Changes In N-acetylaspartate Research Articles

N-acetylaspartate in the motor and sensory cortices following functional recovery after surgery for cervical spondylotic myelopathy.

OBJECTIVE Cervical spondylotic myelopathy (CSM) is the most common cause of reversible spinal cord dysfunction in people over the age of 55 years. Following surgery for symptomatic CSM, patients demonstrate motor improvement early in the postoperative course, whereas sensory improvement can lag behind. The authors of the present study hypothesized that changes in the concentration of N-acetylaspartate (NAA) in the motor and sensory cortices in the brain would emulate the time course of neurological recovery following decompression surgery for CSM. Their aim was to compare and contrast how metabolite levels in the motor and sensory cortices change after surgery to reverse downstream spinal cord compression. METHODS Twenty-four patients with CSM and 8 control subjects were studied using proton MR spectroscopy (1H-MRS) images acquired on a 3.0-T Siemens MRI unit. The 1H-MRS data (TE 135 msec, TR 2000 msec) were acquired to measure absolute levels of NAA from the motor and sensory cortices in the cerebral hemisphere contralateral to the side of greater deficit at baseline in each subject. Data were also acquired at 6 weeks and 6 months following surgery. Control subjects were also evaluated at 6 weeks and 6 months following baseline data acquisition. Neurological function was measured in each subject at all time points using the Neck Disability Index (NDI), modified Japanese Orthopaedic Association (mJOA) questionnaire, and the American Spinal Injury Association (ASIA) neurological classification. RESULTS In the motor cortex of patients, NAA levels decreased significantly (p < 0.05) at 6 weeks and 6 months postsurgery compared with baseline levels. In the sensory cortex of patients, NAA levels decreased significantly (p < 0.05) only at 6 months after surgery compared with baseline and 6-week levels. No significant changes in NAA were found in control subjects. Clinical scores demonstrated significant (p < 0.05) motor recovery by 6 weeks, whereas sensory improvements (p < 0.05) appeared at only 6 months. CONCLUSIONS Findings suggest that metabolite changes in both the motor and sensory cortices mimic the time course of functional motor and sensory recovery in patients with CSM. The temporal course of neurological recovery may be influenced by metabolic changes in respective cortical regions.

Polyphenon E, non-futile at neuroprotection in multiple sclerosis but unpredictably hepatotoxic: Phase I single group and phase II randomized placebo-controlled studies

