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The focus of this work was to identify the optimal magnetic resonance imaging (MRI) contrast between orthotopic U-87 MG tumours and normal appearing brain with the eventual goal of treatment response monitoring. U-87 MG human glioblastoma cells were injected into the brain of RNU nude rats (n = 9). The rats were imaged at 7 T at three timepoints for all animals: 3-5, 7-9, and 11-13 days after implantation. Whole-brain T 1 -weighted (before and after gadolinium contrast agent injection), diffusion, and fluid-attenuated inversion recovery scans were performed. In addition, single-slice saturation-transfer-weighted chemical exchange saturation transfer (CEST), magnetization transfer (MT), and water saturation shift referencing (WASSR) contrast Z-spectra and T 1 and T 2 maps were also acquired. The MT and WASSR Z-spectra and T 1 map were fitted to a two-pool quantitative MT model to estimate the T 2 of the free and macromolecular-bound water molecules, the relative macromolecular pool size (M 0, MT ), and the magnetization exchange rate from the macromolecular pool to the free pool (R MT ). The T 1 -corrected apparent exchange-dependent relaxation (AREX) metric to isolate the CEST contributions was also calculated. The lesion on M 0, MT and AREX maps with a B 1 of 2 μT best matched the hyperintensity on the post-contrast T 1 -weighted image. There was also good separation in Z-spectra between the lesion and contralateral cortex in the 2-μT CEST and 3- and 5-μT MT Z-spectra at all time points. A pairwise Wilcoxon signed-rank tests with Holm-Bonferroni adjustment on MRI parameters was performed and the differences between enhancing lesion and contralateral cortex for the MT ratio with 2 μT saturation at 3.6 ppm frequency offset (corresponding to the amide chemical group) and M 0, MT were both strongly significant (p < 0.001) at all time points. This work has identified that differences between enhancing lesion and contralateral cortex are strongest in MTR with B 1  = 2 μT at 3.6 ppm and relative macromolecular pool size (M 0, MT ) images over entire period of 3-13 days after cancer cell implantation., (© 2024 The Author(s). NMR in Biomedicine published by John Wiley & Sons Ltd.)

Purpose: Treatment response assessment for gliomas currently uses changes in tumour size as measured with T 1 - and T 2 -weighted MRI. However, changes in tumour size may occur many weeks after therapy completion and are confounded by radiation treatment effects. Advanced MRI techniques sensitive to tumour physiology may provide complementary information to evaluate tumour response at early timepoints during therapy. The objective of this review is to provide a summary of the history and current knowledge regarding advanced MRI techniques for early treatment response evaluation in glioma., Methods: The literature survey included perfusion MRI, diffusion-weighted imaging, quantitative magnetization transfer imaging, and chemical exchange transfer MRI. Select articles spanning the history of each technique as applied to treatment response evaluation in glioma were chosen. This report is a narrative review, not formally systematic., Results: Chemical exchange saturation transfer imaging potentially offers the earliest method to detect tumour response due to changes in metabolism. Diffusion-weighted imaging is sensitive to changes in tumour cellularity later during radiotherapy and is prognostic for progression-free and overall survival. Substantial evidence suggests that perfusion MRI can differentiate between tumour recurrence and treatment effect, but consensus regarding acquisition, processing, and interpretation is still lacking. Magnetization transfer imaging shows promise for detecting subtle white matter damage which could indicate tumour invasion, but more research in this area is needed., Conclusion: Advanced MRI techniques show potential for early treatment response assessment, but each technique alone lacks specificity. Multiparametric imaging may be necessary to aid biological interpretation and enable treatment guidance., Competing Interests: Declarations. Ethical approval: The studies used to generate the figures in this article were granted ethics approval by our institution’s Research Ethics Board. Consent to participate: Written informed consent was obtain from all individual participants in the studies used for the figures in this article, including consent to publish anonymized data. Consent to publish: See above. Competing interests: LSPL has accepted travel expenses from Elekta. AS has research grants with Elekta, BrainLab, and Seagen Inc. He has been a consultant for Elekta and BrainLab. He has received honoraria for educational seminars from Elekta, Varian, BrainLab, AstraZeneca, Seagen Inc, Cerapedics, CarboFIX, and Servier. He has also accepted travel expenses from Elekta, BrainLab, and Cerapedics. He is the President of the International Stereotactic Radiosurgery Society (ISRS). SD serves as the Provincial Lead for CNS Cancers at Ontario Health (Cancer Care Ontario). He receives royalties from Oxford University Press and research funding from Synaptive, VPiX and Cure51. He is a speaker for the American Association of Neurological Surgeons and Congress of Neurological Surgeons and is on the advisory board of the Subcortical Surgery Group. PJM, GJS, and AZL have no relevant financial or non-financial interests to disclose., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Introduction: While obesity has been linked to both increased and decreased rate of cognitive decline in Alzheimer's Disease (AD) patients, there is no consensus on the interaction between obesity and AD. Methods: The TgF344-AD rat model was used to investigate the effects of high carbohydrate, high fat (HCHF) diet on brain glucose metabolism and hemodynamics in the presence or absence of AD transgenes, in presymptomatic (6-month-old) vs. symptomatic (12-month-old) stages of AD progression using non-invasive neuroimaging. Results: In presymptomatic AD, HCHF exerted detrimental effects, attenuating both hippocampal glucose uptake and resting perfusion in both non-transgenic and TgAD cohorts, when compared to CHOW-fed cohorts. In contrast, HCHF consumption was beneficial in established AD, resolving the AD-progression associated attenuation in hippocampal glucose uptake and functional hyperemia. Discussion: Whereas HCHF was harmful to the presymptomatic AD brain, it ameliorated deficits in hippocampal metabolism and neurovascular coupling in symptomatic TgAD rats., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Background: Stereotactic radiosurgery (SRS) for the treatment of brain metastases delivers a high dose of radiation with excellent local control but comes with the risk of radiation necrosis (RN), which can be difficult to distinguish from tumor progression (TP). Magnetization transfer (MT) and chemical exchange saturation transfer (CEST) are promising techniques for distinguishing RN from TP in brain metastases. Previous studies used a 2D continuous-wave (ie, block radiofrequency [RF] saturation) MT/CEST approach. The purpose of this study is to investigate a 3D pulsed saturation MT/CEST approach with perfusion MRI for distinguishing RN from TP in brain metastases., Methods: The study included 73 patients scanned with MT/CEST MRI previously treated with SRS or fractionated SRS who developed enhancing lesions with uncertain diagnoses of RN or TP. Perfusion MRI was acquired in 49 of 73 patients. Clinical outcomes were determined by at least 6 months of follow-up or via pathologic confirmation (in 20% of the lesions)., Results: Univariable logistic regression resulted in significant variables of the quantitative MT parameter 1/(R A ·T 2A ), with 5.9 ± 2.7 for RN and 6.5 ± 2.9 for TP. The highest AUC of 75% was obtained using a multivariable logistic regression model for MT/CEST parameters, which included the CEST parameters of AREX Amide,0.625µT ( P  = .013), AREX NOE,0.625µT ( P  = .008), 1/(R A ·T 2A ) ( P  = .004), and T 1 ( P  = .004). The perfusion rCBV parameter did not reach significance., Conclusions: Pulsed saturation transfer was sufficient for achieving a multivariable AUC of 75% for differentiating between RN and TP in brain metastases, but had lower AUCs compared to previous studies that used a block RF approach., Competing Interests: A.S.: Elekta/Elekta AB: Research grant, Consultant, Honorarium for past educational seminars, Travel Expenses. Varian: Honorarium for past educational seminars. BrainLab: Research grant, Consultant, Honorarium for educational seminars, Travel Expenses. AstraZeneca: Honorarium for educational seminars. ISRS: President of the International Stereotactic Radiosurgery Society (ISRS). Seagen Inc: Honorarium for education seminars and research grants. Cerapedics: Honorarium for educational seminars, Travel Expenses. CarboFIX: Honorarium for educational seminars. Servier: Honorarium for educational seminars. C.-L.T.: Travel accommodations/expenses & honoraria for past educational seminars by Elekta; belongs to the Elekta MR-Linac Research Consortium; advisor/consultant with Sanofi and AbbVie. S.M.: Research support from Novartis AG, honoraria from Novartis AG and Ipsen. None related to this work., (© The Author(s) 2024. Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology.)

