Total N-acetylaspartate Research Articles

Metabolite Alterations in the Left Dorsolateral Prefrontal Cortex and its Association with Cognitive Assessments in Amyotrophic Lateral Sclerosis: A Longitudinal Magnetic Resonance Spectroscopy Study.

To characterize the longitudinal metabolite profile of the left dorsolateral prefrontal cortex (DLPFC) in amyotrophic lateral sclerosis (ALS) using magnetic resonance spectroscopy (MRS) and to examine its correlation with cognitive assessments. Thirteen patients at baseline and ten at follow-up, along with 14 age-, sex-, and handedness-matched healthy controls (HCs), were recruited. Three Tesla with a 64-channel coil, Point-RESolved Spectroscopy (PRESS) sequence (TR=1500 ms and TE=140 ms) was used. Metabolites in the left DLPFC were quantified using LCModel. Cognitive performance and functional impairment were assessed using the Edinburgh Cognitive and Behavioral ALS Screen (ECAS) and Revised ALS Functional Rating Scale (ALSFRS-R), respectively. Group comparisons were adjusted for multiple comparisons (p < 0.05, Bonferroni correction). The links between the brain metabolites and cognitive function were investigated using relevant correlation tests (Pearson's or Spearman's). Our analysis revealed a significant difference in the choline-to-creatine ratio (tCho/tCr) among the three groups. Baseline ALS patients showed a higher tCho/tCr ratio than HCs (p = 0.033, Bonferroni-corrected). Interestingly, the total N-acetyl aspartate (tNAA)/tCr ratio, a marker of neuronal health, was strongly positively correlated with visuospatial cognitive scores at baseline and follow-up. Furthermore, at follow-up, tNAA/tCr was positively correlated with the total scores and specific sub-scores on the ECAS, encompassing both ALS-specific and non-specific cognitive domains. At follow-up, positive correlations emerged between tNAA/tCr and the total language and executive function scores. Metabolite alterations and correlations with cognition were observed in the left DLPFC of ALS patients, supporting extra-motor involvement and its association with cognitive decline.

Early Diagnosis of Huntington Disease: Insights from Magnetic Resonance Spectroscopy-A Systematic Review.

Background/Objectives: Huntington's disease (HD) is a fully penetrant neurodegenerative disease with a profound effect on quality of life. In recent years, there has been rapid growth in the description of its pathogenesis and diagnosis. Magnetic resonance spectroscopy (MRS) measurements can aid in the discrimination between premanifest Huntington's disease (Pre-HD) and healthy control (HC) subjects to establish early supportive and symptomatic management. Our objective was to evaluate metabolic changes using MRS to shed light on its potential as a biomarker through a systematic review. Methods: We followed the PRISMA guidelines, extracting articles from PubMed, Scopus, and the Virtual Health Library. We included patients with pre-HD, HD, and HC subjected to MRS, reporting the concentration of metabolites in at least one brain region. Results: In the putamen, N-acetyl Aspartate (NAA) was significantly decreased in 77.9% and total NAA (tNAA) was decreased in 72.4% of cases; no significant difference was found in 27.5% (n = 19) of cases. Furthermore, when looking into HD vs. pre-HD in the putamen, tNAA and NAA were decreased in 100% of participants. In the caudate nucleus, NAA and creatine were significantly decreased in 100% of HD in comparison to pre-HD participants, whereas tNAA showed a significant decrease in only 50%. Conclusions: MRS can be a relevant tool for the early diagnosis of HD; potential objective biomarkers related to its onset and pathogenesis exist and show differences between controls, pre-HD and HD patients. However, an effort should be made to standardize MRS methodology and reporting in subsequent studies.

Diffuse white matter pathology in multiple sclerosis during treatment with dimethyl fumarate-An observational study of changes in normal-appearing white matter using proton magnetic resonance spectroscopy.