ObjectivesPhase I (PhI): assess the safety of Polyphenon E in people with multiple sclerosis (MS) and determine the futility of Polyphenon E as a neuroprotective agent. Correlate plasma levels of EGCG with neuroprotective effects.Phase II (PhII): Further assess safety and confirm the neuroprotective effects of Polyphenon E. DesignPhI: single group futility study. PhII: parallel group randomized double-blind placebo-controlled study. ParticipantsRecruitment area (both studies): LSU MS Center, New Orleans, LA and general public from surrounding areas.Inclusion criteria (both studies): 1) MS per 2005 McDonald criteria; 2) relapsing remitting or secondary progressive MS; 3) stable for six months prior to enrollment on either no therapy or glatiramer acetate (GA) for the PhI study and on either on GA or Interferon β for the PhII study.Exclusion criteria (both studies): 1) complete bone marrow ablation or alentuzumab use at any time; 2) mitoxantrone, cyclophosphamide, natalizumab or fingolimod use in the prior nine months; 3) liver problems or significant medical problems. InterventionsPhI: Polyphenon E, a green tea extract containing 50% of the antioxidant Epigallocatechin-gallate (EGCG), two capsules twice daily (200mg of EGCG per capsule; total daily dose 800mg) for six months.PhII: Polyphenon E or matching placebo capsules, same dose for one year. Only the research pharmacist knew treatment assignment and she randomized participants (one-to-one, stratified by GA or Interferon β, blocks of 4 or 6). Outcome evaluators did not discuss side effects with participants. Outcome measuresPhI: 1) adverse events (AE); 2) futility: decrease in N-acetyl aspartate (NAA) from baseline to six months of 10% or more; 3) association between EGCG plasma levels and change in NAA.PhII: 1) AEs; 2) difference in the rate of change of NAA-levels over twelve months.We measured NAA using a point resolved magnetic resonance spectroscopic imaging sequence (TE30/TR2000) on a 10cm×10cm×1cm volume of interest (VOI) located just superior to the lateral ventricles. The field of view was 16×16 resulting in 1cm3 voxels. We quantified NAA and creatine/phosphocreatine (Cr) levels using LCModel for post-processing. ResultsPhI: Ten participants enrolled and completed all assessments with no serious AEs. One discontinued therapy due to grade (G) I abnormal liver function tests (LFTs). We included all participants in the analysis. NAA adjusted for creatine increased by 10% [95% CI(3.4%,16.2%), p<0.01] rejecting the futility endpoint.PhII: Thirteen participants enrolled and twelve started treatment. The DSMB stopped the study because 5/7 participants on Polyphenon E had abnormal LFTs (G I, and 1G III). Median time to onset of abnormal LFTs was 20weeks [Inter-Quartile Range (IQR) (10,23)]. Only two participants completed the six-month visit, so we could not analyze the NAA levels.PhI participants took capsules from lot 189I1107 while 6/7 PhII participants took capsules from a new lot (L0206306). Both lots had similar levels of EGCG but differed in the levels of minor catechins. There were no significant differences between the lots on participants' median free EGCG plasma levels at either 3h or 8h as well as conjugated EGCG levels at 3h (all p>0.4, Wilcoxon exact test).Free EGCG levels at 8h correlated with changes in NAA adjusted by water content. A 1ng/ml higher EGCG plasma concentration correlated with a 0.9% increase in NAA[95% CI(0.5%,1.4%), visit*level interaction F=14.4, p<0.001]. However, EGCG plasma concentrations did not correlate with NAA adjusted by creatine (1ng/ml higher EGCG was associated with 0.02%,[95% CI(−0.27%,0.3%) change in NAA, p>0.5]). There was a trend towards an increase in creatine levels (referenced to water content) from baseline to exit (1 5% increase, [95% CI(−6%,17%), p=0.4]). The free EGCG levels at 8hours correlated significantly with change in creatine levels (1ng/ml higher EGCG level at 8h was associated with a 1.1% increase in creatine [95% CI(0.6%,1.6%)]). Thus it is possible that the discrepancy between the correlation of the EGCG 8h levels with NAA changes referenced to water and the 8h EGCG levels with NAA changes referenced to creatine was due to a change in creatine among the subjects with higher EGCG levels.Conjugated 3h and 8h levels and free 3h levels did not correlate with NAA changes (all p >0.5). Conclusions/classification of evidenceClass III evidence: Polyphenon E at a dose of 400mg of EGCG twice a day is not futile at increasing brain NAA levels. Class I evidence: some lots of Polyphenon E have a high risk of hepatotoxicity. FundingNational Center for Complementary and Alternative Medicine K23AT004433, National Multiple Sclerosis Society RG4816-A-1 and National Institute of General Medical Sciences 1 U54 GM104940. Mitsui Norin provided Polyphenon E and placebo and their representative reviewed the manuscript prior to publication. Mitsui Norin was not involved in other aspects of the study. The decision to submit the manuscript remained with the investigators. RegistrationNCT00836719 and NCT01451723NCT00836719NCT01451723.

N-acetylaspartate reduction in the medial prefrontal cortex following 8 weeks of risperidone treatment in first-episode drug-naïve schizophrenia patients.

It is unclear whether N-acetylaspartate (NAA) depletions documented in schizophrenia patients might be due to the disease progression or medications. Here we investigated longitudinal NAA changes in drug-naïve first-episode patients (FEP) who are relatively free from chronicity. Forty-two drug-naïve FEP and 38 controls were enrolled in this study to explore the effect of 8-week risperidone monotherapy on NAA. All spectra were obtained from the medial prefrontal cortex (MPFC) on a 3.0 T MRI and analyzed with LCModel. At baseline, patients presented no significant differences in NAA (P = 0.084) or NAA/Cr + Pcr (P = 0.500) compared to controls; NAA levels were negatively correlated with PANSS total scores (P = 0.001) and WCST-PE (P = 0.041). After treatment, patients demonstrated significant reductions of NAA (P < 0.001) and NAA/Cr + Pcr (P < 0.001), and significant improvement in PANSS-P (P < 0.001) and PANSS-G (P < 0.001) symptoms. We detected no significant correlations between NAA alterations and PANSS-P (P = 0.679) or PANSS-G (P = 0.668) symptom changes; nor did NAA/Cr + Pcr changes with alterations in PANSS-P (P = 0.677) and PANSS-G (P = 0.616). This is the first evidence that short-term risperidone treatment induces an acute reduction of MPFC NAA during the early phase of schizophrenia, which may be a previously unavailable biomarker to indicate risperidone with a similar pharmacological mechanism, although the functional significance is still unclear.

No change in N-acetyl aspartate in first episode of moderate depression after antidepressant treatment: (1)H magnetic spectroscopy study of left amygdala and left dorsolateral prefrontal cortex.