Background: Preclinical studies have demonstrated that tumour cell death can be enhanced 10- to 40-fold when radiotherapy is combined with focussed ultrasound-stimulated microbubble (FUS-MB) treatment. The acoustic exposure of microbubbles (intravascular gas microspheres) within the target volume causes bubble cavitation, which induces perturbation of tumour vasculature and activates endothelial cell apoptotic pathways responsible for the ablative effect of stereotactic body radiotherapy. Subsequent irradiation of a microbubble-sensitised tumour causes rapid increased tumour death. The study here presents the mature safety and efficacy outcomes of magnetic resonance (MR)-guided FUS-MB (MRgFUS-MB) treatment, a radioenhancement therapy for breast cancer., Methods and Findings: This prospective, single-center, single-arm Phase 1 clinical trial included patients with stages I-IV breast cancer with in situ tumours for whom breast or chest wall radiotherapy was deemed adequate by a multidisciplinary team (clinicaltrials.gov identifier: NCT04431674). Patients were excluded if they had contraindications for contrast-enhanced MR or microbubble administration. Patients underwent 2 to 3 MRgFUS-MB treatments throughout radiotherapy. An MR-coupled focussed ultrasound device operating at 800 kHz and 570 kPa peak negative pressure was used to sonicate intravenously administrated microbubbles within the MR-guided target volume. The primary outcome was acute toxicity per Common Terminology Criteria for Adverse Events (CTCAE) v5.0. Secondary outcomes were tumour response at 3 months and local control (LC). A total of 21 female patients presenting with 23 primary breast tumours were enrolled and allocated to intervention between August/2020 and November/2022. Three patients subsequently withdrew consent and, therefore, 18 patients with 20 tumours were included in the safety and LC analyses. Two patients died due to progressive metastatic disease before 3 months following treatment completion and were excluded from the tumour response analysis. The prescribed radiation doses were 20 Gy/5 fractions (40%, n = 8/20), 30 to 35 Gy/5 fractions (35%, n = 7/20), 30 to 40 Gy/10 fractions (15%, n = 3/20), and 66 Gy/33 fractions (10%, n = 2/20). The median follow-up was 9 months (range, 0.3 to 29). Radiation dermatitis was the most common acute toxicity (Grade 1 in 16/20, Grade 2 in 1/20, and Grade 3 in 2/20). One patient developed grade 1 allergic reaction possibly related to microbubbles administration. At 3 months, 18 tumours were evaluated for response: 9 exhibited complete response (50%, n = 9/18), 6 partial response (33%, n = 6/18), 2 stable disease (11%, n = 2/18), and 1 progressive disease (6%, n = 1/18). Further follow-up of responses indicated that the 6-, 12-, and 24-month LC rates were 94% (95% confidence interval [CI] [84%, 100%]), 88% (95% CI [75%, 100%]), and 76% (95% CI [54%, 100%]), respectively. The study's limitations include variable tumour sizes and dose fractionation regimens and the anticipated small sample size typical for a Phase 1 clinical trial., Conclusions: MRgFUS-MB is an innovative radioenhancement therapy associated with a safe profile, potentially promising responses, and durable LC. These results warrant validation in Phase 2 clinical trials., Trial Registration: clinicaltrials.gov, identifier NCT04431674., Competing Interests: I.K. received honorarium for EMD Serono advisory board on locally advanced Head and neck cancers (Nov 2023), (Copyright: © 2024 Moore-Palhares et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background and Purpose: Survival in glioblastoma might be extended by escalating the radiotherapy dose to treatment-resistant tumour and adapting to tumour changes. Diffusion-weighted imaging (DWI) on MRI-linear accelerators (MR-Linacs) could be used to identify a dose escalation target, but its prognostic value must be demonstrated. The purpose of this study was to determine whether MR-Linac DWI can assess treatment response in glioblastoma and whether changes in DWI show greater prognostic value than changes in the contrast-enhancing gross tumour volume (GTV)., Materials and Methods: Seventy-five patients with glioblastoma were treated with chemoradiotherapy, of which 32 were treated on a 1.5 T MRI-linear accelerator (MR-Linac). Patients were imaged with simulation MRI scanners (MR-sim) at treatment planning and weeks 2, 4, and 10 after treatment start. Twenty-eight patients had additional MR-Linac DWI sequences. Cox modelling was used to evaluate the correlation of overall and progression-free survival (OS and PFS) with clinical variables and volumetric changes in the GTV and low-ADC regions (ADC < 1.25 µm 2 /ms within GTV)., Results: In total, 479 MR-Linac DWI and 289 MR-sim DWI datasets were analyzed. MR-Linac low-ADC changes between weeks 2 and 5 inclusive were prognostic for OS (hazard ratio lower limits ≥ 1.2, p-values ≤ 0.02). MR-sim low-ADC changes showed greater correlation with OS and PFS than GTV changes (e.g., OS hazard ratio at week 2 was 3.4 (p <0.001) for low-ADC versus 2.0 (p = 0.022) for GTV)., Conclusion: MR-Linac DWI can measure low-ADC tumour volumes that correlate with OS and PFS better than contrast-enhancing GTV. Low-ADC regions could serve as dose escalation targets., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

In this study, hyperpolarized 13 C MRI (HP- 13 C MRI) was used to investigate changes in the uptake and metabolism of pyruvate with age. Hyperpolarized 13 C-pyruvate was administered to healthy aging individuals (N = 35, ages 21-77) and whole-brain spatial distributions of 13 C-lactate and 13 C-bicarbonate production were measured. Linear mixed-effects regressions were performed to compute the regional percentage change per decade, showing a significant reduction in both normalized 13 C-lactate and normalized 13 C-bicarbonate production with age: - 7 % ± 2 % per decade for 13 C-lactate and - 9 % ± 4 % per decade for 13 C-bicarbonate. Certain regions, such as the right medial precentral gyrus, showed greater rates of change while the left caudate nucleus had a flat 13 C-lactate versus age and a slightly increasing 13 C-bicarbonate versus age. The results show that both the production of lactate (visible as 13 C-lactate signal) as well as the consumption of monocarboxylates to make acetyl-CoA (visible as 13 C-bicarbonate signal) decrease with age and that the rate of change varies by brain region., (© 2023 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.)

Background: High radiation doses of stereotactic radiosurgery (SRS) for brain metastases (BM) can increase the likelihood of radiation necrosis (RN). Advanced MRI sequences can improve the differentiation between RN and tumor progression (TP)., Purpose: To use saturation transfer MRI methods including chemical exchange saturation transfer (CEST) and magnetization transfer (MT) to distinguish RN from TP., Study Type: Prospective cohort study., Subjects: Seventy patients (median age 60; 73% females) with BM (75 lesions) post-SRS., Field Strength/sequence: 3-T, CEST imaging using low/high-power (saturation B 1  = 0.52 and 2.0 μT), quantitative MT imaging using B 1  = 1.5, 3.0, and 5.0 μT, WAter Saturation Shift Referencing (WASSR), WAter Shift And B 1 (WASABI), T 1 , and T 2 mapping. All used gradient echoes except T 2 mapping (gradient and spin echo)., Assessment: Voxel-wise metrics included: magnetization transfer ratio (MTR); apparent exchange-dependent relaxation (AREX); MTR asymmetry; normalized MT exchange rate and pool size product; direct water saturation peak width; and the observed T 1 and T 2 . Regions of interests (ROIs) were manually contoured on the post-Gd T 1 w. The mean (of median ROI values) was compared between groups. Clinical outcomes were determined by clinical and radiologic follow-up or histopathology., Statistical Tests: t-Test, univariable and multivariable logistic regression, receiver operating characteristic, and area under the curve (AUC) with sensitivity/specificity values with the optimal cut point using the Youden index, Akaike information criterion (AIC), Cohen's d. P < 0.05 with Bonferroni correction was considered significant., Results: Seven metrics showed significant differences between RN and TP. The high-power MTR showed the highest AUC of 0.88, followed by low-power MTR (AUC = 0.87). The combination of low-power CEST scans improved the separation compared to individual parameters (with an AIC of 70.3 for low-power MTR/AREX). Cohen's d effect size showed that the MTR provided the largest effect sizes among all metrics., Data Conclusion: Significant differences between RN and TP were observed based on saturation transfer MRI., Evidence Level: 3 Technical Efficacy: Stage 2., (© 2022 International Society for Magnetic Resonance in Medicine.)

Chemical exchange saturation transfer (CEST) is a relatively novel magnetic resonance imaging (MRI) technique with an image contrast designed for in vivo measurement of certain endogenous molecules with protons that are exchangeable with water protons, such as amide proton transfer commonly used for neuro-oncology applications. Recent technological advances have made it feasible to implement CEST on clinical grade scanners within practical acquisition times, creating new opportunities to integrate CEST in clinical workflow. In addition, the majority of CEST applications used in neuro-oncology are performed without the use gadolinium-based contrast agents which are another appealing feature of this technique. This review is written for clinicians involved in neuro-oncologic care (nonphysicists) as the target audience explaining what they need to know as CEST makes its way into practice. The purpose of this article is to (1) review the basic physics and technical principles of CEST MRI, and (2) review the practical applications of CEST in neuro-oncology., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Arjun Sahgal: Consultant with Varian (Medical Advisory Group), Elekta (Gamma Knife Icon), BrainLAB, Merck, Abbvie, RocheVice President with International Stereotactic Radiosurgery Society (ISRS) Advisory Board with VieCureCo-Chair with AO Spine Knowledge Forum TumorPast educational seminars (honorarium) with AstraZeneca, Elekta AB, Varian (CNS Teaching Faculty), BrainLAB, Medtronic Kyphon, Accuray, Seagen Inc.Research Grant: Elekta AB, Varian, Seagen Inc.Travel accommodations/expenses: Elekta, Varian, BrainLABBelongs to the Elekta MR Linac Research Consortium, Elekta Spine, Elekta Oligometastases and Elekta Linac Based SRS Consortia.All other authors declare no conflicts.

Purpose: This study reports the workflow and initial clinical experience of high grade glioma (HGG) radiotherapy on the 1.5 T MR-Linac (MRL), with a focus on the temporal variations of the tumor and feasibility of multi-parametric image (mpMRI) acquisition during routine treatment workflow., Materials and Methods: Ten HGG patients treated with radiation within the first year of the MRL's clinical operation, between October 2019 and August 2020, were identified from a prospective database. Workflow timings were recorded and online adaptive plans were generated using the Adapt-To-Position (ATP) workflow. Temporal variation within the FLAIR hyperintense region (FHR) was assessed by the relative FHR volumes (n = 281 contours) and migration distances (maximum linear displacement of the volume). Research mpMRIs were acquired on the MRL during radiation and changes in selected functional parameters were investigated within the FHR., Results: All patients completed radiotherapy to a median dose of 60 Gy (range, 54-60 Gy) in 30 fractions (range, 30-33), receiving a total of 287 fractions on the MRL. The mean in-room time per fraction with or without post-beam research imaging was 42.9 minutes (range, 25.0-69.0 minutes) and 37.3 minutes (range, 24.0-51.0 minutes), respectively. Three patients (30%) required re-planning between fractions 9 to 12 due to progression of tumor and/or edema identified on daily MRL imaging. At the 10, 20, and 30-day post-first fraction time points 3, 3, and 4 patients, respectively, had a FHR volume that changed by at least 20% relative to the first fraction. Research mpMRIs were successfully acquired on the MRL. The median apparent diffusion coefficient (ADC) within the FHR and the volumes of FLAIR were significantly correlated when data from all patients and time points were pooled ( R =0.68, p <.001)., Conclusion: We report the first clinical series of HGG patients treated with radiotherapy on the MRL. The ATP workflow and treatment times were clinically acceptable, and daily online MRL imaging triggered adaptive re-planning for selected patients. Acquisition of mpMRIs was feasible on the MRL during routine treatment workflow. Prospective clinical outcomes data is anticipated from the ongoing UNITED phase 2 trial to further refine the role of MR-guided adaptive radiotherapy., Competing Interests: C-LT has received travel accommodations/expenses & honoraria for past educational seminars by Elekta and belongs to the Elekta MR-Linac Research Consortium. JS is employed at Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada. SM has received research support from Novartis AG, honoraria from Novartis AG and Ipsen and travel support from Elekta, none related to this work. SD serves as the Provincial Lead for CNS Oncology at Ontario Health, Cancer Care Ontario; he receives laboratory research support from Alkermes; he serves on the advisory board of the Subcortical Surgery Group and Xpan Medical; he is a speaker for the Congress of Neurological Surgeons. MR is a co‐inventor of and owns associated intellectual property specific to the image‐guidance system on the Gamma Knife Icon, none related to this work. AS has been a consultant for Varian, Elekta Gamma Knife Icon, BrainLAB, Merck, Abbvie, Roche; Vice President of the International Stereotactic Radiosurgery Society ISRS; Co-Chair of the AO Spine Knowledge Forum Tumor; received honorarium for past educational seminars for AstraZeneca, Elekta AB, Varian, BrainLAB, Accuray, Seagen Inc.; research grant with Elekta AB, Varian, Seagen Inc., BrainLAB; and travel accommodations/expenses with Elekta, Varian and BrainLAB. AS also belongs to the Elekta MR Linac Research Consortium and is a Clinical Steering Committee Member, and chairs the Elekta Oligometastases Group and the Elekta Gamma Knife Icon Group. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Tseng, Chen, Stewart, Lau, Chan, Lawrence, Myrehaug, Soliman, Detsky, Lim-Fat, Lipsman, Das, Heyn, Maralani, Binda, Perry, Keller, Stanisz, Ruschin and Sahgal.)

