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BACKGROUND: Patients with recurrent glioblastoma (GBM) are often treated with antiangiogenic agents, such as bevacizumab (BEV). Despite therapeutic promise, conventional MRI methods fail to help determine which patients may not benefit from this treatment. PURPOSE: To use MR spectroscopic imaging (MRSI) with intermediate and short echo time to measure corrected myo-inositol (mI)normalized by contralateral creatine (hereafter, mI/c-Cr) in participants with recurrent GBM treated with BEV and to investigate whether such measurements can help predict survivorship before BEV initiation (baseline) and at 1 day, 4 weeks, and 8 weeks thereafter. MATERIALS AND METHODS: In this prospective longitudinal study (2016–2020), spectroscopic data on mI—a glial marker and osmoregulator within the brain—normalized by contralateral creatine in the intratumoral, contralateral, and peritumoral volumes of patients with recurrent GBM were evaluated. Area under the receiver operating characteristic curve (AUC) was calculated for all volumes at baseline and 1 day, 4 weeks, and 8 weeks after treatment to determine the ability of mI/c-Cr to help predict survivorship. RESULTS: Twenty-one participants (median age ± standard deviation, 62 years ± 12; 15 men) were evaluated. Lower mI/c-Cr in the tumor before and during BEV treatment was predictive of poor survivorship, with receiver operating characteristic analyses showing an AUC of 0.75 at baseline, 0.87 at 1 day after treatment, and 1 at 8 weeks after. A similar result was observed in contralateral normal-appearing tissue and the peritumoral volume, with shorter-term survivors having lower levels of mI/c-Cr. In the contralateral volume, a lower ratio of mI to creatine (hereafter, mI/Cr) predicted shorter-term survival at baseline and all other time points. Within the peritumoral volume, lower mI/c-Cr levels were predictive of shorter-term survival at baseline (AUC, 0.80), at 1 day after treatment (AUC, 0.93), and at 4 weeks after treatment (AUC, 0.68). CONCLUSION: Lower levels of myo-inositol normalized by contralateral creatine within intratumoral, contralateral, and peritumoral volumes were predictive of poor survivorship and antiangiogenic treatment failure as early as before bevacizumab treatment. Adapting MR spectroscopic imaging alongside conventional MRI modalities conveys critical information regarding the biologic characteristics of tumors to help better treat individuals with recurrent glioblastoma. Clinical trial registration no. NCT02843230 © RSNA, 2021 Online supplemental material is available for this article.

BACKGROUND Fibromyalgia is a centralized multidimensional chronic pain syndrome, but its pathophysiology is not fully understood. METHODS We applied 3D magnetic resonance spectroscopic imaging (MRSI), covering multiple cortical and subcortical brain regions, to investigate the association between neuro-metabolite (e.g. combined glutamate and glutamine, Glx; myo-inositol, mIno; and combined (total) N-acetylaspartate and N-acetylaspartylglutamate, tNAA) levels and multidimensional clinical/behavioural variables (e.g. pain catastrophizing, clinical pain severity and evoked pain sensitivity) in women with fibromyalgia (N = 87). RESULTS Pain catastrophizing scores were positively correlated with Glx and tNAA levels in insular cortex, and negatively correlated with mIno levels in posterior cingulate cortex (PCC). Clinical pain severity was positively correlated with Glx levels in insula and PCC, and with tNAA levels in anterior midcingulate cortex (aMCC), but negatively correlated with mIno levels in aMCC and thalamus. Evoked pain sensitivity was negatively correlated with levels of tNAA in insular cortex, MCC, PCC and thalamus. CONCLUSIONS These findings support single voxel placement targeting nociceptive processing areas in prior 1 H-MRS studies, but also highlight other areas not as commonly targeted, such as PCC, as important for chronic pain pathophysiology. Identifying target brain regions linked to multidimensional symptoms of fibromyalgia (e.g. negative cognitive/affective response to pain, clinical pain, evoked pain sensitivity) may aid the development of neuromodulatory and individualized therapies. Furthermore, efficient multi-region sampling with 3D MRSI could reduce the burden of lengthy scan time for clinical research applications of molecular brain-based mechanisms supporting multidimensional aspects of fibromyalgia. SIGNIFICANCE This large N study linked brain metabolites and pain features in fibromyalgia patients, with a better spatial resolution and brain coverage, to understand a molecular mechanism underlying pain catastrophizing and other aspects of pain transmission. Metabolite levels in self-referential cognitive processing area as well as pain-processing regions were associated with pain outcomes. These results could help the understanding of its pathophysiology and treatment strategies for clinicians.

Several clinical upper motor neuron burden scales (UMNSs) variably measure brain dysfunction in amyotrophic lateral sclerosis (ALS). Here, we compare relationship of two widely used clinical UMNSs in ALS (Penn and MGH UMNSs) with (a) neuroimaging markers of brain dysfunction and (b) neurological impairment status using the gold-standard functional measure, the revised ALS Functional Rating Scale (ALSFRS-R). MGH UMNS measures hyperreflexia alone, and Penn UMNS measures hyperreflexia, spasticity, and pseudobulbar affect. Twenty-eight ALS participants underwent both Penn and MGH UMNSs, at a matching time-point as a simultaneous [11C]PBR28 positron emission tomography (PBR28-PET)/Magnetic Resonance scan and ALSFRS-R. The two UMNSs were compared for localization and strength of association with neuroimaging markers of: (a) neuroinflammation, PBR28-PET and MR Spectroscopy metabolites (myo-inositol and choline) and (b) corticospinal axonal loss, fractional anisotropy (FA), and MR Spectroscopy metabolite (N-acetylaspartate). Among clinical UMN manifestations, segmental hyperreflexia, spasticity, and pseudobulbar affect occurred in 100, 43, and 18% ALS participants, respectively. Pseudobulbar affect did not map to any specific brain regional dysfunction, while hyperreflexia and spasticity subdomains significantly correlated and colocalized neurobiological changes to corticospinal pathways on whole brain voxel-wise analyses. Both UMNS total scores showed significant and similar strength of association with (a) neuroimaging changes (PBR28-PET, FA, MR Spectroscopy metabolites) in primary motor cortices and (b) severity of functional decline (ALSFRS-R). Hyperreflexia is the most frequent clinical UMN manifestation and correlates best with UMN molecular imaging changes in ALS. Among Penn UMNS's subdomains, hyperreflexia carries the weight of association with neuroimaging markers of biological changes in ALS. A clinical UMN scale comprising hyperreflexia items alone is clinically relevant and sufficient to predict the highest yield of molecular neuroimaging abnormalities in ALS.

Issues with model fitting (i.e. suboptimal standard deviation, linewidth/full-width-at-half-maximum, and/or signal-to-noise ratio) in multi-voxel MRI spectroscopy, or chemical shift imaging (CSI) can result in the significant loss of usable voxels. A potential solution to minimize this problem is to estimate the value of unusable voxels by utilizing information from reliable voxels in the same image. We assessed an image restoration method called inpainting as a tool to restore unusable voxels, and compared it with traditional interpolation methods (nearest neighbor, trilinear interpolation and tricubic interpolation). In order to evaluate the performance across varying image contrasts and spatial resolutions, we applied the same techniques to a T1-weighted MRI brain dataset, and N-acetylaspartate (NAA) spectroscopy maps from a CSI dataset. For all image types, inpainting exhibited superior performance (lower normalized root-mean-square errors, NRMSE) compared to all other methods considered (p's < 0.001). Inpainting maintained an average NRMSE of less than 5% even with 50% missing voxels, whereas the other techniques demonstrated up to three times that value, depending on the nature of the image. For CSI maps, inpainting maintained its superiority whether the previously unusable voxels were randomly distributed, or located in regions most commonly affected by voxel loss in real-world data. Inpainting is a promising approach for recovering unusable or missing voxels in voxel-wise analyses, particularly in imaging modalities characterized by low SNR such as CSI. We hypothesize that this technique may also be applicable for datasets from other imaging modalities, such as positron emission tomography, or dynamic susceptibility contrast MRI.