Multiple sclerosis (MS) is an inflammatory demyelinating disease with neurodegenerative features causing risk for neurologic irreversible disability over time. Examination of normal-appearing white matter (NAWM) changes in MS by proton magnetic resonance spectroscopy (1H-MRS), may detect diffuse white matter pathology that is associated with neurodegeneration. In this observational study of in total twenty-six patients with MS, starting treatment with dimethyl fumarate (DMF), we measured the absolute concentration of metabolites in periventricular NAWM using 1H-MRS at baseline and after one and three years of treatment. Metabolite concentrations were analyzed both cross-sectionally, in relation to 10 controls and longitudinally in relation to disease activity. Patients with MS had higher concentrations of myo-inositol (mIns) in NAWM at baseline compared with controls (mean 5.98 ± 1.37 (SD) and 4.32 ± 1.16 (SD), p<0.01, independent samples t-test). The disease duration was inversely correlated with concentrations of total N-acetylaspartate and N-acetylaspartylglutamate (tNA) (r = -0.62, p<0.01) in NAWM as well as positively to the ratio of mIns and tNA (r = 0.51, p = 0.03). Metabolite concentrations during one-year (n = 19) and three-years (n = 11) follow-up were generally stable. The dropouts were caused by treatment switch after one year, mainly due to new MRI activity. Cross-sectional analyses showed that there was an inverse correlation between concentrations of tNA and mIns at both baseline and at 1 and 3-years follow-up (r = -0.44 to -0.65, p = 0.04 to 0.004). Metabolite concentrations were stable during 1-year follow-up independently of disease activity. Higher concentrations of the astrogliosis marker mIns in MS compared to controls, the inverse relation between MS disease duration and the neuroaxonal integrity marker tNA, as well as the consistent inverse relation between these two metabolites during follow-up, showed that non-lesional white matter pathology is present in this cohort of MS patients in early disease stages. However, metabolite concentrations during follow-up were generally stable and did not reflect differences in disease activity among patients.

Examination of methods to separate overlapping metabolites at 7T.

Neurochemicals of interest quantified by MRS are often composites of overlapping signals. At higher field strengths (i.e., 7T), there is better separation of these signals. As the availability of higher field strengths is increasing, it is important to re-evaluate the separability of overlapping metabolite signals. This study compares the ability of stimulated echo acquisition mode (STEAM-8; TE = 8 ms), short-TE semi-LASER (sLASER-34; TE = 34 ms), and long-TE semi-LASER (sLASER-105; TE = 105 ms) acquisitions to separate the commonly acquired neurochemicals at 7T (Glx, consisting of glutamate and glutamine; total N-acetyl aspartate, consisting of N-acetyl aspartate and N-acetylaspartylglutamate; total creatine, consisting of creatine and phosphocreatine; and total choline, consisting of choline, phosphocholine, and glycerophosphocholine). sLASER-34 produced the lowest fit errors for most neurochemicals; however, STEAM-8 had better within-subject reproducibility and required fewer subjects to detect a change between groups. However, this is dependent on the neurochemical of interest. We recommend short-TE STEAM for separation of most standard neurochemicals at 7T over short-TE or long-TE sLASER.

Recurrent neural network-aided processing of incomplete free induction decays in 1H-MRS of the brain

In the case of limited sampling windows or truncation of free induction decays (FIDs) for artifact removal in proton magnetic resonance spectroscopy (1H‐MRS) and spectroscopic imaging (1H‐MRSI), metabolite quantification needs to be performed on incomplete FIDs. Given that FIDs are naturally time-domain sequential data, we investigated the potential of recurrent neural network (RNN)-types of neural networks (NNs) in the processing of incomplete human brain FIDs with or without FID restoration prior to quantitative analysis at 3.0T.First, we employed an RNN encoder-decoder and developed it to restore incomplete FIDs (rRNN) with different amounts of sampled data. The quantification of metabolites from the rRNN-restored FIDs was achieved by using LCModel. Second, we modified the RNN encoder-decoder and developed it to convert incomplete brain FIDs into incomplete metabolite-only FIDs without restoration, followed by linear regression using a metabolite basis set for quantitative analysis (cRNN). In consideration of the practical benefit of the FID restoration with respect to pure zero-filling, development and analysis of the NNs were focused particularly on the incomplete FIDs with only the first 64 data points retained. All NNs were trained on simulated data and tested mainly on in vivo data acquired from healthy volunteers (n = 27).Strong correlations were obtained between the NN-derived and ground truth metabolite content (LCModel-derived content on fully sampled FIDs) for myo‐inositol, total choline, and total creatine (normalized to total N-acetylaspartate) on the in vivo data using both rRNN (R = 0.83–0.94; p ≤ 0.05) and cRNN (R = 0.86–0.91; p ≤ 0.05).RNN-types of NNs have potential in the quantification of the major brain metabolites from the FIDs with substantially reduced sampled data points. For the metabolites with low to medium SNR, the performance of the NNs needs to be further improved, for which development of more elaborate and advanced simulation techniques would be of help, but remains challenging.