Purpose: Target localization, for stereotactic radiosurgery (SRS) treatment with Gamma Knife, has become increasingly reliant on the co-registration between the planning MRI and the stereotactic cone-beam computed tomography (CBCT). Validating image registration between modalities would be particularly beneficial when considering the emergence of novel functional and metabolic MRI pulse sequences for target delineation. This study aimed to develop a phantom-based methodology to quantitatively compare the co-registration accuracy of the standard clinical imaging protocol to a representative MRI sequence that was likely to fail co-registration. The comparative methodology presented in this study may serve as a useful tool to evaluate the clinical translatability of novel MRI sequences., Methods: A realistic human skull phantom with fiducial marker columns was designed and manufactured to fit into a typical MRI head coil and the Gamma Knife patient positioning system. A series of "optimized" 3D MRI sequences-T 1 -weighted Dixon, T 1 -weighted fast field echo (FFE), and T 2 -weighted fluid-attenuated inversion recovery (FLAIR)-were acquired and co-registered to the CBCT. The same sequences were "compromised" by reconstructing without geometric distortion correction and re-collecting with lower signal-to-noise-ratio (SNR) to simulate a novel MRI sequence with poor co-registration accuracy. Image similarity metrics-structural similarity (SSIM) index, mean squared error (MSE), and peak SNR (PSNR)-were used to quantitatively compare the co-registration of the optimized and compromised MR images., Results: The ground truth fiducial positions were compared to positions measured from each optimized image volume revealing a maximum median geometric uncertainty of 0.39 mm (LR), 0.92 mm (AP), and 0.13 mm (SI) between the CT and CBCT, 0.60 mm (LR), 0.36 mm (AP), and 0.07 mm (SI) between the CT and T 1 -weighted Dixon, 0.42 mm (LR), 0.23 mm (AP), and 0.08 mm (SI) between the CT and T 1 -weighted FFE, and 0.45 mm (LR), 0.19 mm (AP), and 1.04 mm (SI) between the CT and T 2 -weighted FLAIR. Qualitatively, pairs of optimized and compromised image slices were compared using a fusion image where separable colors were used to differentiate between images. Quantitatively, MSE was the most predictive and SSIM the second most predictive metric for evaluating co-registration similarity. A clinically relevant threshold of MSE, SSIM, and/or PSNR may be defined beyond which point an MRI sequence should be rejected for target delineation based on its dissimilarity to an optimized sequence co-registration. All dissimilarity thresholds calculated using correlation coefficients with in-plane geometric uncertainty would need to be defined on a sequence-by-sequence basis and validated with patient data., Conclusion: This study utilized a realistic skull phantom and image similarity metrics to develop a methodology capable of quantitatively assessing whether a modern research-based MRI sequence can be co-registered to the Gamma Knife CBCT with equal or less than equal accuracy when compared to a clinically accepted protocol., (© 2022 American Association of Physicists in Medicine.)

Alteration in brain metabolism predates clinical onset of Alzheimer's Disease (AD). Realizing its potential as an early diagnostic marker, however, requires understanding how early AD metabolic dysregulation manifests on non-invasive brain imaging. We presently utilized magnetic resonance imaging and spectroscopy to map glucose and ketone metabolic profiles and image cerebrovascular function in a rat model of early stage AD - 9-month-old TgF344-AD (TgAD) rats - and their age-matched non-transgenic (nTg) littermates. Compared to the nTg rats, TgAD rats displayed attenuation in global cerebral and hippocampal vasoreactivity to hypercapnia, by 49 ± 17% and 58 ± 19%, respectively, while their functional hyperemia to somatosensory stimulation diminished by 69 ± 5%. To assess brain glucose uptake, rats were fasted overnight and then challenged with an intravenous infusion of 2-deoxy-D-glucose (2DG). Compared to their non-transgenic littermates, TgAD rats exhibited 99 ± 10% and 52 ± 5% smaller glucose uptake in the entorhinal cortex and the hippocampus, respectively. Moreover, hippocampal glucose uptake reduction in male TgAD rats compared to the nTg was 54 ± 36% greater than the reduction seen in female TgAD rats. TgAD rats also showed a 59 ± 42% increase in total choline level in the hippocampus, suggesting increased membrane turnover. In combination with our earlier findings of impaired electrophysiological metrics at this early stage of AD pathology progression, our findings suggest that subtle neuronal function alterations that would be difficult to assess in a clinical population may be accompanied by MRI-detectable changes in brain glucose metabolism and cerebrovascular function., Competing Interests: Conflict of interests The authors declare that they have no conflicts of interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Amide proton transfer-weighted (APTw) MR imaging shows promise as a biomarker of brain tumor status. Currently used APTw MRI pulse sequences and protocols vary substantially among different institutes, and there are no agreed-on standards in the imaging community. Therefore, the results acquired from different research centers are difficult to compare, which hampers uniform clinical application and interpretation. This paper reviews current clinical APTw imaging approaches and provides a rationale for optimized APTw brain tumor imaging at 3 T, including specific recommendations for pulse sequences, acquisition protocols, and data processing methods. We expect that these consensus recommendations will become the first broadly accepted guidelines for APTw imaging of brain tumors on 3 T MRI systems from different vendors. This will allow more medical centers to use the same or comparable APTw MRI techniques for the detection, characterization, and monitoring of brain tumors, enabling multi-center trials in larger patient cohorts and, ultimately, routine clinical use., (© 2022 The Authors. Magnetic Resonance in Medicine published by Wiley Periodicals LLC on behalf of International Society for Magnetic Resonance in Medicine.)

The intestinal microbiome composition and dietary supplementation with psychobiotics can result in neurochemical alterations in the brain, which are possible due to the presence of the brain-gut-microbiome axis. In the present study, magnetic resonance spectroscopy (MRS) and behavioural testing were used to evaluate whether treatment with Lacticaseibacillus rhamnosus JB-1 (JB‑1) bacteria alters brain metabolites' levels and behaviour during continuous exposure to chronic stress. Twenty Wistar rats were subjected to eight weeks of a chronic unpredictable mild stress protocol. Simultaneously, half of them were fed with JB-1 bacteria, and the second half was given a daily placebo. Animals were examined at three-time points: before starting the stress protocol and after five and eight weeks of stress onset. In the elevated plus maze behavioural test the placebo group displayed increased anxiety expressed by almost complete avoidance of exploration, while the JB-1 dietary supplementation mitigated anxiety which resulted in a longer exploration time. Hippocampal MRS measurements demonstrated a significant decrease in glutamine + glutathione concentration in the placebo group compared to the JB-1 bacteria-supplemented group after five weeks of stress. With the progression of stress the decrease of glutamate, glutathione, taurine, and macromolecular concentrations were observed in the placebo group as compared to baseline. The level of brain metabolites in the JB-1-supplemented rats were stable throughout the experiment, with only the taurine level decreasing between weeks five and eight of stress. These data indicated that the JB-1 bacteria diet might stabilize levels of stress-related neurometabolites in rat brain and could prevent the development of anxiety/depressive-like behaviour.

Background and Purpose: MRI linear accelerators (MR-Linacs) may allow treatment adaptation to be guided by quantitative MRI including diffusion-weighted imaging (DWI). The aim of this study was to evaluate the accuracy and precision of apparent diffusion coefficient (ADC) measurements from DWI on a 1.5 T MR-Linac in patients with central nervous system (CNS) tumours through comparison with a diagnostic scanner., Materials and Methods: CNS patients were treated using a 1.5 T Elekta Unity MR-Linac. DWI was acquired during MR-Linac treatment and on a Philips Ingenia 1.5 T. The agreement between the two scanners on median ADC over the gross tumour/clinical target volumes (GTV/CTV) and in brain regions (white/grey matter, cerebrospinal fluid (CSF)) was computed. Repeated scans were used to estimate ADC repeatability. Daily changes in ADC over the GTV of high-grade gliomas were characterized from MR-Linac scans., Results: DWI from 59 patients was analyzed. MR-Linac ADC measurements showed a small bias relative to Ingenia measurements in white matter, grey matter, GTV, and CTV (bias: -0.05 ± 0.03, -0.08 ± 0.05, -0.1 ± 0.1, -0.08 ± 0.07 μm 2 /ms). ADC differed substantially in CSF (bias: -0.5 ± 0.3 μm 2 /ms). The repeatability of MR-Linac ADC over white/grey matter was similar to previous reports (coefficients of variation for median ADC: 1.4%/1.8%). MR-Linac ADC changes in the GTV were detectable., Conclusions: It is possible to obtain ADC measurements in the brain on a 1.5 T MR-Linac that are comparable to those of diagnostic-quality scanners. This technical validation study adds to the foundation for future studies that will correlate brain tumour ADC with clinical outcomes., Competing Interests: Conflicts of Interest Dr. Arjun Sahgal: Advisor/consultant with Abbvie, Merck, Roche, Varian (Medical Advisory Group), Elekta (Gamma Knife Icon), BrainLAB, and VieCure (Medical Advisory Board); Past educational seminars with Elekta AB, Accuray Inc., Varian (CNS Teaching Faculty), BrainLAB, Medtronic Kyphon; Research grant with Elekta AB; Travel accommodations/expenses by Elekta, Varian, BrainLAB. Dr. Chia-Lin Tseng: Travel accommodations/expenses & honoraria for past educational seminars by Elekta; belongs to the Elekta MR-Linac Research Consortium; advisor/consultant with Sanofi. Dr. Sten Myrehaug: Received research support from Novartis AG, honoraria from Novartis AG and Ipsen and travel support from Elekta. None related to this work. Dr. Mark Ruschin: Co‐inventor of and owns associated intellectual property specific to the image‐guidance system on the Gamma Knife Icon. None related to this work. Mrs. Mikki Campbell: Received honorarium for past educational seminars with Elekta AB; received research grants with Elekta AB; and travel accommodations/expenses by Elekta; belongs to the Elekta MR Linac Research Consortium. Dr. Brige Chugh: Previously held an industry partnership grant with Modus QA., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Chemical exchange saturation transfer (CEST) MRI was performed for the evaluation of cerebral metabolic changes in a rat model of depressive-like disease induced by chronic unpredictable mild stress (CUMS). CEST Z-spectra were acquired on a 7 T MRI with two saturation B 1 amplitudes (0.5 and 0.75 µT) to measure the magnetization transfer ratio (MTR), CEST and relayed nuclear Overhauser effect (rNOE). Cerebral cortex and hippocampus were examined in two groups of animals: healthy control (n = 10) and stressed (n = 14), the latter of which was exposed to eight weeks of the CUMS protocol. The stressed group Z-spectrum parameters, primarily MTRs, were significantly lower than in controls, at all selected frequency offsets (3.5, 3.0, 2.0, - 3.2, - 3.6 ppm) in the cortex (the largest difference of ~ 3.5% at - 3.6 ppm, p = 0.0005) and the hippocampus (MTRs measured with a B 1  = 0.5 µT). The hippocampal rNOE contributions decreased significantly in the stressed brains. Glutamate concentration (assessed using ELISA) and MTR at 3 ppm correlated positively in both brain regions. GABA concentration also correlated positively with CEST contributions in both cerebral areas, while such correlation with MTR was positive in hippocampus, and nonsignificant in cortex. Results indicate that CEST is sensitive to neurometabolic changes following chronic stress exposure., (© 2021. The Author(s).)

