Lower N-acetylaspartate Levels Research Articles

Multimodal, Longitudinal Profiling of SCA1 Identifies Predictors of Disease Severity and Progression.

Spinocerebellar ataxia type 1 (SCA1) is a rare autosomal dominant neurodegenerative disease. Objective surrogate markers sensitive to detect changes in disease severity are needed to reduce sample sizes in interventional trials and identification of predictors of faster disease progression would facilitate patient selection, enrichment, or stratification in such trials. We performed a prospective 1-year longitudinal, multimodal study in 34 ataxic SCA1 individuals and 21 healthy controls. We collected clinical, patient-reported outcomes, biochemical and magnetic resonance (MR) biomarkers at baseline and after 1 year. We determined 1-year progression and evaluated the potential predictive value of several baseline markers on 1-year disease progression. At baseline, multiple structural and spectroscopic MR markers in pons and cerebellum differentiated SCA1 from healthy controls and correlated with disease severity. Plasma and cerebrospinal fluid (CSF) neurofilament light (NfL) chain and CSF glial fibrillary acidic protein (GFAP) were elevated in SCA1. In longitudinal analysis, total brainstem and pontine volume change, inventory of non-ataxia signs (INAS) count, and SCA functional index (SCAFI) showed larger responsiveness compared to the Scale for Assessment and Rating of Ataxia (SARA). Longer disease duration, longer non-expanded CAG repeat length, and higher disease burden were associated with faster SARA increase after 1-year in the SCA1 group. Similarly, lower baseline brainstem, pontine, and cerebellar volumes, as well as lower levels of N-acetylaspartate and glutamate in the cerebellar white matter, were also associated with faster SARA increase. Our results guide the selection of the most sensitive measures of disease progression in SCA1 and have identified features associated with accelerated progression that could inform the design of clinical trials. ANN NEUROL 2024.

Association of Cortical Lesions With Regional Glutamate, GABA, N-Acetylaspartate, and Myoinositol Levels in Patients With Multiple Sclerosis.

Cortical lesions contribute to disability in multiple sclerosis (MS), but their impact on regional neurotransmitter levels remains to be clarified. We tested the hypothesis that cortical lesions are associated with regional glutamate and gamma-aminobutyric acid (GABA) concentrations within the affected cortical region. In this cross-sectional study, we used structural 7T MRI to segment cortical lesions and 7T proton MR-spectroscopy of the bilateral sensorimotor hand areas to quantify regional GABA, glutamate, N-acetylaspartate, and myoinositol concentrations in patients with MS (inclusion criteria: diagnosis of relapsing-remitting [RR] or secondary progressive MS [SPMS]; age 18-80 years) and age and sex-matched healthy controls. Data were collected at a single center between August 2018 and September 2020. Linear mixed-effects models were used to test for associations between metabolite concentrations and cortical lesion volumes within the same MR-spectroscopy voxel. Forty-seven patients with MS (34 RRMS, 13 SPMS; 45.1 ± 12.5 years; 31 women) and 23 healthy controls (44.4 ± 13 years, 15 women) were studied. In patients, higher regional glutamate and lower regional GABA concentrations were associated with larger cortical lesion volume within the MR-spectroscopy voxel [glutamate: 0.61 (95% CI 0.19-1.03) log(mm3), p = 0.005, GABA: -0.71 (-1.24 to -0.18) log(mm3), p = 0.01]. In addition, lower N-acetylaspartate levels [-0.37 (-0.67 to -0.07) log(mm3), p = 0.016] and higher myoinositol levels [0.48 (0.03-0.93) log(mm3), p = 0.037] were associated with a larger regional cortical lesion volume. Furthermore, glutamate concentrations were reduced in patients with SPMS compared with healthy participants [-0.75 (-1.3 to -0.19) mM, p = 0.005] and patients with RRMS [-0.55 (-1.07 to -0.02) mM, p = 0.04]. N-acetylaspartate levels were lower in both patients with RRMS [-0.81 (-1.39 to -0.24) mM, p = 0.003] and SPMS [-1.31 (-2.07 to -0.54) mM, p < 0.001] when compared with healthy controls. Creatine-normalized N-acetylaspartate levels were associated with performance in the 9-hole peg test of the contralateral hand [-0.004 (-0.007 to -0.002) log(s), p = 0.002], and reduced mean creatine-normalized glutamate was associated with increased Expanded Disability Status Scale (R = -0.39, p = 0.02). Cortical lesions are associated with local increases in glutamate and a reduction in GABA concentration within the lesional or perilesional tissue. Further studies are needed to investigate the causal relationship between cortical lesions and changes in neurotransmitter concentrations.