Evidence for biexponential glutamate T2 relaxation in human visual cortex at 3T: A functional MRS study.

Functional magnetic resonance spectroscopy (fMRS) measures dynamic changes in metabolite concentration in response to neural stimulation. The biophysical basis of these changes remains unclear. One hypothesis suggests that an increase or decrease in the glutamate signal detected by fMRS could be due to neurotransmitter movements between cellular compartments with different T2 relaxation times. Previous studies reporting glutamate (Glu) T2 values have generally sampled at echo times (TEs) within the range of 30-450 ms, which is not adequate to observe a component with short T2 (<20 ms). Here, we acquire MRS measurements for Glu, (t) total creatine (tCr) and total N-acetylaspartate (tNAA) from the visual cortex in 14 healthy participants at a range of TE values between 9.3-280 ms during short blocks (64 s) of flickering checkerboards and rest to examine both the short- and long-T2 components of the curve. We fit monoexponential and biexponential Glu, tCr and tNAA T2 relaxation curves for rest and stimulation and use Akaike information criterion to assess best model fit. We also include power calculations for detection of a 2% shift of Glu between compartments for each TE. Using pooled data over all participants at rest, we observed a short Glu T2-component with T2 = 10ms and volume fraction of 0.35, a short tCr T2-component with T2 = 26 ms and volume fraction of 0.25 and a short tNAA T2-component around 15 ms with volume fraction of 0.34. No statistically significant change in Glu, tCr and tNAA signal during stimulation was detected at any TE. The volume fractions of short-T2 component between rest and active conditions were not statistically different. This study provides evidence for a short T2-component for Glu, tCr and tNAA but no evidence to support the hypothesis of task-related changes in glutamate distribution between short and long T2 compartments.

Associations Between Brain Metabolites Measured With MR Spectroscopy and Head Impacts in High School American Football Athletes.

While changes in brain metabolites after injury have been reported, relationships between metabolite changes and head impacts are less characterized. To investigate alterations in neurochemistry in high school athletes as a function of head impacts, concussion, and the use of a jugular vein compression (JVC) collar. Prospective controlled trial. A total of 284 male American football players, divided into JVC collar and noncollar groups; 215 included in final analysis (age = 15.9 ± 1.0 years; 114 in collar group). 3 Tesla/T1-weighted gradient echo, 1H point resolved spectroscopy, acquired between August and November 2018. Head impacts were quantified using accelerometers. Concussion was diagnosed by medical professionals for each team. Pre- to postseason differences in total N-acetylaspartate (tNAA), total choline (tCho), myo-inositol (myoI), and glutamate + glutamine (Glx), in primary motor cortex (M1) and anterior cingulate cortex (ACC), relative to total creatine (tCr), were determined. Group-wise comparisons were performed using Wilcoxon signed-rank, Friedman's, and Mann-Whitney U tests. Relationships between ∆metabolite/tCr and mean g-force were analyzed using linear regressions accounting for concussion and JVC collar. Significance was set at P ≤ 0.05. In participants without concussion, a significant decrease in tCho/tCr (0.233 ± 1.40 × 10-3 to 0.227 ± 1.47 × 10-7) and increase in Glx/tCr (1.60 ± 8.75 × 10-3 to 1.63 ± 1.08 × 10-2) in ACC were observed pre- to postseason. The relationship between ∆tCho/tCr in M1 and ACC and mean g-force from >80 g to >140 g differed significantly between participants with and without concussion (M1 β ranged from 3.9 × 10-3 to 2.1 × 10-3; ACC β ranged from 2.7 × 10-3 to 2.1 × 10-3). Posthoc analyses revealed increased tCho/tCr in M1 was positively associated with mean g-force >100 g (β = 3.6 × 10-3) and >110 g (β = 2.9 × 10-3) in participants with concussion. Significant associations between in ACC and mean g-force >110 g (β = -1.1 × 10-3) and >120 g (β = -1.1 × 10-3) were observed in the collar group only. Diagnosed concussion and the use of a JVC collar result in distinct neurochemical trends after repeated head impacts. 2 TECHNICAL EFFICACY: Stage 3.

Myo-inositol and total NAA in the hippocampus are linked to CSF tau pathology in cognitively normal older adults.

