Measurement Of N-acetylaspartate Research Articles

Could thalamic biochemical changes correlate to cognitive impairment in idiopathic generalized epilepsy?

BackgroundThe thalamus is crucial in the development of idiopathic generalized epilepsy (IGE), which could lead to cognitive dysfunctions, according to data from neuropsychology and advanced neuroimaging investigations. This research aimed to measure the metabolic changes in the thalamus and to assess if could be contributed to cognitive impairment in IGE patients. Thirty IGE patients and thirty healthy volunteers with matched ages, genders, and educational levels participated in this cross-sectional case–control research. The IGE patients and controls were evaluated neuropsychologically using Intelligence Quotient (IQ) to assess general cognitive ability, Digit span for attention, Wechsler memory scale (WMS) for verbal memory, cube drawing test for visuospatial memory, Trail making test for executive functions, and Controlled Oral Word Association test (COWAT) for verbal fluency and quantitative multi-voxel MR spectroscopy (MRS) measurements of N-acetyl aspartate (NAA), choline (Cho), creatine (Cr), NAA/Cr, NAA/Cho and Cho/Cr ratios at 1.5 T scanner. The voxels were located over the right and left thalamus.ResultsThe IGE patients showed worse cognitive performance in IQ, attention, executive function, and verbal and visuospatial memory domains compared to the controls. The IGE patients exhibited a significantly decrease NAA in the right thalamus (p = 0.004) and a lower NAA/Cr ratio in the left thalamus (p = 0.01). the mean thalamus NAA level exhibited a positive correlation with CDT (r = 0.45, p = P = 0.01), and WMS-R (r = 0.39, p = 0.03) and a negative correlation with trail-making A test (r = 0.42, P = 0.01).Conclusionsit was concluded that IGE patients exhibited poor cognition which could be attributed to thalamic neurometabolic changes due to impaired thalamic cortical circuits.

Proton MR spectroscopic features of the cisternal segment of the trigeminal nerve in patients with trigeminal neuralgia: A pilot study

PurposeTo investigate normal quantitative proton magnetic resonance spectroscopy (MRS) features of the cisternal segment of the trigeminal nerve and evaluate possible metabolite concentration differences in the affected and unaffected nerves of trigeminal neuralgia patients. Material and methodsA total of 33 consecutive patients who underwent a MR study of the internal auditory canal/posterior fossa and dedicated trigeminal nerve multivoxel MRS were enrolled. Measurements of N-acetyl aspartate (NAA), creatine (Cr), choline (Cho), myoinositol (mI), glutamate-glutamine (Glx) concentrations, and ratios of NAA-to-Cr, Cho-to-Cr, and Cho-to-NAA were automatically calculated by the dedicated software. Vascular conflicts were also recorded. ResultsThe mean Cr concentration was significantly higher on the affected sides in all parts of the nerve (p < 0.05), while the mean NAA concentration was significantly higher in only the distal portion (p = 0.04). Mean mI concentration was significantly higher in the middle and distal parts (p < 0.05). NAA-to-Cr ratio was significantly higher in the proximal and middle parts (p < 0.05), while Cho-to-Cr ratio was significantly higher only in the middle portion (p = 0.028). Finally, the Cho-to-NAA ratio was significantly higher only in the distal portion (p = 0.04). Vascular conflicts were observed in 24 patients (72.7%), and in 20 of them (60.6%) the conflict was on the same side as the neuralgia symptoms. ConclusionAlthough the detected statistical relationships were variable in the spectroscopic measurements, metabolite concentrations and ratios were successfully exhibited in all patients. Features of a normal trigeminal nerve were able to determine by MRS. All calculated metabolite concentrations were higher in the affected nerves; however, only some of them were statistically significant. No statistically significant relationships were found between the MRS measurements and nerves with and without vascular compression.

7T Brain MRS in HIV Infection: Correlation with Cognitive Impairment and Performance on Neuropsychological Tests.