Association between brain N-acetylaspartate levels and sensory and motor dysfunction in patients who have spinal cord injury with spasticity: an observational case-control study.

Spinal cord injury is a severe and devastating disease, and spasticity is a common and severe complication that is notoriously refractory to treatment. However, the pathophysiological mechanisms underlying spasticity and its development remain largely unknown. The goal of the present study was to find differences, if any, in metabolites of the left precentral gyrus and basal ganglia of patients who have spinal cord injury with or without spasticity, and to explore the relationship between the brain metabolite concentrations and clinical status. Thirty-six participants were recruited for magnetic resonance spectroscopic examination: 23 with spinal cord injury (12 with spasticity and 11 without spasticity) and 13 healthy controls. We acquired localized proton spectra from the precentral gyrus and basal ganglia via 10 mm3 voxels. Notably, univariate linear regression analysis demonstrated that the lower that the N-acetylaspartate concentration (a marker for neuronal loss) was in the precentral gyrus of the patients, the lower their ASIA (American Spinal Injury Association) light-touch scores, pinprick scores, and motor scores. Additionally, longer durations of injury were associated with higher N-acetylaspartate levels in the precentral gyrus. Compared with the healthy participants and patients without spasticity, N-acetylaspartate levels in the patients with spasticity were significantly lower in both the precentral gyrus and basal ganglia. Lower N-acetylaspartate levels also correlated with greater sensory and motor dysfunction in the patients who had spinal cord injury with spasticity.

Normal Appearing White Matter N-Acetylaspartate Changes Impact on Fatigue in Multiple Sclerosis

Background: Fatigue is one of the most frequent complaints presented by multiple sclerosis patients. Fatigue may be multifactorial. Proton magnetic resonance spectroscopy studies have shown significant reductions in N-acetylaspartate/creatine ratios in multiple brain regions among fatigued multiple sclerosis patients in comparison to non-fatigued multiple sclerosis patients, suggesting axonal loss as a contributing factor. Females are twice as likely to develop the disease. Aim: To evaluate gender variability in fatigue scores in relapsing-remitting multiple sclerosis patients. To explore potential gender differences in metabolite profiles of normal appearing white matter. To correlate metabolite changes distribution with fatigue severity and to evaluate the gender impact. Methods: We enrolled 50 relapsing-remitting multiple sclerosis patients on disease modifying treatment and 28 healthy controls. All participants underwent proton magnetic resonance spectroscopy of normal appearing white matter corresponding regions and fatigue severity evaluation. Results: We found higher fatigue scores in the multiple sclerosis group, due to greater severity in female subjects. We found a significant decrease of N-acetylaspartate/creatine ratio with increase in N-acetylaspartate, choline, and creatine levels in multiple sclerosis subjects. N-acetylaspartate and choline levels were significantly higher in the multiple sclerosis males. Female multiple sclerosis patients presented with lower N-acetylaspartate levels than healthy controls and greater increases in Fatigue Severity Scale score. Regression analysis revealed metabolite specific relationships between fatigue against metabolite variables. Conclusion: Proton magnetic resonance spectroscopy registered differences in metabolite profiles in normal appearing white matter male and female multiple sclerosis subjects. We might presume gender dependent specifiers in metabolite profiles in relapsing- remitting multiple sclerosis. They impact fatigue severity. N- acetyaspartate might be crucial contributor in central fatigue in multiple sclerosis. Bioenergetic role of N-acetylaspartate needs further collaborative research on genetics and electrical properties of neurons to reveal the underlying mechanism of fatigue and conductivity deterioration.

Brain metabolite alterations related to alcohol use: a meta-analysis of proton magnetic resonance spectroscopy studies.

Alcohol misuse and alcohol use disorder (AlUD) have neurobiological consequences. This meta-analysis of proton magnetic resonance spectroscopy (MRS) studies aimed to assess the differences in brain metabolite levels in alcohol misuse and AUD relative to controls (PROSPERO registration: CRD42020209890). Hedge's g with random-effects modeling was used. Sub-group and meta-regression techniques explored potential sources of demographic and MRS parameter heterogeneity. A comprehensive literature review identified 43 studies, resulting in 69 models across gray and white matter (GM, WM). Lower N-acetylaspartate levels were found in frontal, anterior cingulate cortex (ACC), hippocampal, and cerebellar GM, and frontal and parietal WM, suggesting decreased neuronal and axonal viability. Lower choline-containing metabolite levels (all metabolites contributing to choline peak) were found in frontal, temporal, thalamic, and cerebellar GM, and frontal and parietal WM, suggesting membrane alterations related to alcohol misuse. Lower creatine-containing metabolite levels (Cr; all metabolites contributing to Cr peak) were found in temporal and occipital cortical GM, while higher levels were noted in midbrain/brainstem GM; this finding may have implications for using Cr as an internal reference. The lack of significant group differences in glutamate-related levels is possibly related to biological and methodological complexities. The few studies reporting on GABA found lower levels restricted to the ACC. Confounding variables were age, abstinence duration, treatment status, and MRS parameters (echo time, quantification type, data quality). This first meta-analysis of proton MRS studies consolidates the numerous individual studies to identify neurometabolite alterations within alcohol misuse and AUD. Future studies can leverage this new formalized information to investigate treatments that might effectively target the observed disturbances.