Understanding relationships between in vivo neurometabolic changes and Alzheimer's disease (AD) pathology in the hippocampus, a region vulnerable to early changes in AD, will support early diagnosis. Two studies using 1 H-MRS examined concentrations of myo-inositol (MI), total creatine (tCr) and total NAA (tNAA) in the hippocampus. The first study compared hippocampal metabolite concentrations in healthy young and older adults and the second study assessed relationships between hippocampal metabolites and cerebrospinal fluid (CSF) measurements of Aβ42, phosphotau 181 (pTau181), and total tau (t-Tau) while adjusting for demographic covariates and spectral characteristics (linewidth, signal- to-noise ratio) in a separate group of older adults ranging from cognitively normal (CN) to AD-dementia. Hippocampal MI, but not tCr or tNAA, was increased in cognitively normal older versus young adults. Within the second older adult group, MI and tNAA, but not tCr, were linked to increases in CSF pTau181 and t-Tau, but not Aβ42. Tau deposition in cognitively normal individuals is associated with biochemical changes related to glial reactivity and neural integrity in the hippocampus.

Probing diffusion of water and metabolites to assess white matter microstructure in Duchenne muscular dystrophy.

Duchenne muscular dystrophy (DMD) is a progressive X-linked neuromuscular disorder caused by the absence of functional dystrophin protein. In addition to muscle, dystrophin is expressed in the brain in both neurons and glial cells. Previous studies have shown altered white matter microstructure in patients with DMD using diffusion tensor imaging (DTI). However, DTI measures the diffusion properties of water, a ubiquitous molecule, making it difficult to unravel the underlying pathology. Diffusion-weighted spectroscopy (DWS) is a complementary technique which measures diffusion properties of cell-specific intracellular metabolites. Here we performed both DWS and DTI measurements to disentangle intra- and extracellular contributions to white matter changes in patients with DMD. Scans were conducted in patients with DMD (15.5 ± 4.6 y/o) and age- and sex-matched healthy controls (16.3 ± 3.3 y/o). DWS measurements were obtained in a volume of interest (VOI) positioned in the left parietal white matter. Apparent diffusion coefficients (ADCs) were calculated for total N-acetylaspartate (tNAA), choline compounds (tCho), and total creatine (tCr). The tNAA/tCr and tCho/tCr ratios were calculated from the non-diffusion-weighted spectrum. Mean diffusivity (MD), radial diffusivity (RD), axial diffusivity (AD), and fractional anisotropy of water within the VOI were extracted from DTI measurements. DWS and DTI data from patients with DMD (respectively n= 20 and n= 18) and n= 10 healthy controls were included. No differences in metabolite ADC or in concentration ratios were found between patients with DMD and controls. In contrast, water diffusion (MD, t= -2.727, p= 0.011; RD, t= -2.720, p= 0.011; AD, t= -2.715, p= 0.012) within the VOI was significantly higher in patients compared with healthy controls. Taken together, our study illustrates the potential of combining DTI and DWS to gain a better understanding of microstructural changes and their association with disease mechanisms in a clinical setting.

Metabolic changes assessed by 1H MR spectroscopy in the corpus callosum of post-COVID patients

ObjectiveMany patients with long COVID experience neurological and psychological symptoms. Signal abnormalities on MR images in the corpus callosum have been reported. Knowledge about the metabolic profile in the splenium of the corpus callosum (CCS) may contribute to a better understanding of the pathophysiology of long COVID.Materials and methodsEighty-one subjects underwent proton MR spectroscopy examination. The metabolic concentrations of total N-acetylaspartate (NAA), choline-containing compounds (Cho), total creatine (Cr), myo-inositol (mI), and NAA/Cho in the CCS were statistically compared in the group of patients containing 58 subjects with positive IgG COVID-19 antibodies or positive SARS-CoV-2 qPCR test at least two months before the MR and the group of healthy controls containing 23 subjects with negative IgG antibodies.ResultsAn age-dependent effect of SARS-CoV-2 on Cho concentrations in the CCS has been observed. Considering the subjective threshold of age = 40 years, older patients showed significantly increased Cho concentrations in the CCS than older healthy controls (p = 0.02). NAA, Cr, and mI were unchanged. All metabolite concentrations in the CCS of younger post-COVID-19 patients remained unaffected by SARS-CoV-2. Cho did not show any difference between symptomatic and asymptomatic patients (p = 0.91).DiscussionOur results suggest that SARS-CoV-2 disproportionately increases Cho concentration in the CCS among older post-COVID-19 patients compared to younger ones. The observed changes in Cho may be related to the microstructural reorganization in the CCS also reported in diffusion measurements rather than increased membrane turnover. These changes do not seem to be related to neuropsychological problems of the post-COVID-19 patients. Further metabolic studies are recommended to confirm these observations.