Purpose: To describe the implementation and initial results of using Chemical Exchange Saturation Transfer (CEST) for monitoring patients with central nervous system (CNS) tumours treated using a 1.5 tesla MR-guided radiotherapy system., Methods: CNS patients were treated with up to 30 fractions (total dose up to 60 Gy) using a 1.5 T Elekta Unity MR-Linac. CEST scans were obtained in 54 subjects at one or more time points during treatment. CEST metrics, including the amide magnetization transfer ratio (MTR Amide ), nuclear Overhauser effect (NOE) MTR (MTR NOE ) and asymmetry, were quantified in phantoms and CNS patients. The signal was investigated between tumour and white matter, across time, and across disease categories including high- and low-grade tumours., Results: The gross tumour volume (GTV) exhibited lower MTR Amide and MTR NOE and higher asymmetry compared to contralateral normal appearing white matter. Signal changes in the GTV during fractionated radiotherapy were observed. There were differences between high- and low-grade tumours, with higher CEST asymmetry associated with higher grade disease., Conclusion: CEST MRI using a 1.5 T MR-Linac was demonstrated to be feasible for in vivo imaging of CNS tumours. CEST images showed tumour/white-matter contrast, temporal CEST signal changes, and associations with tumour grade. These results show promise for the eventual goal of using metabolic imaging to inform the design of adaptive radiotherapy protocols., (Copyright © 2021 The Author(s). Published by Elsevier B.V. All rights reserved.)

The brain-gut-microbiome axis is a bidirectional communication pathway between the gut microbiota and the central nervous system. The growing interest in the gut microbiota and mechanisms of its interaction with the brain has contributed to the considerable attention given to the potential use of probiotics, prebiotics and postbiotics in the prevention and treatment of depressive disorders. This review discusses the up-to-date findings in preclinical and clinical trials regarding the use of pro-, pre- and postbiotics in depressive disorders. Studies in rodent models of depression show that some of them inhibit inflammation, decrease corticosterone level and change the level of neurometabolites, which consequently lead to mitigation of the symptoms of depression. Moreover, certain clinical studies have indicated improvement in mood as well as changes in biochemical parameters in patients suffering from depressive disorders.

Purpose. To investigate the feasibility of using a single MRI acquisition for fiducial marker identification and synthetic CT (sCT) generation towards MRI-only treatment planning for prostate external beam radiation therapy (EBRT). Methods. Seven prostate cancer patients undergoing EBRT, each with three implanted gold fiducial markers, participated in this study. In addition to the planning CT scan, all patients were scanned on a 3 T MR scanner with a 3D double-echo gradient echo (GRE) sequence. Quantitative susceptibility mapping (QSM) was performed for marker localization. QSM-derived marker positions were compared to those from CT. The bulk density assignment technique for sCT generation was adopted. The magnitude GRE images were segmented into muscle, bone, fat, and air using a combination of unsupervised intensity-based classification of soft tissue and convolutional neural networks (CNN) for bone segmentation. Results. All implanted markers were visualized and accurately identified (average error: 0.7 ± 0.5 mm). QSM generated distinctive contrast for hemorrhage, calcifications, and gold fiducial markers. The estimated susceptibility/HU values on QSM/CT for gold and calcifications were 31.5 ± 2.9 ppm/1220 ± 100 HU and 14.6 ± 0.9 ppm/440 ± 100 HU, respectively. The intensity-based soft tissue classification resulted in an average Dice score of 0.97 ± 0.02; bone segmentation using CNN resulted in an average Dice score of 0.93 ± 0.03. Conclusion. This work indicates the feasibility of simultaneous fiducial marker identification and sCT generation using a single MRI acquisition. Future works includes evaluation of the proposed method in a large cohort of patients with optimized acquisition parameters as well as dosimetric evaluations., (© 2021 IOP Publishing Ltd.)

MRI phantom studies often fail to mimic the temperature of the human body, which can negatively impact accuracy. An artifact induced by increasing temperature in liquid phantoms was observed, presenting a significant challenge to temperature-controlled experiments. In this study we characterize and provide a solution to eliminate this temperature-induced MRI artifact. Low concentration (0.5-2.5 mM) agar phantoms were prepared. Utilizing a temperature-controlled phantom holder, T 1 - and T 2 -weighted structural images were acquired at 7 T along with quantitative B 0 , B 1 , T 1 , T 2 and ADC maps at both 25 and 37°C. Additionally, computer simulations were conducted to demonstrate the fluid flow and thermal flux patterns in water to provide an insight into the origins of the artifact. Evidence from computer simulation and quantitative MRI strongly suggest the artifact was caused by heat transfer in the form of natural convection leading to structured patterns of signal loss in MR images. The artifact was present up to agar concentrations of 1.5 mM (T 1 = 3068 ± 16 ms, T 2 = 1052 ± 20 ms, ADC = 2.29 ± 0.36 × 10 -3 mm 2 /s at 25°C; T 1 = 3928 ± 44 ms, T 2 = 1122 ± 24 ms, ADC = 2.64 ± 0.49 × 10 -3 mm 2 /s at 37°C), above which point increased sample viscosity no longer allows for convection currents, thereby eliminating the artifact. The methodology described in this work simplifies quantitative MR acquisition of liquid phantoms at physiological temperature by suppressing convection currents with relatively small changes to intrinsic MR parameters (T 1 increased by 1.4% and T 2 decreased by 17% for 1.5 mM agar at 25°C)., (© 2021 John Wiley & Sons, Ltd.)

Purpose: Quantitative MRI (qMRI) was performed using a 1.5T protocol that includes a novel chemical exchange saturation transfer/magnetization transfer (CEST/MT) approach. The purpose of this prospective study was to determine if qMRI metrics at baseline, at the 10th and 20th fraction during a 30 fraction/6 week standard chemoradiation (CRT) schedule, and at 1 month following treatment could be an early indicator of response for glioblastoma (GBM)., Methods: The study included 51 newly diagnosed GBM patients. Four regions-of-interest (ROI) were analyzed: (i) the radiation defined clinical target volume (CTV), (ii) radiation defined gross tumor volume (GTV), (iii) enhancing-tumor regions, and (iv) FLAIR-hyperintense regions. Quantitative CEST, MT, T 1 and T 2 parameters were compared between those patients progressing within 6.9 months (early), and those progressing after CRT (late), using mixed modelling. Exploratory predictive modelling was performed to identify significant predictors of early progression using a multivariable LASSO model., Results: Results were dependent on the specific tumor ROI analyzed and the imaging time point. The baseline CEST asymmetry within the CTV was significantly higher in the early progression cohort. Other significant predictors included the T 2 of the MT pools (for semi-solid at fraction 20 and water at 1 month after CRT), the exchange rate (at fraction 20) and the MGMT methylation status., Conclusions: We observe the potential for multiparametric qMRI, including a novel pulsed CEST/MT approach, to show potential in distinguishing early from late progression GBM cohorts. Ultimately, the goal is to personalize therapeutic decisions and treatment adaptation based on non-invasive imaging-based biomarkers.

Histopathology is currently the most reliable tool in assessing the aggressiveness and prognosis of solid tumours. However, developing non-invasive modalities for tumour evaluation remains crucial due to the side effects and complications caused by biopsy procedures. In this study, saturation transfer MRI was used to investigate the microstructural and metabolic properties of tumour xenografts in mice derived from the prostate cancer cell lines 22Rv1 and DU145, which express different aggressiveness. The magnetization transfer (MT) and chemical exchange saturation transfer (CEST) effects, which are associated with the microstructural and metabolic properties in biological tissue, respectively, were analyzed quantitatively and compared amongst different tumour types and regions. Histopathological staining was performed as a reference. Higher cellular density and metabolism expressed in more aggressive tumours (22Rv1) were associated with larger MT and CEST effects. High collagen content in the necrotic regions might explain their higher MT effects compared to tumour regions.

Purpose: The diagnosis of monoamine-related psychiatric disorders is based on the phenomenological evaluation of symptoms and behavior by trained clinicians. The CEST technique can be sensitive to monoamines such as serotonin. This study quantifies the CEST properties of the compounds in the serotonin biosynthesis pathway with the goal of developing noninvasive techniques aimed at advancing the diagnostic assessment of serotonin dysfunction., Methods: Saturation transfer-weighted images of L-tryptophan, 5-hydroxytryptophan, serotonin, 5-hydroxyindoleacetic acid, and melatonin phantoms were acquired over a range of saturation amplitudes and frequency offsets along with observed T 1 , T 2 , and B 1 efficiency maps at physiological temperature and pH of 5.5, 6.7, and 7.4. The CEST and MT data were fitted to a three-pool Bloch-McConnell model of exchange to estimate the model parameters., Results: At a pH of 5.5, tryptophan, 5-hydroxytryptophan and serotonin exhibited significant CEST contrast at resonance frequency offset, Δω between 2.64 ppm and 2.71 ppm, and magnetization transfer ratio asymmetry amplitudes up to 20% per 30 mM. At a pH of 7.4, all molecules exhibited significant CEST contrast between 5.11 ppm and 5.47 ppm, and magnetization transfer ratio asymmetry amplitudes up to 9.5% per 30 mM. At a pH of 6.7, all studied compounds except melatonin exhibited a CEST peak from each of the preceding two pHs., Conclusion: At a pH of 5.5, tryptophan, 5-hydroxytryptophan, and serotonin CEST contrast originates from the NH 3 + side chain, whereas at a pH of 7.4, CEST contrast is due to the chemical exchange between water and the NH proton on the indole ring. The data in this study could be used to inform future investigations aimed at detecting and measuring in vivo serotonin., (© 2020 International Society for Magnetic Resonance in Medicine.)