Magnetic Resonance Spectroscopy (MRS) and Positron Emission Tomography (PET) Imaging in Obsessive-Compulsive Disorder.

Obsessive-compulsive disorder (OCD) is characterised by structural and functional deficits in the cortico-striato-thalamic-cortical (CSTC) circuitry and abnormal neurochemical changes are thought to modulate these deficits. The hypothesis that an imbalanced concentration of the brain neurotransmitters, in particular glutamate (Glu) and gamma-amino-butyric acid (GABA), could impair the normal functioning of the CSTC, thus leading to OCD symptoms, has been tested in humans using magnetic resonance spectroscopy (MRS) and positron emission tomography (PET). This chapter summarises these neurochemical findings and represents an attempt to condense such scattered literature. We also discuss potential challenges in the field that may explain the inconsistent findings and suggest ways to overcome them. There is some convergent research from MRS pointing towards abnormalities in the brain concentration of neurometabolite markers of neuronal integrity, such as N-acetylaspartate (NAA) and choline (Cho). Lower NAA levels have been found in dorsal and rostral ACC of OCD patients (as compared to healthy volunteers), which increase after CBT and SSRI treatment, and higher Cho concentration has been reported in the thalamus of the OCD brain. However, findings for other neurometabolites are very inconsistent. Studies have reported abnormalities in the concentrations of creatine (Cr), GABA, glutamate (Glu), glutamine (Gln), Ins (myo-inositol), and serotonin (5-HT), but most of the results were not replicated. The question remains whether the NAA and Cho findings are genuinely the only neurochemical abnormalities in OCD or whether the lack of consistent findings for the other neurometabolites is caused by the lower magnetic field (1-3 Tesla (T)) used by the studies conducted so far, their small sample sizes or a lack of proper control for medication effects. To answer these questions and to further inform the biological underpinning of the symptoms and the cognitive problems at the basis of OCD we need better controlled studies using clear medicated vs unmedicated groups, larger sample sizes, stronger magnetic fields (e.g. at 7T), and more consistency in the definition of the regions of interest.

Altered neurochemistry in the anterior white matter of bipolar children and adolescents: a multivoxel 1H MRS study.

Abnormalities within frontal lobe grey and white matter of bipolar disorder (BD) patients have been consistently reported in adult and pediatric studies, yet little is known about the neurochemistry of the anterior white matter (AWM) in pediatric BD and how medication status may affect it. The present cross-sectional 3T 1H MRS study is the first to use a multivoxel approach to study the AWM of BD youth. Absolute metabolite levels from four bilateral AWM voxels were collected from 49 subjects between the ages of eight and eighteen (25 healthy controls (HC); 24 BD) and quantified. Our study found BD subjects to have lower levels of N-acetylaspartate (NAA) and glycerophosphocholine plus phosphocholine (GPC+PC), metabolites that are markers of neuronal viability and phospholipid metabolism and have also been implicated in adult BD. Further analysis indicated that the observed patterns were mostly driven by BD subjects who were medicated at the time of scanning and had an ADHD diagnosis. Although limited by possible confounding effects of mood state, medication, and other mood comorbidities, these findings serve as evidence of altered neurochemistry in BD youth that is sensitive to medication status and ADHD comorbidity.

Neurotransmitters and Neurometabolites in Late-Life Depression: A Preliminary Magnetic Resonance Spectroscopy Study at 7T