BackgroundThe role of brain metabolites as biological correlates of the intensity, symptoms, and course of major depression has not been determined. It has also been inconclusive whether the change in brain metabolites, measured with proton magnetic spectroscopy, could be correlated with the treatment outcome.MethodsProton magnetic spectroscopy was performed in 29 participants with a first episode of moderate depression occurring in the left dorsolateral prefrontal cortex and left amygdala at baseline and after 8 weeks of antidepressant treatment with escitalopram. The Montgomery-Asberg Depression Rating Scale, the Hamilton Rating Scale for Depression, and the Beck Depression Inventory were used to assess the intensity of depression at baseline and at the endpoint of the study. At endpoint, the participants were identified as responders (n=17) or nonresponders (n=12) to the antidepressant therapy.ResultsThere was no significant change in the N-acetyl aspartate/creatine ratio (NAA/Cr) after treatment with antidepressant medication. The baseline and endpoint NAA/Cr ratios were not significantly different between the responder and nonresponder groups. The correlation between NAA/Cr and changes in the scores of clinical scales were not significant in either group.ConclusionThis study could not confirm any significant changes in NAA after antidepressant treatment in the first episode of moderate depression, or in regard to therapy response in the left dorsolateral prefrontal cortex or left amygdala. Further research is necessary to conclude whether NAA alterations in the first episode of depression could possibly be different from chronic or late-onset depression, and whether NAA alterations in stress-induced (reactive) depression are different from endogenous depression. The potential role of NAA as a biomarker of a treatment effect has yet to be established.

In vivo evidence of glutamate toxicity in multiple sclerosis.

There is increasing evidence that altered glutamate (Glu) homeostasis is involved in the pathophysiology of multiple sclerosis (MS). The aim of this study was to evaluate the in vivo effects of excess brain Glu on neuroaxonal integrity measured by N-acetylaspartate (NAA), brain volume, and clinical outcomes in a large, prospectively followed cohort of MS subjects. We used multivoxel spectroscopy at 3T to longitudinally estimate Glu and NAA concentrations from large areas of normal-appearing white and gray matter (NAWM and GM) in MS patients (n = 343) with a mean follow-up time of 5 years. Using linear mixed-effects models, Glu was examined as a predictor of NAA decline, annualized percentage brain volume change, and evolution of clinical outcomes (Multiple Sclerosis Functional Composite [MSFC], Paced Auditory Serial Addition Test-3 [PASAT], and Expanded Disability Status Scale). Glu/NAA ratio was tested as a predictor of brain volume loss and clinical outcomes. Baseline Glu[NAWM] was predictive of accelerated longitudinal decline in NAA[GM] (-0.06mM change in NAA[GM] /yr for each unit increase in Glu; p = 0.004). The sustained elevation of Glu[NAWM] was predictive of a loss of 0.28mM/yr in NAA[NAWM] (p < 0.001) and 0.15mM/yr in NAA[GM] (p = 0.056). Each 10% increase in Glu/NAA[NAWM] was associated with a loss of 0.33% brain volume/yr (p = 0.001), 0.009 standard deviations/yr in MSFC z-score (p < 0.001), and 0.17 points/yr on the PASAT (p < 0.001). These results indicate that higher Glu concentrations increase the rate of NAA decline, and higher Glu/NAA[NAWM] ratio increases the rate of decline of brain volume, MSFC, and PASAT. This provides evidence of a relationship between brain Glu and markers of disease progression in MS.

N-acetyl-aspartate (NAA) as a correlate of pharmacological treatment in psychiatric disorders: A systematic review

The amino-acid N-acetyl-aspartate (NAA) is located in neurons and the concentration of NAA correlates with neuronal mitochondrial function. The signal of NAA, as measured with proton magnetic resonance spectroscopy (1H-MRS), is considered to reflect both, neuronal density and integrity of neuronal mitochondria. A reduction of the NAA concentrations has been found in several psychiatric disorders. Newer studies report reversal of decreased NAA concentration with treatment. The objective of this review is to summarize the literature on NAA changes in association with psychopharmacological treatment in psychiatric disorders (affective disorders, obsessive-compulsive disorder, schizophrenia and dementia). The majority of studies identified increased NAA concentrations in response to treatment, while a smaller number of studies did not find this effect. The NAA increase seems to be neither specific for a certain disorder nor for a specific intervention. This suggests that the reduction of NAA may represent an altered functional (metabolic) state of neurons common to different psychiatric disorders and the increase after treatment to indicate functional restoration as one general effect of interventions.

