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Objective: To evaluate progressive cerebral degeneration in amyotrophic lateral sclerosis (ALS) by assessing alterations in N -acetylaspartate (NAA) ratios in the motor and prefrontal cortex within clinical subgroups of ALS., Methods: Seventy-six patients with ALS and 59 healthy controls were enrolled in a prospective, longitudinal, multicenter study in the Canadian ALS Neuroimaging Consortium. Participants underwent serial clinical evaluations and magnetic resonance spectroscopy at baseline and 4 and 8 months using a harmonized protocol across 5 centers. NAA ratios were quantified in the motor cortex and prefrontal cortex. Patients were stratified into subgroups based on disease progression rate, upper motor neuron (UMN) signs, and cognitive status. Linear mixed models were used for baseline and longitudinal comparisons of NAA metabolite ratios., Results: Patients with ALS had reduced NAA ratios in the motor cortex at baseline ( p < 0.001). Ratios were lower in those with more rapid disease progression and greater UMN signs ( p < 0.05). A longitudinal decline in NAA ratios was observed in the motor cortex in the rapidly progressing ( p < 0.01) and high UMN burden ( p < 0.01) cohorts. The severity of UMN signs did not change significantly over time. NAA ratios were reduced in the prefrontal cortex only in cognitively impaired patients ( p < 0.05 ) ; prefrontal cortex metabolites did not change over time., Conclusions: Progressive degeneration of the motor cortex in ALS is associated with more aggressive clinical presentations. These findings provide biological evidence of variable spatial and temporal cerebral degeneration linked to the disease heterogeneity of ALS. The use of standardized imaging protocols may have a role in clinical trials for patient selection or subgrouping., Classification of Evidence: This study provides Class II evidence that MRS NAA metabolite ratios of the motor cortex are associated with more rapid disease progression and greater UMN signs in patients with ALS., Trial Registration Information: ClinicalTrials.gov Identifier: NCT02405182., (© 2021 American Academy of Neurology.)

Different lines of evidence suggest an abnormal cerebral energy metabolism as being critical to the pathophysiology of schizophrenia. However, it is unknown as to whether levels of creatine (Cr) would be involved in these anomalies. The study involved 33 unmedicated first episode psychosis patients and 41 healthy controls. Proton magnetic resonance spectroscopy ((1) H-MRS) was performed at 3 T using a long TE (TE/TM/TR of 240/27/3000 ms) such that within the total phosphocreatine (PCr) plus Cr signal (tCr(240)), mainly Cr was detectable. The target region was an 18 cm(3) prefrontal volume. A negative association was found between age of patients and tCr(240) levels referenced to internal water, with 20% of the variance in tCr(240) accounted for by Age. A secondary finding revealed 16% reduction of tCr(240) levels in patients, solely when comparing participants older than the median age of patients. No association existed between tCr(240) levels and clinical variables. These findings support previous data reporting abnormalities in brain creatine kinase isoenzymes involved with the maintenance of energy pools in schizophrenia. The implications of using a long TE are discussed in terms of the relative proportions of Cr and PCr within the tCr(240) signal, and of potential group differences in T(2) times., (Copyright © 2012 Wiley Periodicals, Inc.)

The pathophysiological underpinnings of bipolar disorder are not fully understood. However, they may be due in part to changes in the phosphatidylinositol second messenger system (PI-cycle) generally, or changes in myo-inositol concentrations more specifically. Dextro-amphetamine has been used as a model for mania in several human studies as it causes similar subjective and physiological symptoms. We wanted to determine if dextro-amphetamine altered myo-inositol concentrations in vivo as it would clearly define a mechanism linking putative changes in the PI-cycle to the subjective psychological changes seen with dextro-amphetamine administration. Fifteen healthy human volunteers received a baseline scan, followed by second scan 75 min after receiving a 25 mg oral dose of dextro-amphetamine. Stimulated echo proton magnetic resonance spectroscopy (MRS) scans were preformed at 3.0 Tesla (T) in the dorsal medial prefrontal cortex (DMPFC). Metabolite data were adjusted for tissue composition and analyzed using LCModel. Twelve adult male rats were treated acutely with a 5-mg/kg intraperitoneal dose of dextro-amphetamine. After 1 h rats were decapitated and the brains were rapidly removed and frozen until dissection. Rat brains were dissected into frontal, temporal, and occipital cortical areas, as well as hippocampus. Tissue was analyzed using a Varian 18.8 T spectrometer. Metabolites were identified and quantified using Chenomx Profiler software. The main finding in the present study was that myo-inositol concentrations in the DMPFC of human volunteers and in the four rat brain regions were not altered by acute dextro-amphetamine. While it remains possible that the PI-cycle may be involved in the pathophysiology of bipolar disorder, it is not likely that the subjective and physiological of dextro-amphetamine are mediated, directly or indirectly, via alternations in myo-inositol concentrations.