BackgroundMagnetic resonance spectroscopy (MRS) methods have quantified changes in levels of neurotransmitters and neurometabolites in patients with major depression across the lifespan. The application of 7T field strengths and greater have not been a major focus of study in patients with late-life depression (LLD). MethodsNine LLD patients who met DSM-IV criteria for a current major depressive episode and nine non-depressed, healthy, age-matched controls underwent clinical and neuropsychological assessment and single-voxel 7T 1H-MRS at baseline and after 10-12 weeks of antidepressant treatment (Citalopram; patients only). Spectra were acquired from two brain regions implicated in both depressive symptoms and neuropsychological deficits in LLD, the anterior (ACC) and posterior cingulate (PCC). Levels of γ-aminobutyric acid (GABA), glutamate (Glu), glutathione (GSH), N-acetylaspartylglutamate (NAAG), N-acetylaspartate (NAA), and myo-inositol (mI) were quantified relative to total creatine (tCr) using linear-combination modeling. ResultsBaseline Glu/tCr levels were not significantly different between groups. Decreased Glu/tCr levels after Citalopram treatment were observed in a subset of LLD patients. Exploratory analyses showed that LLD patients had lower NAA levels in the PCC relative to controls. Higher levels of ml in the LLD patients relative to the controls and decreases after Citalopram treatment had large effect sizes but were not statistically significant. Further, decreases in PCC Glu/tCr and increases in ACC GSH/tCr were associated with improvement in depressive symptoms. LimitationsSample size. ConclusionsThese preliminary results suggest a role of neurochemicals and neurometabolites in the neurobiology of LLD and antidepressant treatment response.

Sensorimotor cortex neurometabolite levels as correlate of motor performance in normal aging: evidence from a 1H-MRS study

Aging is associated with gradual alterations in the neurochemical characteristics of the brain, which can be assessed in-vivo with proton-magnetic resonance spectroscopy (1H-MRS). However, the impact of these age-related neurochemical changes on functional motor behavior is still poorly understood. Here, we address this knowledge gap and specifically focus on the neurochemical integrity of the left sensorimotor cortex (SM1) and the occipital lobe (OCC), as both regions are main nodes of the visuomotor network underlying bimanual control. 1H-MRS data and performance on a set of bimanual tasks were collected from a lifespan (20–75 years) sample of 86 healthy adults. Results indicated that aging was accompanied by decreased levels of N-acetylaspartate (NAA), glutamate-glutamine (Glx), creatine ​+ ​phosphocreatine (Cr) and myo-inositol (mI) in both regions, and decreased Choline (Cho) in the OCC region. Lower NAA and Glx levels in the SM1 and lower NAA levels in the OCC were related to poorer performance on a visuomotor bimanual coordination task, suggesting that NAA could serve as a potential biomarker for the integrity of the motor system supporting bimanual control. In addition, lower NAA, Glx, and mI levels in the SM1 were found to be correlates of poorer dexterous performance on a bimanual dexterity task. These findings highlight the role for 1H-MRS to study neurochemical correlates of motor performance across the adult lifespan.

Assessing Brain Metabolism With 7-T Proton Magnetic Resonance Spectroscopy in Patients With First-Episode Psychosis

The use of high-field magnetic resonance spectroscopy (MRS) in multiple brain regions of a large population of human participants facilitates in vivo study of localized or diffusely altered brain metabolites in patients with first-episode psychosis (FEP) compared to healthy participants. To compare metabolite levels in 5 brain regions between patients with FEP (evaluated within 2 years of onset) and healthy controls, and to explore possible associations between targeted metabolite levels and neuropsychological test performance. Cross-sectional design used 7-T MRS at a research MR imaging facility in participants recruited from clinics at the Johns Hopkins Schizophrenia Center and the local population. Eighty-one patients who had received a DSM-IV diagnosis of FEP within the last 2 years and 91 healthy age-matched (but not sex-matched) volunteers participated. Brain metabolite levels including glutamate, glutamine, γ-aminobutyric acid (GABA), N-acetylaspartate, N-acetylaspartyl glutamate, and glutathione, as well as performance on neuropsychological tests. The mean (SD) age of 81 patients with FEP was 22.3 (4.4) years and 57 were male, while the mean (SD) age of 91 healthy participants was 23.3 (3.9) years and 42 were male. Compared with healthy participants, patients with FEP had lower levels of glutamate (F1,162 = 8.63, P = .02), N-acetylaspartate (F1,161 = 5.93, P = .03), GABA (F1,163 = 6.38, P = .03), and glutathione (F1,162 = 4.79, P = .04) in the anterior cingulate (all P values are corrected for multiple comparisons); lower levels of N-acetylaspartate in the orbitofrontal region (F1,136 = 7.23, P = .05) and thalamus (F1,133 = 6.78, P = .03); and lower levels of glutathione in the thalamus (F1,135 = 7.57, P = .03). Among patients with FEP, N-acetylaspartate levels in the centrum semiovale white matter were significantly correlated with performance on neuropsychological tests, including processing speed (r = 0.48; P < .001), visual (r = 0.33; P = .04) and working (r = 0.38; P = .01) memory, and overall cognitive performance (r = 0.38; P = .01). Seven-tesla MRS offers insights into biochemical changes associated with FEP and may be a useful tool for probing brain metabolism that ranges from neurotransmission to stress-associated pathways in participants with psychosis.

