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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.

Brain lesions caused by Cryptococcus neoformans or C. gattii (cryptococcomas) are typically difficult to diagnose correctly and treat effectively, but rapid differential diagnosis and treatment initiation are crucial for good outcomes. In previous studies, cultured cryptococcal isolates and ex vivo lesion material contained high concentrations of the virulence factor and fungal metabolite trehalose. Here, we studied the in vivo metabolic profile of cryptococcomas in the brain using magnetic resonance spectroscopy (MRS) and assessed the relationship between trehalose concentration, fungal burden, and treatment response in order to validate its suitability as marker for early and noninvasive diagnosis and its potential to monitor treatment in vivo. We investigated the metabolites present in early and late stage cryptococcomas using in vivo 1H MRS in a murine model and evaluated changes in trehalose concentrations induced by disease progression and antifungal treatment. Animal data were compared to 1H and 13C MR spectra of Cryptococcus cultures and in vivo data from 2 patients with cryptococcomas in the brain. In vivo MRS allowed the noninvasive detection of high concentrations of trehalose in cryptococcomas and showed a comparable metabolic profile of cryptococcomas in the murine model and human cases. Trehalose concentrations correlated strongly with the fungal burden. Treatment studies in cultures and animal models showed that trehalose concentrations decrease following exposure to effective antifungal therapy. Although further cases need to be studied for clinical validation, this translational study indicates that the noninvasive MRS-based detection of trehalose is a promising marker for diagnosis and therapeutic follow-up of cryptococcomas.

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.

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.

Currently TAR DNA binding protein 43 (TDP-43) pathology, underlying Amyotrophic Lateral Sclerosis (ALS), remains poorly understood which hinders both clinical diagnosis and drug discovery efforts. To better comprehend the disease pathophysiology, positron emission tomography (PET) and multi-parametric magnetic resonance imaging (mp-MRI) provide a non-invasive mode to investigate molecular, structural, and neurochemical abnormalities in vivo. For the first time, we report the findings of a longitudinal PET-MR study in the TDP-43A315T ALS mouse model, investigating disease-related changes in the mouse brain. 2-deoxy-2-[18F]fluoro-D-glucose [18F]FDG PET showed significantly lowered glucose metabolism in the motor and somatosensory cortices of TDP-43A315T mice whereas metabolism was elevated in the region covering the bilateral substantia nigra, reticular and amygdaloid nucleus between 3 and 7 months of age, as compared to non-transgenic controls. MR spectroscopy data showed significant changes in glutamate + glutamine (Glx) and choline levels in the motor cortex and hindbrain of TDP-43A315T mice compared to controls. Cerebral blood flow (CBF) measurements, using an arterial spin labelling approach, showed no significant age- or group-dependent changes in brain perfusion. Diffusion MRI indices demonstrated transient changes in different motor areas of the brain in TDP-43A315T mice around 14 months of age. Cytoplasmic TDP-43 proteinaceous inclusions were observed in the brains of symptomatic, 18-month-old mice, but not in non-symptomatic transgenic or wild-type mice. Our results reveal that disease- and age-related functional and neurochemical alterations, together with limited structural changes, occur in specific brain regions of transgenic TDP-43A315T mice, as compared to their healthy counterparts. Altogether these findings shed new light on TDP-43A315T disease pathogenesis and may prove useful for clinical management of ALS. ispartof: Neuroimage-Clinical vol:27 ispartof: location:Netherlands status: published

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.

In a longitudinal rat model of alcohol consumption, we showed that exposure to alcohol decreased the concentration of glutamate in the prefrontal cortex, whereas a normalization occurred during abstinence. 18F-FPEB PET scans revealed that pre-exposure mGluR5 availability in the nucleus accumbens was associated with future alcohol preference. Finally, alcohol exposure induced a decrease in mGluR5 availability in the bilateral hippocampus and amygdala compared with baseline, and in the hippocampus and striatum compared with saccharin (Figure). ispartof: ADDICTION BIOLOGY vol:24 issue:4 pages:696-706 ispartof: location:United States status: published

Cocaine addiction is a disorder that still lacks diagnostic biomarkers or effective pharmacotherapy. We present findings in a rat model of cocaine self-administration that was followed-up longitudinally using the metabotropic glutamate receptor 5 (mGluR5) tracer 18F-FPEB positron emission tomography (PET), proton magnetic resonance spectroscopy (1H-MRS) and behavioral tests. Methods: Forty-two Wistar rats were scanned with 18F-FPEB PET and 1H-MRS before and after sucrose or IV cocaine self-administration, during withdrawal and relapse. All animals performed a rodent Iowa Gambling Task (rIGT) at baseline to evaluate decision-making. Baseline values were used in a mixed model to assess associations with later cocaine use and follow-up measurements were compared to the values before drug exposure. Results: Pre-exposure rIGT scores were significantly related to both cocaine and sucrose use during the drug-exposure phase. However, only cocaine self-administration induced a decrease in 18F-FPEB binding. This decrease was most pronounced in the bilateral hippocampus, where mGluR5 availability correlated with the amount of cocaine used during relapse. Compared to the sucrose group, a larger decrease was observed in the hippocampo-prefrontal cortex pathway. Pre-exposure glutamate and glycine concentrations in the prefrontal cortex were significantly associated with cocaine use during the drug-exposure phase. Moreover, prefrontal glutamate exhibited a distinct, reversible decrease when animals had access to cocaine, but not sucrose. Conclusion: Baseline values of prefrontal glutamate and glycine are associated with future cocaine use. Furthermore, baseline rIGT scores are associated with both sucrose and cocaine. Finally, we found that both glutamate concentration and mGluR5 availability decrease during exposure to cocaine. ispartof: Journal of Nuclear Medicine vol:59 issue:6 pages:952-959 ispartof: location:United States status: published