Validated neuroimaging markers of HIV-associated neurocognitive disorder in patients on antiretroviral therapy are urgently needed for clinical trials. The purpose of this study was to explore the relationship between cognitive impairment and brain metabolism in older subjects with HIV infection. It was hypothesized that MR spectroscopy measurements related to neuronal health and function (particularly N-acetylaspartate and glutamate) would be lower in HIV-positive subjects with worse cognitive performance. Forty-five HIV-positive patients (mean age, 58.9 ± 5.3 years; 33 men) underwent detailed neuropsychological testing and brain MR spectroscopy at 7T. Twenty-four subjects were classified as having asymptomatic cognitive impairment, and 21 were classified as having symptomatic cognitive impairment. Single-voxel proton MR spectra were acquired from 5 brain regions and quantified using LCModel software. Brain metabolites and neuropsychological test results were compared using nonparametric statistics and Pearson correlation coefficients. Differences in brain metabolites were found between symptomatic and asymptomatic subjects, with the main findings being lower measures of N-acetylaspartate in the frontal white matter, posterior cingulate cortex, and precuneus. In the precuneus, glutamate was also lower in the symptomatic group. In the frontal white matter, precuneus, and posterior cingulate cortex, NAA and glutamate measurements showed significant positive correlation with better performance on neuropsychological tests. Compared with asymptomatic subjects, symptomatic HIV-positive subjects had lower levels of NAA and glutamate, most notably in the frontal white matter, which also correlated with performance on neuropsychological tests. High-field MR spectroscopy offers insight into the pathophysiology associated with cognitive impairment in HIV and may be useful as a quantitative outcome measure in future treatment trials.

Early Life Stress Associated With Increased Striatal N-Acetyl-Aspartate: Cerebrospinal Fluid Corticotropin-Releasing Factor Concentrations, Hippocampal Volume, Body Mass, and Behavioral Correlates

Introduction Using proton magnetic resonance spectroscopy imaging, the effects of early life stress on nonhuman primate striatal neuronal integrity were examined as reflected by N-acetyl aspartate (NAA) concentrations. NAA measures were interrogated through examining their relationship to previously documented early life stress markers—cerebrospinal fluid corticotropin-releasing factor concentrations, hippocampal volume, body mass, and behavioral timidity. Rodent models of depression exhibit increases in neurotrophic effects in the nucleus accumbens. We hypothesized that rearing under conditions of early life stress (variable foraging demand, VFD) would produce persistent elevations of NAA concentrations (in absolute or ratio form) in ventral striatum/caudate nucleus (VS/CN) with altered correlation to early life stress markers. Methods Eleven bonnet macaque males reared under VFD conditions and seven age-matched control subjects underwent proton magnetic resonance spectroscopy imaging during young adulthood. Voxels were placed over VS/CN to capture nucleus accumbens. Cisternal cerebrospinal fluid corticotropin-releasing factor concentrations, hippocampal volume, body mass, and response to a human intruder had been previously determined. Results VFD-reared monkeys exhibited significantly increased NAA/creatine concentrations in right VS/CN in comparison to normally reared controls, controlling for multiple comparisons. In comparison to controls, VFD cerebrospinal fluid corticotropin-releasing factor concentrations were directly associated with right VS/CN absolute NAA. Left hippocampal volume was inversely associated with left VS/CN NAA/creatine in VFD reared but not in controls. Disruption of a normative inverse correlation between left VS/CN NAA and body mass was noted in VFD. Only non-VFD subjects exhibited a direct relationship between timidity response to an intruder and right VS/CN NAA. Conclusion Early life stress produced persistent increases in VS/CN NAA, which demonstrated specific patterns of association (or lack thereof) to early life stress markers in comparison to non-VFD subjects. The data are broadly consistent with a stable nonhuman primate phenotype of anxiety and mood disorder vulnerability whereby in vivo indicators of neuronal integrity, although reduced in hippocampus, are increased in striatum. The findings may provide a catalyst for further studies in humans and other species regarding a reciprocal hippocampal/nucleus accumbens relationship in affective disorders.

Simultaneous measurement of Aspartate, NAA, and NAAG using HERMES spectral editing at 3 Tesla

It has previously been shown that the HERMES method (‘Hadamard Encoding and Reconstruction of MEGA-Edited Spectroscopy’) can be used to simultaneously edit pairs of metabolites (such as N-acetyl-aspartate (NAA) and N-acetyl aspartyl glutamate (NAAG), or glutathione and GABA). In this study, HERMES is extended for the simultaneous editing of three overlapping signals, and illustrated for the example of NAA, NAAG and Aspartate (Asp). Density-matrix simulations were performed in order to optimize the HERMES sequence. The method was tested in NAA and Asp phantoms, and applied to the centrum semiovale of the nine healthy control subjects that were scanned at 3T. Both simulations and phantom experiments showed similar metabolite multiplet patterns with good segregation of all three metabolites. In vivo measurements show consistent relative signal intensities and multiplet patterns with concentrations in agreement with literature values. Simulations indicate co-editing of glutathione, glutamine, and glutamate, but their signals do not significantly overlap with the detected aspartyl resonances. This study demonstrates that a four-step Hadamard-encoded editing scheme can be used to simultaneously edit three otherwise overlapping metabolites, and can measure NAA, NAAG, and Asp in vivo in the brain at 3T with minimal crosstalk.