Brain Metabolite Changes in the Anterior Cingulate Cortex of Chronic Low Back Pain Patients and Correlations Between Metabolites and Psychological State.

In chronic low back pain (CLBP) patients, study of altered brain metabolites in the anterior cingulate cortex (ACC) using magnetic resonance spectroscopy (MRS) could reveal the detailed pathology of CLBP and depression. The aim was to detect the central difference between CLBP and controls by means of measuring the metabolites in the ACC, and to analyze the correlations between depression and metabolites in ACC. MRS was performed in CLBP (n=60) and control participants (n=56) to evaluate the effects of CLBP on metabolites in the ACC and to analyze the correlations between metabolites and questionnaire scores in a cross-sectional study. Adjusting for age and sex, a negative effect of CLBP on the N-acetylaspartate (NAA) level (estimated regression slope coefficient [B]=-0.685, P<0.001) and positive effects on the glutamate +glutamine (Glx)/creatine (B=0.136, P=0.016) and Glx/myoinositol (B=0.140, P<0.048) ratios in the ACC were found. The correlation analysis demonstrated that there was a significant moderate correlation between some questionnaire scores of emotional disorders and metabolites in the ACC of CLBP participants (absolute r>0.4, P<0.05). Lower NAA levels and higher Glx/creatine and Glx/myoinositol ratios in the ACC of CLBP participants compared with controls were revealed. The result suggests the hypothesis that excessive Glx leads to neuronal dysfunction and/or death, which was reflected as a low NAA level in the ACC of individuals with CLBP. Measurement of these metabolites using MRS potentially helps evaluate CLBP patients' condition and psychological status objectively.

Magnetic resonance spectroscopy of current hand amputees reveals evidence for neuronal-level changes in former sensorimotor cortex.

Deafferentation is accompanied by large-scale functional reorganization of maps in the primary sensory and motor areas of the hemisphere contralateral to injury. Animal models of deafferentation suggest a variety of cellular-level changes including depression of neuronal metabolism and even neuronal death. Whether similar neuronal changes contribute to patterns of reorganization within the contralateral sensorimotor cortex of chronic human amputees is uncertain. We used functional MRI-guided proton magnetic resonance spectroscopy to test the hypothesis that unilateral deafferentation is associated with lower levels of N-acetylaspartate (NAA, a putative marker of neuronal integrity) in the sensorimotor hand territory located contralateral to the missing hand in chronic amputees (n = 19) compared with the analogous hand territory of age- and sex-matched healthy controls (n = 28). We also tested whether former amputees [i.e., recipients of replanted (n = 3) or transplanted (n = 2) hands] exhibit NAA levels that are indistinguishable from controls, possible evidence for reversal of the effects of deafferentation. As predicted, relative to controls, current amputees exhibited lower levels of NAA that were negatively and significantly correlated with the time after amputation. Contrary to our prediction, NAA levels in both replanted and transplanted patients fell within the range of the current amputees. We suggest that lower levels of NAA in current amputees reflects altered neuronal integrity consequent to chronic deafferentation. Thus local changes in NAA levels may provide a means of assessing neuroplastic changes in deafferented cortex. Results from former amputees suggest that these changes may not be readily reversible through reafferentation.NEW & NOTEWORTHY This study is the first to use functional magnetic resonance-guided magnetic resonance spectroscopy to examine neurochemical mechanisms underlying functional reorganization in the primary somatosensory and motor cortices consequent to upper extremity amputation and its potential reversal through hand replantation or transplantation. We provide evidence for selective alteration of cortical neuronal integrity associated with amputation-related deafferentation that may not be reversible.

Neurochemical correlates of rapid treatment response to electroconvulsive therapy in patients with major depression.