Motor cortex glutathione deficit in ALS measured in vivo with the J-editing technique

This study compared in vivo levels of the antioxidant glutathione (GSH) in the motor cortex of 11 ALS patients with those in 11 age-matched healthy volunteers (HV). Using the standard J-edited spin-echo difference MRS technique, GSH spectra were recorded on a 3.0T GE MR system from a single precentral gyrus voxel. GSH levels expressed as ratios to the unsuppressed voxel tissue water (W) were 31% lower in ALS patients than in HV (p=.005), and 36% lower in ALS than in HV (p=.02) when expressed as ratios to the total creatine peak (tCr), supporting a role for oxidative stress in ALS. Levels of the putative neuronal marker N-acetylaspartate (NAA) relative to W did not differ between ALS and HV (p=.26), but were lower by 9% in ALS than in HV (p=.013) when expressed as ratios relative to tCr. This discrepancy is attributed to small but opposite changes in NAA and tCr in ALS that, as a ratio, resulted in a statistically significant group difference, further suggesting caution in using tCr as an internal reference under pathological conditions.

Hippocampal Neurochemical Changes in Senescent Mice Induced with Chronic Injection of D-Galactose and NaNO2: An In Vitro High-Resolution NMR Spectroscopy Study at 9.4T

Proton magnetic resonance spectroscopy (1H-MRS) has been used to provide useful information about the neurochemical changes reflecting early pathological alterations in Alzheimer's disease (AD) brain. In this study, we have longitudinally measured the hippocampal neurochemical profile in vitro in senescent mice induced with chronic injection of D-Galactose and NaNO2, at different time point from day 30 to day 70 with a 10-day interval. Pathological brain alterations induced by D-Galactose and NaNO2 were monitored through hematoxylin and eosin (HE) staining, Congo red staining and bielschowsky silver staining, and the cognition deficits were assessed via Morris Water Maze (MWM) test. This D-galactose and NaNO2 treated mouse model, characterized by an early-onset memory dysfunction, a robust neuronal loss, amyloid plaques and neurofibrillary tangles in hippocampal subdivision, well mimics a prodromal Alzheimer's phenotype. Consistent with previously published in vivo 1H MRS findings in human AD patients and AD transgenic mice, our in vitro 1H MRS on the perchloric acid extractions of hippocampus in senescent mice observed significant decreases of N-acetylaspartate (NAA) and Glutamate (Glu) but an increase in Myo-inositol (mIns). Elevated mIns occurred prior to the reduction of NAA and Glu during the progression of aging. In addition, changes in mIns, NAA and Glu were found to precede pathological abnormalities. Overall, our in vitro findings in senescent mice validated the concept that hippocampal neurochemical alternations preceded the pathological changes of the brain, and could serve as potential markers of AD progression. Reductions of NAA and Glu can be interpreted in terms of neuronal degeneration and dysfunctions in glutamatergic activity that may contribute to the pathophysiological mechanisms underlying AD. Elevated mIns might be related to glial activation. Further experiments are needed to explore the potential value of mIns in the early diagnosis of AD, to verify whether glial cell proliferation occurs earlier than neuronal changes.

The Molecular Mechanisms Affecting N-Acetylaspartate Homeostasis Following Experimental Graded Traumatic Brain Injury

To characterize the molecular mechanisms of N-acetylaspartate (NAA) metabolism following traumatic brain injury (TBI), we measured the NAA, adenosine triphosphate (ATP) and adenosine diphosphate (ADP) concentrations and calculated the ATP/ADP ratio at different times from impact, concomitantly evaluating the gene and protein expressions controlling NAA homeostasis (the NAA synthesizing and degrading enzymes N-acetyltransferase 8-like and aspartoacylase, respectively) in rats receiving either mild or severe TBI. The reversible changes in NAA induced by mild TBI were due to a combination of transient mitochondrial malfunctioning with energy crisis (decrease in ATP and in the ATP/ADP ratio) and modulation in the gene and protein levels of N-acetyltransferase 8-like and increase of aspartoacylase levels. The irreversible decrease in NAA following severe TBI, was instead characterized by profound mitochondrial malfunctioning (constant 65% decrease of the ATP/ADP indicating permanent impairment of the mitochondrial phosphorylating capacity), dramatic repression of the N-acetyltransferase 8-like gene and concomitant remarkable increase in the aspartoacylase gene and protein levels. The mechanisms underlying changes in NAA homeostasis following graded TBI might be of note for possible new therapeutic approaches and will help in understanding the effects of repeat concussions occurring during particular periods of the complex NAA recovery process, coincident with the so called window of brain vulnerability.