Single-shot diffusion trace spectroscopic imaging using radial echo planar trajectories.

Demonstrate the feasibility and evaluate the performance of single-shot diffusion trace-weighted radial echo planar spectroscopic imaging (Trace DW-REPSI) for quantifying the trace ADC in phantom and in vivo using a 3T clinical scanner. Trace DW-REPSI datasets were acquired in 10 phantom and 10 healthy volunteers, with a maximum b-value of 1601 s/mm2 and diffusion time of 10.75 ms. The self-navigation properties of radial acquisitions were used for corrections of shot-to-shot phase and frequency shift fluctuations of the raw data. In vivo trace ADCs of total NAA (tNAA), total creatine (tCr), and total choline (tCho) extrapolated to pure gray and white matter fractions were compared, as well as trace ADCs estimated in voxels within white or gray matter-dominant regions. Trace ADCs in phantom show excellent agreement with reported values, and in vivo ADCs agree well with the expected differences between gray and white matter. For tNAA, tCr, and tCho, the trace ADCs extrapolated to pure gray and white matter ranged from 0.18-0.27 and 0.26-0.38 μm2/ms, respectively. In sets of gray and white matter-dominant voxels, the values ranged from 0.21 to 0.27 and 0.24 to 0.31 μm2/ms, respectively. The overestimated trace ADCs from this sequence can be attributed to the short diffusion time. This study presents the first demonstration of the single-shot diffusion trace-weighted spectroscopic imaging sequence using radial echo planar trajectories. The Trace DW-REPSI sequence could provide an estimate of the trace ADC in a much shorter scan time compared to conventional approaches that require three separate measurements.

Metabolite T1 relaxation times decrease across the adult lifespan.

Relaxation correction is an integral step in quantifying brain metabolite concentrations measured by in vivo magnetic resonance spectroscopy (MRS). While most quantification routines assume constant T1 relaxation across age, it is possible that aging alters T1 relaxation rates, as is seen for T2 relaxation. Here, we investigate the age dependence of metabolite T1 relaxation times at 3 T in both gray- and white-matter-rich voxels using publicly available metabolite and metabolite-nulled (single inversion recovery TI = 600 ms) spectra acquired at 3 T using Point RESolved Spectroscopy (PRESS) localization. Data were acquired from voxels in the posterior cingulate cortex (PCC) and centrum semiovale (CSO) in 102 healthy volunteers across 5 decades of life (aged 20-69 years). All spectra were analyzed in Osprey v.2.4.0. To estimate T1 relaxation times for total N-acetyl aspartate at 2.0 ppm (tNAA2.0) and total creatine at 3.0 ppm (tCr3.0), the ratio of modeled metabolite residual amplitudes in the metabolite-nulled spectrum to the full metabolite signal was calculated using the single-inversion-recovery signal equation. Correlations between T1 and subject age were evaluated. Spearman correlations revealed that estimated T1 relaxation times of tNAA2.0 (rs = -0.27; p < 0.006) and tCr3.0 (rs = -0.40; p < 0.001) decreased significantly with age in white-matter-rich CSO, and less steeply for tNAA2.0 (rs = -0.228; p = 0.005) and (not significantly for) tCr3.0 (rs = -0.13; p = 0.196) in graymatter-rich PCC. The analysis harnessed a large publicly available cross-sectional dataset to test an important hypothesis, that metabolite T1 relaxation times change with age. This preliminary study stresses the importance of further work to measure age-normed metabolite T1 relaxation times for accurate quantification of metabolite levels in studies of aging.

Radiation-induced bystander effect on the brain after fractionated spinal cord irradiation of aging rats