Electroconvulsive therapy (ECT) is a highly effective brain stimulation treatment for severe depression. Identifying neurochemical changes linked with ECT may point to biomarkers and predictors of successful treatment response. We used proton magnetic resonance spectroscopy (1H-MRS) to measure longitudinal changes in glutamate/glutamine (Glx), creatine (Cre), choline (Cho) and N-acetylaspartate (NAA) in the dorsal (dACC) and subgenual anterior cingulate cortex (sgACC) and bilateral hippocampus in patients receiving ECT scanned at baseline, after the second ECT session and after the ECT treatment series. Patients were compared with demographically similar controls at baseline. Controls were assessed twice to establish normative values and variance. We included 50 patients (mean age 43.78 ± 14 yr) and 33 controls (mean age 39.33 ± 12 yr) in our study. Patients underwent a mean of 9 ± 4.1 sessions of ECT. At baseline, patients showed reduced Glx in the sgACC, reduced NAA in the left hippocampus and increased Glx in the left hippocampus relative to controls. ECT was associated with significant increases in Cre in the dACC and sgACC and decreases in NAA in the dACC and right hippocampus. Lower NAA levels in the dACC at baseline predicted reductions in depressive symptoms. Both ECT and symptom improvement were associated with decreased Glx in the left hippocampus and increased Glx in the sgACC. Attrition and clinical heterogeneity may have masked more subtle findings. ECT elicits robust effects on brain chemistry, impacting Cre, NAA and Glx, which suggests restorative and neurotrophic processes. Differential effects of Glx in the sgACC and hippocampus, which approach control values with treatment, may reflect previously implicated underactive cortical and overactive subcortical limbic circuitry in patients with major depression. NAA levels at baseline are predictive of therapeutic outcome and could inform future treatment strategies.

Metabolic alterations in the anterior cingulate cortex and related cognitive deficits in late adolescent methamphetamine users.

The adolescent brain, with ongoing prefrontal maturation, may be more vulnerable to drug use-related neurotoxic changes as compared to the adult brain. We investigated whether the use of methamphetamine (MA), a highly addictive psychostimulant, during adolescence affect metabolic and cognitive functions of the anterior cingulate cortex (ACC). In adolescent MA users (n = 44) and healthy adolescents (n = 53), the levels of N-acetyl aspartate (NAA), a neuronal marker, were examined in the ACC using proton magnetic resonance spectroscopy. The Stroop color-word task was used to assess Stroop interference, which may reflect cognitive functions of behavior monitoring and response selection that are mediated by the ACC. Adolescent MA users had lower NAA levels in the ACC (t = -2.88, P = 0.005) and relatively higher interference scores (t = 2.03, P = 0.045) than healthy adolescents. Moreover, there were significant relationships between lower NAA levels in the ACC and worse interference scores in adolescent MA users (r = -0.61, P < 0.001). Interestingly, early onset of MA use, as compared to late onset, was related to both lower NAA levels in the ACC (t = -2.24, P = 0.03) as well as lower performance on interference measure of the Stroop color-word task (t = 2.25, P = 0.03). The current findings suggest that metabolic dysfunction in the ACC and its related cognitive impairment may play an important role in adolescent-onset addiction, particularly during early adolescence.

Spectroscopy markers of suicidal risk and mental pain in depressed patients

ObjectiveSuicidal behavior has been associated with structural and functional impairments in neuroimaging studies, mainly localized in the prefrontal cortex. However, little is known of the in vivo biochemical alterations that could be markers of suicidal risk. MethodsProton magnetic resonance spectroscopy was used to measure at-rest levels of 9 metabolites (glutamate, glutamine, glutathione, GABA, N-acetylaspartate (NAA), N-acetylaspartylglutamate, myo-inositol, aspartate, total choline), in the right dorsal prefrontal cortex of 25 unmedicated depressed patients, including 15 with a history of suicidal behavior, and 33 healthy controls. We compared metabolite levels between groups, and run correlations with 9 clinical variables relevant for suicide risk. ResultsWe found very significant associations between NAA levels and psychological pain measured by a simple analog scale (r=−0.47, p<10−3), and between choline levels and current suicidal ideas (r=0.53, p<10−3). These associations were independent from group, gender, age or depression level. While psychological pain and suicidal ideas were highly inter-correlated (r=0.61, p<10−3), the above-mentioned associations with compounds were independent. Mental pain was also correlated with Stroop interference, verbal fluency and (indirectly) decision-making, all cognitive measures previously associated with suicidal risk. Lower NAA levels, and higher glutamine levels were found in suicide attempters and in all patients relative to healthy controls, but these differences did not survive co-variation with age or Bonferroni's correction. ConclusionThis preliminary study suggests that markers of impaired neuronal and glial functioning in right dorsal prefrontal cortex underlie cardinal symptoms of the suicidal crisis. Targeting this region may be relevant for the short-term suicidal prevention. This study also supports a dimensional perspective in research on suicidal behavior.

