3D APT and NOE CEST-MRI of healthy volunteers and patients with non-enhancing glioma at 3 T

Objective Clinical application of chemical exchange saturation transfer (CEST) can be performed with investigation of amide proton transfer (APT) and nuclear Overhauser enhancement (NOE) effects. Here, we investigated APT- and NOE-weighted imaging based on advanced CEST metrics to map tumor heterogeneity of non-enhancing glioma at 3 T. Materials and methods APT- and NOE-weighted maps based on Lorentzian difference (LD) and inverse magnetization transfer ratio (MTRREX) were acquired with a 3D snapshot CEST acquisition at 3 T. Saturation power was investigated first by varying B1 (0.5–2 µT) in 5 healthy volunteers then by applying B1 of 0.5 and 1.5 µT in 10 patients with non-enhancing glioma. Tissue contrast (TC) and contrast-to-noise ratios (CNR) were calculated between glioma and normal appearing white matter (NAWM) and grey matter, in APT- and NOE-weighted images. Volume percentages of the tumor showing hypo/hyperintensity (VPhypo/hyper,CEST) in APT/NOE-weighted images were calculated for each patient. Results LD APT resulting from using a B1 of 1.5 µT was found to provide significant positive TCtumor,NAWM and MTRREX NOE (B1 of 1.5 µT) provided significant negative TCtumor,NAWM in tissue differentiation. MTRREX-based NOE imaging under 1.5 µT provided significantly larger VPhypo,CEST than MTRREX APT under 1.5 µT. Conclusion This work showed that with a rapid CEST acquisition using a B1 saturation power of 1.5 µT and covering the whole tumor, analysis of both LD APT and MTRREX NOE allows for observing tumor heterogeneity, which will be beneficial in future studies using CEST-MRI to improve imaging diagnostics for non-enhancing glioma.

A tractometry investigation of white matter tract network structure and relationships with cognitive function in relapsing-remitting multiple sclerosis

Understanding the brain changes underlying cognitive dysfunction is a key priority in multiple sclerosis to improve monitoring and treatment of this debilitating symptom. Functional connectivity network changes are associated with cognitive dysfunction, but it is less well understood how changes in normal appearing white matter relate to cognitive symptoms. If white matter tracts share a similar network structure it would be expected that tracts within a network are similarly affected by MS pathology. In the present study, we used a tractometry approach to explore patterns of variance in diffusion metrics across white matter (WM) tracts. We investigated whether separate networks, based on normal variation or pathology, appear, and how this relates to neuropsychological test performance across cognitive domains. A sample of 102 relapsing-remitting MS patients and 27 healthy controls underwent MRI and neuropsychological testing. Tractography was performed on diffusion MRI data to extract 40 WM tracts and microstructural measures were extracted from each tract. Principal component analysis (PCA) was used to decompose metrics from all tracts to assess the presence of any co-variance structure among the tracts. Similarly, PCA was applied to cognitive test scores to identify the main cognitive domains. Finally, we assessed the ability of tract components to predict test performance across cognitive domains. We found that a single component which captured pathology across all tracts explained the most variance and that there was little evidence for separate, smaller network patterns of pathology. WM tract components were weak, but significant, predictors of cognitive function in MS. These findings highlight the need to investigate the relationship between the normal appearing white matter and cognitive impairment further and on a more granular level, to improve the understanding of the network structure of the brain in MS.

Patterns of brain neurodegeneration in early-stage relapsing-remitting multiple sclerosis

Recurrent neuroinflammation in relapsing-remitting MS (RRMS) is thought to lead to neurodegeneration, resulting in progressive disability. Repeated magnetic resonance imaging (MRI) of the brain provides non-invasive measures of atrophy over time, a key marker of neurodegeneration. This study investigates regional neurodegeneration of the brain in early-stage RRMS using volumetry and voxel-based morphometry (VBM). RRMS patients (N=354) underwent 3T structural MRI at diagnosis and 1-year follow-up, as part of the Scottish multicentre 'FutureMS' study. MRI data were processed using FreeSurfer to derive volumetrics, and FSL for VBM (grey matter [GM] only), to establish patterns of change in GM and normal-appearing white matter (NAWM) over time throughout the cerebrum, cerebellum and brainstem. Volumetric analyses showed a decrease over time (q<0.05) in bilateral cortical GM and NAWM, multiple subcortical structures, cerebellar GM and the brainstem. Additionally, NAWM and GM volume decreased respectively in the following cortical regions, frontal: 14 out of 28 regions and 17/28; temporal: 18/18 and 15/18; parietal: 14/14 and 11/14; occipital: 7/8 and 8/8. Left GM and NAWM asymmetry was observed in the frontal lobe. GM VBM analysis showed three major clusters of decrease over time: 1) temporal lobe and subcortical areas, 2) cerebellum, 3) anterior cingulum and supplementary motor cortex; and four smaller clusters within the occipital lobe. Widespread neurodegeneration was observed in early-stage RRMS; particularly in the brainstem, cerebellar GM, and subcortical and occipital-temporal regions. Volumetric and VBM results emphasise different as well as overlapping patterns of longitudinal change, and provide potential response markers for existing therapies and trials of neuroprotective agents.