Converging preclinical evidence links extrastriatal dopamine release and glutamatergic transmission via the metabotropic glutamate receptor 5 (mGluR5) to the rewarding properties of alcohol. To date, human evidence is lacking on how and where in the brain these processes occur. Mesocorticolimbic dopamine release upon intravenous alcohol administration and mGluR5 availability were measured in 11 moderate social drinkers by single-session [18F]fallypride and [18F]FPEB positron emission tomography, respectively. Additionally, baseline and postalcohol glutamate and glutamine levels in the anterior cingulate cortex (ACC) were measured by using proton-magnetic resonance spectroscopy. To investigate differences in reward domains linked to both neurotransmitters, regional imaging data were related to subjective alcohol responses. Alcohol induced significant [18F]fallypride displacement in the prefrontal cortex (PFC), temporal and parietal cortices and thalamus (P

Recently, several promising treatments for high-grade gliomas (HGGs) failed to provide significant benefit when translated from the preclinical setting to patients. Improving the animal models is fundamental to overcoming this translational gap. To address this need, we developed and comprehensively characterized a new in vivo model based on the orthotopic implantation of CT-2A cells cultured in neurospheres (NS/CT-2A). Murine CT-2A methylcholanthrene-induced HGG cells (C57BL/6 background) were cultured in monolayers (ML) or NS and orthotopically inoculated in syngeneic animals. ML/CT-2A and NS/CT-2A tumors’ characterization included the analysis of tumor growth, immune microenvironment, glioma stem cells (GSCs), vascularization and metabolites. The immuno-modulating properties of NS/CT-2A and ML/CT-2A cells on splenocytes were tested in vitro. Mice harboring NS/CT-2A tumors had a shorter survival than those harboring ML/CT-2A tumors (P=0.0033). Compared to standard ML/CT-2A tumors, NS/CT-2A tumors showed more abundant GSCs (P=0.0002 and 0.0770 for Nestin and CD133, respectively) and regulatory T cells (Tregs, P=0.0074), and a strong tendency towards an increased vascularization (P=0.0503). There were no significant differences in metabolites’ composition between NS/ and ML/CT-2A tumors. In vitro, NS were able to drive splenocytes towards a more immunosuppressive status by reducing CD8+ T cells (P=0.0354) and by promoting Tregs (P=0.0082), macrophages (MF, P=0.0019) and their M2 subset (P=0.0536). Compared to standard ML/CT-2A tumors, NS/CT-2A tumors show a more aggressive phenotype with increased immunosuppression and GSCs proliferation. Because of these specific features, the NS/CT-2A model represents a clinically relevant platform in the search for new HGG treatments aimed at reducing immunosuppression and eliminating GSCs., SCOPUS: ar.j, info:eu-repo/semantics/published

Previous MRI and proton spectroscopy (1H-MRS) studies have revealed impaired neuronal integrity and altered neurometabolite concentrations in the motor cortex of patients with amyotrophic lateral sclerosis (ALS). Here, we aim to use MRI with conventional and novel MRS sequences to further investigate neurometabolic changes in the motor cortex of ALS patients and their relation to clinical parameters. We utilized the novel HERMES (Hadamard Encoding and Reconstruction of MEGA-Edited Spectroscopy) MRS sequence to simultaneously quantify the inhibitory neurotransmitter GABA and antioxidant glutathione in ALS patients (n = 7) and healthy controls (n = 7). In addition, we have also quantified other MRS observable neurometabolites using a conventional point-resolved MR spectroscopy (PRESS) sequence in ALS patients (n = 20) and healthy controls (n = 20). We observed a trend towards decreasing glutathione concentrations in the motor cortex of ALS patients (p = 0.0842). In addition, we detected a 11% decrease in N-acetylaspartate (NAA) (p = 0.025), a 15% increase in glutamate + glutamine (Glx) (p = 0.0084) and a 21% increase in myo-inositol (mIns) (p = 0.0051) concentrations for ALS patients compared to healthy controls. Furthermore, significant positive correlations were found between GABA-NAA (p = 0.0480; Rρ = 0.7875) and NAA-mIns (p = 0.0448; Rρ = −0.4651) levels among the patients. NAA levels in the bulbar-onset patient group were found to be significantly (p = 0.0097) lower compared to the limb-onset group. A strong correlation (p