Whole-brain patterns of (1)H-magnetic resonance spectroscopy imaging in Alzheimer's disease and dementia with Lewy bodies.

Magnetic resonance spectroscopy has demonstrated metabolite changes in neurodegenerative disorders such as Alzheimer's disease (AD) and dementia with Lewy bodies (DLB); however, their pattern and relationship to clinical symptoms is unclear. To determine whether the spatial patterns of brain-metabolite changes in AD and DLB are regional or diffused, and to examine whether the key metabolite levels are associated with cognitive and non-cognitive symptoms, we acquired whole-brain spatially resolved 3T magnetic resonance spectroscopic imaging (MRSI) data from subjects with AD (N=36), DLB (N=35) and similarly aged controls (N=35). Voxel-wise measurement of N-acetylaspartate to creatine (NAA/Cr), choline to Cr (Cho/Cr), myo-inositol to Cr (mI/Cr) as well as glutamate and glutamine to Cr (Glx/Cr) ratios were determined using MRSI. Compared with controls, AD and DLB groups showed a significant decrease in most brain metabolites, with NAA/Cr, Cho/Cr and mI/Cr levels being reduced in posterior cingulate, thalamus, frontotemporal areas and basal ganglia. The Glx/Cr level was more widely decreased in DLB (posterior cingulate, hippocampus, temporal regions and caudate) than in AD (only in posterior cingulate). DLB was also associated with increased levels of Cho/Cr, NAA/Cr and mI/Cr in occipital regions. Changes in metabolism in the brain were correlated with cognitive and non-cognitive symptoms in the DLB but not in the AD group. The different patterns between AD and DLB may have implications for improving diagnosis, better understanding disease-specific neurobiology and targeting therapeutics. In addition, the study raised important questions about the role of occipital neuroinflammation and glial activation as well as the glutamatergic treatment in DLB.

Investigation of NAA and NAAG dynamics underlying visual stimulation using MEGA-PRESS in a functional MRS experiment

N-acetyl-aspartate (NAA) is responsible for the majority of the most prominent peak in 1H-MR spectra, and has been used as diagnostic marker for several pathologies. However, ~10% of this peak can be attributed to N-acetyl-aspartyl-glutamate (NAAG), a neuropeptide whose release may be triggered by intense neuronal activation. Separate measurement of NAA and NAAG using MRS is difficult due to large superposition of their spectra. Specifically, in functional MRS (fMRS) experiments, most work has evaluated the sum NAA+NAAG, which does not appear to change during experiments. The aim of this work was to design and perform an fMRS experiment using visual stimulation and a spectral editing sequence, MEGA-PRESS, to further evaluate the individual dynamics of NAA and NAAG during brain activation. The functional paradigm used consisted of three blocks, starting with a rest (baseline) block of 320s, followed by a stimulus block (640s) and a rest block (640s). Twenty healthy subjects participated in this study. On average, subjects followed a pattern of NAA decrease and NAAG increase during stimulation, with a tendency to return to basal levels at the end of the paradigm, with a peak NAA decrease of –(21±19)% and a peak NAAG increase of (64±62)% (Wilcoxon test, p<0.05). These results may relate to: 1) the only known NAAG synthesis pathway is from NAA and glutamate; 2) a relationship between NAAG and the BOLD response.

Proton MR Spectroscopy in Patients with Structural MRI-Negative Temporal Lobe Epilepsy.

