Changes In Cerebral Metabolites Research Articles

Proton magnetic resonance spectroscopy detects cerebral metabolic derangement in a mouse model of brain coenzyme a deficiency

BackgroundPantothenate kinase (PANK) is the first and rate-controlling enzymatic step in the only pathway for cellular coenzyme A (CoA) biosynthesis. PANK-associated neurodegeneration (PKAN), formerly known as Hallervorden–Spatz disease, is a rare, life-threatening neurologic disorder that affects the CNS and arises from mutations in the human PANK2 gene. Pantazines, a class of small molecules containing the pantazine moiety, yield promising therapeutic effects in an animal model of brain CoA deficiency. A reliable technique to identify the neurometabolic effects of PANK dysfunction and to monitor therapeutic responses is needed.MethodsWe applied 1H magnetic resonance spectroscopy as a noninvasive technique to evaluate the therapeutic effects of the newly developed Pantazine BBP-671.Results1H MRS reliably quantified changes in cerebral metabolites, including glutamate/glutamine, lactate, and N-acetyl aspartate in a neuronal Pank1 and Pank2 double-knockout (SynCre+Pank1,2 dKO) mouse model of brain CoA deficiency. The neuronal SynCre+Pank1,2 dKO mice had distinct decreases in Glx/tCr, NAA/tCr, and lactate/tCr ratios compared to the wildtype matched control mice that increased in response to BBP-671 treatment.ConclusionsBBP-671 treatment completely restored glutamate/glutamine levels in the brains of the mouse model, suggesting that these metabolites are promising clinically translatable biomarkers for future therapeutic trials.

Self-Regulation of Cerebral Metabolism and Its Neuroprotective Effect After Hypoxic-Ischemic Injury: Evidence From 1H-MRS.

1H-MRS technology can be used to non-invasively detect the content of cerebral metabolites, to assess the severity of hypoxic-ischemic (HI) injury, and to predict the recovery of compromised neurological function. However, changes to the cerebral self-regulation process after HI are still unclear. This study investigated the changes in cerebral metabolites and the potential relationship with the number of neurons and neural stem/progenitor cells (NSPC) using 1H-MRS, and finally clarifies the self-regulation of cerebral metabolism and neuroprotection after HI injury. Newborn Yorkshire pigs (28 males, 1.0–1.5 kg) aged 3–5 days were used for the HI model in this study. The pigs were randomly divided into the HI group (n = 24) and the control group (n = 4), then the experimental group was subdivided according to different recovery time after HI into the following groups: 0–2 h (n = 4), 2–6 h (n = 4), 6–12 h (n = 4), 12–24 h (n = 4), 24–48 h (n = 4), and 48–72 h (n = 4). Following the HI timepoints, 1H-MRS scans were performed and processed using LCModel software, and brain tissue was immunohistochemically stained for Nestin and NeuN. Immunofluorescence staining of creatine phosphokinase-BB (CK-BB), N-acetylaspartylglutamate synthetase (NAAGS), glutamate carboxypeptidase II (GCP-II), glutamate-cysteine ligase catalytic subunit (GCLC), glutathione synthase (GS), and excitatory amino acid carrier 1 (EAAC1) was then performed. The 1H-MRS results showed that cerebral N-acetylaspartylglutamate (NAAG), glutathione (GSH), and creatine (Cr) content reached their peaks at 12–24 h, which was consistent with the recovery time of hippocampal NSPCs and neurons, indicating a potential neuroprotective effect of NAAG, GSH, and Cr after HI injury.