Background: Women who suffer from premenstrual dysphoric disorder (PMDD) classically display depressive and anxiety symptoms in the premenstrum. Preclinical and clinical studies have suggested a role of glutamate in anxiety and depression. This investigation aims at demonstrating fluctuations of glutamate across the menstrual cycle in the medial prefrontal cortex of women who suffer from PMDD and healthy control subjects (HCs)., Methods: Twelve PMDD women and 13 HCs were randomized to two single-voxel 3 Tesla proton magnetic resonance spectroscopy examinations of the medial prefrontal cortex during the follicular phase and the luteal phase., Results: A phase effect was observed; the levels of glutamate/creatine plus phosphocreatine (Cr) were significantly lower during the luteal phase compared with the follicular phase. However, no statistically significant diagnosis or phase x diagnosis effects were found., Conclusions: The optimized stimulated echo acquisition mode (STEAM) pulse timings selected in this study (echo time [TE], mixing time [TM] = 240, 27 msec) allow us to interpret our results as the first report of alterations of brain glutamate levels across the menstrual cycle. Hormonal fluctuations associated with the menstrual cycle likely contribute to these glutamate level variations. Although PMDD women undergo a similar decrease in glutamate during the luteal phase as the HCs, PMDD women may display an increased behavioral sensitivity to those phase-related alterations. These menstrual cycle-related variations of glutamate levels may also contribute to the influence of the phases of the menstrual cycle in other neuropsychiatric disorders.

Glutamate was quantified by proton magnetic resonance spectroscopy ((1)H-MRS) in the medial frontal lobes of 15 adult siblings of individuals with schizophrenia (HR) and 14 healthy volunteers (HV), all of whom also completed a Continuous Performance Test (CPT). Subjects were free of psychopathology but the HR group showed greater variability in glutamate levels. After median stratification, the high glutamate group contained a larger proportion of HR than HV subjects and scored lower on the CPT. Elevated glutamate may relate to poor sustained attention and elevated risk of schizophrenia, suggesting a potential role for glutamate in an endophenotype for schizophrenia.

A new (1)H-MRS filtering strategy for selective measurement of glycine (Gly) in human brain in vivo at 3.0T is proposed. Investigation of multiple refocusing following a 90 degrees excitation pulse indicated that triple refocusing is most effective for suppression of the strongly coupled resonances of myo-inositol (mI) at the Gly 3.55-ppm resonance. The echo times of the triple refocusing were optimized, with numerical analysis of the filtering performance, as {TE(1), TE(2), TE(3)} = {67, 62, 69} ms. Compared with the 90 degrees -acquired mI signal the mI suppression ratios of the filter were 170 and 1000, in terms of peak amplitude and area, respectively, between 3.51 and 3.59 ppm. From LCModel analyses, using density-matrix calculated spectra as basis functions, the concentration of Gly in parieto-occipital cortex of healthy adults was estimated to be 0.5 +/- 0.1 mM (mean +/- SD, n = 6), with reference to creatine at 8 mM., (2007 Wiley-Liss, Inc)

Objective Perimenopause is associated with an increased risk of developing a major depressive (MD) episode. A significant number of women develop their first MD episode during perimenopause, suggesting a unique pathophysiology of perimenopausal (PM) depression. Previous research has shown that depression is associated with decreased gamma-aminobutyric acid (GABA) levels in the medial prefrontal cortex (MPFC) of MD patients. The objective of this study was to compare MPFC GABA+ levels in healthy reproductive-aged (RD) and PM women. Methods A total of 18 healthy PM and 20 RD women were included in the study. MPFC GABA+ levels, which include homocarnosine and macromolecules, were measured via magnetic resonance spectroscopy using a 3 Tesla magnet. MPFC GABA+ levels were referenced to creatine + phosphocreatine (Cr+PCr). Absence of current or past psychiatric diagnosis was confirmed via a structured interview. RD participants were scanned during the early follicular phase of the menstrual cycle. PM women were scanned outside of ovulatory cycles. Results Mean MPFC GABA+ concentrations (relative to Cr+PCr) were decreased in the PM group compared with the RD group (PM mean = 0.08 ± 0.02, RD mean = 0.09 ± 0.02, t  = −2.03, df  = 36, P  = .05) even after correcting for in percentage in gray matter (GM). Because PM women were inherently older than RD women (aged 48.8 ± 3.55 and 31.5 ± 9.66 years, respectively), the age difference between the 2 groups was statistically significant (P  < .001). When age was treated as an independent covariate and included in the model, the difference in GABA+ between PM and RD women was no longer significant (P  = .092). Conclusion Perimenopause is associated with decreased MPFC GABA+/Cr+PCr levels, which may contribute to the increased risk of experiencing a MD episode during PM. [ABSTRACT FROM AUTHOR]