Patients with recurrent glioblastoma (rGBM) are often started on anti-angiogenic therapy such as bevacizumab. However, determining treatment failure using conventional MRI methods remains challenging. We prospectively collected longitudinal MR spectroscopy data in 33 patients with rGBM and quantified various metabolites including N-acetylaspartate (NAA), Choline (Cho), and Lactate (Lac). After stratifying patients by 9 month survival, we found that longer-term survivors had decreased Lac/NAA and increased NAA/Cho compared to shorter-term survivors. ROC analyses illustrated that intratumoral changes in NAA/Cho were predictive of survival at 1 day (AUC 0.92), 2 weeks (AUC 0.75), 8 weeks (AUC 0.71) and 16 weeks (AUC 0.85) but not 4 weeks (AUC 0.60). Intratumoral changes in Lac/NAA were predictive of survival at all time points tested (AUCs > 0.76 for all time points). At 8 weeks, 90% of patients with increased Lac/NAA from baseline and 88% of patients with decreased NAA/Cho did not survive 9 months. Changes in NAA/Cho and Lac/NAA may serve as early biomarkers of anti-angiogenic treatment failure.

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

SummaryBackgroundThe impact of COVID-19 on human health extends beyond the morbidity and death toll directly caused by the SARS-CoV-2 virus. In fact, accumulating evidence indicates a global increase in the incidence of fatigue, brain fog and depression, including among non-infected, since the pandemic onset. Motivated by previous evidence linking those symptoms to neuroimmune activation in other pathological contexts, we hypothesized that subjects examined after the enforcement of lockdown/stay-at-home measures would demonstrate increased neuroinflammation.MethodsWe performed simultaneous brain Positron Emission Tomography / Magnetic Resonance Imaging in healthy volunteers either before (n=57) or after (n=15) the 2020 Massachusetts lockdown, using [11C]PBR28, a radioligand for the glial marker 18 kDa translocator protein (TSPO). First, we compared [11C]PBR28 signal across pre- and post-lockdown cohorts. Then, we evaluated the link between neuroinflammatory signals and scores on a questionnaire assessing mental and physical impacts of the pandemic. Further, we investigated multivariate associations between the spatial pattern of [11C]PBR28 post-lockdown changes and constitutive brain gene expression in post-mortem brains (Allen Human Brain Atlas). Finally, in a subset (n=13 pre-lockdown; n=11 post-lockdown), we also used magnetic resonance spectroscopy to quantify brain (thalamic) levels of myoinositol (mIns), another neuroinflammatory marker.FindingsBoth [11C]PBR28 and mIns signals were overall stable pre-lockdown, but markedly elevated after lockdown, including within brain regions previously implicated in stress, depression and “sickness behaviors”. Moreover, amongst the post-lockdown cohort, subjects endorsing higher symptom burden showed higher [11C]PBR28 PET signal compared to those reporting little/no symptoms. Finally, the post-lockdown [11C]PBR28 signal changes were spatially aligned with the constitutive expression of several genes highly expressed in glial/immune cells and/or involved in neuroimmune signaling.InterpretationOur results suggest that pandemic-related stressors may have induced sterile neuroinflammation in healthy individuals that were not infected with SARS-CoV-2. This work highlights the possible impact of the COVID-19 pandemic-related lifestyle disruptions on human brain health.FundingR01-NS094306-01A1, R01-NS095937-01A1, R01-DA047088-01, The Landreth Family Foundation.

Objective Our study aimed to quantify structural changes in relation to metabolic abnormalities in the cerebellum, thalamus, and parietal cortex of patients with late-onset GM2-gangliosidosis (LOGG), which encompasses late-onset Tay-Sachs disease (LOTS) and Sandhoff disease (LOSD). Methods We enrolled 10 patients with LOGG (7 LOTS, 3 LOSD) who underwent a neurological assessment battery and 7 age-matched controls. Structural MRI and MRS were performed on a 3 T scanner. Structural volumes were obtained from FreeSurfer and normalized by total intracranial volume. Quantified metabolites included N-acetylaspartate (NAA), choline (Cho), myo-inositol (mI), creatine (Cr), and combined glutamate-glutamine (Glx). Metabolic concentrations were corrected for partial volume effects. Results Structural analyses revealed significant cerebellar atrophy in the LOGG cohort, which was primarily driven by LOTS patients. NAA was lower and mI higher in LOGG, but this was also significantly driven by the LOTS patients. Clinical ataxia deficits (via the Scale for the Assessment and Rating of Ataxia) were associated with neuronal injury (via NAA), neuroinflammation (via mI), and volumetric atrophy in the cerebellum. Interpretation The decrease of NAA in the cerebellum suggests that, in addition to cerebellar atrophy, there is ongoing impaired neuronal function and/or loss, while an increase in mI indicates possible neuroinflammation in LOGG (more so within the LOTS subvariant). Quantifying cerebellar atrophy in relation to neurometabolic differences in LOGG may lead to improvements in assessing disease severity, progression, and pharmacological efficacy. Lastly, additional neuroimaging studies in LOGG are required to contrast LOTS and LOSD more accurately.

BackgroundType 2 diabetes mellitus is known to be associated with neurobiological and cognitive deficits; however, their extent, overlap with aging effects, and the effectiveness of existing treatments in the context of the brain are currently unknown.MethodsWe characterized neurocognitive effects independently associated with T2DM and age in a large cohort of human subjects from the UK Biobank with cross-sectional neuroimaging and cognitive data. We then proceeded to evaluate the extent of overlap between the effects related to T2DM and age by applying correlation measures to the separately characterized neurocognitive changes. Our findings were complemented by meta-analyses of published reports with cognitive or neuroimaging measures for T2DM and healthy controls (HC). We also evaluated in a cohort of T2DM diagnosed individuals using UK Biobank how disease chronicity and metformin treatment interact with the identified neurocognitive effects.ResultsThe UK Biobank dataset included cognitive and neuroimaging data (N=20,314) including 1,012 T2DM and 19,302 HC, aged between 50 and 80 years. Duration of T2DM ranged from 0–31 years (mean 8.5±6.1 years); 498 were treated with metformin alone, while 352 were unmedicated. Our meta-analysis evaluated 34 cognitive studies (N=22,231) and 60 neuroimaging studies: 30 of T2DM (N=866) and 30 of aging (N=1,088). As compared to age, sex, education, and hypertension-matched HC, T2DM was associated with marked cognitive deficits, particularly in executive functioning and processing speed. Likewise, we found that the diagnosis of T2DM was significantly associated with gray matter atrophy, primarily within the ventral striatum, cerebellum, and putamen, with reorganization of brain activity (decreased in the caudate and premotor cortex and increased in the subgenual area, orbitofrontal cortex, brainstem and posterior cingulate cortex). The structural and functional changes associated with T2DM show marked overlap with the effects correlating with age but appear earlier, with disease duration linked to more severe neurodegeneration. Metformin treatment status was not associated with improved neurocognitive outcomes.ConclusionsThe neurocognitive impact of T2DM suggests marked acceleration of normal brain aging. T2DM gray matter atrophy occurred approximately 26% ± 14% faster than seen with normal aging; disease chronicity was associated with faster atrophy. Mechanistically, our results suggest a neurometabolic component to brain aging. Clinically, neuroimaging-based biomarkers may provide a valuable adjunctive measure of T2DM progression and treatment efficacy based on neurological effects.FundingThe research described in this paper was funded by the W. M. Keck Foundation (to LRMP), the White House Brain Research Through Advancing Innovative Technologies (BRAIN) Initiative (NSFNCS-FR 1926781 to LRMP), and the Baszucki Brain Research Fund (to LRMP). None of the funding sources played any role in the design of the experiments, data collection, analysis, interpretation of the results, the decision to publish, or any aspect relevant to the study. DJW reports serving on data monitoring committees for Novo Nordisk. None of the authors received funding or in-kind support from pharmaceutical and/or other companies to write this manuscript.