BIMG-23. SINGLE-VOXEL VERSUS MULTI-SLICE MRSI IN PATIENTS WITH GLIOMA ON A KETOGENIC DIET INTERVENTION

BACKGROUNDKetogenic diet therapies (KDTs) may be beneficial by exploiting glioma metabolic vulnerabilities. The GLioma modified Atkins-based Diet study (GLAD; NCT02286167) evaluated systemic and cerebral (MR spectroscopy) biomarkers to determine the feasibility and biological effects of a KDT in glioma patients. While we observed metabolic changes in tumor and normal brain after KDT using single-voxel MRS (SV-MRS), optimal voxel placement was not always achieved. AIMS: We performed an exploratory analysis comparing cerebral metabolite changes using multi-slice MRSI (MS-MRSI) versus SV-MRS acquisition.METHODSWe evaluated four patients from the GLAD study (mean age 39years; 2 female, 3 AA IDH-mutant, 1 GBM IDH-wildtype) who underwent MRS at baseline and following eight weeks of KDT. SV-MRS (sLASER, TR/TE 2.2s/34ms) was acquired from a 2x2x2cm voxel placed in the residual tumor and the contralateral homologous brain. MS-MRSI was acquired with a multi-slice spin echo sequence (TR/TE 3.6/144ms, 4 slices, nominal resolution 13x7x7mm, SENSE factor 3) and maps of total choline (tCho), total N-acetyl-aspartate (tNAA), and lactate (Lac) were reconstructed and normalized relative to creatine. Metabolite levels were measured on the MS-MRSI maps using a region of interest placed in the same areas studied with the SV-MRS.RESULTSLesional tCho and tNAA levels showed strong correlation between SV-MRS and MS-MRSI both at baseline (Pearson’s r=0.92 and 0.97, respectively) and after 8 weeks of KDT (r=0.96 and 0.84, respectively). tCho and tNAA correlated less robustly between SV-MRS and MS-MRSI in the contralesional region (r=0.56–0.96). Lesional Lac was significantly lower after KDT (1.01±0.48 versus 0.59±0.24, paired t-test p=0.02).CONCLUSIONSWhile SV and MS-MRSI provided generally concordant lesional results, MS-MRSI offers added potential to map regional variations not captured by SV-MRS and thus may better define the control regions. MS-MRSI detected a decrease in tumoral lactate levels following study intervention, suggesting KDT-related changes in tumoral energy metabolism.

The Effect of Tryptophan 2,3-Dioxygenase Inhibition on Kynurenine Metabolism and Cognitive Function in the APP23 Mouse Model of Alzheimer's Disease.

Alzheimer’s disease (AD) is associated with progressive endogenous neurotoxicity and hampered inflammatory regulation. The kynurenine (Kyn) pathway, which is controlled by tryptophan 2,3-dioxygenase (TDO), produces neuroactive and anti-inflammatory metabolites. Age-related Kyn pathway activation might contribute to AD pathology in humans, and inhibition of TDO was found to reduce AD-related cellular toxicity and behavioral deficits in animal models. To further explore the effect of aging on the Kyn pathway in the context of AD, we analyzed Kyn metabolite profiles in serum and brain tissue of the APP23 amyloidosis mouse model. We found that aging had genotype-independent effects on Kyn metabolite profiles in serum, cortex, hippocampus and cerebellum, whereas serum concentrations of many Kyn metabolites were reduced in APP23 mice. Next, to further establish the role of TDO in AD-related behavioral deficits, we investigated the effect of long-term pharmacological TDO inhibition on cognitive performance in APP23 mice. Our results indicated that TDO inhibition reversed recognition memory deficits without producing measurable changes in cerebral Kyn metabolites. TDO inhibition did not affect spatial learning and memory or anxiety-related behavior. These data indicate that age-related Kyn pathway activation is not specific for humans and could represent a cross-species phenotype of aging. These data warrant further investigation on the role of peripheral Kyn pathway disturbances and cerebral TDO activity in AD pathophysiology.

Combined diffusion tensor imaging and magnetic resonance spectroscopy to predict neurological outcome before transjugular intrahepatic portosystemic shunt.

