOF) MR-angiography (MRA) and susceptibility-weighted imaging (SWI) of radiation-induced cerebral microbleeds (CMBs), intracranial arteries, and veins.MethodsA four-echo gradient-echo sequence was implemented on a 7T scanner. The first echo was used to create TOF-MRA images, while the remaining echoes were combined to visualize CMBs and veins on SWI images. The sequence was evaluated on eight brain tumor patients with known radiation-induced CMBs. Single-echo images were also acquired to visually and quantitatively compare the contrast-to-noise ratio (CNR) of small- and intermediate-vessels between acquisitions. The number of CMBs detected with each acquisition was also quantified. Statistical significance was determined using a Wilcoxon signed-rank test.ResultsCompared with the single-echo sequences, the CNR of small and intermediate arteries increased 7.6% (P < 0.03) and 9.5% (P = 0.06), respectively, while the CNR of small and intermediate veins were not statistically different between sequences (P = 0.95 and P = 0.46, respectively). However, these differences were not discernible by visual inspection. Also the multi-echo sequence detected 18.3% more CMBs (P < 0.008) due to higher slice resolution.ConclusionThe proposed 7T multi-echo sequence depicts arteries, veins, and CMBs on a single image to facilitate quantitative evaluation of radiation-induced vascular injury.

BackgroundThe purpose of this study was to evaluate the feasibility of using a short echo time, three-dimensional H-1 magnetic resonance spectroscopic imaging (MRSI) sequence at 7 Tesla (T) to assess the metabolic signature of lesions for patients with glioma.MethodsTwenty-nine patients with glioma were studied. MRSI data were obtained using CHESS water suppression, spectrally selective adiabatic inversion-recovery pulses and automatically prescribed outer-volume-suppression for lipid suppression, and spin echo slice selection (echo time = 30 ms). An interleaved flyback echo-planar trajectory was applied to shorten the total acquisition time (∼10 min). Relative metabolite ratios were estimated in tumor and in normal-appearing white and gray matter (NAWM, GM).ResultsLevels of glutamine, myo-inositol, glycine, and glutathione relative to total creatine (tCr) were significantly increased in the T2 lesions for all tumor grades compared with those in the NAWM (P

To evaluate metrics that describe changes in apparent diffusion coefficient (ADC) and to examine their association with clinical outcome for patients with newly diagnosed GBM who were participating in a Phase II clinical trial of treatment with radiation (RT), temozolomide, erlatonib and bevacizumab. Thirty six patients were imaged after surgery but prior to therapy and at regular follow-up time points. The following ADC metrics were evaluated: (1) histogram percentiles within the T2-hyperintense lesion (T2L) at serial follow-ups; (2) parameters obtained by fitting a two-mixture normal distribution to the histogram within the contrast-enhancing lesion (CEL) at baseline; (3) parameters obtained using both traditional and graded functional diffusion maps within the CEL and T2L. Cox Proportional Hazards models were employed to assess the association of the ADC parameters with overall survival (OS) and progression-free survival (PFS). A lower ADC percentile value within the T2L at early follow-up time points was associated with worse outcome. Of particular interest is that, even when adjusting for clinical prognostic factors, the ADC10% within the T2L at 2 months was strongly associated with OS (p < 0.001) and PFS (p < 0.007). fDM metrics showed an association with OS and PFS within the CEL when considered by univariate analysis, but not in the T2L. Our study emphasizes the value of ADC metrics obtained from the T2L at the post-RT time point as non-invasive biomarkers for assessing residual tumor in patients with newly diagnosed GBM being treated with combination therapy that includes the anti-angiogenic agent bevacizumab.