Highlights • Participants with ALS exhibited impaired function between the cortex and cerebellum. • The cerebellum is associated with complex motor and cognitive processing tasks. • These findings add to the growing number of ALS reports implicating the cerebellum., Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease of the central nervous system that results in a progressive loss of motor function and ultimately death. It is critical, yet also challenging, to develop non-invasive biomarkers to identify, localize, measure and/or track biological mechanisms implicated in ALS. Such biomarkers may also provide clues to identify potential molecular targets for future therapeutic trials. Herein we report on a pilot study involving twelve participants with ALS and nine age-matched healthy controls who underwent high-resolution resting state functional magnetic resonance imaging at an ultra-high field of 7 Tesla. A group-level whole-brain analysis revealed a disruption in long-range functional connectivity between the superior sensorimotor cortex (in the precentral gyrus) and bilateral cerebellar lobule VI. Post hoc analyses using atlas-derived left and right cerebellar lobule VI revealed decreased functional connectivity in ALS participants that predominantly mapped to bilateral postcentral and precentral gyri. Cerebellar lobule VI is a transition zone between anterior motor networks and posterior non-motor networks in the cerebellum, and is associated with a wide range of key functions including complex motor and cognitive processing tasks. Our observation of the involvement of cerebellar lobule VI adds to the growing number of studies implicating the cerebellum in ALS. Future avenues of scientific investigation should consider how high-resolution imaging at 7T may be leveraged to visualize differences in functional connectivity disturbances in various genotypes and phenotypes of ALS along the ALS-frontotemporal dementia spectrum.

Background Determining failure to anti-angiogenic therapy in recurrent glioblastoma (GBM) (rGBM) remains a challenge. The purpose of the study was to assess treatment response to bevacizumab-based therapy in patients with rGBM using MR spectroscopy (MRS). Methods We performed longitudinal MRI/MRS in 33 patients with rGBM to investigate whether changes in N-acetylaspartate (NAA)/Choline (Cho) and Lactate (Lac)/NAA from baseline to subsequent time points after treatment can predict early failures to bevacizumab-based therapies. Results After stratifying based on 9-month survival, longer-term survivors had increased NAA/Cho and decreased Lac/NAA levels compared to shorter-term survivors. ROC analyses for intratumoral NAA/Cho correlated with survival at 1 day, 2 weeks, 8 weeks, and 16 weeks. Intratumoral Lac/NAA ROC analyses were predictive of survival at all time points tested. At the 8-week time point, 88% of patients with decreased NAA/Cho did not survive 9 months; furthermore, 90% of individuals with an increased Lac/NAA from baseline did not survive at 9 months. No other metabolic ratios tested significantly predicted survival. Conclusions Changes in metabolic levels of tumoral NAA/Cho and Lac/NAA can serve as early biomarkers for predicting treatment failure to anti-angiogenic therapy as soon as 1 day after bevacizumab-based therapy. The addition of MRS to conventional MR methods can provide better insight into how anti-angiogenic therapy affects tumor microenvironment and predict patient outcomes.

Background: Oxidative stress and protein aggregation are key mechanisms in amyotrophic lateral sclerosis (ALS) disease. Reduced glutathione (GSH) is the most important intracellular antioxidant that protects neurons from reactive oxygen species. We hypothesized that levels of GSH measured by MR spectroscopic imaging (MRSI) in the motor cortex and corticospinal tract are linked to clinical trajectory of ALS patients.Objectives: Investigate the value of GSH imaging to probe clinical decline of ALS patients in combination with other neurochemical and structural parameters.Methods: Twenty-four ALS patients were imaged at 3 T with an advanced MR protocol. Mapping GSH levels in the brain is challenging, and for this purpose, we used an optimized spectral-edited 3D MRSI sequence with real-time motion and field correction to image glutathione and other brain metabolites. In addition, our imaging protocol included (i) an adiabatic T1ρ sequence to image macromolecular fraction of brain parenchyma, (ii) diffusion tensor imaging (DTI) for white matter tractography, and (iii) high-resolution anatomical imaging.Results: We found GSH in motor cortex (r = −0.431, p = 0.04) and corticospinal tract (r = −0.497, p = 0.016) inversely correlated with time between diagnosis and imaging. N-Acetyl-aspartate (NAA) in motor cortex inversely correlated (r = −0.416, p = 0.049), while mean water diffusivity (r = 0.437, p = 0.033) and T1ρ (r = 0.482, p = 0.019) positively correlated with disease progression measured by imputed change in revised ALS Functional Rating Scale. There is more decrease in the motor cortex than in the white matter for GSH compared to NAA, glutamate, and glutamine.Conclusions: Our study suggests that a panel of biochemical and structural imaging biomarkers defines a brain endophenotype, which can be used to time biological events and clinical progression in ALS patients. Such a quantitative brain endophenotype may stratify ALS patients into more homogeneous groups for therapeutic interventions compared to clinical criteria.

The weak association between disability levels and "peripheral" (ie, knee) findings suggests that central nervous system alterations may contribute to the pathophysiology of knee osteoarthritis (KOA). Here, we evaluated brain metabolite alterations in patients with KOA, before and after total knee arthroplasty (TKA), using 1H-magnetic resonance spectroscopy (MRS). Thirty-four presurgical patients with KOA and 13 healthy controls were scanned using a PRESS sequence (TE = 30 ms, TR = 1.7 seconds, voxel size = 15 × 15 × 15 mm). In addition, 13 patients were rescanned 4.1 ± 1.6 (mean ± SD) weeks post-TKA. When using creatine (Cr)-normalized levels, presurgical KOA patients demonstrated lower N-acetylaspartate (NAA) (P0.001), higher myoinositol (mIns) (P0.001), and lower Choline (Cho) (P0.05) than healthy controls. The mIns levels were positively correlated with pain severity scores (r = 0.37, P0.05). These effects reached statistical significance also using water-referenced concentrations, except for the Cho group differences (P ≥ 0.067). Post-TKA patients demonstrated an increase in NAA (P0.01), which returned to the levels of healthy controls (P0.05), irrespective of metric. In addition, patients demonstrated postsurgical increases in Cr-normalized (P0.001), but not water-referenced mIns, which were proportional to the NAA/Cr increases (r = 0.61, P0.05). Because mIns is commonly regarded as a glial marker, our results are suggestive of a possible dual role for neuroinflammation in KOA pain and post-TKA recovery. Moreover, the apparent postsurgical normalization of NAA, a putative marker of neuronal integrity, might implicate mitochondrial dysfunction, rather than neurodegenerative processes, as a plausible pathophysiological mechanism in KOA. More broadly, our results add to a growing body of literature suggesting that some pain-related brain alterations can be reversed after peripheral surgical treatment.