Hepatic encephalopathy (HE) may occur after transjugular intrahepatic portosystemic shunt (TIPSS) placement. Multimodal magnetic resonance imaging (MRI), combining anatomical sequences, diffusion tensor imaging (DTI) and 1 H magnetic resonance spectroscopy, is modified in cirrhotic patients. To describe multimodal MRI images before TIPSS, to assess if TIPSS induces changes in multimodal MRI, and to find predictors of HE after TIPSS in patients with cirrhosis. Consecutive cirrhotic patients with an indication for TIPSS were prospectively screened. Diagnosis of minimal HE was performed using psychometric HE test score. Multimodal MRI was performed before and 3months after TIPSS placement. Twenty-five consecutive patients were analysed (median age=59, male gender 76%, median Child-Pugh score=8 [5-8], MELD score=12 [9-17], indication for TIPSS placement: ascites/secondary prophylaxis of variceal bleeding/other 20/3/2), no HE/minimal HE/overt HE: 21/4/0. 8/25 patients developed HE after TIPSS. Before TIPSS placement, metabolite concentrations were different in patients with or without minimal HE (lower myo-inositol, mI, higher glutamate/glutamine), but there were no differences in DTI data. TIPSS placement induced changes in metabolite concentrations even in asymptomatic patients, but not in DTI metrics. Baseline fractional anisotropy was significantly lower in patients who developed HE after TIPSS in five regions of interest. TIPSS placement induced significant changes in cerebral metabolites, even in asymptomatic patients. Patients who developed HE after TIPSS displayed lower fractional anisotropy before TIPSS. Brain MRI with DTI acquisition may help selecting patients at risk of HE.

Changes in cerebral metabolites in obstructive sleep apnea: a systemic review and meta-analysis.

Cognitive impairment is associated with changes in cerebral metabolites in patients with obstructive sleep apnea (OSA). Several studies have used magnetic resonance spectroscopy (MRS) to detect variations in cerebral metabolites; however, the results have been inconsistent. This meta-analysis summarizes the differences in cerebral metabolites between patients with OSA and controls. Two electronic databases, PubMed and Embase, were searched for articles (published before March 31, 2016) describing studies that used MRS to evaluate the cerebral metabolite changes. The overall effects were measured using the weighted mean difference with a 95% confidence interval. Subgroup analysis and sensitivity analysis were used to explore the sources of between-study heterogeneity and the stability of the results. Publication bias was also evaluated. Thirteen studies were ultimately included. In the hippocampus, the N-acetylaspartate (NAA)/creatine ratio was lower in patients with OSA. In the frontal lobe, only the NAA/choline ratio was lower in patients with OSA. Cerebral metabolites are significantly altered in the hippocampus in patients with OSA. Further clinical studies are needed to explore the underlying mechanisms between OSA and the changes in cerebral metabolites in the brain.

Magnetic Resonance Spectroscopy in Alzheimer's Disease: Systematic Review and Meta-Analysis.

The application of non-invasive proton magnetic resonance spectroscopy (1H-MRS) could potentially identify changes in cerebral metabolites in the patients with Alzheimer's disease (AD). However, whether these metabolites can serve as biomarkers for the diagnosis of AD remains unclear. Using meta-analysis, we aimed to investigate the patterns of cerebral metabolite changes in several cerebral regions that are strongly associated with cognitive decline in AD patients. Using Hedges' g effect size, a systematic search was performed in PubMed, Cochrane Library, Ovid, Embase, and EBSCO, and 38 studies were integrated into the final meta-analysis. According to the observational studies, N-acetyl aspartate (NAA) in AD patients was significantly reduced in the posterior cingulate (PC) (effect size (ES) =-0.924, p < 0.005) and bilateral hippocampus (left hippocampus: ES =-1.329, p < 0.005; right hippocampus: ES =-1.287, p < 0.005). NAA/Cr (creatine) ratio decreased markedly in the PC (ES =-1.052, p < 0.005). Simultaneously, significant elevated myo-inositol (mI)/Cr ratio was found not only in the PC but also in the parietal gray matter. For lack of sufficient data, we failed to elucidate the efficacy of pharmacological interventions with the metabolites changes. The available data indicates that NAA, mI, and the NAA/Cr ratio might be potential biomarkers of brain dysfunction in AD subjects. Choline (Cho)/Cr and mI/NAA changes might also contribute toward the diagnostic process. Thus, large, well-designed studies correlated with cerebral metabolism are needed to better estimate the cerebral extent of alterations in brain metabolite levels in AD patients.

Patients with type 2 diabetes exhibit cognitive impairment with changes of metabolite concentration in the left hippocampus.