With conventional magnetic resonance imaging (MRI), 20-30% of patients with temporal lobe epilepsy (TLE) have negative pathological MRI findings. Further investigations of the role of magnetic resonance spectroscopy (MRS) in the pre-surgical evaluation of patients with MRI-negative TLE are important to avoid intracranial EEG recording and to better understand the mechanism of the epileptogenic process. This study aimed to compare the measurements of N-acetylaspartate (NAA), creatine (Cr), and choline (Cho) in the hippocampi of MRI-negative TLE patients and normal subjects. Twenty patients with MRI-negative TLE and 10 age-matched healthy control subjects underwent MRI and MRS. The concentrations of NAA, Cr, and Cho and the ratios of NAA/Cr and NAA/(Cr+Cho) were measured. Seven of these 20 patients also underwent surgical treatment for TLE. Their pathological results and surgical outcomes were evaluated. In the hippocampi ipsilateral to the seizure side, the NAA/Cr and NAA/(Cr+Cho) ratios were significantly decreased compared with the ratios of the hippocampi contralateral to the seizure side and the normal control hippocampi. There was no significant difference between the hippocampi contralateral to the seizure side and the normal control hippocampi. The pathological results from the patients who underwent temporal lobe resection indicated mild to moderate gliosis and minimal loss of neurons. Five patients were seizure-free during the follow-up period of 9- 47 months (mean 27.7 months). In MRI-negative TLE, significant reductions in the NAA/Cr and NAA/(Cr+Cho) ratios ipsilateral to the seizure side may help lateralize and localize the epileptogenic zone.

Similarities of biochemical abnormalities between major depressive disorder and bipolar depression: A proton magnetic resonance spectroscopy study

BackgroundDepression in the context of bipolar disorder (BD) is often misdiagnosed as major depressive disorder (MDD), leading to mistreatments and poor clinical outcomes for many bipolar patients. Previous neuroimaging studies found mixed results on brain structure, and biochemical metabolism of the two disorders. To eliminate the compounding effects of medication, and aging, this study sought to investigate the brain biochemical changes of treatment-naïve, non-late-life patients with MDD and BD in white matter in prefrontal (WMP) lobe, anterior cingulate cortex (ACC) and hippocampus by using proton magnetic resonance spectroscopy (1H-MRS). MethodsThree groups of participants were recruited: 26 MDD patients, 20 depressed BD patients, and 13 healthy controls. The multi-voxel 1H-MRS [repetition time (TR)=1000ms; echo-time (TE)=144ms] was used for the measurement of N-acetylaspartate(NAA), choline containg compounds (Cho), and creatine (Cr) in three brain locations: white matter in prefrontal (WMP) lobe, anterior cingulate cortex (ACC), and hippocampus. Two ratios of NAA/Cr and Cho/Cr as a measure of brain biochemical changes were compared among three experimental groups. ResultsOn the comparison of brain biochemical changes, both MDD patients and BD patients showed many similarities compared to the controls. They both had a significantly lower NAA/Cr ratio in the left WMP lobe. There were no significant differences among three experimental groups for Cho/Cr ratio in the WMP lobe, and for the ratios of NAA/Cr and Cho/Cr in the bilateral ACC and hippocampus. The only difference between MDD and BD patients existed for the NAA/Cr ratio in the right WMP lobe. While MDD patients had a significantly lower NAA/Cr ratio than controls, BD patients showed no such differences. On the comparison of correlation of medical variables and brain biochemical changes, all participants demonstrated no significant correlations. ConclusionReduced NAA/Cr ratio at the left WMP lobe indicated the dysfunction of neuronal viability in deep white matter, in both MDD and BD patients who shared similarities of brain biochemical abnormalities, which might imply an overlap in neuropathology of depression.

Moderate relationships between NAA and cognitive ability in healthy adults: implications for cognitive spectroscopy

Background: Proton Magnetic Resonance Spectroscopy (1H-MRS) is a non-invasive imaging technique that enables quantification of neurochemistry in vivo and thereby facilitates investigation of the biochemical underpinnings of human cognitive variability. Studies in the field of cognitive spectroscopy have commonly focused on relationships between measures of N-acetyl aspartate (NAA), a surrogate marker of neuronal health and function, and broad measures of cognitive performance, such as IQ.Methodology/Principal Findings: In this study, we used 1H-MRS to interrogate single-voxels in occipitoparietal and frontal cortex, in parallel with assessments of psychometric intelligence, in a sample of 40 healthy adult participants. We found correlations between NAA and IQ that were within the range reported in previous studies. However, the magnitude of these effects was significantly modulated by the stringency of data screening and the extent to which outlying values contributed to statistical analyses.Conclusions/Significance: 1H-MRS offers a sensitive tool for assessing neurochemistry non-invasively, yet the relationships between brain metabolites and broad aspects of human behavior such as IQ are subtle. We highlight the need to develop an increasingly rigorous analytical and interpretive framework for collecting and reporting data obtained from cognitive spectroscopy studies of this kind.