We investigated the influence of the so-called bystander effect on metabolic and histopathological changes in the rat brain after fractionated spinal cord irradiation. The study was initiated with adult Wistar male rats (n = 20) at the age of 9 months. The group designated to irradiation (n = 10) and the age-matched control animals (n = 10) were subjected to an initial measurement using in vivo proton magnetic resonance spectroscopy (1H MRS) and magnetic resonance imaging (MRI). After allowing the animals to survive until 12 months, they received fractionated spinal cord irradiation with a total dose of 24 Gy administered in 3 fractions (8 Gy per fraction) once a week on the same day for 3 consecutive weeks. 1H MRS and MRI of brain metabolites were performed in the hippocampus, corpus striatum, and olfactory bulb (OB) before irradiation (9-month-old rats) and subsequently 48 h (12-month-old) and 2 months (14-month-old) after the completion of irradiation. After the animals were sacrificed at the age of 14 months, brain tissue changes were investigated in two neurogenic regions: the hippocampal dentate gyrus (DG) and the rostral migratory stream (RMS). By comparing the group of 9-month-old rats and individuals measured 48 h (at the age of 12 months) after irradiation, we found a significant decrease in the ratio of total N-acetyl aspartate to total creatine (tNAA/tCr) and gamma-aminobutyric acid to tCr (GABA/tCr) in OB and hippocampus. A significant increase in myoinositol to tCr (mIns/tCr) in the OB persisted up to 14 months of age. Proton nuclear magnetic resonance (1H NMR)-based plasma metabolomics showed a significant increase in keto acids and decreased tyrosine and tricarboxylic cycle enzymes. Morphometric analysis of neurogenic regions of 14-month-old rats showed well-preserved stem cells, neuroblasts, and increased neurodegeneration. The radiation-induced bystander effect more significantly affected metabolite concentration than the distribution of selected cell types.

Relating depressive and manic symptomatology to 1H-MRS spectra

BackgroundAlterations in neurochemical levels are potential biomarkers of affective disorders and offer a window into illness etiology. Much of the research done to date limits focus to few metabolites and relies on dichotomous diagnoses. Here, using 1H magnetic resonance spectroscopy (MRS), we generate profiles of association between depressive and manic symptom rating scales and numerous metabolites. MethodsMRS data were collected in 30 individuals (7 = major depressive disorder; 5 bipolar disorder and 18 unaffected individuals) in the right anterior cingulate cortex (ACC), insula and hippocampus. All participants were administered mania and depression symptom scales. ResultsSmall to medium relationships were observed between total choline (tCho), N-acetylaspartate (NAA), myo-inositol (mIns) and depressive and manic symptoms. Associations between NAA and mania (r = –0.47, p = 8.88×10−03) in the hippocampus, and tCho (r = –0.48, p = 8.79×10−03) and NAA (r = –0.44, p = 0.01) and mania in the ACC withstood multiple testing correction. ConclusionsElevated levels of choline-containing compounds (tCho) and reduced NAA measured in the ACC and hippocampus are associated with mania indexed dimensionally. These metabolites may represent potential in vivo biomarkers for bipolar disorder symptomatology that warrant follow-up.

Resistance exercise effects on hippocampus subfield volumes and biomarkers of neuroplasticity and neuroinflammation in older adults with low and high risk of mild cognitive impairment: a randomized controlled trial

Physical exercise is suggested to promote hippocampal neuroplasticity by increasing circulating neurotrophic and anti-inflammatory factors. Our aim was to explore the interplay between the effect of progressive resistance exercise on blood biomarker levels, hippocampal neurometabolite levels and hippocampal volume in older adults with a low compared to a high risk of mild cognitive impairment (MCI). Seventy apparently healthy male/female older adults (aged 60–85 years old) were randomly allocated to a 12 week lower limb progressive resistance or no intervention, stratified for low (< 26/30) or high (≥ 26/30) Montreal Cognitive Assessment (MoCA) score, indicating MCI risk. Outcome measures were blood levels of insulin-like growth factor-1 (IGF-1), interleukin-6 (IL-6) or kynurenine (KYN); hippocampal total and subfield volumes of the cornu ammonis 1 (CA1) and 4 (CA4), subiculum, presubiculum, and dentate gyrus measured with magnetic resonance imaging (MRI); and hippocampus neurometabolites including total N-acetylaspartate (NAA), myo-inositol (mIns), and total creatine (Cr) measured with proton magnetic resonance spectroscopy (1H-MRS). We evaluated the intervention effect, cognitive status effect, their interaction and the bivariate relationship between exercise-induced changes between the outcome measures. Higher kynurenine levels (p = 0.015) and lower subiculum volumes (p = 0.043) were found in older adults with high MCI risk compared to older adults with low MCI risk. Exercise-induced CA1 volume changes were negatively correlated with hippocampal tNAA/mIns level changes (r = -0.605, p = 0.006). This study provides valuable insight in the multifactorial processes related to resistance training in older adults with low or high MCI risk.

Improved Detection of Target Metabolites in Brain Tumors with Intermediate TE, High SNR, and High Bandwidth Spin-Echo Sequence at 5T.