Major depressive disorder is a stress-related disease associated with brain metabolic dysregulation in the glutamine-glutamate/γ-aminobutyric acid (Gln-Glu/GABA) cycle. Recent studies have demonstrated that microbiome-gut-brain interactions have the potential to influence mental health. The hypothesis of this study was that Lactobacillus rhamnosus JB-1 (LR-JB1™) dietary supplementation has a positive impact on neuro-metabolism which can be quantified in vivo using magnetic resonance spectroscopy (MRS). A rat model of depressive-like disorder, chronic unpredictable mild stress (CUMS), was used. Baseline comparisons of MRS and behavior were obtained in a control group and in a stressed group subjected to CUMS. Of the 22 metabolites measured using MRS, stressed rats had significantly lower concentrations of GABA, glutamate, glutamine + glutathione, glutamate + glutamine, total creatine, and total N-acetylaspartate (tNAA). Stressed rats were then separated into 2 groups and supplemented with either LR-JB1™ or placebo and re-evaluated after 4 weeks of continued CUMS. The LR-JB1™ microbiotic diet restored these metabolites to levels previously observed in controls, while the placebo diet resulted in further significant decrease of glutamate, total choline, and tNAA. LR-JB1™ treated animals also exhibited calmer and more relaxed behavior, as compared with placebo treated animals. In summary, significant cerebral biochemical downregulation of major brain metabolites following prolonged stress were measured in vivo using MRS, and these decreases were reversed using a microbiotic dietary supplement of LR-JB1™, even in the presence of continued stress, which also resulted in a reduction of stress-induced behavior in a rat model of depressive-like disorder., (Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Local response prediction for brain metastases (BM) after stereotactic radiosurgery (SRS) is challenging, particularly for smaller BM, as existing criteria are based solely on unidimensional measurements. This investigation sought to determine whether radiomic features provide additional value to routinely available clinical and dosimetric variables to predict local recurrence following SRS., Methods: Analyzed were 408 BM in 87 patients treated with SRS. A total of 440 radiomic features were extracted from the tumor core and the peritumoral regions, using the baseline pretreatment volumetric post-contrast T1 (T1c) and volumetric T2 fluid-attenuated inversion recovery (FLAIR) MRI sequences. Local tumor progression was determined based on Response Assessment in Neuro-Oncology‒BM criteria, with a maximum axial diameter growth of >20% on the follow-up T1c indicating local failure. The top radiomic features were determined based on resampled random forest (RF) feature importance. An RF classifier was trained using each set of features and evaluated using the area under the receiver operating characteristic curve (AUC)., Results: The addition of any one of the top 10 radiomic features to the set of clinical features resulted in a statistically significant (P < 0.001) increase in the AUC. An optimized combination of radiomic and clinical features resulted in a 19% higher resampled AUC (mean = 0.793; 95% CI = 0.792-0.795) than clinical features alone (0.669, 0.668-0.671)., Conclusions: The increase in AUC of the RF classifier, after incorporating radiomic features, suggests that quantitative characterization of tumor appearance on pretreatment T1c and FLAIR adds value to known clinical and dosimetric variables for predicting local failure., (© The Author(s) 2020. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Saturation transfer MRI can be useful in the characterization of different tumour types. It is sensitive to tumour metabolism, microstructure, and microenvironment. This study aimed to use saturation transfer to differentiate between intratumoural regions, demarcate tumour boundaries, and reduce data acquisition times by identifying the imaging scheme with the most impact on segmentation accuracy. Saturation transfer-weighted images were acquired over a wide range of saturation amplitudes and frequency offsets along with T 1 and T 2 maps for 34 tumour xenografts in mice. Independent component analysis and Gaussian mixture modelling were used to segment the images and identify intratumoural regions. Comparison between the segmented regions and histopathology indicated five distinct clusters: three corresponding to intratumoural regions (active tumour, necrosis/apoptosis, and blood/edema) and two extratumoural (muscle and a mix of muscle and connective tissue). The fraction of tumour voxels segmented as necrosis/apoptosis quantitatively matched those calculated from TUNEL histopathological assays. An optimal protocol was identified providing reasonable qualitative agreement between MRI and histopathology and consisting of T 1 and T 2 maps and 22 magnetization transfer (MT)-weighted images. A three-image subset was identified that resulted in a greater than 90% match in positive and negative predictive value of tumour voxels compared to those found using the entire 24-image dataset. The proposed algorithm can potentially be used to develop a robust intratumoural segmentation method.

The pathogenesis of spinal cord injury (SCI) remains poorly understood and treatment remains limited. Emerging evidence indicates that post-SCI inflammation is severe but the role of reactive astrogliosis not well understood given its implication in ongoing inflammation as damaging or neuroprotective. We have completed an extensive systematic study with MRI, histopathology, proteomics and ELISA analyses designed to further define the severe protracted and damaging inflammation after SCI in a rat model. We have identified 3 distinct phases of SCI: acute (first 2 days), inflammatory (starting day 3) and resolution (>3 months) in 16 weeks follow up. Actively phagocytizing, CD68+/CD163- macrophages infiltrate myelin-rich necrotic areas converting them into cavities of injury (COI) when deep in the spinal cord. Alternatively, superficial SCI areas are infiltrated by granulomatous tissue, or arachnoiditis where glial cells are obliterated. In the COI, CD68+/CD163- macrophage numbers reach a maximum in the first 4 weeks and then decline. Myelin phagocytosis is present at 16 weeks indicating ongoing inflammatory damage. The COI and arachnoiditis are defined by a wall of progressively hypertrophied astrocytes. MR imaging indicates persistent spinal cord edema that is linked to the severity of inflammation. Microhemorrhages in the spinal cord around the lesion are eliminated, presumably by reactive astrocytes within the first week post-injury. Acutely increased levels of TNF-alpha, IL-1beta, IFN-gamma and other pro-inflammatory cytokines, chemokines and proteases decrease and anti-inflammatory cytokines increase in later phases. In this study we elucidated a number of fundamental mechanisms in pathogenesis of SCI and have demonstrated a close association between progressive astrogliosis and reduction in the severity of inflammation., Competing Interests: The authors have declared that no competing interests exist.

Purpose: The current magnetic resonance imaging-computed tomography (MRI-CT) fusion-based workflow for postimplant dosimetry of low-dose-rate (LDR) prostate brachytherapy takes advantage of the superior soft tissue contrast of MRI, but still relies on CT for seed visualization and detection. Recently an MR-only workflow has been proposed that employs standard MR sequences and visualizes conventional implanted seed with positive contrast solely through MR postprocessing. In this work, the novel MR-only based workflow is compared with the clinical CT-MRI fusion approach., Methods and Materials: Twenty-four prostate patients with a total of 1775 implanted LDR seeds were scanned using a 3-dimensional multiecho gradient echo sequence on a 3 Tesla MR scanner within 30 days after implantation. Quantitative susceptibility mapping was used for seed visualization. Seeds were automatically segmented and localized on the quantitative susceptibility mapping using convolutional neural network and k-means clustering, respectively. To assess the MR-only seed localization error, CT and MR-derived seed positions were coregistered, and ultimately, the resulting dose-volume histograms were compared., Results: The MR-based seed visualization, segmentation, and localization generated comparable results to the CT-MR registration approach. The accuracy of the MRI-only based seed identification was 99.1%. After a rigid registration between the MR and CT-derived seed centroids, the average localization error was 0.8 ± 0.8 mm. The average prostate D 90 , V 100 , V 150 , and V 200 for MRI-only and CT-MR fusion based dosimetry were 114.3 ± 12.5% versus 113.9 ± 11.9%, 95.1 ± 3.7% versus 95.3 ± 3.8%, 54.5 ± 14.5% versus 55.0 ± 13.2% and 22.9 ± 6.8% versus 23.2 ± 6.7%, respectively. No significant differences were observed in 3-dimensional seed positions and dosimetric parameters between MR-only and CT-MR fusion-based workflows (P > 0.2)., Conclusions: The MRI-only LDR postimplant dosimetry is feasible and has very good potential to eliminate the need for CT-based seed identification., (Copyright © 2019 Elsevier Inc. All rights reserved.)

About 20-40% of cancer patients develop brain metastases, causing significant morbidity and mortality. Stereotactic radiation treatment is an established option that delivers high dose radiation to the target while sparing the surrounding normal tissue. However, up to 20% of metastatic brain tumours progress despite stereotactic treatment, and it can take months before it is evident on follow-up imaging. An early predictor of radiation therapy outcome in terms of tumour local failure (LF) is crucial, and can facilitate treatment adjustments or allow for early salvage treatment. In this study, an MR-based radiomics framework was proposed to derive and investigate quantitative MRI (qMRI) biomarkers for the outcome of LF in brain metastasis patients treated with hypo-fractionated stereotactic radiation therapy (SRT). The qMRI biomarkers were constructed through a multi-step feature extraction/reduction/selection framework using the conventional MR imaging data acquired from 100 patients (133 lesions), and were applied in conjunction with machine learning techniques for outcome prediction and risk assessment. The results indicated that the majority of the features in the optimal qMRI biomarkers characterize the heterogeneity in the surrounding regions of tumour including edema and tumour/lesion margins. The optimal qMRI biomarker consisted of five features that predict the outcome of LF with an area under the curve (AUC) of 0.79, and a cross-validated sensitivity and specificity of 81% and 79%, respectively. The Kaplan-Meier analyses showed a statistically significant difference in local control (p-value < 0.0001) and overall survival (p = 0.01). Findings from this study are a step towards using qMRI for early prediction of local failure in brain metastasis patients treated with SRT. This may facilitate early adjustments in treatment, such as surgical resection or salvage radiation, that can potentially improve treatment outcomes. Investigations on larger cohorts of patients are, however, required for further validation of the technique.