Non-invasive measures of neuroinflammatory processes in humans could substantially aid diagnosis and therapeutic development for many disorders, including chronic pain. Several proton Magnetic Resonance Spectroscopy ((1)H-MRS) metabolites have been linked with glial activity (i.e. choline and myo-inositol) and found to be altered in chronic pain patients, but their role in the neuroinflammatory cascade is not well known. Our multimodal study evaluated resting fMRI connectivity and (1)H-MRS metabolite concentration in insula cortex in 43 patients suffering from fibromyalgia, a chronic centralized pain disorder previously demonstrated to include a neuroinflammatory component, and 16 healthy controls. Patients demonstrated elevated choline (but not myo-inositol) in anterior insula (p=0.03), with greater choline levels linked with worse pain interference (r=0.41, p=0.01). In addition, reduced resting functional connectivity between anterior insula and putamen was associated with both pain interference (whole brain analysis, p(corrected)

Brain magnetic resonance spectroscopic imaging (MRSI) was performed in three consecutive COVID-19 patients, as part of a pilot investigation of the pathophysiological processes underlying the brain involvement by the SARS-CoV-2 infection. These included one with necrotizing leukoencephalopathy, one after recent PEA cardiac arrest without leukoencephalopathy, and one without frank encephalopathy or recent severe hypoxic episode. The MRSI findings were compared to those of two patients with white matter pathology not SARS-CoV2 infection related, and a control patient without clinical encephalopathy. The N-acetylaspartate reduction, choline elevation, and glutamate/glutamine elevation found in the COVID necrotizing leukoencephalopathy patient and, to a lesser degree, the COVID post-cardiac arrest patient, follow a similar pattern as seen with the delayed post-hypoxic leukoencephalopathy patient. Lactate elevation was most pronounced in the patient with COVID necrotizing leukoencephalopathy.

Brain multivoxel MR spectroscopic imaging was performed in 3 consecutive patients with coronavirus disease 2019 (COVID-19). These included 1 patient with COVID-19-associated necrotizing leukoencephalopathy, another patient who had a recent pulseless electrical activity cardiac arrest with subtle white matter changes, and a patient without frank encephalopathy or a recent severe hypoxic episode. The MR spectroscopic imaging findings were compared with those of 2 patients with white matter pathology not related to Severe Acute Respiratory Syndrome coronavirus 2 infection and a healthy control subject. The NAA reduction, choline elevation, and glutamate/glutamine elevation found in the patient with COVID-19-associated necrotizing leukoencephalopathy and, to a lesser degree, the patient with COVID-19 postcardiac arrest, follow a similar pattern as seen with the patient with delayed posthypoxic leukoencephalopathy. Lactate elevation was most pronounced in the patient with COVID-19 necrotizing leukoencephalopathy.

Issues with model fitting (i.e. suboptimal standard deviation, linewidth/full-width-at-half-maximum, and/or signal-to-noise ratio) in multi-voxel MRI spectroscopy, or chemical shift imaging (CSI), can result in the significant loss of usable voxels. A potential solution to minimize this problem is to estimate the value of unusable voxels by utilizing information from reliable voxels in the same image. We assessed an image restoration method called inpainting as a tool to restore unusable voxels and compared it with traditional interpolation methods (nearest neighbor, trilinear interpolation and tricubic interpolation). We applied these techniques to N-acetylaspartate (NAA) spectroscopy maps from a CSI dataset. Inpainting exhibited superior performance (lower normalized root-mean-square errors, NRMSE) compared to all other methods considered (p’sClinical RelevanceThe presence of missing voxels can be problematic, particularly when data are analyzed in standard space, given that only voxels that are contributed to by all participants can be interrogated in these analyses. Inpainting is a promising approach for recovering unusable or missing voxels in voxelwise analyses, particularly in imaging modalities characterized by low SNR such as CSI.

Objective To test the safety, tolerability, and urate‐elevating capability of the urate precursor inosine taken orally or by feeding tube in people with amyotrophic lateral sclerosis (ALS). Methods This was a pilot, open‐label trial in 25 participants with ALS. Treatment duration was 12 weeks. The dose of inosine was titrated at pre‐specified time points to elevate serum urate levels to 7–8 mg/dL. Primary outcomes were safety (as assessed by the occurrence of adverse events [AEs]) and tolerability (defined as the ability to complete the 12‐week study on study drug). Secondary outcomes included biomarkers of oxidative stress and damage. As an exploratory analysis, observed outcomes were compared with a virtual control arm built using prediction algorithms to estimate ALSFRS‐R scores. Results Twenty‐four out of 25 participants (96%) completed 12 weeks of study drug treatment. One participant was unable to comply with study visits and was lost to follow‐up. Serum urate rose to target levels in 6 weeks. No serious AEs attributed to study drug and no AEs of special concern, such as urolithiasis and gout, occurred. Selected biomarkers of oxidative stress and damage had significant changes during the study period. Observed changes in ALSFRS‐R did not differ from baseline predictions. Interpretation Inosine appeared safe, well tolerated, and effective in raising serum urate levels in people with ALS. These findings, together with epidemiological observations and preclinical data supporting a neuroprotective role of urate in ALS models, provide the rationale for larger clinical trials testing inosine as a potential disease‐modifying therapy for ALS.

Objective To determine the relationship between brain tissue metabolites measured by in vivo magnetic resonance spectroscopy (1H-MRS), and glial activation assessed with [11C]-PBR28 uptake in people with amyotrophic lateral sclerosis (ALS). Methods Forty ALS participants were evaluated clinically using the revised ALS functional rating scale (ALSFRS-R) and upper motor neuron burden (UMNB). All participants underwent simultaneous brain [11C]-PBR28 PET and MR imaging including diffusion tensor imaging to acquire fractional anisotropy (FA). [11C]-PBR28 uptake was measured as standardized uptake values normalized by whole brain mean (SUVR). 1H-MRS metabolite ratios (myo-inositol/creatine, mI/Cr; N-acetylaspartate/creatine, NAA/Cr) were measured within the precentral gyri and brain stem (regions known to be involved in ALS pathophysiology), and precuneus (which served as a control region). Whole brain voxel-wise correlation analyses were employed to identify brain regions exhibiting an association between metabolites within the VOIs and [11C]-PBR28 uptake. Results In the precentral gyri, [11C]-PBR28 uptake correlated positively with mI/Cr and negatively with NAA/Cr. The same correlations were not statistically significant in the brain stem, or in the control precuneus region. Whole brain voxel-wise correlation analyses between the estimated brain metabolites within the VOIs and SUVR were highly correlated in the precentral gyri. Decreased FA values in the precentral gyri were correlated with reduced NAA/Cr and elevated mI/Cr. Higher UMNB was correlated with increased [11C]-PBR28 uptake and mI/Cr, and decreased NAA/Cr. ALSFRS-R total score correlated positively with NAA/Cr and negatively with mI/Cr. Conclusion Integrated PET-MR and 1H-MRS imaging demonstrates associations between markers for neuronal integrity and neuroinflammation and may provide valuable insights into disease mechanisms in ALS., Highlights • This study evaluates the relationship between 1H-MRS and [11C]-PBR28 PET-MR measures in people with ALS. • Myo-inositol/Creatine correlates positively with glial activation measured by [11C]-PBR28 PET, and negatively with fractional anisotropy. • N-acetyl-aspartate/Creatine correlates negatively with [11C]-PBR28 PET, and positively with fractional anisotropy. • Myo-inositol/Creatine and N-acetyl-aspartate/Creatine correlate with ALS-functional rating scale and upper motor neuron burden. • 1H-MRS and PET-MR measures provide complementary information to better understand brain pathology in people with ALS.