Type 2 diabetes mellitus (T2DM) is associated with cognitive dysfunction. Previous studies have reported the relationship between cerebral metabolite changes and glucose levels. However, the specific aspects of cognition that are affected by metabolic changes in T2DM- related cognitive impairment remain undetermined. In this study, 188 T2DM patients and 266 controls were recruited. Proton magnetic resonance spectra with a single voxel stimulated echo acquisition mode (STEAM) were acquired from the left hippocampus and the frontal lobe. Presence of T2DM negatively affected the scores of Mini-Mental State Examination (MMSE), sub-tests (i.e., attention and language) of MMSE, Montreal Cognitive Assessment (MoCA) according to the Beijing version, and sub-tests (i.e., visuospatial/executive reasoning, attention, and language) of MoCA, rather than the Wechsler Memory Scale – Revised in China (WMS-RC), and all memory sub-tests contained with the MMSE and MoCA frameworks. T2DM positively affected creatine and myoinositol peak areas from the left hippocampus, rather than metabolites in the left frontal lobe. Negative correlations were shown between the left hippocampal myoinositol levels and language scores, and between the left hippocampal creatine levels and visuospatial/executive scores in T2DM. These findings suggest that T2DM may be an independent risk factor for cognitive impairment. Further, the cognitive domains of visuospatial /executive reasoning, attention and language may be predominantly impaired in the early phases of T2DM-related cognitive impairment. In addition, left hippocampal myoinositol and creatine concentrations were associated with cognitive impairment in patients with T2DM.

Functional Neuroimaging Changes Subsequent to Electroconvulsive Therapy in Unipolar Depression

Electroconvulsive therapy (ECT) is an effective treatment for major depressive episodes; however, the neural mechanisms underlying its therapeutic effects remain largely unknown. This review summarizes the findings of functional neuroimaging studies on the effects of the ECT treatment in patients with unipolar depression. Functional neuroimaging studies show that ECT induces changes in cerebral metabolism, blood flow, neurotransmitter activity, neuronal metabolites, and brain functional connectivity. Nevertheless, most of these studies are cross-sectional, with small sample sizes, and the findings across these studies are inconsistent and often contradictory. The levels of brain functional changes are seldom correlated with alleviation of depressive symptoms. Based on the results of current functional neuroimaging studies, one cannot draw any conclusions about the exact neural mechanisms of the antidepressant effect of ECT. Additional multicenter, large-sample, unified-protocol studies with long-term follow-up and multiple observational markers are needed to clarify and cross-validate the neural mechanisms of the antidepressant effect of ECT and to explore validated neuroimaging markers for predicting and evaluating the clinical efficacy of ECT treatment.

Longitudinal cerebral metabolic changes in pig-tailed macaques infected with the neurovirulent virus SIVsmmFGb.

Longitudinal cerebral metabolite changes in pig-tailed macaques inoculated with the simian immunodeficiency virus SIVsmmFGb were evaluated with in vivo proton MRS at 3 T. Blood sample collection, and MRS were carried out before and 2, 4, 8, 12, 16, 20, and 24 weeks after SIV inoculation. Significant reduction of N-acetylaspartate (NAA)/creatine (Cr) and choline (Cho)/Cr ratios in prefrontal gray matter (PGM) and glutamate/glutamine(Glx)/Cr ratio in striatum, and increase of myo-inositol (mI)/Cr in striatum were observed during acute SIV infection. The metabolite alterations during the SIVsmmFGb infection are largely in agreement with previous findings in other non-human primate models and HIV patients. Also, NAA/Cr in PGM and striatum and Glx/Cr in striatum are negatively correlated with the percentage of CD8+ T cells after the SIV infection, suggesting the interaction between brain metabolite and immune dysfunction. The present study complements previous studies by describing the time course of alterations of brain metabolites during SIVsmmFGb infection. The findings further demonstrate the efficacy of the SIVsmmFGb-infected macaque as a model to characterize central nervous system infection using novel neuroimaging approaches and also as a tool for exploration of novel and advanced neuroimaging techniques in HIV/AIDS studies.

Cerebral metabolite changes prior to and after antiretroviral therapy in primary HIV infection.