T2 relaxation effects on apparent N-acetylaspartate concentration in proton magnetic resonance studies of schizophrenia

Over the past two decades, many magnetic resonance spectroscopy (MRS) studies reported lower N-acetylaspartate (NAA) in key brain regions of patients with schizophrenia (SZ) compared to healthy subjects. A smaller number of studies report no difference in NAA. Many sources of variance may contribute to these discordant results including heterogeneity of the SZ subject populations and methodological differences such as MRS acquisition parameters, and post-acquisition analytic methods. The current study reviewed proton MRS literature reporting measurements of NAA in SZ with a focus on methodology. Studies which reported lower NAA were significantly more likely to have used longer echo times (TEs), while studies with shorter TEs reported no concentration difference. This suggests that NAA quantitation using MRS was affected by the choice of TE, and that published MRS literature reporting NAA in SZ using a long TE is confounded by apparent differential T2 relaxation effects between SZ and healthy control groups. Future MRS studies should measure T2 relaxation times. This would allow for spectral concentration measurements to be appropriately corrected for these relaxation effects. In addition, as metabolite concentration and T2 relaxation times are completely independent variables, this could offer distinct information about the metabolite of interest.

Magnetic resonance spectroscopy biomarkers in premanifest and early Huntington disease

To evaluate in vivo brain metabolite differences in control subjects, individuals with premanifest Huntington disease (pre-HD), and individuals with early HD using ¹H magnetic resonance spectroscopy (MRS) and to assess their relationship with motor performance. Eighty-five participants (30 controls, 25 pre-HD, and 30 early HD) were recruited as part of the TRACK-HD study. Eighty-four were scanned at 3 T with single-voxel spectroscopy in the left putamen. Disease burden score was >220 among pre-HD individuals. Subjects underwent TRACK-HD motor assessment including Unified Huntington's Disease Rating Scale (UHDRS) motor scoring and a novel quantitative motor battery. Statistical analyses included linear regression and one-way analysis of variance. Total N-acetylaspartate (tNAA), a neuronal integrity marker, was lower in early HD (∼15%) vs controls (p < 0.001). N-acetylaspartate (NAA), a constituent of tNAA, was lower in pre-HD (∼8%) and early HD (∼17%) vs controls (p < 0.05). The glial cell marker, myo-inositol (mI), was 50% higher in early HD vs pre-HD (p < 0.01). In early HD, mI correlated with UHDRS motor score (R² = 0.23, p < 0.05). Across pre-HD and early HD, tNAA correlated with performance on a tongue pressure task (R² = 0.30, p < 0.0001) and with disease burden score (R² = 0.17, p < 0.005). We demonstrate lower putaminal tNAA in early HD compared to controls in a cross-section of subjects. A novel biomarker role for mI in early HD was also identified. These findings resolve disagreement in the literature about the role of MRS as an HD biomarker. We conclude that putaminal MRS measurements of NAA and mI are promising potential biomarkers of HD onset and progression.

In Vivo Measurement of Brain GABA Concentrations by Magnetic Resonance Spectroscopy in Smelters Occupationally Exposed to Manganese

BackgroundExposure to excessive levels of manganese (Mn) is known to induce psychiatric and motor disorders, including parkinsonian symptoms. Therefore, finding a reliable means for early detection of Mn neurotoxicity is desirable.ObjectivesOur goal was to determine whether in vivo brain levels of γ-aminobutyric acid (GABA), N-acetylaspartate (NAA), and other brain metabolites in male smelters were altered as a consequence of Mn exposure.MethodsWe used T1-weighted magnetic resonance imaging (MRI) to visualize Mn deposition in the brain. Magnetic resonance spectroscopy (MRS) was used to quantify concentrations of NAA, glutamate, and other brain metabolites in globus pallidus, putamen, thalamus, and frontal cortex from a well-established cohort of 10 male Mn-exposed smelters and 10 male age-matched control subjects. We used the MEGA-PRESS MRS sequence to determine GABA levels in a region encompassing the thalamus and adjacent parts of the basal ganglia [GABA-VOI (volume of interest)].ResultsSeven of 10 exposed subjects showed clear T1-hyperintense signals in the globus pallidus indicating Mn accumulation. We found a significant increase (82%; p = 0.014) in the ratio of GABA to total creatine (GABA/tCr) in the GABA-VOI of Mn-exposed subjects, as well as a distinct decrease (9%; p = 0.04) of NAA/tCr in frontal cortex that strongly correlated with cumulative Mn exposure (R = −0.93; p < 0.001).ConclusionsWe demonstrated elevated GABA levels in the thalamus and adjacent basal ganglia and decreased NAA levels in the frontal cortex, indicating neuronal dysfunction in a brain area not primarily targeted by Mn. Therefore, the noninvasive in vivo MRS measurement of GABA and NAA may prove to be a powerful tool for detecting presymptomatic effects of Mn neurotoxicity.