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The role played by medial prefrontal cortex (MPFC) glutamate (Glu) and gamma-aminobutyric acid (GABA) in the pathophysiology and the treatment of major depression (MD) is increasingly recognized. Although measurements of MPFC GABA and Glu have been shown to be sensitive to physiological fluctuations of female hormones, none of the magnetic resonance spectroscopy (MRS) investigations of MPFC Glu and GABA in MD have controlled for possible bias effect of the reproductive stage of the women included. MPFC Glu and GABA+ (which include homocarnosine and macromolecules) referenced to creatine and phosphocreatine, were measured via magnetic resonance spectroscopy (MRS) using a 3-Tesla magnet in 24 women with MD and 24 healthy women paired for reproductive status. All participants were unmedicated. There were no statistical differences in either MPFC Glu [95 % CI: (−0.025, 0.034)] or MPFC GABA+ [95 % CI: (−0.005, 0.017)] between women with MD and healthy controls. Our investigation does not support abnormalities in measurement of MPFC Glu and GABA in MD women when stringent control for reproductive status is performed. As a result of the inherent limitations of MRS methodology, our results do not preclude glutamatergic and GABAergic dysregulations in the MPFC of women with MD. • A stringent control for reproductive status was performed for healthy females and females experiencing depression. • All participants were age and sex matched. • MPFC Glu and GABA+ were not significantly different between groups when reproductive status was controlled. [ABSTRACT FROM AUTHOR]

Background: There is a paucity of data connecting the metabolic and cognitive functioning of abstinent cocaine users. This is a pressing public health concern as approximately 1% of the Canadian population and 0.4% of the global population is estimated to have used cocaine in the past year.Methods: Our clinical study compared the in vivo neurochemical profiles in the prefrontal cortex to cognitive tests associated with the same region in 21 moderate term abstinent cocaine users (average 187days abstinent, range 15-1432days), and 30 healthy controls using 3T 1H MRS.Results: The abstinent cocaine users exhibited a 10% decrease in N-acetylaspartate (NAA) relative to healthy control subjects (p<0.01, Cohen's d=1.15). When subdivided by method of administration, a significant decrease in glutamate levels in former crack smokers compared to healthy controls (p<0.05) was observed, this decrease was not present in powder users. Abstinent users were significantly worse than healthy controls on the Trail Making Test B (p<0.05), and performance on this task was inversely related to NAA levels (p<0.05). Abstinent cocaine users showed deficits in the Wisconsin card sorting test with failures to maintain set (p<0.01).Conclusions: Our work suggests that there are subtle but important changes in the brain that remain even with the moderate term cessation of cocaine use. [ABSTRACT FROM AUTHOR]

Background: Postmortem studies have shown robust prefrontal cortex glial losses and more subtle neuronal changes in major depressive disorder (MDD). Earlier proton magnetic resonance spectroscopy (1H-MRS) studies of the glial marker myo-inositol in MDD were subject to potential confounds. The primary hypothesis of this study was that MDD patients would show reduced prefrontal/anterior cingulate cortex levels of myo-inositol. Methods: Thirteen nonmedicated moderate–severe MDD patients and 13 matched control subjects were studied (six male, seven female per group). Proton magnetic resonance spectroscopy stimulated echo acquisition mode spectra (3.0 T; echo time = 168 msec; mixing time = 28 msec; repetition time = 3000 msec) were obtained from prefrontal/anterior cingulate cortex. Metabolite data were adjusted for tissue composition. Results: Patients with MDD showed significantly lower myo-inositol/creatine ratios (.94 ± .23) than control subjects (1.32 ± .37) [F(1,23) = 6.9; p = .016]. Conclusions: These data suggest a reduction of myo-inositol in prefrontal/anterior cingulate cortex in MDD, which could be a consequence of glial loss or altered glial metabolism. Additional in vivo studies of glial markers could add to the understanding of the pathophysiology of MDD. [Copyright &y& Elsevier]