Reduction in Glutamine/Glutamate Levels in the Cerebral Cortex after Adrenocorticotropic Hormone Therapy in Patients with West Syndrome

West syndrome (WS), an intractable epileptic encephalopathy of infancy, is refractory to many antiepileptic drugs; however, adrenocorticotropic hormone (ACTH) is an effective treatment for WS. The mechanism behind the efficacy of ACTH is mediated by biochemical processes that remain unknown. We examined the effects of ACTH therapy with tetracosactide (TCS), a synthetic ACTH analogue, on brain metabolism in patients with WS, using (1)H magnetic resonance spectroscopy (¹H-MRS). In six patients with cryptogenic WS, we performed single-voxel ¹H-MRS at the occipital lobe cortex. Measurements were taken prior to TCS treatment, a few days after therapy, and several months after therapy. Data were also compared with subjects having only mild psychomotor delays. The metabolites measured were glutamine plus glutamate (Glx), N-acetylaspartate (NAA), choline (Cho), and myoinositol (mI); each was expressed as a ratio with creatine plus phosphocreatine (total creatine: tCr). The Glx/tCr ratio was significantly reduced after the TCS treatment. The NAA/tCr ratio was also significantly reduced after the treatment compared with the control group, although the change in NAA signal was heterogeneous among patients, correlating with respective outcomes. The Cho/tCr and mI/tCr ratios were not affected by TCS treatment. The reduction in Glx suggests a decrease in the glutamate-glutamine cycle, which plays a pivotal role in synthesizing neurotransmitters such as glutamate and GABA. TCS-induced Glx reduction may induce changes in synaptic signal transduction, thereby accounting for the effect of TCS on WS. The change in NAA indicates altered neuronal activity, which may be correlated with outcome in WS patients.

Structure-specific glial response in a macaque model of neuroAIDS

As ~40% of persons with HIV also suffer neurocognitive decline, we sought to assess metabolic dysfunction in the brains of simian immunodeficiency virus (SIV)-infected rhesus macaques, an advanced animal model, in structures involved in cognitive function. We test the hypothesis that SIV-infection produces proton-magnetic resonance spectroscopic imaging (H-MRSI)-observed decline in the neuronal marker, N-acetylaspartate (NAA), and elevations in the glial marker, myo-inositol (mI), and associated creatine (Cr) and choline (Cho) in these structures. Pre- and 4-6 weeks post-SIV infection (with CD8 T-lymphocyte depletion) was monitored with T2-weighted quantitative MRI and 16×16×4 multivoxel H-MRSI (TE/TR = 33/1400 ms) in the brains of five rhesus macaques. Exploiting the high-resolution H-MRSI grid, we obtained absolute, cerebrospinal fluid partial volume-corrected NAA, Cr, Cho and mI concentrations from centrum semiovale, caudate nucleus, putamen, thalamus and hippocampus regions. Pre- to post-infection mean Cr increased in the thalamus: 7.2±0.4 to 8.0±0.8 mmol/l (+11%, P<0.05); mI increased in the centrum semiovale: 5.1±0.8 to 6.6±0.8 mmol/l, caudate: 5.7±0.7 to 7.3±0.5 mmol/l, thalamus: 6.8±0.8 to 8.5±0.8 mmol/l and hippocampus: 7.7±1.2 to 9.9±0.4 mmol/l (+29%, +27%, +24% and +29%, all P<0.05). NAA and Cho changes were not significant. SIV-infection appears to cause brain injury indirectly, through glial activation, while the deep gray matter structures' neuronal cell bodies are relatively spared. Treatment regimens to reduce gliosis may, therefore, prevent neuronal damage and its associated neurocognitive impairment.

The correlation between abnormal metabolism in anterior cingulum cortex and executive dysfunction with major depression patients before and after antidepressant treatment