Riluzole decreases synthesis of N-acetylaspartate and N-acetylaspartylglutamate in SH-SY5Y human neuroblastoma cells

N-acetylaspartate (NAA) is present at very high concentrations in the brain and is used as a non-invasive marker of neuronal viability in magnetic resonance spectroscopy. N-acetylaspartylglutamate (NAAG) is an acetylated dipeptide formed from NAA, and may be an agonist of the mGluR3 receptor. Both NAA and NAAG are synthesized primarily in neurons. Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder resulting in motor neuron death, and progressive paralysis. Levels of both NAA and NAAG are reported to be decreased in ALS. Riluzole is a glutamatergic modulating agent used to treat ALS, but there are conflicting results in the literature concerning the recovery of NAA after riluzole treatment. We studied the effects of riluzole on the biosynthesis of both NAA and NAAG in SH-SY5Y human neuroblastoma cells. We used two methodologies to examine the effect; one involving radiolabel incorporation from corresponding substrates into NAA and NAAG, and the other involving the measurement of endogenous NAA and NAAG levels using HPLC. We show that riluzole treatment, which decreases glutamatergic neuronal excitation, decreases the synthesis and levels of both NAA and NAAG in SH-SY5Y cells in a dose and time dependant manner. These results suggest that the synthesis of NAA and NAAG may be coupled to glutamatergic neurotransmission, and further investigations along these lines are warranted.

Magnetic Resonance Spectroscopy Findings in Photosensitive Idiopathic Generalized Epilepsy

Studies investigating the pathophysiology of epileptic photosensitivity indicate variable involvement of particular brain regions. Our aim was to identify metabolic differences between photosensitive idiopathic generalized epilepsy (IGE) patients and nonphotosensitive IGE patients and normal healthy subjects by using Magnetic Resonance Spectroscopy (MRS). Fourteen patients diagnosed with photosensitive IGE were investigated. The control groups consisted of 14 age- and sex-matched healthy volunteers and 14 IGE patients without photosensitivity. MRS measurements of N-acetylaspartate (NAA), choline-containing compounds (Cho), creatine (Cr) were performed in the frontal and occipital cortex and the thalamus bilaterally using a stimulated echo acquisition mode (STEAM) technique with a voxel size of 20 x 20 x 20 mm. The values of the patients with IGE were compared with those of the normal controls and within subgroups according to the clinical variables by appropriate statistical tests. Photosensitive IGE patients showed significantly decreased concentrations of NAA in the right frontal lobe and left thalamus, decreased NAA/Cr ratio in left thalamus and significantly increased concentrations of Cho/Cr ratio in the right frontal lobe and NAA/Cr in the left occipital lobe when compared to normal controls. Furthermore, left occipital NAA concentration increased and left thalamus NAA/Cr ratios were decreased from the IGE patients without photosensitivity but without reaching statistical significance. Our results support previous MR studies suggesting an asymmetrical neuronal dysfunction in favor of the dominant occipital cortex and thalamus in photosensitive IGE patients.

Development and application of a liquid chromatography/tandem mass spectrometric assay for measurement of N-acetylaspartate, N-acetylaspartylglutamate and glutamate in brain slice superfusates and tissue extracts

A liquid chromatography–tandem mass spectrometric method has been developed for measurement of N-acetylaspartate, N-acetylaspartylglutamate and glutamate. The analytes were separated within 5 min using an anion exchange/reverse phase column. The lower limit of quantification for Glu, NAA and NAAG was found to be 5, 50 and 6 nM, respectively, with a signal-to-noise ratio of 5:1. Using this methodology the basal levels of Glu, NAA and NAAG could be measured consistently in in vitro superfusion samples from rat hippocampus. The assay was also used for measurement of the distribution of Glu, NAA and NAAG in different regions of the rat brain.