We examined the longitudinal effects of primary HIV infection (PHI) and responses to early antiretroviral therapy (ART) on the brain using high-field magnetic resonance spectroscopy (MRS). Cerebral metabolites were measured longitudinally with 4T proton MRS and assessed for ART effects in participants with PHI. Levels of glutamate (Glu), N-acetylaspartate (NAA), myo-inositol (MI), and choline-containing metabolites (Cho) were measured relative to creatine + phosphocreatine (Cr) in anterior cingulate, basal ganglia, frontal white matter, and parietal gray matter. Fifty-three participants recruited at median 3.7 months post HIV transmission were followed a median 6.0 months. A total of 23 participants initiated ART during follow-up. Prior to ART, increases per month were observed in Cho/Cr (slope = 0.0012, p = 0.005) and MI/Cr (slope = 0.0041, p = 0.005) in frontal white matter as well as increases in MI/Cr (slope = 0.0041, p < 0.001) and NAA/Cr (slope = 0.0024, p = 0.030) in parietal gray matter. After initiation of ART, prior positive slopes were no longer significantly different from zero, while Glu/Cr in basal ganglia decreased (slope = -0.0038, p = 0.031). Early in HIV infection, increases of Cho/Cr and MI/Cr in treatment-naive participants suggest progressive inflammation and gliosis in the frontal white matter and parietal gray matter, which is attenuated after initiation of ART. Elevated baseline Glu/Cr in basal ganglia may signal excitotoxicity; its subsequent stabilization and downward trajectory with ART may lend further support for early ART initiation.

Dose-dependent influence of short-term intermittent ethanol intoxication on cerebral neurochemical changes in rats detected by ex vivo proton nuclear magnetic resonance spectroscopy

The aim of this study was to quantitatively assess the effects of short-term intermittent ethanol intoxication on cerebral metabolite changes among sham controls (CNTL), low-dose ethanol (LDE)-exposed, and high-dose ethanol (HDE)-exposed rats, which were determined with ex vivo high-resolution spectra. Eight-week-old male Wistar rats were divided into three groups. Twenty rats in the LDE (n=10) and the HDE (n=10) groups received ethanol doses of 1.5 and 2.5g/kg, respectively, through oral gavage every 8h for 4days. At the end of the 4-day intermittent ethanol exposure, one-dimensional ex vivo 500-MHz 1H nuclear magnetic resonance spectra were acquired from 30 samples of the frontal cortex region (from the three groups). Normalized total N-acetylaspartate (tNAA: NAA+NAAG [N-acetylaspartyl-glutamate]), GABA, and glutathione (GSH) levels were significantly lower in the frontal cortex of the HDE-exposed rats than that of the LDE-exposed rats. Moreover, compared to the CNTL group, the LDE rats exhibited significantly higher normalized GABA levels. The six pairs of normalized metabolite levels were positively (+) or negatively (−) correlated in the rat frontal cortex as follows: tNAA and GABA (+), tNAA and aspartate (Asp) (+), myo-Inositol (mIns) and Asp (−), mIns and alanine (+), mIns and taurine (+), and mIns and tNAA (−). Our results suggested that short-term intermittent ethanol intoxication might result in neuronal degeneration and dysfunction, changes in the rate of GABA synthesis, and oxidative stress in the rat frontal cortex. Our ex vivo 1H high-resolution magic angle spinning nuclear magnetic resonance spectroscopy results suggested some novel metabolic markers for the dose-dependent influence of short-term intermittent ethanol intoxication in the frontal cortex.

SU-E-I-63: In Vivo Proton MR Spectroscopy Quantification of Cerebral Neurochemical Changes in Acute Binge Ethanol Exposed Rats