496. From Gene Therapy to Gene Enhancement: Optimized Pre-Clinical Gene Therapy Transforms Mice with the Severest Canavan Disease Phenotype Into “Supermice”

Canavan Disease (CD) is a rare and lethal inherited CNS disorder caused by autosomal recessive mutations in the aspartoacylase gene. To date, there is no effective treatment available. Gene replacement therapy is an attractive approach for this devastating disease, although the physiologic function of AspA and its metabolite N-acetylaspartate (NAA) is still not fully understood.We previously reported that systemic delivery of the human aspartoacylase (hAspA) gene by recombinant adeno-associated virus (rAAV) to the CNS of CD mice ameliorated symptoms, partially restored motor function and increased life expectancy to the extent of wild-type (WT) mice. We further sought to investigate the mechanism behind this pre-clinical gene therapy for CD and to improve therapeutic potency. We hypothesized that Kozak sequence and codon modification of hAspA cDNA enhance therapeutic expression to transform our 1st generation AspA expression cassette into a more potent 2nd generation pre-clinical remedy and a better tool to study the physiologic role of AspA.We created expression cassettes containing codon-optimized (Opt) hAspA cDNA together with different Kozak sequences (i.e. HKz and FKz). Our in vitro and in vivo data demonstrate stronger hAspA expression and enzyme activity of the FKzhAspA-Opt vector over all other tested constructs as well as decreased NAA in the CNS below WT level by MRS analysis. Interestingly, rAAVFKzhAspA-Opt treated CD mice perform equally on inverted screen and balance beam but significantly (>50%) better than WT at p28, p90 and p180 on rotarod, suggesting that ubiquitously high expressed hAspA exerts some enhancing effect on treated mice. To confirm these findings, we moved to another mouse model of CD (Nur7 mouse). FKzhAspA-Opt treated Nur7 pups show a similar trend as seen in the CD mice on motor function tests. In addition, open-field testing to measure overall activity and anxiety demonstrates that treated Nur7 mice are more mobile with significantly longer travel distance but anxiety levels equal to WT mice. Currently, we are investigating the molecular mechanism underlying this enhanced performance of treated versus WT mice by studying the metabolome, microRNAome and the possibility of achieving therapeutic efficacy with reduced doses of the optimized vector.Overall, our data demonstrate that our 2nd generation gene therapy for CD not only completely restores the disease phenotype but also achieves motor function performance and overall activity superior to WT mice in two different CD mouse models. Using the same AAV serotype with identical tissue and cell tropism as previously published by our group, implies that excessive NAA is highly detrimental to normal physiology and the NAA re duction independent of the hAspA expressing cell type is sufficient for therapeutic success, which might also suggest a positive correlation of higher AspA activity and lower NAA levels with gene therapeutic outcome for this inborn error of NAA metabolism.

An In Vivo 1H Magnetic Resonance Spectroscopy Study of the Deep Cerebellar Nuclei in Children with Fetal Alcohol Spectrum Disorders

Prenatal alcohol exposure has been linked to impairment in cerebellar structure and function, including eyeblink conditioning. The deep cerebellar nuclei, which play a critical role in cerebellar-mediated learning, receive extensive inputs from brain stem and cerebellar cortex and provide the point of origin for most of the output fibers to other regions of the brain. We used in vivo (1) H magnetic resonance spectroscopy (MRS) to examine effects of prenatal alcohol exposure on neurochemistry in this important cerebellar region. MRS data from the deep cerebellar nuclei were acquired from 37 children with heavy prenatal alcohol exposure and 17 non- or minimally exposed controls from the Cape Coloured (mixed ancestry) community in Cape Town, South Africa. Increased maternal alcohol consumption around time of conception was associated with lower N-Acetylaspartate (NAA) levels in the deep nuclei (r = -0.33, p < 0.05). Higher levels of alcohol consumption during pregnancy were related to lower levels of the choline-containing metabolites (r = -0.37, p < 0.01), glycerophosphocholine plus phosphocholine (Cho). Alcohol consumption levels both at conception (r = 0.35, p < 0.01) and during pregnancy (r = 0.38, p < 0.01) were related to higher levels of glutamate plus glutamine (Glx). All these effects continued to be significant after controlling for potential confounders. The lower NAA levels seen in relation to prenatal alcohol exposure may reflect impaired neuronal integrity in the deep cerebellar nuclei. Our finding of lower Cho points to disrupted Cho metabolism of membrane phospholipids, reflecting altered neuropil development with potentially reduced content of dendrites and synapses. The alcohol-related alterations in Glx may suggest a disruption of the glutamate-glutamine cycling involved in glutamatergic excitatory neurotransmission.