Brain lithium, N‐acetyl aspartate and myo‐inositol levels in older adults with bipolar disorder treated with lithium: a lithium‐7 and proton magnetic resonance spectroscopy study

We investigated the relationship between brain lithium levels and the metabolites N-acetyl aspartate (NAA) and myo-inositol (myo-Ino) in the anterior cingulate cortex of a group of older adults with bipolar disorder (BD). This cross-sectional assessment included nine subjects (six males and three females) with bipolar I disorder and currently treated with lithium, who were examined at McLean Hospital's Geriatric Psychiatry Research Program and Brain Imaging Center. The subjects' ages ranged from 56 to 85 years (66.0 +/- 9.7 years) and all subjects had measurements of serum and brain lithium levels. Brain lithium levels were assessed using lithium magnetic resonance spectroscopy. All subjects also had proton magnetic resonance spectroscopy to obtain measurements of NAA and myo-Ino. Brain lithium levels were associated with higher NAA levels [df = (1, 8), Beta = 12.53, t = 4.09, p < 0.005] and higher myo-Ino levels [df = (1, 7), F = 16.81, p < 0.006]. There were no significant effects of serum lithium levels on any of the metabolites. Our findings of a relationship between higher brain lithium levels and elevated NAA levels in older adult subjects with BD may support previous evidence of lithium's neuroprotective, neurotrophic, and mitochondrial function-enhancing effects. Elevated myo-Ino related to elevated brain lithium levels may reflect increased inositol monophosphatase (IMPase) activity, which would lead to an increase in myo-Ino levels. This is the first study to demonstrate alterations in NAA and myo-Ino in a sample of older adults with BD treated with lithium.

Impact of the Brain-Derived Neurotrophic Factor Val66Met Polymorphism on Levels of Hippocampal N-Acetyl-Aspartate Assessed by Magnetic Resonance Spectroscopic Imaging at 3 Tesla

This study was conducted to corroborate prior evidence of an effect of the brain-derived neurotrophic factor (BDNF) valine (val) to methionine (met) amino acid substitution at codon 66 (val66met) polymorphism on measures of N-acetyl-aspartate (NAA) containing compounds in healthy subjects. The NAA to creatine (Cre) ratio (NAA/Cre), NAA to choline (Cho) ratio (NAA/Cho), and Cho to Cre ratio (Cho/Cre) were measured in the left and right hippocampi, left and right dorsolateral prefrontal cortices, occipital lobe, anterior cingulate, and white matter of the centrum semiovale of 69 carefully screened healthy volunteers utilizing proton magnetic resonance spectroscopic imaging (MRSI) at 3 Tesla (T). Val/met subjects exhibited significantly reduced levels of left hippocampal NAA/Cre and NAA/Cho compared with val/val subjects. This effect was independent of age, IQ, number of voxels, hippocampal volume, or gray matter content in the voxels of interest. Analysis of other brain regions showed no effect of BDNF genotype on NAA measures. We confirmed the association between the met-BDNF variant and reduced levels of hippocampal NAA found with a similar technique at 1.5T. The consonance of our results with prior findings adds to the evidence that the BDNF val/met genotype affects hippocampal biology with implications for a variety of neuropsychiatric disorders.

TEMPORAL WINDOW OF METABOLIC BRAIN VULNERABILITY TO CONCUSSION

ABSTRACT OBJECTIVE In the present study, the occurrence of the temporal window of brain vulnerability was evaluated in concussed athletes by measuring N-acetylaspartate (NAA) using proton magnetic resonance (1H-MR) spectroscopy. METHODS Thirteen nonprofessional athletes who had a sport-related concussive head injury were examined for NAA determination by means of 1H-MR spectroscopy at 3, 15, and 30 days postinjury. All athletes but three suspended their physical activity. Those who continued their training had a second concussive event and underwent further examination at 45 days from the initial injury. The single case of one professional boxer, who was studied before the match and 4, 7, 15, and 30 days after a knockout, is also presented. Before each magnetic resonance examination, patients were asked for symptoms of mild traumatic brain injury, including physical, cognitive, emotional, and sleep disturbances. Data for 1H-MR spectroscopy recorded in five normal, age-matched, control volunteers, who were previously screened to exclude previous head injuries, were used for comparison. Semiquantitative analysis of NAA relative to creatine (Cr)- and choline (Cho)-containing compounds was performed from proton spectra obtained with a 3-T magnetic resonance system. RESULTS Regarding the values of the NAA-to-Cr ratio (2.21 ± 0.11) recorded in control patients, singly concussed athletes, at 3 days after the concussion, showed a decrease of 18.5% (1.80 ± 0.04; P &amp;lt; 0.001). Only a modest 3% recovery was observed at 15 days (1.88 ± 0.1; P &amp;lt; 0.001); at 30 days postinjury, the NAA-to-Cr ratio was 2.15 ± 0.1, revealing full metabolic recovery with values not significantly different from those of control patients. These patients declared complete resolution of symptoms at the time of the 3-day study. The three patients who had a second concussive injury before the 15-day study showed an identical decrease of the NAA-to-Cr ratio at 3 days (1.78 ± 0.08); however, at 15 days after the second injury, a further diminution of the NAA-to-Cr ratio occurred (1.72 ± 0.07; P &amp;lt; 0.05 with respect to singly concussed athletes). At 30 days, the NAA-to-Cr ratio was 1.82 ± 0.1, and at 45 days postinjury, the NAA-to-Cr ratio showed complete recovery (2.07 ± 0.1; not significant with respect to control patients). This group of patients declared a complete resolution of symptoms at the time of the 30-day study. CONCLUSION Results of this pilot study carried out in a cohort of singly and doubly concussed athletes, examined by 1H-MR spectroscopy for their NAA cerebral content at different time points after concussive events, demonstrate that also in humans, concussion opens a temporal window of brain metabolic imbalance, the closure of which does not coincide with resolution of clinical symptoms. The recovery of brain metabolism is not linearly related to time. A second concussive event prolonged the time of NAA normalization by 15 days. Although needing confirmation in a larger group of patients, these results show that NAA measurement by 1H-MR spectroscopy is a valid tool in assessing the full cerebral metabolic recovery after concussion, thereby suggesting its use in helping to decide when to allow athletes to return to play after a mild traumatic brain injury.