Purpose: The cerebral metabolite changes in vivo were quantitatively assessed in binge ethanol ‐ intoxicated rats by using a 4.7‐T proton magnetic resonance spectroscopy (1H‐MRS). Methods: Thirteen 8‐week‐old, male Sprague‐Dawley rats were used and divided into 2 groups (control group: n=6; binge ‐ ethanol group: n=7). 7 binge ethanol group rats received an initial dose of 5 g/kg (30% w/v solution) via oral gavage method, followed by a maximum dose of 2 g/kg (25% w/v solution) every 8‐h (at 1400, 2200, and 0600) for 4 days. The 6 control group rats simultaneously received equal volumes (about 3.55ml) of normal saline (at 1500, 2300, and 0700). Oral gavage ethanol was administered based on body weight. After 4‐days of oral gavage, in vivo scanning was performed on all animals by using a 4.7‐T Bruker BIOSPEC. The volume of interest (VOI, 6×2×3 mm3; volume: 36 μL; Thirteen water suppressed 1H‐MRS spectra were acquired using PRESS sequences (TR/TE = 4000/20 ms; number of acquisitions = 384; number of data points = 2048). Results: Figure 1 shows the representative fitted spectra from hippocampus of binge ethanol and control group rats. Our results showed that total choline (tCho; phosphocholine+glycerophosphocholine [GPC+PCh]) concentrations were significantly lower (p=0.038) in the binge ethanol group than that in the control group (Fig.2). Moreover, tCho/total N‐acetylaspartate (tNAA: NAA+N‐acetylaspartylglutamate [NAAG]) ratios were significantly lower (p=0.043) in the binge‐ethanol group than that in the control group (Fig.3). However, Glutamine/Glutamate ratios showed no significant differences between the 2 groups. Conclusion: According to our findings and from results in previous studies, significantly low tCho concentrations and tCho/tNAA ratios may indicate the cell membrane turnover abnormalities of phosphatidylcholine and changed adaptive mechanism in the hippocampus of binge ethanol intoxicated rats. Thus, we provide quantitative in vivo evidence that binge‐ethanol exposure causes cerebral neurochemical profile changes in rats, in the hippocampal region.

NMR-based metabonomic in hippocampus, nucleus accumbens and prefrontal cortex of methamphetamine-sensitized rats

1H NMR spectroscopy was applied to investigate the changes of cerebral metabolites in brain hippocampus, nucleus accumbens (NAC) and prefrontal cortex (PFC) of the rats subjected to subcutaneous twice-daily injections of 2.5mg/kg methamphetamine (MAP) for 7 days. The results indicated that MAP exposure induced significant behavioral sensitization and altered cerebral metabolites in rats. The neurotransmitters glutamate, glutamine and GABA significantly decreased in hippocampus, NAC and PFC. Specifically, increased succinic acid semialdehyde, a metabolism product of GABA, was observed in hippocampus. Additionally, decreased serotonin was observed in both NAC and PFC, whereas decreased dopamine was only observed in NAC after repeated MAP treatment. Glutathione obviously decreased in above brain regions, whereas acetylcysteine declined in hippocampus and NAC, and taurine declined in NAC and PFC. Homocysteic acid was elevated in hippocampus and NAC by repeated MAP administration. Membrane ingredients like phosphocholine elevated in response to MAP administration in NAC and PFC. N-Acetyl-aspartate, a marker of neuronal viability, decreased in the three regions; however, myo-inositol, a glial cell marker, increased in hippocampus and PFC. Tricarboxylic acid cycle intermediate products, such as α-ketoglutarate, succinate, citrate and the methionine significantly decreased in above three brain regions after MAP administration; however, ADP decreased in hippocampus. These results indicate that repeated MAP treatment causes neurotransmitters disturbance, imbalance between oxidative stress and antioxidants, and gliosis in hippocampus, NAC and PFC. Profound metabolic changes detected across brain regions provide the first evidence of metabonomic changes in MAP-induced sensitized rats.

Postoperative Changes in Cerebral Metabolites Associated with Cognitive Improvement and Impairment after Carotid Endarterectomy: A 3T Proton MR Spectroscopy Study

Cognitive function can improve or decline after carotid endarterectomy. Proton MR spectroscopy can be used evaluate cerebral metabolites, such as N-acetylaspartate, choline, and creatine, in vivo. The purpose of the present study was to determine whether postoperative changes in cerebral metabolites measured by using 3T proton MR spectroscopy were associated with changes in cognitive function after CEA. In 100 patients undergoing CEA for ipsilateral cervical internal carotid artery stenosis (≥70%), brain proton MR spectroscopy was performed before and after surgery. NAA/Cr and Cho/Cr ratios were measured in regions of interest placed in the centrum semiovale of both cerebral hemispheres. Neuropsychological testing was also performed preoperatively and 1 month postoperatively. Multivariate statistical analysis of factors related to postoperatively changed cognition was performed, and odds ratios with 95% confidence intervals were calculated. On the basis of the neuropsychological assessments, 10 (10%), 80 (80%), and 10 (10%) patients were defined as having postoperatively improved, unchanged, and impaired cognition, respectively. A positive and high ΔNAA/Cr ratio (postoperative value-preoperative value) in the cerebral hemisphere ipsilateral to the operative site was significantly associated with postoperatively improved cognition (95% CI, 13.3-21.3; P = .0016). Negative and high absolute values of the ΔNAA/Cr ratio (95% CI, 0.018-0.101; P = .0039) and ΔCho/Cr ratio (95% CI, 0.042-0.135; P = .0046) in the ipsilateral cerebral hemisphere were significantly associated with postoperatively impaired cognition. Postoperative changes in cerebral metabolites measured by using proton MR spectroscopy were associated with changes in cognitive function after CEA.