Purpose: To compare magnetization transfer (MT) and CEST effects between 1.5T and 3T in phantom and in vivo experiments., Methods: A pulsed saturation scheme using block-shaped pulses separated by gaps was used to overcome the single RF amplifier duty cycle limitations of a clinical 1.5T scanner. Modeling was performed by incorporating the extended phase graph formalism into a Bloch-McConnell simulation. Two saturation pulse types (with long and short pulses) were used. Estimated parameters for MT (the semi-solid pool fraction, M 0 B ; the semi-solid transverse relaxation time, T 2 B ) and CEST (asymmetry; areas) were compared between 1.5T and 3T in phantoms and in the healthy brain., Results: Improved fits were shown after inclusion of extended phase graphs. Semi-solid pool fractions in phantom (for agar with ammonium chloride) were higher for short compared to long pulses at 3T (by 19% over all concentrations) and higher at 1.5T compared to 3T (by 5%) using short pulses. In the in vivo experiments, differentiation of white and gray matter was seen in the brain at both field strengths with improved white-gray matter contrast at 3T. In white matter, the mean semi-solid fractions were 18 ± 2% at 3T and 15 ± 2% at 1.5T. The CEST asymmetry in white matter was negative (-4.9 ± 0.4%) at 3T and zero (0.0 ± 0.3%) at 1.5T., Conclusions: The pulsed saturation method with short pulses, using the extended phase graph formalism in the Bloch McConnell simulations, led to improved model fits to the data, when compared to those without extended phase graphs., (© 2019 International Society for Magnetic Resonance in Medicine.)

Purpose: The lack of positive contrast from brachytherapy seeds in conventional MR images remains a major challenge toward an MRI-only workflow for postimplant dosimetry of low-dose-rate brachytherapy. In this work, the feasibility of our recently proposed MRI-only workflow in clinically relevant scenarios is investigated and the necessary modifications in image acquisition and processing pipeline are proposed for transition to the clinic., Methods and Materials: Four prostate phantoms with a total of 321 I-125 implanted dummy seeds and three patients with a total of 168 implanted seeds were scanned using a gradient echo sequence on 1.5 T and 3T MR scanners. Quantitative susceptibility mapping (QSM) was performed for seed visualization. Before QSM, the seed-induced distortion correction was performed followed by edge enhancement. Seed localization was performed using spatial clustering algorithms and was compared with CT. In addition, feasibility of the proposed method on detection of prostatic calcifications was studied., Results: The proposed susceptibility-based algorithm generated consistent positive contrast for the seeds in phantoms and patients. All the 321 seeds in the four phantoms were correctly identified; the MR-derived seeds centroids agreed well with CT-derived positions (average error = 0.5 ± 0.3 mm). The proposed algorithm for seed visualization was found to be orientation invariant. In patient cases, all seeds were visualized and correctly localized (average error = 1.2 ± 0.9 mm); no significant differences between dose volume histogram parameters were found. Prostatic calcifications were depicted with negative contrast on QSM and spatially agreed with CT., Conclusions: The proposed MRI-based approach has great potential to replace the current CT-based practices. Additional patient studies are necessary to further optimize and validate the workflow., (Copyright © 2019 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved.)

Magnetic resonance-guided radiation therapy (MR-GRT) offers great potential to improve radiation treatment outcomes by providing more accurate and patient-tailored therapy. Despite superior soft tissue contrast in MRI, one of the challenges towards MRI-only workflows is that the process often requires some sort of 'MR-invisible' metal-based devices. In this study, the feasibility of quantitative susceptibility mapping (QSM) for visualization of some MR-invisible radiation therapy devices was studied. Our recently proposed QSM-based algorithm for brachytherapy seed visualization was modified and the feasibility of the optimized algorithm for visualization of different devices including: brachytherapy seeds, plastic interstitial needles, CT-markers and obturators, and different types of fiducial markers in agar, prostate and meat phantoms were studied. All phantoms were scanned using 3T MR scanner with a 3D multi-echo gradient recalled echo (ME-GRE) pulse sequence. The QSM results in all phantoms were compared to CT images for spatial accuracy of the QSM. The applied post-processing algorithm was found to be insensitive to the seeds' type; also, presence of nearby calcifications had no effect on seed visualization. QSM successfully generated positive contrast for both types of investigated fiducial markers with high spatial accuracy compared to CT. Interstitial needles containing both aluminum-based CT-maker and titanium-based obturators were accurately depicted on the QSM. The proposed QSM-based technique relies on the standard MR pulse sequences and visualize the conventional MR-invisible metallic devices with CT-like positive contrast solely through post-processing. Upon in vivo validation of the technique, QSM may have the potential to replace CT for an MR-only guided radiation therapy.

Brain metastasis is the most common intracranial malignancy with a poor overall survival (OS) after treatment. The standard stereotactic radiation therapy (SRT) planning procedure for brain metastasis requires delineating the tumour volume on magnetic resonance (MR) images. MR images are also acquired at multiple follow-up scans after SRT to monitor the treatment outcome through measuring changes in the physical dimensions of the tumour. Such measurements require manual segmentation of the tumour volume on multiple slices of several follow-up images which is tedious and impedes the SRT evaluation work flow considerably. In this study, an automatic framework was proposed to segment the tumour volume on longitudinal MR images acquired at standard follow-up scans after SRT. The multi-step segmentation framework was based on region growing and morphological snakes models that applied the standard SRT planning tumour contour as a basis to approximate the tumour shape and location at each follow-up scan for an accurate automatic segmentation of tumour volume. The framework was evaluated using the MR imaging data acquired from five patients prior to and at three follow-up scans after SRT. The preliminary results indicated that the Dice similarity coefficient between the ground truth tumour masks and their automatically segmented counterparts ranged between 0.84 and 0.90, while the average Dice coefficient for all the follow-up scans was 0.88. The results obtained implied a good potential of the proposed framework for being incorporated into the SRT treatment planning and evaluation systems as well as outcome prediction models.

Despite recent advances in cancer treatment, patients with brain metastasis still suffer from poor overall survival (OS) after standard treatment. Predicting the treatment outcome before or early after the treatment can potentially assist the physicians in improving the therapy outcome by adjusting a standard treatment on an individual patient basis. In this study, a data-driven computational framework was proposed and investigated to predict the local control/failure (LC/LF) outcome in patients with brain metastasis treated with hypo-fractionated stereotactic radiation therapy (SRT). The framework extracted several geometrical and textural features from the magnetic resonance (MR) images of the tumour and edema regions acquired for 38 patients. Subsequent to a multi-step feature reduction/selection, a quantitative MR biomarker consisting of two features was constructed. A support vector machine classifier was used for outcome prediction using the constructed MR biomarker. The bootstrap .632+ and leave-one-patient-out cross-validation methods were used to assess the model's performance. The results indicated that the outcome of LF after SRT could be predicted with an area under the curve of 0.80 and a cross-validated accuracy of 82%. The results obtained implied a good potential of the proposed framework for local outcome prediction in patients with brain metastasis treated with SRT and encourage further investigations on a larger cohort of patients.

Brain metastases are the most common intracranial tumors and occur in 20-40% of all cancer patients. Lung cancer, breast cancer, and melanoma are the most frequent primary cancers to develop brain metastases. Treatment options include surgical resection, whole brain radiotherapy, stereotactic radiosurgery, and systemic treatment such as targeted or immune therapy. Anatomical magnetic resonance imaging (MRI) of the tumor (in particular post-Gadolinium T 1 -weighted and T 2 -weighted FLAIR) provide information about lesion morphology and structure, and are routinely used in clinical practice for both detection and treatment response evaluation for brain metastases. Advanced MRI biomarkers that characterize the cellular, biophysical, micro-structural and metabolic features of tumors have the potential to improve the management of brain metastases from early detection and diagnosis, to evaluating treatment response. Magnetic resonance spectroscopy (MRS), chemical exchange saturation transfer (CEST), quantitative magnetization transfer (qMT), diffusion-based tissue microstructure imaging, trans-membrane water exchange mapping, and magnetic susceptibility weighted imaging (SWI) are advanced MRI techniques that will be reviewed in this article as they pertain to brain metastases.

The goal of this study was to identify neurostructural frontal lobe correlates of cognitive and speaking rate changes in amyotrophic lateral sclerosis (ALS). 17 patients diagnosed with ALS and 12 matched controls underwent clinical, bulbar, and neuropsychological assessment and structural neuroimaging. Neuropsychological testing was performed via a novel computerized frontal battery (ALS-CFB), based on a validated theoretical model of frontal lobe functions, and focused on testing energization, executive function, emotion processing, theory of mind, and behavioral inhibition via antisaccades. The measure of speaking rate represented bulbar motor changes. Neuroanatomical assessment was performed using volumetric analyses focused on frontal lobe regions, postcentral gyrus, and occipital lobes as controls. Partial least square regressions (PLS) were used to predict behavioral (cognitive and speech rate) outcomes using volumetric measures. The data supported the overall hypothesis that distinct behavioral changes in cognition and speaking rate in ALS were related to specific regional neurostructural brain changes. These changes did not support a notion of a general dysexecutive syndrome in ALS. The observed specificity of behavior-brain changes can begin to provide a framework for subtyping of ALS. The data also support a more integrative framework for clinical assessment of frontal lobe functioning in ALS, which requires both behavioral testing and neuroimaging.

Accurate characterization of the craniomaxillofacial (CMF) skeleton using finite element (FE) modeling requires representation of complex geometries, heterogeneous material distributions, and physiological loading. Musculature in CMF FE models are often modeled with simple link elements that do not account for fiber bundles (FBs) and their differential activation. Magnetic resonance (MR) diffusion-tensor imaging (DTI) enables reconstruction of the three-dimensional (3D) FB arrangement within a muscle. However, 3D quantitative validation of DTI-generated FBs is limited. This study compares 3D FB arrangement in terms of pennation angle (PA) and fiber bundle length (FBL) generated through DTI in a human masseter to manual digitization. CT, MR-proton density, and MR-DTI images were acquired from a single cadaveric specimen. Bone and masseter surfaces were reconstructed from CT and MR-proton density images, respectively. PA and FBL were estimated from FBs reconstructed from MR-DTI images using a streamline tracking (STT) algorithm (n = 193) and FBs identified through manual digitization (n = 181) and compared using the Mann-Whitney test. DTI-derived PAs did not differ from the digitized data (p = 0.411), suggesting that MR-DTI can be used to simulate FB orientation and the directionality of transmitted forces. Conversely, a significant difference was observed in FBL (p < 0.01) which may have resulted due to the tractography stopping criterion leading to early tract termination and greater length variability. Overall, this study demonstrated that DTI can yield muscle FB orientation data suitable to representative directionality of physiologic muscle loading in patient-specific CMF FE modeling.