Fibromyalgia is a multidimensional chronic pain syndrome. It is thought to result mainly from central nervous system dysfunction, but its working mechanism is not fully understood. In this study, we applied multi-slice magnetic resonance spectroscopy imaging (MRSI) to investigate the relationship between brain metabolite (e.g., combined glutamate and glutamine, Glx; myo-inositol, mIno; and combined N-acetylaspartate and N-acetylaspartylglutamate; tNAA) levels and the severity of multidimensional clinical/behavioral metrics (e.g., pain catastrophizing, clinical pain severity, and evoked pain sensitivity) in fibromyalgia patients (N=87). Fibromyalgia patients showed greater pain catastrophizing and hyperalgesia compared with age-matched healthy controls (N=40). In fibromyalgia patients, pain catastrophizing scale scores were positively correlated with Glx and tNAA levels in the insular cortex, and were negatively correlated with mIno levels in the posterior cingulate cortex (PCC). Clinical pain severity showed positive correlations with Glx levels in the insular and PCC, and with tNAA levels in the anterior middle cingulate cortex (aMCC), but negatively with mIno levels in the aMCC and thalamus. The level of tNAA in the insular cortex, MCC, PCC, and thalamus, were negatively correlated with evoked pain sensitivity. These results highlight the utility of MRSI in the understanding of molecular mechanisms underlying multidimensional aspects of fibromyalgia. This work was supported by the NIH (National Institute of Arthritis and Musculoskeletal and Skin Diseases grant R01-AR064367, National Center for Complementary and Integrative Health grants R01-AT007550, R61-AT009306, and P01-AT AT009965, and National Center for Research Resources grants P41-RR14075, S10-RR021110, and S10-RR023043). Development of MRSI pulse sequence and processing was funded by NIH/NCI grants K22CA178269 and R01CA211080.

The weak association between disability levels and “peripheral” (i.e., knee) findings suggests that central nervous system alterations may contribute to the pathophysiology of knee osteoarthritis (KOA). Here, we evaluated brain metabolite alterations in KOA patients, before and after total knee arthroplasty (TKA), using 1H-magnetic resonance spectroscopy (MRS). Thirty-four pre-surgical KOA patients and 13 healthy controls were scanned using a PRESS sequence (TE=30ms, TR=1.7s, voxel size=15 × 15 × 15mm). Additionally, a subset of patients (n=13) were re-scanned 4.1±1.6 (mean±SD) weeks post-TKA. When using Creatine (Cr)-normalized levels, pre-surgical KOA patients demonstrated lower N-acetylaspartate (NAA) (p≤0.01) and higher myoinositol (mIns) (p≤0.001), compared to healthy controls. The mIns levels were positively correlated with pain severity scores (r=0.37, p 0.05), irrespective of metric. Additionally, patients demonstrated post-surgical increases in Cr-normalized (p

Magnetic resonance spectroscopy (MRS) is a magnetic resonance-based imaging modality that allows noninvasive sampling of metabolic changes in normal and abnormal brain parenchyma. MRS is particularly useful in the differentiation of developmental or non-neoplastic disorders from neoplastic processes. MRS is also useful during routine imaging follow-up after radiation treatment or during antiangiogenic treatment and for predicting outcomes and treatment response. The objective of this article is to provide a concise but thorough review of the basic physical principles, important applications of MRS in brain tumor imaging, and future directions.

OBJECTIVE Investigating consequences of early or late antiretroviral therapy (ART) initiation in infancy on young brain development using magnetic resonance spectroscopy. DESIGN Most pediatric HIV/ART-related neurological studies are from neuropsychological/clinical perspectives. Magnetic resonance spectroscopy can elucidate the mechanisms underpinning neurocognitive outcomes by quantifying the brain's chemical condition through localized metabolism to provide insights into health and development. METHODS Basal ganglia metabolite concentrations were assessed in thirty-eight 5-year-old HIV-infected children previously participating in a randomized trial comparing early limited ART to deferred continuous ART, as well as 15 uninfected controls (12 HIV exposed). Metabolite levels were compared between 26 infected children who initiated ART at/before 12 weeks and 12 who initiated afterward, and were correlated with clinical HIV and treatment-related measures. RESULTS HIV-infected children initiating ART after 12 weeks had lower creatine, choline and glutamate (P

Light modulates multiple neurophysiologic pathways within brain. The effect of light therapy on these pathways may be assessed using a variety of techniques including symptom inventories, neurocognitive testing, and neuroimaging. This chapter describes various neuroimaging techniques that may be employed in studying the effect light has on brain in a variety of conditions and diseases such as traumatic brain injury, dementia syndromes, stroke, Parkinson disease, and others. While the chapter focuses on traumatic brain injury, the described neuroimaging methods are general and may be applied to any neurological condition.

This chapter is a practical "why, how to, and when" chapter, written in three parts to address three questions that arise when the epileptologist or neuroimager evaluates a patient with epilepsy. Why do magnetic resonance spectroscopy (MRS)? How to do MRS in the patient with epilepsy? When, that is, in what clinical-imaging setting, can MRS help to diagnose or manage the patient with epilepsy?

Despite the advent of highly active anti-retroviral therapy HIV-associated neurocognitive disorders (HAND) continue to be a significant problem. Furthermore, the precise pathogenesis of this neurodegeneration is still unclear. The objective of this study was to examine the relationship between infection by the simian immunodeficiency virus (SIV) and neuronal injury in the rhesus macaque using in vivo and postmortem sampling techniques. The effect of SIV infection in 23 adult rhesus macaques was investigated using an accelerated NeuroAIDS model. Disease progression was modulated either with combination anti-retroviral therapy (cART, 4 animals) or minocycline (7 animals). Twelve animals remained untreated. Viral loads were monitored in the blood and cerebral spinal fluid, as were levels of activated monocytes in the blood. Neuronal injury was monitored in vivo using magnetic resonance spectroscopy. Viral RNA was quantified in brain tissue of each animal postmortem using reverse transcription polymerase chain reaction (RT-PCR), and neuronal injury was assessed by immunohistochemistry. Without treatment, viral RNA in plasma, cerebral spinal fluid, and brain tissue appears to reach a plateau. Neuronal injury was highly correlated both to plasma viral levels and a subset of infected/activated monocytes (CD14+CD16+), which are known to traffic the virus into the brain. Treatment with either cART or minocycline decreased brain viral levels and partially reversed alterations in in vivo and immunohistochemical markers for neuronal injury. These findings suggest there is significant turnover of replicating virus within the brain and the severity of neuronal injury is directly related to the brain viral load.