1H NMR-based metabonomics in brain nucleus accumbens and striatum following repeated cocaine treatment in rats

Studies have shown a few cerebral metabolites modified by cocaine in brain regions; however, endogenous metabolic profiling has been lacking. Ex vivo 1H NMR (hydrogen-1 nuclear magnetic resonance) spectroscopy-based metabonomic approach coupled with partial least squares was applied to investigate the changes of cerebral metabolites in nucleus accumbens (NAc) and striatum of rats subjected to cocaine treatment. Our results showed that both single and repeated cocaine treatment can induce significant changes in a couple of cerebral metabolites. The increase of neurotransmitters glutamate and gamma-amino butyric acid (GABA) were observed in NAc and striatum from the rats repeatedly treated with cocaine. Creatine and taurine increased in NAc whereas taurine increased and creatine decreased in striatum after repeated cocaine treatment. Elevation of N-acetylaspartate in NAc and striatum and decrease of lactate in striatum were observed, which may reflect the mitochondria dysregulation caused by cocaine; moreover, alterations of choline, phosphocholine and glycerol in NAc and striatum could be related to membrane disruption. Moreover, groups of rats with and without conditioned place preference (CPP) apparatus are presenting difference in metabolites. Collectively, our results provide the first evidence of metabonomic profiling of NAc and striatum in response to cocaine, exhibiting a regionally-specific alteration patterns. We find that repeated cocaine administration leads to significant metabolite alterations, which are involved in neurotransmitter disturbance, oxidative stress, mitochondria dysregulation and membrane disruption in brain.

Magnetic Resonance Spectroscopy and Neurocognitive Dysfunction in Obstructive Sleep Apnea before and after CPAP Treatment

To determine whether cerebral metabolite changes may underlie abnormalities of neurocognitive function and respiratory control in OSA. Observational, before and after CPAP treatment. Two tertiary hospital research institutes. 30 untreated severe OSA patients, and 25 age-matched healthy controls, all males free of comorbidities, and all having had detailed structural brain analysis using voxel-based morphometry (VBM). Single voxel bilateral hippocampal and brainstem, and multivoxel frontal metabolite concentrations were measured using magnetic resonance spectroscopy (MRS) in a high resolution (3T) scanner. Subjects also completed a battery of neurocognitive tests. Patients had repeat testing after 6 months of CPAP. There were significant differences at baseline in frontal N-acetylaspartate/choline (NAA/Cho) ratios (patients [mean (SD)] 4.56 [0.41], controls 4.92 [0.44], P = 0.001), and in hippocampal choline/creatine (Cho/Cr) ratios (0.38 [0.04] vs 0.41 [0.04], P = 0.006), (both ANCOVA, with age and premorbid IQ as covariates). No longitudinal changes were seen with treatment (n = 27, paired t tests), however the hippocampal differences were no longer significant at 6 months, and frontal NAA/Cr ratios were now also significantly different (patients 1.55 [0.13] vs control 1.65 [0.18] P = 0.01). No significant correlations were found between spectroscopy results and neurocognitive test results, but significant negative correlations were seen between arousal index and frontal NAA/Cho (r = -0.39, corrected P = 0.033) and between % total sleep time at SpO(2) < 90% and hippocampal Cho/Cr (r = -0.40, corrected P = 0.01). OSA patients have brain metabolite changes detected by MRS, suggestive of decreased frontal lobe neuronal viability and integrity, and decreased hippocampal membrane turnover. These regions have previously been shown to have no gross structural lesions using VBM. Little change was seen with treatment with CPAP for 6 months. No correlation of metabolite concentrations was seen with results on neurocognitive tests, but there were significant negative correlations with OSA severity as measured by severity of nocturnal hypoxemia.