Background and Purpose- Recent evidence suggests great potential of metabolically targeted interventions for treating neurological disorders. We investigated the use of the endogenous ketone body β-hydroxybutyrate (BHB) as an alternate metabolic substrate for the brain in the acute phase of ischemia because postischemic hyperglycemia and brain glucose metabolism elevation compromise functional recovery. Methods- We delivered BHB (or vehicle) 1 hour after ischemic insult induced by cortical microinjection of endothelin-1 in sensorimotor cortex of rats. Two days after ischemic insult, the rats underwent multimodal characterization of the BHB effects. We examined glucose uptake on 2-Deoxy-d-glucose chemical exchange saturation transfer magnetic resonance imaging, cerebral hemodynamics on continuous arterial spin labeling magnetic resonance imaging, resting-state field potentials by intracerebral multielectrode arrays, Neurological Deficit Score, reactive oxygen species production, and astrogliosis and neuronal death. Results- When compared with vehicle-administered animals, BHB-treated cohort showed decreased peri-infarct neuronal glucose uptake which was associated with reduced oxidative stress, diminished astrogliosis and neuronal death. Functional examination revealed ameliorated neuronal functioning, normalized perilesional resting perfusion, and ameliorated cerebrovascular reactivity to hypercapnia, suggesting improved functioning. Cellular and functional recovery of the neurogliovascular unit in the BHB-treated animals was associated with improved performance on the withdrawal test. Conclusions- We characterize the effects of the ketone body BHB administration at cellular and system levels after focal cortical stroke. The results demonstrate that BHB curbs the peri-infarct glucose-metabolism driven production of reactive oxygen species and astrogliosis, culminating in improved neurogliovascular and functional recovery.

Purpose: The objective was to investigate (with quantitative MRI) whether the normal appearing white matter (NAWM) of glioblastoma (GBM) patients on the contralateral side (cNAWM) was different from NAWM of healthy controls., Methods: Thirteen patients with newly diagnosed GBM and nine healthy age-matched controls were MRI-scanned with quantitative magnetization transfer (qMT), chemical exchange saturation transfer (CEST), and transverse relaxation time (T 2 )-mapping. MRI scans were performed after surgery and before chemo-radiation treatment. Comprehensive qMT, CEST, T 2 data were acquired. A two-pool MT model was fit to qMT data in transient state, to calculate MT model parameters [Formula: see text]. CEST signal was isolated by removing the contributions from the MT and direct water saturation, and CEST signal was calculated for Amide (CEST Amide ), Amine (CEST Amine ) and nuclear overhauser effect, NOE (CEST NOE )., Results: There was no difference between GBM patients and normal controls in the qMT properties of the macromolecular pool [Formula: see text]. However, their free water pool spectrum was different (1/R a T 2a , patient  = 28.1 ± 3.9, 1/R a T 2a , control  = 25.0 ± 1.1, p = 0.03). This difference could be attributed to the difference in their T 2 time ([Formula: see text] = 83 ± 4, [Formula: see text] = 88 ± 1, p = 0.004). CEST signals were statistically significantly different with the CEST Amide having the largest difference between the two cohorts (CEST Amide,patient  = 2.8 ± 0.4, CEST Amide,control  = 3.4 ± 0.5, p = 0.009)., Conclusions: CEST in cNAWM of GBM patients was lower than healthy controls which could be caused by modified brain metabolism due to tumor cell infiltration. There was no difference in MT properties of the patients and controls, however, the differences in free water pool properties were mainly due to reduced T 2 in cNAWM of the patients (resulting from structural changes and increased cellularity).

Purpose: Detecting cell death and predicting tumor response early in a course of chemotherapy could help optimize treatment regimens and improve clinical outcomes. Chemical exchange saturation transfer (CEST) MRI was investigated in vivo to study properties that may be able to detect cancer death., Results: Using a magnetization transfer ratio (MTR) cutoff of 0.12 at 1.8 ppm was able to differentiate between viable tumor and cell death regions. Comparison of MTR values at this frequency showed significant differences ( p < 0.0001) between viable tumor and cell death regions, matching patterns seen on histology. Using this cutoff, the mean increase in cell death index (± standard error of the mean) after chemotherapy was 4 ± 4%, 10% ± 7%, 10 ± 8%, and 4 ± 9% at 4, 8, 12, and 24 h, respectively., Conclusions: CEST MRI can detect cell death in MDA-231 xenografts but further work is needed to characterize the clinical applications of this finding. Maximum response to chemotherapy occurred at 8-12 h after chemotherapy injection in this in vivo tumor model., Materials and Methods: Breast cancer xenografts (MDA-MB-231) were scanned using 7 T MRI before and after chemotherapy. As a measure of CEST effect at 0.5 µT saturation amplitude, MTR values at frequency offsets of 1.8 and -3.3 ppm were evaluated. CEST signals after chemotherapy treatment were compared to cell-death histopathology of tumors., Competing Interests: CONFLICTS OF INTEREST All authors state that they have no conflicts of interest to declare.

The ability of MRI to differentiate between normal and radioresistant cancer was investigated in prostate tumour xenografts in mice. Specifically, the process of magnetization exchange between water and other molecules was studied. It was found that magnetization transfer from semisolid macromolecules (MT) and chemical exchange saturation transfer (CEST) combined were significantly different between groups (p < 0.01). Further, the T 2 relaxation of the semisolid macromolecular pool (T 2,B ), a parameter specific to MT, was found to be significantly different (p < 0.01). Also significantly different were the rNOE contributions associated with methine groups at -0.9 ppm with a saturation B 1 of 0.5 µT (p < 0.01) and with other aliphatic groups at -3.3 ppm with 0.5 and 2 µT (both p < 0.05). Independently, using a live-cell metabolic assay, normal cells were found to have a greater metabolic rate than radioresistant ones. Thus, MRI provides a novel, in vivo method to quantify the metabolic rate of tumours and predict their radiosensitivity.

Purpose: To monitor cellular and metabolic characteristics of glioblastoma (GBM) over the course of standard 6-week chemoradiation treatment with chemical exchange saturation transfer (CEST)-MRI; and to identify the earliest time point CEST could determine subsequent therapeutic response., Methods and Materials: Nineteen patients with newly diagnosed GBM were recruited, and CEST-MRI was acquired immediately before (Day 0 ), 2 weeks (Day 14 ) and 4 weeks (Day 28 ) into treatment, and 1 month after the end of treatment (Day 70 ). Several CEST metrics, including magnetization transfer ratio and area under the curve of CEST peaks corresponding to nuclear Overhauser effect (NOE) and amide protons (MTR NOE , MTR Amide , CEST NOE , and CEST Amide respectively), magnetization transfer (MT), and direct water effect were investigated. Lack of early progression was determined as no increase in tumor size or worsening of clinical symptoms according to routine post-chemoradiation serial structural MRI., Results: Changes in MTR NOE (nonprogressors = 1.35 ± 0.18, progressors = 0.97 ± 0.22, P = .006) and MTR Amide (nonprogressors = 1.25 ± 0.17, progressors = 0.99 ± 0.10, P = .017) between baseline (Day 0 ) and Day 14 resulted in the best separation of nonprogressors from progressors. Moreover, the baseline (Day 0 ) MTR NOE (nonprogressors = 6.5% ± 1.6%, progressors = 9.1% ± 2.1%, P = .015), MTR Amide (nonprogressors = 6.7% ± 1.7%, progressors = 8.9% ± 1.9%, P = .028), MT (nonprogressors = 3.8% ± 0.9%, progressors = 5.4% ± 1.4%, P = .019), and CEST NOE (nonprogressors = 4.1%ċHz ± 1.7%ċHz, progressors = 6.1%ċHz ± 1.9%ċHz, P = .044) were able to identify progressors even before the start of the treatment., Conclusions: Chemical exchange saturation transfer (CEST) provides imaging-based biomarkers of GBM response as early as 2 weeks into the treatment. Certain CEST metrics can characterize tumor aggressiveness and identify early progressors even before beginning the treatment. Such an early biomarker of response may allow for adjusting the GBM treatment plan for adaptive radiation therapy in early progressors and more confidently continuing standard adjuvant treatment for nonprogressors., (Copyright © 2018 Elsevier Inc. All rights reserved.)