A multi-center imaging trial by the American College of Radiology Imaging Network (ACRIN) "A Multicenter, phase II assessment of tumor hypoxia in glioblastoma using 18F Fluoromisonidazole (FMISO) with PET and MRI (ACRIN 6684)", was conducted to assess hypoxia in patients with glioblastoma (GBM). The aims of this study were to support the role of proton magnetic resonance spectroscopic imaging (1H MRSI) as a prognostic marker for brain tumor patients in multi-center clinical trials. Seventeen participants from four sites had analyzable 3D MRSI datasets acquired on Philips, GE or Siemens scanners at either 1.5T or 3T. MRSI data were analyzed using LCModel to quantify metabolites N-acetylaspartate (NAA), creatine (Cr), choline (Cho), and lactate (Lac). Receiver operating characteristic curves for NAA/Cho, Cho/Cr, lactate/Cr, and lactate/NAA were constructed for overall survival at 1-year (OS-1) and 6-month progression free survival (PFS-6). The OS-1 for the 17 evaluable patients was 59% (10/17). Receiver operating characteristic analyses found the NAA/Cho in tumor (AUC = 0.83, 95% CI: 0.61 to 1.00) and in peritumoral regions (AUC = 0.95, 95% CI 0.85 to 1.00) were predictive for survival at 1 year. PFS-6 was 65% (11/17). Neither NAA/Cho nor Cho/Cr was effective in predicting 6-month progression free survival. Lac/Cr in tumor was a significant negative predictor of PFS-6, indicating that higher lactate/Cr levels are associated with poorer outcome. (AUC = 0.79, 95% CI: 0.54 to 1.00). In conclusion, despite the small sample size in the setting of a multi-center trial comprising different vendors, field strengths, and varying levels of expertise at data acquisition, MRS markers NAA/Cho, Lac/Cr and Lac/NAA predicted overall survival at 1 year and 6-month progression free survival. This study validates that MRSI may be useful in evaluating the prognosis in glioblastoma and should be considered for incorporating into multi-center clinical trials.

OBJECTIVE As ~40% of persons with HIV also suffer neurocognitive decline, we sought to assess metabolic dysfunction in the brains of simian immunodeficiency virus (SIV)-infected rhesus macaques, an advanced animal model, in structures involved in cognitive function. We test the hypothesis that SIV-infection produces proton-magnetic resonance spectroscopic imaging (H-MRSI)-observed decline in the neuronal marker, N-acetylaspartate (NAA), and elevations in the glial marker, myo-inositol (mI), and associated creatine (Cr) and choline (Cho) in these structures. DESIGN Pre- and 4-6 weeks post-SIV infection (with CD8 T-lymphocyte depletion) was monitored with T2-weighted quantitative MRI and 16×16×4 multivoxel H-MRSI (TE/TR = 33/1400 ms) in the brains of five rhesus macaques. METHODS Exploiting the high-resolution H-MRSI grid, we obtained absolute, cerebrospinal fluid partial volume-corrected NAA, Cr, Cho and mI concentrations from centrum semiovale, caudate nucleus, putamen, thalamus and hippocampus regions. RESULTS Pre- to post-infection mean Cr increased in the thalamus: 7.2±0.4 to 8.0±0.8 mmol/l (+11%, P

Magnetic resonance spectroscopy (MRS) is indicated in the imaging protocol of the patient with epilepsy to screen for metabolic derangements such as inborn errors of metabolism and to characterize masses that may be equivocal on conventional magnetic resonance imaging for dysplasia versus neoplasia. Single-voxel MRS with echo time of 35 milliseconds may be used for this purpose as a quick screening tool in the epilepsy imaging protocol. MRS is useful in the evaluation of both focal and generalized epilepsy.

The prognosis for patients with recurrent glioblastoma remains poor. The purpose of this study was to assess the potential role of MR spectroscopy as an early indicator of response to anti-angiogenic therapy.Thirteen patients with recurrent glioblastoma were enrolled in RTOG 0625/ACRIN 6677, a prospective multicenter trial in which bevacizumab was used in combination with either temozolomide or irinotecan. Patients were scanned prior to treatment and at specific timepoints during the treatment regimen. Postcontrast T1-weighted MRI was used to assess 6-month progression-free survival. Spectra from the enhancing tumor and peritumoral regions were defined on the postcontrast T1-weighted images. Changes in the concentration ratios of n-acetylaspartate/creatine (NAA/Cr), choline-containing compounds (Cho)/Cr, and NAA/Cho were quantified in comparison with pretreatment values.NAA/Cho levels increased and Cho/Cr levels decreased within enhancing tumor at 2 weeks relative to pretreatment levels (P = .048 and P = .016, respectively), suggesting a possible antitumor effect of bevacizumab with cytotoxic chemotherapy. Nine of the 13 patients were alive and progression free at 6 months. Analysis of receiver operating characteristic curves for NAA/Cho changes in tumor at 8 weeks revealed higher levels in patients progression free at 6 months (area under the curve = 0.85), suggesting that NAA/Cho is associated with treatment response. Similar results were observed for receiver operating characteristic curve analyses against 1-year survival. In addition, decreased Cho/Cr and increased NAA/Cr and NAA/Cho in tumor periphery at 16 weeks posttreatment were associated with both 6-month progression-free survival and 1-year survival.Changes in NAA and Cho by MR spectroscopy may potentially be useful as imaging biomarkers in assessing response to anti-angiogenic treatment.

Creatine monohydrate (creatine) has potential neuroprotective properties and is a commonly used supplement in amyotrophic lateral sclerosis (ALS) and other neurodegenerative disorders. Minimum therapeutic and maximum tolerated dosages of creatine are not yet known, nor is it known what systemic plasma concentrations result from specific dosage regimens. The objectives of this study were to establish steady-state plasma pharmacokinetics of creatine at several dosages, and to evaluate the effects of creatine on brain metabolites using proton magnetic resonance spectroscopy ((1)H-MRS). Six participants with ALS received creatine at three weekly escalating oral dosages (5, 10, and 15 g b.i.d.). Plasma creatine levels and MR spectra were obtained at baseline and with each dosage increase. Mean pre-dose steady-state creatine plasma concentrations were 20.3, 39.3, and 61.5 ug/ml at 5, 10, and 15 g b.i.d., respectively. Creatine spectra increased by 8% (p = 0.06) and glutamate + glutamine signals decreased by 17% (p = 0.039) at higher dosages. There were no safety concerns at any of the dosages. In conclusion, creatine plasma concentrations increased in a dose-dependent manner. Creatine appears to cross the blood-brain barrier, and oral administration of 15 g b.i.d. is associated with increased in vivo brain creatine concentrations and decreased glutamate concentrations.

The accuracy of metabolic quantification in MR spectroscopy is limited by the unknown radiofrequency field and T(1). To address both issues in proton ((1)H) MR spectroscopy, we obtained radiofrequency field-corrected T(1) maps of N-acetylaspartate, choline, and creatine in five healthy rhesus macaques at 3 T. For efficient use of the 4 hour experiment, we used a new three-point protocol that optimizes the precision of T(1) in three-dimensional (1)H-MR spectroscopy localization for extensive, approximately 30%, brain coverage at 0.6 x 0.6 x 0.5 cm(3) = 180-microL spatial resolution. The resulting mean T(1)s in 700 voxels were N-acetylaspartate = 1232 +/- 44, creatine = 1238 +/- 23 and choline = 1107 +/- 56 ms (mean +/- standard error of the mean). Their histograms from all 140 voxels in each animal were similar in position and shape, characterized by standard errors of the mean of the full width at half maximum divided by their means of better than 8%. Regional gray matter N-acetylaspartate, choline, and creatine T(1)s (1333 +/- 43, 1265 +/- 52, and 1131 +/- 28 ms) were 5-10% longer than white matter: 1188 +/- 34, 1201 +/- 24, and 1082 +/- 50 ms (statistically significant for the N-acetylaspartate only), all within 10% of the corresponding published values in the human brain.