BIOM-09. MYO-INOSITOL LEVELS ON MR SPECTROSCOPY CAN PREDICT FAILURE OF ANTI-ANGIOGENIC TREATMENT IN RECURRENT GLIOBLASTOMA

BACKGROUND Recurrent glioblastoma (rGBM) patients are often treated with anti-angiogenic agents such as bevacizumab (BEV). Despite therapeutic promise, conventional MR methods fail to determine which patients may not benefit. PURPOSE: The purpose of this study was to utilize magnetic resonance spectroscopic imaging (MRSI) with intermediate and short echo time to generate corrected Myo-inositol normalized by contralateral creatine (mI/c-Cr) in patients with rGBM treated with BEV and investigate whether it can predict survivorship prior to BEV initiation (baseline) and at 1-day, 4-weeks, and 8-weeks thereafter. METHODS We conducted a prospective, longitudinal study and evaluated spectroscopic data of myo-inositol (mI), a glial marker and osmoregulator within the brain, normalized to contralateral-creatine (mI/c-Cr) in the intratumoral, contralateral normal appearing white matter, and peritumoral volumes of rGBM patients. Area under the ROC curve (AUC) was calculated for all volumes at baseline, 1-day, 4-weeks, and 8-weeks after treatment to determine mI/c-Cr’s ability to predict survivorship. RESULTS 21 participants (62 ± 12 years, 15 men) were evaluated. Lower mI/c-Cr in the tumor prior to and during BEV treatment predicted poor survivorship, with ROC analyses illustrating an AUC of 0.75 at baseline, 0.87 at 1-day, and 1 at 8 weeks. Lower levels of mI/c-Cr were also observed in the contralateral and the peritumoral volumes for shorter-term survivors. In the contralateral volume, lower mI/Cr was predictive of shorter-term survival at baseline and all other timepoints. Within the peritumoral volume, lower mI/c-Cr was predictive of shorter-term survival at baseline (AUC=0.80), 1-day (AUC=0.93), and 4-weeks (AUC=0.68). CONCLUSIONS Lower levels of mI/c-Cr within intratumoral, contralateral, and peritumoral volumes were predictive of poor survivorship and anti-angiogenic treatment failure as early as one month before BEV treatment. Acquiring MRSI alongside conventional MR imaging modalities can convey critical information regarding tumor microenvironment that informs management of patients with rGBM.

NIMG-43. ADVANCED MULTI-PARAMETRIC HYPERPOLARIZED 13C/1H IMAGING OF GBM

INTRODUCTION The goal of this study was to characterize progressive and pseudoprogressive GBM using multi-parametric hyperpolarized (HP)-13C / 1H MRI. METHODS Dynamic HP-13C MRI was acquired from 13 patients with progressive GBM [patients (scans): 2(3) IDH-mutant; 11(13) IDH-wildtype] and 2 IDH-wildtype patients (3 scans) demonstrating pseudo-progression following intravenous injection of HP [1-13C]pyruvate. Frequency-selective echo-planar imaging (3s temporal resolution, 3.38 cm3 spatial resolution) captured [1-13C]pyruvate metabolism to [1-13C]lactate and 13C-bicarbonate in the brain. Dynamic 13C data were kinetically modeled to obtain the pyruvate-to-lactate conversion rate constant k PL and temporally summed to calculate 13C-metabolite percentiles and ratios (linearly interpolated 2x in-plane). 1H imaging included T2, post-Gd T1, perfusion (nCBV, %recovery), diffusion (ADC), and lactate-edited spectroscopy (CNI, choline-to-NAA index; 1H-lactate). The normal-appearing white matter (NAWM), non-enhancing lesion (NEL), and contrast-enhancing lesion (CEL) were segmented from 1H images. 13C-resolution masks were iteratively applied on a voxel-wise basis to evaluate 1H imaging parameters within each ROI and multi-parametric data were collectively evaluated using a mixed effects model in R. RESULTS Progressive IDH-mutant GBM compared to wildtype counterparts displayed increased perfusion %recovery (p &lt; 0.001) and k PL (p &lt; 0.01), together with reduced 1H-lactate (p &lt; 0.001) and pyruvate percentile (p &lt; 0.01), in the T2 lesion. Among IDH-wildtype progressive GBM, the CEL was distinguished from NEL/NAWM by increased nCBV (p &lt; 0.05/0.001), 1H-lactate (p &lt; 0.05/0.001); and decreased bicarbonate / lactate (p &lt; 0.05/0.001). The CEL and NEL were collectively distinguished from NAWM by elevated CNI (p &lt; 0.001/0.001), ADC (p &lt; 0.05/0.001), pyruvate percentile (p &lt; 0.001/0.001), lactate percentile (p &lt; 0.001/0.001), and relative lactate / pyruvate (p &lt; 0.001/0.05). Psuedo-progressive IDH-wildtype GBM displayed lower k PL (T2 Lesion; p &lt; 0.01) and nCBV (CEL; p &lt; 0.01) compared to progressive GBM. CONCLUSION HP-13C parameters can potentially augment proton imaging and demonstrated Warburg-associated metabolic alterations.