Heritable temperament traits have been linked to several neuropsychiatric illnesses, including disorders associated with metabotropic glutamate receptor 5 (mGluR5) and dopaminergic dysfunctions. Considering its modulating effect on neurotransmission, we hypothesized that cerebral mGluR5 availability is associated with temperament traits in healthy humans. Methods: Forty-four nonsmoking healthy volunteers (mean age +/- SD, 40 +/- 14 y; age range, 22-66 y; 22 women) were included in this cross-sectional investigation. Brain mGluR5 availability was quantified on both a voxel-by-voxel and a volume-of-interest basis using the total distribution volume of the radioligand F-18-3-fluoro-5-[(pyridin-3-yl)ethynyl]benzonitrile (F-18-FPEB) with 90-min dynamic PET and arterial input function. Moreover, glutamate-glutamine concentrations in the anterior cingulate cortex were measured using MR spectroscopy. These measures were related to the temperament traits of the 240-item Cloninger temperament and character inventory using a regression analysis with age and sex as nuisance variables. Results: High novelty-seeking temperament was robustly associated with increased mGluR5 availability in various regions including the thalamus (r = 0.71; the strongest association), amygdala, parahippocampus, insula, anterior and posterior cingulate cortex, and several primary sensory areas (all r > 0.58; P < 0.05, corrected for familywise error). These associations were specific because no correlations were found with other temperament scales or with spectroscopic measures of glutamatergic transmission. Conclusion: Overall, these data posit mGluR5 in key paralimbic areas as a strong determinant of the temperament trait novelty seeking. These data add to our understanding of how brain neurochemistry accounts for the variation in human behavior and strongly support further research on mGluR5 as a potential therapeutic target in neuropsychiatric disorders associated with abnormal novelty-seeking behaviors.

Aging is associated with gradual alterations in the neurochemical characteristics of the brain, which can be assessed in-vivo with proton-magnetic resonance spectroscopy (1H-MRS). However, the impact of these age-related neurochemical changes on functional motor behavior is still poorly understood. Here, we address this knowledge gap and specifically focus on the neurochemical integrity of the left sensorimotor cortex (SM1) and the occipital lobe (OCC), as both regions are main nodes of the visuomotor network underlying bimanual control. 1H-MRS data and performance on a set of bimanual tasks were collected from a lifespan (20–75 years) sample of 86 healthy adults. Results indicated that aging was accompanied by decreased levels of N-acetylaspartate (NAA), glutamate-glutamine (Glx), creatine ​+ ​phosphocreatine (Cr) and myo-inositol (mI) in both regions, and decreased Choline (Cho) in the OCC region. Lower NAA and Glx levels in the SM1 and lower NAA levels in the OCC were related to poorer performance on a visuomotor bimanual coordination task, suggesting that NAA could serve as a potential biomarker for the integrity of the motor system supporting bimanual control. In addition, lower NAA, Glx, and mI levels in the SM1 were found to be correlates of poorer dexterous performance on a bimanual dexterity task. These findings highlight the role for 1H-MRS to study neurochemical correlates of motor performance across the adult lifespan. This work was supported by the KU Leuven Special Research Fund (grant C16/15/070), the Research Foundation – Flanders (FWO; G.089818N), the Excellence of Science grant (EOS, 30446199, MEMODYN), and the Francqui Foundation awarded to SPS and coworkers. AW and UH acknowledge financial support by the EC-FP7 MC ITN ’TRANSACT’ 2012 (No. 316679) and the KU Leuven program financing ‘IMIR’ (PF10/017). BRK acknowledges financial support by European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement (No. 703490) and a postdoctoral fellowship from the Research Foundation-Flanders (FWO; No 132635). The authors wish to thank Joren Bosman and Jeroen Buvé for assistance with data processing.

Several lines of evidence point to alterations in glutamatergic signaling in Parkinson's disease (PD) and levodopa-induced dyskinesia (LID), involving the metabotropic glutamate receptor type 5 (mGluR5). Using small-animal positron emission tomography (PET) with [18F]FPEB and proton magnetic resonance spectroscopy, we investigated cerebral changes in the mGluR5 and glutamate/glutamine availability invivo in PD rats and following onset of LIDs. In parallel, behavioral tests were performed. Comparing PD to control rats, mGluR5 binding potential was decreased in a cluster comprising the bilateral caudate-putamen (CP), ipsilateral motor cortex and somatosensory cortex, and the contralateral somatosensory cortex and parietal association cortex, with the most pronounced reduction in the ipsilateral CP. mGluR5 binding potentials were not significantly altered upon levodopa (L-DOPA) treatment. However, following L-DOPA, an increase in relative mGluR5 uptake was present in the contralateral motor cortex and somatosensory cortex. Glutamate and glutamine concentrations did not differ between control and untreated PD rats or between hemispheres. Though, glutamine levels were higher in the contralateral CP of saline- and L-DOPA-treated rats as compared to the ipsilateral side. Relative mGluR5 uptake in the CP of levodopa-treated rats was also found positively correlated with abnormal involuntary movement scores. Conclusively, mGluR5 availability and glutamine concentrations in the CP are involved in PD, whereas mGluR5 availability in cortical regions may be involved in LID pathology.