The purpose of this work was to design and implement constant adiabadicity gradient modulated pulses that have improved slice profiles and reduced artifacts for spectroscopic imaging on 3T clinical scanners equipped with standard hardware. The newly proposed pulses were designed using the gradient offset independent adiabaticity (GOIA, Tannus and Garwood, 1997) method using WURST modulation for RF and gradient waveforms. The GOIA-WURST pulses were compared with GOIA-HSn (GOIA based on nth-order hyperbolic secant) and FOCI (Frequency Offset Corrected Inversion) pulses of the same bandwidth and duration. Numerical simulations and experimental measurements in phantoms and healthy volunteers are presented. GOIA-WURST pulses provide improved slice profile that have less slice smearing for off-resonance frequencies compared to GOIA-HSn pulses. The peak RF amplitude of GOIA-WURST is much lower (40% less) than FOCI but slightly higher (14.9% more) to GOIA-HSn. The quality of spectra as shown by the analysis of line-shapes, eddy currents artifacts, subcutaneous lipid contamination and SNR is improved for GOIA-WURST. GOIA-WURST pulse tested in this work shows that reliable spectroscopic imaging could be obtained in routine clinical setup and might facilitate the use of clinical spectroscopy.

A significant number of HIV-infected patients develop neurological symptoms ranging from minor cognitive impairment to severe dementia (known HIV-associated dementia, HAD). Without combination antiretroviral therapy (cART) HAD occurs in 20–40 % of HIV positive subjects, with the advent of cART the incident has decreased to 5–10 %, although milder forms of cognitive deficits may occur in 30–50 % of those infected with HIV. It is believed that HIV enters the CNS during the early stages of infection by infected immune cells which initiate an inflammatory cascade which results in neuronal injury and loss. Imaging has been widely used to evaluate the effect of HIV to the brain. Specifically, proton magnetic resonance spectroscopy (1H MRS) is one of the most informative methods employed in patients suffering from HIV-associated neurocognitive disorders (HAND). MRS is able to noninvasively measure metabolic changes pertaining to neuronal injury and inflammation, thus, it can assist in the diagnosis of the disease and measure the severity of injury. In animal models of neuroAIDS, MRS has been proven extremely powerful to assess disease progression and response to treatment. Here we review the literature of preclinical models as well as MRS studies of HIV+ adults and children before and after the advent of cART regiments. In addition, we discuss technical considerations related to the disease and finally talk about future direction in HAND using MRS.

Proton magnetic resonance spectroscopy (1H MRS) is a noninvasive imaging technique that can easily be added to the conventional magnetic resonance (MR) imaging sequences. Using MRS one can directly compare spectra from pathologic or abnormal tissue and normal tissue. Metabolic changes arising from pathology that can be visualized by MRS may not be apparent from anatomy that can be visualized by conventional MR imaging. In addition, metabolic changes may precede anatomic changes. Thus, MRS is used for diagnostics, to observe disease progression, monitor therapeutic treatments, and to understand the pathogenesis of diseases. MRS may have an important impact on patient management. The purpose of this chapter is to provide practical guidance in the clinical application of MRS of the brain. This chapter provides an overview of MRS-detectable metabolites and their significance. In addition some specific current clinical applications of MRS will be discussed, including brain tumors, inborn errors of metabolism, leukodystrophies, ischemia, epilepsy, and neurodegenerative diseases. The chapter concludes with technical considerations and challenges of clinical MRS.

Purpose: Structural and functional alterations in tumor vasculature are thought to contribute to tumor hypoxia which is a primary driver of malignancy through its negative impact on the efficacy of radiation, immune surveillance, apoptosis, genomic stability, and accelerated angiogenesis. We performed a prospective, multicenter study to test the hypothesis that abnormal tumor vasculature and hypoxia, as measured with MRI and PET, will negatively impact survival in patients with newly diagnosed glioblastoma. Experimental Design: Prior to the start of chemoradiation, patients with glioblastoma underwent MRI scans that included dynamic contrast enhanced and dynamic susceptibility contrast perfusion sequences to quantitate tumor cerebral blood volume/flow (CBV/CBF) and vascular permeability (ktrans) as well as 18F-Fluoromisonidazole (18F-FMISO) PET to quantitate tumor hypoxia. ROC analysis and Cox regression models were used to determine the association of imaging variables with progression-free and overall survival. Results: Fifty patients were enrolled of which 42 had evaluable imaging data. Higher pretreatment 18F-FMISO SUVpeak (P = 0.048), mean ktrans (P = 0.024), and median ktrans (P = 0.045) were significantly associated with shorter overall survival. Higher pretreatment median ktrans (P = 0.021), normalized RCBV (P = 0.0096), and nCBF (P = 0.038) were significantly associated with shorter progression-free survival. SUVpeak [AUC = 0.75; 95% confidence interval (CI), 0.59–0.91], nRCBV (AUC = 0.72; 95% CI, 0.56–0.89), and nCBF (AUC = 0.72; 95% CI, 0.56–0.89) were predictive of survival at 1 year. Conclusions: Increased tumor perfusion, vascular volume, vascular permeability, and hypoxia are negative prognostic markers in newly diagnosed patients with gioblastoma, and these important physiologic markers can be measured safely and reliably using MRI and 18F-FMISO PET. Clin Cancer Res; 22(20); 5079–86. ©2016 AACR.

The objective was to determine if it is useful to routinely add magnetic resonance spectroscopy (MRS) to magnetic resonance imaging (MRI) in the evaluation of seizure in the pediatric patient. Specifically, how often does MRS contribute information to conventional MRI?A retrospective search, over a period of 3 years, of patients18 years of age who underwent both MRI and MRS as part of the evaluation of seizures yielded a total of 233 cases in 216 patients. The medical records were reviewed to determine how many patients carried a diagnosis relevant to seizures. The MRIs and MRSs were reviewed by two neuroradiologists and an MR physicist/spectroscopist who determined by consensus in how many cases MRS contributed information regarding management, diagnosis, or prognosis, in addition to the findings on MRI alone.In 100 of 233 cases (43%), MRS contributed information additional to MRI. In 40 cases, MRS contributed information relevant to patient management by prompting an evaluation for an underlying inborn error of metabolism. MRS contributed information relevant to diagnosis in 24 of 100 cases (e.g., neoplasm versus dysplasia). MRS contributed information relevant to prognosis in 36 cases (e.g., hypoxic-ischemic injury). MRS added more information in cases where the patients had a diagnosis relevant to seizure before imaging. Interestingly, in 25 cases where the MRI was normal, MRS was found to be abnormal, which prompted evaluation for an inborn error of metabolism.These results suggest that MRS is a useful evaluation tool in addition to MRI for children undergoing imaging for the evaluation of seizures.