Objective To investigate neuro-biochemical changes of bilateral anterior cingulate cortex (ACC) in the patients with major depressive disorder (MDD) and the correlation between abnormal metabolism and the cognitive function before and after treatment. Methods Fifteen patients with major depression and 15 age-, sex- and education-matched healthy controls (HC) were involved. The neurochemical abnormalities including the levels of N-acetylaspartate (NAA), choline-containing compounds, glutamate/glutamine and myoinostol were measured by single-voxel proton magnetic resonance spectroscopic (1H-MRS). The subjects were then assessed with executive function with neuropsychological tests including Wisconsin cards sorting test (WCST), verbal fluency Task (vF), StrooP Color and Word Test(SCWT). After this, the patients took selectivity serotonin reuptake inhibitors (SSRIs) for eight weeks. Then, we examined the changes in NAA, Cho, Glx and MI in ACC of patients and assessed their executive function with the neuropsychological tests again. Results 1) In ACC, baseline NAA((7.36±1.67)mmol/L), GLx((11.68±1.65)mmol/L) and MI levels ((5.28±0.66)mmol/L)were significantly lower in MDD compared to those of HC(NAA(9.27±1.37)mmol/L、Glx(15.20±1.91)mmol/L、MI(7.80±2.73)mmol/L)(P<0.01); After treatment, the NAA ((9.34±2.45)mmol/L)and Glx ((16.79±3.96)mmol/L)increased significantly after treatment compared to those prior to pretreatment(NAA(7.36±1.67)mmol/L, Glx(11.68±1.65)mmol/L, P<0.05).2) The normal controls exhibited better in Performance of WCST and Performance of completion time of SCWT than our MDD patients (P<0.05 or P<0.01). The patients made significant improvements in Performance of WCST and completion time of SCWT(C form) after treatment (P<0.05 or P<0.01). 3) In post-treatment MDD, the ACC Glx level was significantly positively correlated with the categories completes of WCST (r=0.739, P=0.009) and inversely related with the numbers to complete the first categories of WCST (r=-0.699, P=0.017) and the completion time of SCWT(C form) (r=-0.651, P=0.030); elevated MI(r=-0.705, P=0.023)and NAA(r=-0.735, P=0.010)levels in ACC of post-treatment MDD were both negatively correlated with the numbers to complete the first categories of WCST. Conclusion The ACC may be a key region involved in antidepressant treatment in MDD. The increased ACC NAA, Glx and MI in MDD after treatment may be significantly correlated with the improve of executive function. Key words: Major depressive disorder; Anterior cingutate; Magnetic resonance spectroscopy; Executive dysfunction

Atypical Developmental Patterns of Brain Chemistry in Children With Autism Spectrum Disorder

Autism spectrum disorder (ASD) is a neurodevelopmental disorder with symptoms emerging during early childhood. The pathophysiology underlying the disorder remains incompletely understood. To examine cross-sectional and longitudinal patterns of brain chemical concentrations in children with ASD or idiopathic developmental delay (DD) from 3 different age points, beginning early in the clinical course. Proton magnetic resonance spectroscopic imaging data were acquired longitudinally for children with ASD or DD, and primarily cross-sectionally for children with typical development (TD), at 3 to 4, 6 to 7, and 9 to 10 years of age. Recruitment, diagnostic assessments, and magnetic resonance imaging were performed at the University of Washington in Seattle. Seventy-three children (45 with ASD, 14 with DD, and 14 with TD) at 3 to 4 years of age; 69 children (35 with ASD, 14 with DD, and 20 with TD) at 6 to 7 years of age; and 77 children (29 with ASD, 15 with DD, and 33 with TD) at 9 to 10 years of age. Concentrations of N-acetylaspartate (NAA), choline (Cho), creatine (Cr), myo-inositol (mI), and glutamine plus glutamate (Glx) in cerebral gray matter (GM) and white matter (WM) at 3 to 4, 6 to 7, and 9 to 10 years of age, and calculation of rates of change of these chemicals between 3 and 10 years of age. At 3 to 4 years of age, the ASD group exhibited lower NAA, Cho, and Cr concentrations than did the TD group in both GM and WM, alterations that largely were not observed at 9 to 10 years of age. The DD group exhibited reduced GM and WM NAA concentrations at 3 to 4 years of age; GM NAA concentrations remained reduced at 9 to 10 years of age compared with the TD group. There were distinct differences between the ASD and DD groups in the rates of GM NAA, Cho, and Cr changes between 3 and 10 years of age. The GM chemical changes between 3 and 10 years of age differentiated the children with ASD from those with DD. Most notably, a dynamic reversal of GM NAA reductions was observed in the children with ASD. By contrast, persistent GM NAA reductions in the children with DD suggest a different, more static, underlying developmental process.