Mutations of the isocitrate dehydrogenase 1 (IDH1) gene are among the most prevalent in low-grade glioma and secondary glioblastoma, represent an early pathogenic event, and are associated with epigenetically driven modulations of metabolism. Of particular interest is the recently uncovered relationship between the IDH1 mutation and decreased activity of the branched-chain amino acid transaminase 1 (BCAT1) enzyme. Noninvasive imaging methods that can assess BCAT1 activity could therefore improve detection of mutant IDH1 tumors and aid in developing and monitoring new targeted therapies. BCAT1 catalyzes the transamination of branched-chain amino acids while converting α-ketoglutarate (α-KG) to glutamate. Our goal was to use (13)C magnetic resonance spectroscopy to probe the conversion of hyperpolarized [1-(13)C] α-KG to hyperpolarized [1-(13)C] glutamate as a readout of BCAT1 activity. We investigated two isogenic glioblastoma lines that differed only in their IDH1 status and performed experiments in live cells and in vivo in rat orthotopic tumors. Following injection of hyperpolarized [1-(13)C] α-KG, hyperpolarized [1-(13)C] glutamate production was detected both in cells and in vivo, and the level of hyperpolarized [1-(13)C] glutamate was significantly lower in mutant IDH1 cells and tumors compared with their IDH1-wild-type counterparts. Importantly however, in our cells the observed drop in hyperpolarized [1-(13)C] glutamate was likely mediated not only by a drop in BCAT1 activity, but also by reductions in aspartate transaminase and glutamate dehydrogenase activities, suggesting additional metabolic reprogramming at least in our model. Hyperpolarized [1-(13)C] glutamate could thus inform on multiple mutant IDH1-associated metabolic events that mediate reduced glutamate production.

IntroductionCerebral microbleeds have been observed in normal-appearing brain tissue of patients with glioma years after receiving radiation therapy. The contrast of these paramagnetic lesions varies with field strength due to differences in the effects of susceptibility. The purpose of this study was to compare 3T and 7T MRI as platforms for detecting cerebral microbleeds in patients treated with radiotherapy using susceptibility-weighted imaging (SWI).MethodsSWI was performed with both 3T and 7T MR scanners on ten patients with glioma who had received prior radiotherapy. Imaging sequences were optimized to obtain data within a clinically acceptable scan time. Both T2*-weighted magnitude images and SWI data were reconstructed, minimum intensity projection was implemented, and microbleeds were manually identified. The number of microbleeds was counted and compared among datasets.ResultsSignificantly more microbleeds were identified on SWI than magnitude images at both 7T (p = 0.002) and 3T (p = 0.023). Seven-tesla SWI detected significantly more microbleeds than 3T SWI for seven out of ten patients who had tumors located remote from deep brain regions (p = 0.016), but when the additional three patients with more inferior tumors were included, the difference was not significant.ConclusionSWI is more sensitive for detecting microbleeds than magnitude images at both 3T and 7T. For areas without heightened susceptibility artifacts, 7T SWI is more sensitive to detecting radiation therapy-induced microbleeds than 3T SWI. Tumor location should be considered in conjunction with field strength when selecting the most appropriate strategy for imaging microbleeds.

PurposeTo evaluate which common post-processing method applied to gradient-echo DSC-MRI data, acquired with a single gadolinium injection and low flip-angle, most accurately reflects microvascular histopathology for patients with de novo, treatment-naive glioblastoma multiforme (GBM).Materials and methodsSeventy-two tissue samples were collected from 35 patients with treatment-naive GBM. Sample locations were co-registered to preoperative gradient-echo dynamic susceptibility contrast (DSC) MRI acquired with 35° flip-angle and 0.1 mmol/kg gadolinium. Estimates of blood volume and leakiness at each sample location were calculated using four common postprocessing methods (leakage-corrected nonlinear gamma-variate, non-parametric, scaled MR-signal, and unscaled MR-signal). Tissue sample microvascular morphology was characterized using Factor VIII immunohistochemical analysis. A random-effects regression model, adjusted for repeated measures and contrast-enhancement (CE), identified whether MR parameter estimates significantly predicted IHC findings.ResultsElevated blood volume estimates from nonlinear and non-parametric methods significantly predicted increased microvascular hyperplasia. Abnormal microvasculature existed beyond the CE-lesion and was significantly reflected by increased blood volume from nonlinear, non-parametric, and scaled MR-signal analysis.ConclusionThis study provides histopathological support for both non-parametric and nonlinear post-processing of low flip-angle DSC-MRI for characterizing microvascular hyperplasia within GBM. Non-parametric analysis with a single gadolinium injection may be a particularly useful strategy clinically, as it requires less computational expense and limits gadolinium exposure.