NIMG-21. VARIABLE RESOLUTION HYPERPOLARIZED [2-13C]PYRUVATE MRI IN HEALTHY VOLUNTEERS AND PATIENTS WITH IDH-MUTANT GLIOMA

INTRODUCTION Mutations in isocitrate dehydrogenase (IDH) have been investigated as a prognostic biomarker in glioma. The presence of the IDH mutation (IDHm) is associated with 2-hydroxyglutarate (2HG) production and inhibition of glutamate synthesis (McBrayer, Cell 2018). Hyperpolarized carbon-13 (HP-13C) MRI enables dynamic measurements of in-vivo metabolism using a [2-13C]pyruvate labeled probe that undergoes conversion to [2-13C]lactate and [5-13C]glutamate. Here, we present HP [2-13C]pyruvate data from healthy volunteers and patients with IDHm diffuse glioma. Due to its intrinsic low signal-to-noise ratio (SNR), we demonstrate the ability of post-processing denoising to improve its utility and aid in detection of metabolic changes associated with IDHm. METHODS Dynamic HP 13C data were acquired following intravenous injection of [2-13C]pyruvate from five healthy volunteers and one patient with IDHm grade III astrocytoma. A novel multi-resolution frequency specific multislice EPI sequence was used to obtain [2-13C]pyruvate, [5-13C]glutamate, and downfield and upfield [2-13C]lactate signals (3s temporal resolution, pyruvate/lactate/glutamate spatial resolutions = 0.75x0.75cm2/ 2.25x2.25cm2/ 2.25x2.25cm2, 5 slices 3cm thick). Following phase correction, patch-based tensor decomposition denoising was applied to metabolite images. Metabolite differences between normal-appearing white matter (NAWM) and T2 lesion were examined for the patient data. RESULTS HP [2-13C]pyruvate imaging is able to simultaneously probe glycolytic ([2-13C]lactate) and oxidative ([5-13C]glutamate) metabolism. Denoised pyruvate/lactate/glutamate signals achieved a 4-9/3-6/3-7 fold increase in SNR. T2 lesion exhibited decreased glutamate-to-pyruvate and glutamate-to-lactate AUC ratios versus contralateral NAWM (p&lt; 0.018, p &lt; 1.5e-5), consistent with IDH mutant status. CONCLUSION We successfully demonstrated the feasibility of applying variable resolution HP [2-13C]pyruvate metabolic imaging to detect IDHm specific metabolism. This technique addresses a major hurdle in HP 13C MRI by improving SNR while permitting robust metabolism quantification. Future studies will optimize methods for acquiring and processing data to evaluate further data acquired from IDHm glioma patients. Supported by NIH T32 CA151022, P01 CA118816, and NICO.

A.2 Clinical application of T1-w/T2-w ratio images for in vivo comparisons of myelin content in patients with trigeminal neuralgia

Background: Novel magnetic resonance (MR) imaging techniques prompted the emergence of T1-w/T2-w images or “myelin-sensitive maps (MMs)” to measure myelin in vivo. However, acquisition-related variations in MR intensities prevent meaningful quantitative comparisons between MMs. We propose an improved pipeline to standardize MMs that is applied to patients with classic trigeminal neuralgia (CTN) and trigeminal neuralgia secondary to multiple sclerosis (MSTN). Methods: 3T scanner was used to obtain T1-w and T2-w images for 17 CTN and 17 MSTN patients. Template images were obtained from ICBM152 database. MS plaques and normal-appearing white matter (NAWM) were labelled. A Gaussian curve-fit was applied to the histogram of the intensity distribution of each patient image, and transformed to match the Gaussian curve-fit of the template image. Results: MM intensities were decreased within MS plaques, compared to NAWM in MSTN patients (p<0.001) and its corresponding regions in CTN patients (p<0.001). Qualitatively, the standardized patient image and its histogram better resembled the ICBM152 template. Conclusions: MM analysis revealed reduced myelin content in MS plaques compared to corresponding regions in CTN patients and surrounding NAWM in MSTN patients. The standardized MM serves as a non-invasive, clinical tool for quantitative analyses of myelin content between different brain regions and different patients in vivo.