The main objective of this study was to utilize high field (7T) in vivo proton magnetic resonance imaging to increase the ability to detect metabolite changes in people with ALS, specifically, to quantify levels of glutamine and glutamine separately. The second objective of this study was to correlate metabolic markers with clinical outcomes of disease progression. 13 ALS participants and 12 age-matched healthy controls (HC) underwent 7 Tesla MRI and MRS. Single voxel MR spectra were acquired from the left precentral gyrus using a very short echo time (TE = 5 ms) STEAM sequence. MRS data was quantified using LCModel and correlated to clinical outcome markers. N-acetylaspartate (NAA) and total NAA (tNA, NAA + NAAG) were decreased by 17% in people with ALS compared to HC (P = 0.004 and P = 0.005, respectively) indicating neuronal injury and/or loss in the precentral gyrus. tNA correlated with disease progression as measured by forced vital capacity (FVC) (P = 0.014; Rρ = 0.66) and tNA/tCr correlated with overall functional decline as measured by worsening of the ALS Functional Rating Scale-Revised (ALSFRS-R) (P = 0.004; Rρ = -0.74). These findings underscore the importance of NAA as a reliable biomarker for neuronal injury and disease progression in ALS. Glutamate (Glu) was 15% decreased in people with ALS compared to HC (P = 0.02) while glutamine (Gln) concentrations were similar between the two groups. Furthermore, the decrease in Glu correlated with the decrease in FVC (P = 0.013; Rρ = 0.66), a clinical marker of disease progression. The decrease in Glu is most likely driven by intracellular Glu loss due to neuronal loss and degeneration. Neither choline containing components (Cho), a marker for cell membrane turnover, nor myo-Inositol (mI), a suspected marker for neuroinflammation, showed significant differences between the two groups. However, mI/tNA was correlated with upper motor neuron burden (P = 0.004, Rρ = 0.74), which may reflect a relative increase of activated microglia around motor neurons. In summary, 7T 1H MRS is a powerful non-invasive imaging technique to study molecular changes related to neuronal injury and/or loss in people with ALS.

Introduction: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder affecting lower and upper motor neurons. Degeneration of the lateral corticospinal tract (CST) is a key finding in ALS cervical spinal cord autopsies. We hypothesized that in vivo ultra-high-field MRI of the cervical spinal cord can detect abnormality in the CST. Methods: A patient with ALS (disease duration 23 months) and a healthy control were scanned at 7-T MRI using a 19-channel coil. Multi-echo T2*-weighted imaging was performed in the spinal cord, covering C2–C6. Cross-sectional resolution was 0.37 × 0.37 mm2. Results: We detected clear signal hyperintensity in both segments of the lateral CST in the ALS patient, which was significant when compared with the normal control subject (P < 10−7). Conclusion: We believe there are potential benefits of 7-T MRI for increased sensitivity and spatial accuracy in characterizing pathology in the spinal cord. Muscle Nerve 47: 760–762, 2013

Leukodystrophies are hereditary disorders of white matter that impair brain that is initially normally formed and developed (1, 2). They can affect brain myelin throughout life. The disorders are commonly progressive in nature and ultimately fatal. First manifestations are often cognitive deterioration and neuropsychological problems. Motor and balance difficulties occur, as do visual abnormalities. Classic leukodystrophies lead to a vegetative state or death within months to years. In general, the earlier the onset of symptoms, the more progressive the disease course. Most leukodystrophies are monogenetic disorders. The mutant gene often encodes an enzyme or protein that maintains neuronal and/or glial health and is responsible for regulation of brain metabolism. Many enzymes involved play a role in lipid metabolism. The inability to degrade or synthesize substrate leads to an upstream excess or downstream lack of vital lipids. This can cause a wide range of pathology, from inflammatory demyelination to axonal degeneration and microglial activation. Hence, the often cited prominent demyelination is only one manifestation in leukodystrophies, and myelinforming oligodendrocytes are not the only cells affected in these disorders. Yet, there are some common characteristics that distinguish the pathology in leukodystrophies from that of other disorders. MRI has played a seminal role in visualization of the lesion pattern. (3). The demyelinating lesions are usually confluent and symmetric. Many of the classic disorders, such as X-linked adrenoleukodystrophy (X-ALD), metachromatic leukodystrophy (MLD) and Krabbe, show relative sparing of subcortical fibers. Yet again, other disorders have early involvement of the U fibers and other unique characteristics, such as cystic rarefaction and degeneration. Hereditary disorders that do not show demyelination but rather hypomyelination have come to increasing attention (4). Common neurological features in hypomyelinating disorders are developmental delay, nystagmus, cerebellar ataxia and spasticity. One of the better characterized hypomyelinating disorders is Pelizaeus Merzbacher disease (PMD). Beyond this classic disorder, a multitude of other hypomyelinating disorders exist. Only about half of the patients with evidence of hypomyelination on MRI come to a definitive diagnosis. Yet, specific clinical and MRI features can be pathognomonic and lead to diagnosis.

Approved symptomatic therapies for Alzheimer's disease (AD) provide modest relief. In the future, it is likely that symptomatic treatments will be utilized with AD modifying therapies, the development of which are currently a primary focus of research. The nicotinic α7 receptor agonist may be an attractive drug candidate to potentially improve cognition in Alzheimer's disease patients either as a stand-alone therapy or in combination with other symptomatic treatments. EVP-6124 is a novel, potent, and selective α7 nicotinic receptor agonist. EVP-6124 has an excellent brain to plasma exposure ratio and has shown excellent efficacy and potency in a number of animal models of cognition. Four clinical studies in >125 healthy normal human subjects have been completed with EVP-6124, including a single-ascending-dose study, a 14-day multiple-ascending-dose study, a 21-day multiple-dose study, and a single-dose relative bioavailability, food, and gender effect study. EVP-6124 exhibited linear kinetics over the range of 1 to 180 mg and demonstrated a half-life suitable for once daily dosing. EVP-6124 appears to be safe and well tolerated for up to 21 days as measured by adverse events, vital signs, continuous cardiac monitoring, physical examination, and clinical laboratory evaluations. In addition, in normal volunteers, EVP-6124 demonstrated pro-cognitive effects (CogState testing) in various cognitive domains including executive function. These data suggest that EVP-6124 administered to AD subjects on stable cholinesterase inhibitor therapies may have potential benefit and that further study in this patient population is indicated. Larger phase II studies are currently being initiated in both Alzheimer's disease and schizophrenia.

To study an automatic repositioning method to reduce variability in longitudinal MRSI exams based on a priori image registration. Longitudinal proton MR spectroscopic imaging ((1)H MRSI) exams to study the effects of disease or treatment are becoming increasingly common. However, one source of variability in such exams arises from imperfect relocalization of the MRSI grid in the follow-up exams.Six healthy subjects were each scanned three times during the course of 1 day. In each follow-up exam a manually placed MRSI grid was acquired in addition to the automatically repositioned MRSI grid. Then coefficients of variance between baseline and follow-up scans were calculated for N-acetylaspartate, creatine, and choline. In addition, the overall MRSI grid overlap and individual voxel overlaps were also calculated for both the visually and automatically repositioned voxels.Streamlined workflow, reduced variability of metabolite concentration measurements, and increased voxel overlaps are noted when this automatic repositioning procedure is compared to the visual MRSI grid repositioning approach.Our results suggest that this approach is able to improve reproducibility in longitudinal MRS exams.