Neurochemical Profile of Patients with Type 1 Diabetes Measured by 1H-MRS at 4 T

The impact of type 1 diabetes mellitus (T1DM) on a comprehensive neurochemical profile of the human brain has not been reported yet. Our previous proton magnetic resonance spectroscopy ((1)H-MRS) studies on T1DM were focused exclusively on the assessment of brain glucose levels. In this study, we reexamined our previously acquired data to investigate concentration differences of a broad range of neurochemicals in T1DM subjects relative to nondiabetic controls. We selected MRS data from 13 subjects (4 F/9 M, age = 41 ± 11 years, body mass index = 26 ± 3 kg/m(2)) with well-controlled T1DM (disease duration = 22 ± 12 years, A1C = 7.5% ± 2.0%) and 32 nondiabetic controls (14 F/18 M, age = 36 ± 10 years, body mass index = 27 ± 6 kg/m(2)) acquired during a hyperglycemic clamp (target [Glc]plasma = 300 ± 15 mg/dL). The (1)H-MR spectra were collected from two 15.6-mL voxels localized in gray-matter-rich occipital lobe and in white-matter-rich parieto-occipital region using ultra-short echo-time STEAM at 4 T. LCModel analysis allowed reliable quantification of 17 brain metabolites. Lower levels of N-acetylaspartate (by 6%, P=0.007) and glutamate (by 6%, P=0.045) were observed in the gray matter of T1DM patients as compared with controls, which might indicate a partial neuronal loss or dysfunction as a consequence of long-term T1DM. No other differences in metabolites were observed between subjects with T1DM and controls.

A proton magnetic resonance spectroscopy study in schizoaffective disorder: Comparison of bipolar disorder and schziophrenia

The aim of this study was to compare schizoaffective disorder, bipolar disorder and schizophrenia based on (1)H-MRS metabolite values in dorsolateral prefrontal cortex and executive functions. The subjects comprised 15 patients with bipolar disorder type I (BD), 15 with schizophrenia (SCH), 15 with schizoaffective disorder (SAD) and 15 healthy controls. We performed proton magnetic resonance spectroscopy ((1)H-MRS) of the dorsolateral prefrontal cortex (DLPFC) bilaterally. Levels of N-acetyl aspartate (NAA), choline-containing compounds (Cho) and creatine-containing compounds (Cr) were measured in the DLPFC using (1)H-MRS. We administered the Wisconsin Card Sorting Test (WCST) and the Stroop Test (ST) to evaluate executive functions. The SAD, BD and SCH patients had lower levels of NAA than the control group. The SAD and BD patients had low levels of Cho compared to the control group. The left DLPFC Cr levels in all of the patient groups and the right DLPFC Cr levels in the BD and SAD groups were lower than in the control group. The levels of NAA Cho and Cr were not related to executive functions and attention performance. Cr level were related to attention processes, only in SCH. Our results indicate that NAA levels are reduced in schizoaffective disorder, bipolar disorder and schizophrenia, but the reduction in the levels of NAA is not a distinctive feature among these three illnesses. Schizoaffective and bipolar disorders have similar features related to the levels of compounds containing Cho and Cr. This similarity may be related to these illnesses both having an affective basis.

Near Normalization of Metabolic and Functional Features of the Central Nervous System in Type 1 Diabetic Patients With End-Stage Renal Disease After Kidney-Pancreas Transplantation

OBJECTIVEThe pathogenesis of brain disorders in type 1 diabetes (T1D) is multifactorial and involves the adverse effects of chronic hyperglycemia and of recurrent hypoglycemia. Kidney-pancreas (KP), but not kidney alone (KD), transplantation is associated with sustained normoglycemia, improvement in quality of life, and reduction of morbidity/mortality in diabetic patients with end-stage renal disease (ESRD).RESEARCH DESIGN AND METHODSThe aim of our study was to evaluate with magnetic resonance imaging and nuclear magnetic resonance spectroscopy (1H MRS) the cerebral morphology and metabolism of 15 ESRD plus T1D patients, 23 patients with ESRD plus T1D after KD (n = 9) and KP (n = 14) transplantation, and 8 age-matched control subjects.RESULTSMagnetic resonance imaging showed a higher prevalence of cerebrovascular disease in ESRD plus T1D patients (53% [95% CI 36–69]) compared with healthy subjects (25% [3–6], P = 0.04). Brain 1H MRS showed lower levels of N-acetyl aspartate (NAA)-to-choline ratio in ESRD plus T1D, KD, and KP patients compared with control subjects (control subjects vs. all, P < 0.05) and of NAA-to-creatine ratio in ESRD plus T1D compared with KP and control subjects (ESRD plus T1D vs. control and KP subjects, P ≤ 0.01). The evaluation of the most common scores of psychological and neuropsychological function showed a generally better intellectual profile in control and KP subjects compared with ESRD plus T1D and KD patients.CONCLUSIONSDiabetes and ESRD are associated with a precocious form of brain impairment, chronic cerebrovascular disease, and cognitive decline. In KP-transplanted patients, most of these features appeared to be near normalized after a 5-year follow-up period of sustained normoglycemia.