TEMPORAL WINDOW OF METABOLIC BRAIN VULNERABILITY TO CONCUSSION

In the present study, the occurrence of the temporal window of brain vulnerability was evaluated in concussed athletes by measuring N-acetylaspartate (NAA) using proton magnetic resonance (H-MR) spectroscopy. Thirteen nonprofessional athletes who had a sport-related concussive head injury were examined for NAA determination by means of H-MR spectroscopy at 3, 15, and 30 days postinjury. All athletes but three suspended their physical activity. Those who continued their training had a second concussive event and underwent further examination at 45 days from the initial injury. The single case of one professional boxer, who was studied before the match and 4, 7, 15, and 30 days after a knockout, is also presented. Before each magnetic resonance examination, patients were asked for symptoms of mild traumatic brain injury, including physical, cognitive, emotional, and sleep disturbances. Data for H-MR spectroscopy recorded in five normal, age-matched, control volunteers, who were previously screened to exclude previous head injuries, were used for comparison. Semiquantitative analysis of NAA relative to creatine (Cr)- and choline (Cho)-containing compounds was performed from proton spectra obtained with a 3-T magnetic resonance system. Regarding the values of the NAA-to-Cr ratio (2.21 +/- 0.11) recorded in control patients, singly concussed athletes, at 3 days after the concussion, showed a decrease of 18.5% (1.80 +/- 0.04; P < 0.001). Only a modest 3% recovery was observed at 15 days (1.88 +/- 0.1; P < 0.001); at 30 days postinjury, the NAA-to-Cr ratio was 2.15 +/- 0.1, revealing full metabolic recovery with values not significantly different from those of control patients. These patients declared complete resolution of symptoms at the time of the 3-day study. The three patients who had a second concussive injury before the 15-day study showed an identical decrease of the NAA-to-Cr ratio at 3 days (1.78 +/- 0.08); however, at 15 days after the second injury, a further diminution of the NAA-to-Cr ratio occurred (1.72 +/- 0.07; P < 0.05 with respect to singly concussed athletes). At 30 days, the NAA-to-Cr ratio was 1.82 +/- 0.1, and at 45 days postinjury, the NAA-to-Cr ratio showed complete recovery (2.07 +/- 0.1; not significant with respect to control patients). This group of patients declared a complete resolution of symptoms at the time of the 30-day study. Results of this pilot study carried out in a cohort of singly and doubly concussed athletes, examined by H-MR spectroscopy for their NAA cerebral content at different time points after concussive events, demonstrate that also in humans, concussion opens a temporal window of brain metabolic imbalance, the closure of which does not coincide with resolution of clinical symptoms. The recovery of brain metabolism is not linearly related to time. A second concussive event prolonged the time of NAA normalization by 15 days. Although needing confirmation in a larger group of patients, these results show that NAA measurement by H-MR spectroscopy is a valid tool in assessing the full cerebral metabolic recovery after concussion, thereby suggesting its use in helping to decide when to allow athletes to return to play after a mild traumatic brain injury.