Due to high chemical shift displacement, challenges emerge at ultra-high fields when measuring metabolites using 1H-MRS. Our goal was to investigate how well the high SNR and high bandwidth spin-echo (HISE) technique perform at 5T for detecting target metabolites in brain tumors. Twenty-six subjects suspected of having brain tumors were enrolled. HISE and point-resolved spectroscopy (PRESS) single-voxel spectroscopy scans were collected with a 5T clinical scanner with an intermediate TE (TE = 144 ms). The main metabolites, including total NAA, Cr, and total Cho, were accessed and compared between HISE and PRESS using a paired Student t test, with full width at half maximum and SNR as covariates. The detection rate of specific metabolites, including lactate, alanine, and lipid, and subjective spectral quality were accessed and compared between HISE and PRESS. Twenty-three pathologically confirmed brain tumors were included. Only the full width at half maximum for total NAA was significantly lower with HISE than with PRESS (P < .05). HISE showed a significantly higher SNR for total NAA, Cr, and total Cho compared with PRESS (P < .05). Lactate was detected in 21 of the 23 cases using HISE, but in only 4 cases using PRESS. HISE detected alanine in 8 of 9 meningiomas, whereas PRESS detected alanine in just 3 meningiomas. PRESS found lipid in more cases than HISE, while HISE outperformed PRESS in terms of subjective spectral quality. HISE outperformed the clinical standard PRESS technique in detecting target metabolites of brain tumors at 5T, particularly lactate and alanine.

The developmental trajectory of 1H-MRS brain metabolites from childhood to adulthood.

Human brain development is ongoing throughout childhood, with for example, myelination of nerve fibers and refinement of synaptic connections continuing until early adulthood. 1H-Magnetic Resonance Spectroscopy (1H-MRS) can be used to quantify the concentrations of endogenous metabolites (e.g. glutamate and γ -aminobutyric acid (GABA)) in the human brain in vivo and so can provide valuable, tractable insight into the biochemical processes that support postnatal neurodevelopment. This can feasibly provide new insight into and aid the management of neurodevelopmental disorders by providing chemical markers of atypical development. This study aims to characterize the normative developmental trajectory of various brain metabolites, as measured by 1H-MRS from a midline posterior parietal voxel. We find significant non-linear trajectories for GABA+ (GABA plus macromolecules), Glx (glutamate + glutamine), total choline (tCho) and total creatine (tCr) concentrations. Glx and GABA+ concentrations steeply decrease across childhood, with more stable trajectories across early adulthood. tCr and tCho concentrations increase from childhood to early adulthood. Total N-acetyl aspartate (tNAA) and Myo-Inositol (mI) concentrations are relatively stable across development. Trajectories likely reflect fundamental neurodevelopmental processes (including local circuit refinement) which occur from childhood to early adulthood and can be associated with cognitive development; we find GABA+ concentrations significantly positively correlate with recognition memory scores.

Cortical glutamate, Glx, and total N-acetylaspartate: potential biomarkers of repetitive transcranial magnetic stimulation treatment response and outcomes in major depression

Repetitive transcranial magnetic stimulation (rTMS) is an effective treatment for individuals with major depressive disorder (MDD) who have not improved with standard therapies. However, only 30–45% of patients respond to rTMS. Predicting response to rTMS will benefit both patients and providers in terms of prescribing and targeting treatment for maximum efficacy and directing resources, as individuals with lower likelihood of response could be redirected to more suitable treatment alternatives. In this exploratory study, our goal was to use proton magnetic resonance spectroscopy to examine how glutamate (Glu), Glx, and total N-acetylaspartate (tNAA) predict post-rTMS changes in overall MDD severity and symptoms, and treatment response. Metabolites were measured in a right dorsal anterior cingulate cortex voxel prior to a standard course of 10 Hz rTMS to the left DLPFC in 25 individuals with MDD. MDD severity and symptoms were evaluated via the Inventory of Depression Symptomatology Self-Report (IDS-SR). rTMS response was defined as ≥50% change in full-scale IDS-SR scores post treatment. Percent change in IDS-SR symptom domains were evaluated using principal component analysis and established subscales. Generalized linear and logistic regression models were used to evaluate the relationship between baseline Glu, Glx, and tNAA and outcomes while controlling for age and sex. Participants with baseline Glu and Glx levels in the lower range had greater percent change in full scale IDS-SR scores post-treatment (p < 0.001), as did tNAA (p = 0.007). Low glutamatergic metabolite levels also predicted greater percent change in mood/cognition symptoms (p ≤ 0.001). Low-range Glu, Glx, and tNAA were associated with greater improvement on the immuno-metabolic subscale (p ≤ 0.003). Baseline Glu predicted rTMS responder status (p = 0.025) and had an area under the receiving operating characteristic curve of 0.81 (p = 0.009), demonstrating excellent discriminative ability. Baseline Glu, Glx, and tNAA significantly predicted MDD improvement after rTMS; preliminary evidence also demonstrates metabolite association with symptom subdomain improvement post-rTMS. This work provides feasibility for a personalized medicine approach to rTMS treatment selection, with individuals with Glu levels in the lower range potentially being the best candidates.