Primary somatosensory cortex in chronic low back pain &amp;ndash; a 1H-MRS study

The goal of this study was to investigate whether certain metabolites, specific to neurons, glial cells, and the neuronal-glial neurotransmission system, in the primary somatosensory cortex (SSC), are altered and correlated with clinical characteristics of pain in patients with chronic low back pain (LBP). Eleven LBP patients and eleven age-matched healthy controls were included. N-acetylaspartate (NAA), choline (Cho), myo-inositol (mI), and glutamine/glutamate (Glx) were measured with proton magnetic resonance spectroscopy (1H-MRS) in left and right SSC. Differences in metabolite concentrations relative to those of controls were evaluated as well as analyses of metabolite correlations within and between SSCs. Relationships between metabolite concentrations and pain characteristics were also evaluated. We found decreased NAA in the left SSC (P = 0.001) and decreased Cho (P = 0.04) along with lower correlations between all metabolites in right SSC (P = 0.007) in LBP compared to controls. In addition, we found higher and significant correlations between left and right mI (P < 0.001 in LBP vs P = 0.1 in controls) and between left mI and right Cho (P = 0.048 vs P = 0.6). Left and right NAA levels were negatively correlated with pain duration (P = 0.04 and P = 0.02 respectively) while right Glx was positively correlated with pain severity (P = 0.04). Our preliminary results demonstrated significant altered neuronal-glial interactions in SSC, with left neural alterations related to pain duration and right neuronal-glial alterations to pain severity. Thus, the 1H-MRS approach proposed here can be used to quantify relevant cerebral metabolite changes in chronic pain, and consequently increase our knowledge of the factors leading from these changes to clinical outcomes.

High resolution nuclear magnetic resonance investigation of metabolic disturbances induced by focal traumatic brain injury in a rat model: a pilot study

Experimental models of traumatic brain injury (TBI) provide a useful tool for understanding the cerebral metabolic changes induced by this pathological condition. Here, we report on the time course of changes in cerebral metabolites after TBI using high-resolution proton magnetic resonance spectroscopy (NMR). Extracts from adult male Sprague-Dawley rats were subjected to fluid lateral percussion and were then examined by NMR at 3, 24 and 48 h after the injury. A metabolomic approach was carried out to identify the cerebral metabolites impacted by the TBI and their quantitative temporal changes. Lactate, valine and ascorbate were the three first metabolites to be significantly modified after TBI. The quantitative elevation for these compounds last for the entire experimental time explored. Within 24 hours post-TBI, a significant elevation in choline-derivates, alanine and glucose were also measured. On the other hand, N-acetyl aspartate, a neuronal marker, and myo- inositol, an important organic osmolyte in the mammalian brain, were not significantly impacted in the chronic phase of TBI.

Effects of short-term stress-like cortisol on cerebral metabolism: A proton magnetic resonance spectroscopy study at 3.0 T

Preclinical and clinical studies suggest that glucocorticoids disturb cognitive performance and neuronal integrity. MR spectroscopy studies have tried to track these effects and correlate long-term effects of glucocorticoids with concentration changes of cerebral metabolites. However, a systematic spectroscopic study on short-term exposure to corticosteroids, in a dosage sufficient to impair memory performance, is lacking. Thus, it is not known when glucocorticoid effects become visible at 1H-MRS in vivo. Therefore, employing localized 1H-MRS at 3 T we quantitatively investigated the effects of a 4-day cortisol exposure (160 mg/d) on brain metabolites in vivo in a double blind and placebo-controlled cross-over study of 21 healthy subjects. Spectroscopic measurements were performed in four different brain regions, including the posterior cingulate gyrus, right frontal white matter, left and right anterior hippocampus using the PRESS method. Our results show, after 4 days of cortisol intake and despite a nearly 3-fold increase in serum cortisol concentration, for none of the investigated metabolites a significant corticosteroid-induced concentration change. Our results show that contrary to reported long-term effects, short-term hydrocortisone exposure at a stress-like dosage does not lead to changes of prominent cerebral metabolites, including N-acetylaspartate, creatine and phosphocreatine, choline-containing metabolites, myo-inositol and glutamate.