BackgroundThe objective of this study was to examine the predictive value of parameters of 3D (1)H magnetic resonance spectroscopic imaging (MRSI) prior to treatment with radiation/chemotherapy (baseline) and at a postradiation 2-month follow-up (F2mo) in relationship to 6-month progression-free survival (PFS6) and overall survival (OS).MethodsSixty-four patients with newly diagnosed glioblastoma multiforme (GBM) being treated with radiation and concurrent chemotherapy were involved in this study. Evaluated were metabolite indices and metabolite ratios. Logistic linear regression and Cox proportional hazards models were utilized to evaluate PFS6 and OS, respectively. These analyses were adjusted by age and MR scanner field strength (1.5 T or 3 T). Stepwise regression was performed to determine a subset of the most relevant variables.ResultsAssociated with shorter PFS6 were a decrease in the ratio of N-acetyl aspartate to choline-containing compounds (NAA/Cho) in the region with a Cho-to-NAA index (CNI) >3 at baseline and an increase of the CNI within elevated CNI regions (>2) at F2mo. Patients with higher normalized lipid and lactate at either time point had significantly worse OS. Patients who had larger volumes with abnormal CNI at F2mo had worse PFS6 and OS.ConclusionsOur study found more 3D MRSI parameters that predicted PFS6 and OS for patients with GBM than did anatomic, diffusion, or perfusion imaging, which were previously evaluated in the same population of patients.

BackgroundThe goal of this study was to investigate whether the amount of hypointense signal on susceptibility-weighted imaging within the contrast-enhancing lesion (%SWI-h) on the pretreatment scan could determine response in patients with newly diagnosed glioblastoma multiforme who received external beam radiation therapy with concomitant anti-angiogenic therapy (enzastaurin) and cytotoxic chemotherapy (temozolomide).MethodsTwenty-five patients were imaged before therapy (postsurgical resection) and scanned serially every 2 months until progression. Standard clinical MR imaging and SWI were performed on a 3T scanner. %SWI-h was quantified for each patient's pretreatment scan. Time to progression and death were used to characterize patients into non-, immediate-, and sustained-response groups for both events. Cox proportional hazards models were used to assess the association between %SWI-h and both progression-free survival (PFS) and overall survival (OS). Classification and regression tree analysis were used to determine optimal cutoffs on which to split %SWI-h.ResultsFor both death- and progression-based response categories, %SWI-h was significantly higher in sustained responders than in nonresponders. Cox model coefficients showed an association between %SWI-h and PFS and OS, both in univariate analysis (PFS: hazard ratio [HR] = 0.966, 95% confidence interval [CI] = 0.942-0.988; and OS: HR = 0.945, 95% CI = 0.915-0.976) and when adjusting for baseline KPS, age, sex, and resection extent (PFS: HR = 0.968, 95% CI = 0.940 -0.994; and OS: HR = 0.943, 95% CI = 0.908 -0.976). A cutoff value of 38.1% significantly differentiated patients into 2 groups based on censored OS and into non- and intermediate-response categories based on time to progression.ConclusionsThese early differences suggest that SWI may be able to predict which patients would benefit most from similar combination therapies and may assist clinicians in making important decisions about patient care.

Recent interest in exploring the clinical relevance of cerebral microbleeds (CMBs) has motivated the search for a fast and accurate method to detect them. Visual inspection of CMBs on MR images is a lengthy, arduous task that is highly prone to human error because of their small size and wide distribution throughout the brain. Several computer-aided CMB detection algorithms have recently been proposed in the literature, but their diagnostic accuracy, computation time, and robustness are still in need of improvement. In this study, we developed and tested a semi-automated method for identifying CMBs on minimum intensity projected susceptibility-weighted MR images that are routinely used in clinical practice to visually identify CMBs. The algorithm utilized the 2D fast radial symmetry transform to initially detect putative CMBs. Falsely identified CMBs were then eliminated by examining geometric features measured after performing 3D region growing on the potential CMB candidates. This algorithm was evaluated in 15 patients with brain tumors who exhibited CMBs on susceptibility-weighted images due to prior external beam radiation therapy. Our method achieved heightened sensitivity and acceptable amount of false positives compared to prior methods without compromising computation speed. Its superior performance and simple, accelerated processing make it easily adaptable for detecting CMBs in the clinic and expandable to a wide array of neurological disorders.