Single-session reproducibility of MR spectroscopy measures of glutathione in the mesial temporal lobe with MEGA-PRESS.

Magnetic resonance spectroscopy (MRS) measures neurochemicals in vivo. Glutathione (GSH) is a neuroprotective chemical shown to vary significantly in patients with Alzheimer's disease (AD). This work investigates the reproducibility of GSH measures in the mesial temporal lobe (MTL) to identify its potential clinical utility. MRS data were acquired from eight healthy volunteers (31.1±5.2 years; 4 male/female) using Mescher-Garwood-Point Resolved Spectroscopy (MEGA-PRESS) from the MTL in the left hemisphere across two scan sessions in the same visit. Total N-acetylaspartate (tNAA), choline (tCho), creatine (tCr), and GSH were quantified. Reproducibility of quantifications of these neurochemicals were tested using coefficient of variance (CV) between scan sessions. Reproducibility of voxel placement on the left MTL was calculated by measuring the tissue overlap and percent of hippocampus within that voxel. CV measured across different scan sessions in each individual, with a CV<15% was accepted as "good" reproducibility. Paired t-tests were carried out to establish the significant differences between the two scans across each individual with p<.05 as significant. TNAA (%CV = 7.2; p = .5), tCr (%CV = 7.8; p = .6) and tCho (%CV = 9.3; p = .4), and GSH (%CV = 22; p = .1). The dice coefficient that reflects the level of overlap of hippocampal tissue in the voxel was shown to be 0.8±0.1. Voxel tissue composition were: Scan 1 (cerebrospinal fluid [CSF]: 5 ± 1%, white matter [WM]: 52 ± 3%, gray matter [GM]: 43 ± 3%); Scan 2 (CSF: 5 ± 1%, WM: 52 ± 4%, GM: 44 ± 4%). The data suggest measures of abundant metabolites in the MTL using the MEGA-PRESS sequence has a high reproducibility. Reproducibility of GSH in this area was poorer requiring care when interpreting measures of GSH in the MTL for clinical translational purposes.

Investigating the brain's neurochemical profile at midlife in relation to dementia risk factors.

Changes in the brain's physiology in Alzheimer's disease are thought to occur early in the disease's trajectory. In this study our aim was to investigate the brain's neurochemical profile in a midlife cohort in relation to risk factors for future dementia using single voxel proton magnetic resonance spectroscopy. Participants in the multi-site PREVENT-Dementia study (age range 40-59 year old) underwent 3T magnetic resonance spectroscopy with the spectroscopy voxel placed in the posterior cingulate/precuneus region. Using LCModel, we quantified the absolute concentrations of myo-inositol, total N-acetylaspartate, total creatine, choline, glutathione and glutamate-glutamine for 406 participants (mean age 51.1; 65.3% female). Underlying partial volume effects were accounted for by applying a correction for the presence of cerebrospinal fluid in the magnetic resonance spectroscopy voxel. We investigated how metabolite concentrations related to apolipoprotein ɛ4 genotype, dementia family history, a risk score (Cardiovascular Risk Factors, Aging and Incidence of Dementia -CAIDE) for future dementia including non-modifiable and potentially-modifiable factors and dietary patterns (adherence to Mediterranean diet). Dementia family history was associated with decreased total N-acetylaspartate and no differences were found between apolipoprotein ɛ4 carriers and non-carriers. A higher Cardiovascular Risk Factors, Aging, and Incidence of Dementia score related to higher myo-inositol, choline, total creatine and glutamate-glutamine, an effect which was mainly driven by older age and a higher body mass index. Greater adherence to the Mediterranean diet was associated with lower choline, myo-inositol and total creatine; these effects did not survive correction for multiple comparisons. The observed associations suggest that at midlife the brain demonstrates subtle neurochemical changes in relation to both inherited and potentially modifiable risk factors for future dementia.