Decrease in N-Acetylaspartate Following Concussion May Be Coupled to Decrease in Creatine

To assess the time course changes in N-acetylaspartate (NAA) and creatine (Cr) levels in the brain of athletes who suffered a sport-related concussion. Eleven nonconsecutive athletes with concussive head injury and 11 sex- and age-matched control volunteers : At 3, 15, 30, and 45 days postinjury, athletes were examined by proton magnetic resonance spectroscopy for the determination of NAA, Cr, and choline (Cho) levels. Proton magnetic resonance spectroscopic data recorded for the control group were used for comparison. Compared with controls (2.18 ± 0.19), athletes showed an increase in the NAA/Cr ratio at 3 (2.71 ± 0.16; P < .01) and 15 (2.54 ± 0.21; P < .01) days postconcussion, followed by a decrease and subsequent normalization at 30 (1.95 ± 0.16, P < .05) and 45 (2.17 ± 0.20; P < .05) days postconcussion. The NAA/Cho ratio decreased at 3, 15, and 30 days postinjury (P < .01 compared with controls), with no differences observed in controls at 45 days postconcussion. Compared with controls, significant increase in the Cho/Cr ratio after 3 (+33%, P < .01) and 15 (+31.5%, P < .01) days postinjury was observed whereas no differences were recorded at 30 and 45 days postinjury. This cohort of athletes indicates that concussion may cause concomitant decrease in cerebral NAA and Cr levels. This provokes longer time for normalization of metabolism, as well as longer time for resolution of concussion-associated clinical symptoms.

Longitudinal 1H MRS of rat forebrain from infancy to adulthood reveals adolescence as a distinctive phase of neurometabolite development

This study represents the first longitudinal, within-subject (1) H MRS investigation of the developing rat brain spanning infancy, adolescence and early adulthood. We obtained neurometabolite profiles from a voxel located in a central location of the forebrain, centered on the striatum, with smaller contributions for the cortex, thalamus and hypothalamus, on postnatal days 7, 35 and 60. Water-scaled metabolite signals were corrected for T1 effects and quantified using the automated processing software LCModel, yielding molal concentrations. Our findings indicate age-related concentration changes in N-acetylaspartate + N-acetylaspartylglutamate, myo-inositol, glutamate + glutamine, taurine, creatine + phosphocreatine and glycerophosphocholine + phosphocholine. Using a repeated measures design and analysis, we identified significant neurodevelopment changes across all three developmental ages and identified adolescence as a distinctive phase in normative neurometabolic brain development. Between postnatal days 35 and 60, changes were observed in the concentrations of N-acetylaspartate + N-acetylaspartylglutamate, glutamate + glutamine and glycerophosphocholine + phosphocholine. Our data replicate past studies of early neurometabolite development and, for the first time, link maturational profiles in the same subjects across infancy, adolescence and adulthood.

N-Acetylaspartate reductions in brain injury: impact on post-injury neuroenergetics, lipid synthesis, and protein acetylation.

N-Acetylaspartate (NAA) is employed as a non-invasive marker for neuronal health using proton magnetic resonance spectroscopy (MRS). This utility is afforded by the fact that NAA is one of the most concentrated brain metabolites and that it produces the largest peak in MRS scans of the healthy human brain. NAA levels in the brain are reduced proportionately to the degree of tissue damage after traumatic brain injury (TBI) and the reductions parallel the reductions in ATP levels. Because NAA is the most concentrated acetylated metabolite in the brain, we have hypothesized that NAA acts in part as an extensive reservoir of acetate for acetyl coenzyme A synthesis. Therefore, the loss of NAA after TBI impairs acetyl coenzyme A dependent functions including energy derivation, lipid synthesis, and protein acetylation reactions in distinct ways in different cell populations. The enzymes involved in synthesizing and metabolizing NAA are predominantly expressed in neurons and oligodendrocytes, respectively, and therefore some proportion of NAA must be transferred between cell types before the acetate can be liberated, converted to acetyl coenzyme A and utilized. Studies have indicated that glucose metabolism in neurons is reduced, but that acetate metabolism in astrocytes is increased following TBI, possibly reflecting an increased role for non-glucose energy sources in response to injury. NAA can provide additional acetate for intercellular metabolite trafficking to maintain acetyl CoA levels after injury. Here we explore changes in NAA, acetate, and acetyl coenzyme A metabolism in response to brain injury.

Preoperative and postoperative 1H-MR spectroscopy changes in frontal deep white matter and the thalamus in idiopathic normal pressure hydrocephalus

BackgroundIn a previous study we found significantly decreased N-acetyl aspartate (NAA) and total N-acetyl (tNA) groups in the thalamus of patients with idiopathic normal pressure hydrocephalus (iNPH) compared with healthy...