The rapid formation of hydrazones under physiological conditions was exploited for the detection of aldehydes through chemical exchange saturation transfer magnetic resonance imaging (CEST-MRI). A metal-free, diamagnetic contrast agent derived from N-amino anthranilic acid was introduced, which selectively "turned-on" upon hydrazone formation through an effect termed Hydrazo-CEST. While the hydrazine form of the probe produced no CEST-MRI signal enhancement, the formation of the aryl hydrazone resulted in >20 % intensity decrease in the bulk water signal through the CEST effect, as measured by 300 MHz 1 H NMR, 3 T and 7 T MRI. Both the electronic contributions of the N-amino anthranilate and the aldehyde binding partner were shown to directly impact the exchange rate of the proton on the ring-proximal nitrogen, and thus the imaging signal. Additionally, the presence of the carboxylic acid moiety ortho to the hydrazine was necessary not only for contrast production, but also for rapid hydrazone formation and prolonged hydrazone product stability under physiological conditions. This work provided the first example of an MRI-based contrast agent capable of a "turn on" response upon reaction with bioactive aldehydes, and outlined both the structural and electronic requirements to expand on Hydrazo-CEST, a novel, hydrazone-dependent subtype of diamagnetic CEST-MRI., (© 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Magnetization Transfer Contrast (MTC) and Chemical Exchange Saturation Transfer (CEST) experiments measure the transfer of magnetization from molecular protons to the solvent water protons, an effect that becomes apparent as an MRI signal loss ("saturation"). This allows molecular information to be accessed with the enhanced sensitivity of MRI. In analogy to Magnetic Resonance Spectroscopy (MRS), these saturation data are presented as a function of the chemical shift of participating proton groups, e.g. OH, NH, NH 2 , which is called a Z-spectrum. In tissue, these Z-spectra contain the convolution of multiple saturation transfer effects, including nuclear Overhauser enhancements (NOEs) and chemical exchange contributions from protons in semi-solid and mobile macromolecules or tissue metabolites. As a consequence, their appearance depends on the magnetic field strength (B 0 ) and pulse sequence parameters such as B 1 strength, pulse shape and length, and interpulse delay, which presents a major problem for quantification and reproducibility of MTC and CEST effects. The use of higher B 0 can bring several advantages. In addition to higher detection sensitivity (signal-to-noise ratio, SNR), both MTC and CEST studies benefit from longer water T 1 allowing the saturation transferred to water to be retained longer. While MTC studies are non-specific at any field strength, CEST specificity is expected to increase at higher field because of a larger chemical shift dispersion of the resonances of interest (similar to MRS). In addition, shifting to a slower exchange regime at higher B 0 facilitates improved detection of the guanidinium protons of creatine and the inherently broad resonances of the amine protons in glutamate and the hydroxyl protons in myoinositol, glycogen, and glucosaminoglycans. Finally, due to the higher mobility of the contributing protons in CEST versus MTC, many new pulse sequences can be designed to more specifically edit for CEST signals and to remove MTC contributions., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Quantitative magnetization transfer (qMT) was used as a biomarker to monitor glioblastoma (GBM) response to chemo-radiation and identify the earliest time-point qMT could differentiate progressors from non-progressors. Nineteen GBM patients were recruited and MRI-scanned before (Day 0 ), two weeks (Day 14 ), and four weeks (Day 28 ) into the treatment, and one month after the end of the treatment (Day 70 ). Comprehensive qMT data was acquired, and a two-pool MT model was fit to the data. Response was determined at 3-8 months following the end of chemo-radiation. The amount of magnetization transfer ([Formula: see text]) was significantly lower in GBM compared to normal appearing white matter (p < 0.001). Statistically significant difference was observed in [Formula: see text] at Day 0 between non-progressors (1.06 ± 0.24) and progressors (1.64 ± 0.48), with p = 0.006. Changes in several qMT parameters between Day 14 and Day 0 were able to differentiate the two cohorts with [Formula: see text] providing the best separation (relative [Formula: see text] = 1.34 ± 0.21, relative [Formula: see text] = 1.07 ± 0.08, p = 0.031). Thus, qMT characteristics of GBM are more sensitive to treatment effects compared to clinically used metrics. qMT could assess tumor aggressiveness and identify early progressors even before the treatment. Changes in qMT parameters within the first 14 days of the treatment were capable of separating early progressors from non-progressors, making qMT a promising biomarker to guide adaptive radiotherapy for GBM.

Intravoxel incoherent motion (IVIM) is a magnetic resonance imaging (MRI) technique that is seeing increasing use in neuro-oncology and offers an alternative to contrast-enhanced perfusion techniques for evaluation of tumor blood volume after stereotactic radiosurgery (SRS). To date, IVIM has not been validated against contrast enhanced techniques for brain metastases after SRS. In the present study, we measure blood volume for 20 brain metastases (15 patients) at baseline, 1 week and 1 month after SRS using IVIM and dynamic contrast enhanced (DCE)-MRI. Correlation between blood volume measurements made with IVIM and DCE-MRI show poor correlation at baseline, 1 week, and 1 month post SRS (r = 0.33, 0.14 and 0.30 respectively). At 1 week after treatment, no significant change in tumor blood volume was found using IVIM or DCE-MRI (p = 0.81 and 0.41 respectively). At 1 month, DCE-MRI showed a significant decrease in blood volume (p = 0.0002). IVIM, on the other hand, demonstrated the opposite effect and showed a significant increase in blood volume at 1 month (p = 0.03). The results of this study indicate that blood volume measured with IVIM and DCE-MRI are not equivalent. While this may relate to differences in the type of perfusion information each technique is providing, it could also reflect a limitation of tumor blood volume measurements made with IVIM after SRS. IVIM measurements of tumor blood volume in the month after SRS should therefore be interpreted with caution.

Purpose: The purpose of this work was to determine the predictive value of chemical exchange saturation transfer (CEST) metrics in brain metastases treated with stereotactic radiosurgery (SRS)., Methods: CEST spectra at a radiofrequency power of 0.52 µT were collected on a 3 Tesla (T) magnetic resonance imaging from 25 patients at three time points: pretreatment, 1 week, and 1 month post-treatment. Amide proton transfer-weighted images and maps of the amplitude and width of Lorentzian-shaped CEST peaks and the relaxation-compensated AREX metric were constructed at the offset frequencies of amide, amine, and relayed nuclear Overhauser effect (NOE) from aliphatic groups as well as the broad magnetization transfer effect. Pretreatment CEST metrics, as well as CEST metric changes at 1 week post-treatment, were compared to changes in tumor volume at 1 month., Results: Significant (P < 0.05) 1-week predictive metrics included NOE peak amplitude (R = 0.69) in normal-appearing white matter (NAWM) and width (R = -0.55) in tumor. Baseline NOE in contralateral NAWM was negatively correlated (R = -0.69) with volume changes at 1 month. Metrics-defined outside tumor margins had higher correlation with volume changes than tumor regions of interest., Conclusion: CEST metrics, in particular, the NOE peak amplitude, can predict volume changes 1 month post-SRS. Magn Reson Med 78:1110-1120, 2017. © 2016 International Society for Magnetic Resonance in Medicine., (© 2016 International Society for Magnetic Resonance in Medicine.)

The cuprizone model of demyelination is well established in the mouse as a tool for the study of the mechanisms of both demyelination and remyelination. It is often desirable, however, to have a larger model, such as the rat, especially for imaging-based studies, yet initial work has failed to show demyelination in cuprizone-fed rats. Several recent studies have demonstrated demyelination in the rat, but only in the corpus callosum. In this study, we acquired high-resolution, three-dimensional images of the whole brain every 2 weeks, using a T 1 -weighted magnetization-prepared rapid acquisition gradient echo imaging sequence, optimized for myelin contrast, in order to assess myelination across the entire rat brain over a period of 8 weeks on a 1% cuprizone diet. We observed a consistent pattern of demyelination, beginning in the cerebellum by 4 weeks and involving more rostral regions of the brain by 8 weeks on the cuprizone diet, with validation using Luxol fast blue histology. This imaging technique permits the effects of cuprizone-induced demyelination to be followed longitudinally in a single animal, over the entire brain. In turn, this may facilitate the establishment of the cuprizone model of demyelination in the rat., (Copyright © 2017 John Wiley & Sons, Ltd.)

Purpose: Stroke is the leading cause of adult disability worldwide. The absence of more effective interventions in the chronic stage-that most patients stand to benefit from-reflects uncertainty surrounding mechanisms that govern recovery. The present work investigated the effects of a novel treatment (selective cyclooxygenase-1, COX-1, inhibition) in a model of focal ischemia., Materials and Methods: FR122047 (COX-1 inhibitor) was given beginning 7 days following stroke (cortical microinjection of endothelin-1) in 23 adult male rats. Longitudinal continuous-arterial-spin-labeling was performed prior to treatment (7 days), and repeated following treatment (21 days) on a 7T magnetic resonance imaging (MRI) system to estimate resting perfusion and reactivity to hypercapnia. These in vivo measurements were buttressed by immunohistochemistry., Results: Stroke caused an increase in perilesional resting perfusion (peri-/contralesional perfusion ratio of 170 ± 10%) and perfusion responses to hypercapnia (180 ± 10%) at 7 days. At 21 days, placebo-administered rats showed normalized perilesional perfusion (100 ± 20%) but persistent hyperreactivity (190 ± 20%). Treated animals exhibited sustained perilesional hyperperfusion (180 ± 10%). Further, reactivity lateralization did not persist following treatment (peri- vs. contralesional reactivity: P = 0.002 at 7 vs. P = 0.2 at 21 days). Hemodynamic changes were accompanied by neuronal loss, increased endothelial density, and widespread microglial and astrocytic activation. Moreover, relative to controls, treated rats showed increased perilesional neuronal survival (22 ± 1% vs. 14.9 ± 0.8%, P = 0.02) and decreased microglia/macrophage recruitment (17 ± 1% vs. 20 ± 1%, P = 0.05). Finally, perilesional perfusion was correlated with neuronal survival (slope = 0.14 ± 0.05; R 2  = 0.7, P = 0.03)., Conclusion: These findings shed light on the role of COX-1 in chronic ischemic injury and suggest that delayed selective COX-1 inhibition exerts multiple beneficial effects on the neurogliovascular unit., Level of Evidence: 1 Technical Efficacy: Stage 4 J. MAGN. RESON. IMAGING 2017;46:505-517., (© 2016 International Society for Magnetic Resonance in Medicine.)

Purpose: Stereotactic radiosurgery (SRS) is a common treatment used in patients with brain metastases and is associated with high rates of local control, however, at the risk of radiation necrosis. It is difficult to differentiate radiation necrosis from tumor progression using conventional MRI, making it a major diagnostic dilemma for practitioners. This prospective study investigated whether chemical exchange saturation transfer (CEST) was able to differentiate these two conditions. Experimental Design: Sixteen patients with brain metastases who had been previously treated with SRS were included. Average time between SRS and evaluation was 12.6 months. Lesion type was determined by pathology in 9 patients and the other 7 were clinically followed. CEST imaging was performed on a 3T Philips scanner and the following CEST metrics were measured: amide proton transfer (APT), magnetization transfer (MT), magnetization transfer ratio (MTR), and area under the curve for CEST peaks corresponding to amide and nuclear Overhauser effect (NOE). Results: Five lesions were classified as progressing tumor and 11 were classified as radiation necrosis (using histopathologic confirmation and radiographic follow-up). The best separation was obtained by NOE MTR (NOE MTR,necrosis = 8.9 ± 0.9%, NOE MTR,progression = 12.6 ± 1.6%, P < 0.0001) and Amide MTR (Amide MTR,necrosis = 8.2 ± 1.0%, Amide MTR,progression = 12.0 ± 1.9%, P < 0.0001). MT (MT necrosis = 4.7 ± 1.0%, MT progression = 6.7 ± 1.7%, P = 0.009) and NOE AUC (NOE AUC,necrosis = 4.3 ± 2.0% Hz, NOE AUC,progression = 7.2 ± 1.9% Hz, P = 0.019) provided statistically significant separation but with higher P values. Conclusions: CEST was capable of differentiating radiation necrosis from tumor progression in brain metastases. Both NOE MTR and Amide MTR provided statistically significant separation of the two cohorts. However, APT was unable to differentiate the two groups. Clin Cancer Res; 23(14); 3667-75. ©2017 AACR ., (©2017 American Association for Cancer Research.)