Reversible Loss of N-Acetylaspartate After 15-Min Transient Middle Cerebral Artery Occlusion in Rat: A Longitudinal Study with In Vivo Proton Magnetic Resonance Spectroscopy

It is generally accepted that N-acetylaspartate (NAA) can be used a biochemical marker for assessing neuronal viability/integrity after cerebral ischemia. However, this view has recently been questioned based on observations showing that after a photothrombotic permanent ischemia the acute decline of NAA in the infracted regions, where massive neuronal loss persists, is reversible over time. In this study, we measured the longitudinal changes of NAA and total creatine (Cr) in ischemic rat brain after a 15-min transient middle cerebral artery occlusion (MCAO) by in vivo (1)H magnetic resonance spectroscopy. The results showed that the levels of NAA and total Cr in the ischemic lesion decrease significantly at 1 day post-ichemia, followed by spontaneous recovery to the control levels by 2 weeks and remained stable thereafter up to 16 weeks. The normalization of NAA and total Cr levels was associated histologically with persisted neuronal loss up to 90 % in the ischemic core, and accompanied by marked reactive astrocytic responses occurring with a similar time course. The absolute T(2) relaxation time in the ischemic lesion increased during acute phase, and declined afterwards during subacute and chronic phases of 15-min MCAO. The delayed decreases of T(2) in the ischemic lesion might be associated with deposition of paramagnetic species, such as manganese and iron originated from chronic inflammation, vascular degradation and/or hemorrhagic transformation. The results of this study give further support to the hypothesis that the recovery of NAA after cerebral ischemia might have contributions from reactive glia cells, and caution the use of NAA as a specific neuronal marker during the chronic stage of cerebral ischemia.

Blast‐induced neurotrauma leads to neurochemical changes and neuronal degeneration in the rat hippocampus

Blast-induced neurotrauma is a major concern because of the complex expression of neuropsychiatric disorders after exposure. Disruptions in neuronal function, proximal in time to blast exposure, may eventually contribute to the late emergence of clinical deficits. Using magic angle spinning ¹H MRS and a rodent model of blast-induced neurotrauma, we found acute (24-48 h) decreases in succinate, glutathione, glutamate, phosphorylethanolamine and γ-aminobutyric acid, no change in N-acetylaspartate and increased glycerophosphorylcholine, alterations consistent with mitochondrial distress, altered neurochemical transmission and increased membrane turnover. Increased levels of the apoptotic markers Bax and caspase-3 suggested active cell death, consistent with increased FluoroJade B staining in the hippocampus. Elevated levels of glial fibrillary acidic protein suggested ongoing inflammation without diffuse axonal injury measured by no change in β-amyloid precursor protein. In conclusion, blast-induced neurotrauma induces a metabolic cascade associated with neuronal loss in the hippocampus in the acute period following exposure.

Polyphenon E, a Green Tea Extract, Increases Brain NAA Levels in MS: A Pilot Six Month Open Label Study (P03.050)

Objective: Assess the safety of Polyphenon E in subjects with multiple sclerosis (MS) and determine whether Polyphenon E would be futile as a neuroprotective agent. Background Polyphenon E (Mitsui Norin; Shizuoka, Japan) is an extract from the leaves of green tea. Its main active component is epigallocatechin gallate (EGCG), an antioxidant that accumulates within the mitochondria of neurons and increases their resistance to apoptosis under conditions of oxidative stress. Mitochondrial dysfunction leads to axonal injury in mice with experimental autoimmune encephalomyelitis (EAE). EGCG effectively treats EAE in female SJL/J mice. Design/Methods: Ten subjects with relapsing remitting or secondary progressive MS were recruited for this open-label, six-month pilot study of 400 mg of Polyphenon E twice daily. Adverse events (AE) were assessed monthly. N-acetyl aspartate (NAA) levels were measured using 3T magnetic resonance spectroscopy and differences were assessed between baseline and six-months. Plasma levels of epigallocatechin gallate (EGCG) were measured at one month, 3 and 8 hours after the morning dose. Results: No serious AE occurred. All subjects completed the study assessments. One discontinued therapy after mild elevation of liver enzymes. Treatment with EGCG resulted in an increase of 13% [95%,CI(1%-23%) p Conclusions: There were no safety concerns for treating MS patients with Polyphenon E. Our futility endpoint was rejected, as NAA levels increased. This and the correlated changes in NAA and EGCG levels support a potential neuroprotective effect that should be investigated in a larger randomized, placebo-controlled trial measuring NAA levels over a longer follow-up. Supported by: NCCAM K23AT004433; LSUHSC-New Orleans CTRC. Disclosure: Dr. Ramos has nothing to disclose. Dr. Garrison has nothing to disclose. Dr. Koop has nothing to disclose. Dr. Rooney has nothing to disclose. Dr. Bourdette has received personal compensation for activities with Biogen Idec, Serono, and Teva Neurosciences as a speaker. Dr. Lovera has received personal compensation for activities with EMD Serono, Teva Neuroscience, and Biogen Idec as a consultant.