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1.  Reduced hippocampal N-acetyl-aspartate (NAA) as a biomarker for overweight☆ 
NeuroImage : Clinical  2014;4:326-335.
Objective
We previously demonstrated an inverse relationship between both dentate gyrus neurogenesis – a form of neuroplasticity – and expression of the antiapoptotic gene marker, BCL-2 and adult macaque body weight. We therefore explored whether a similar inverse correlation existed in humans between body mass index (BMI) and hippocampal N-acetyl-aspartate (NAA), a marker of neuronal integrity and putatively, neuroplasticity. We also studied the relationship of a potentially neurotoxic process, worry, to hippocampal NAA in patients with generalized anxiety disorder (GAD) and control subjects (CS).
Methods
We combined two previously studied cohorts of GAD and control subjects. Using proton magnetic resonance spectroscopy imaging (1H MRSI) in medication-free patients with GAD (n = 29) and a matched healthy control group (n = 22), we determined hippocampal concentrations of (1) NAA (2) choline containing compounds (CHO), and (3) Creatine + phosphocreatine (CR). Data were combined from 1.5 T and 3 T scans by converting values from each cohort to z-scores. Overweight and GAD diagnosis were used as categorical variables while the Penn State Worry Questionnaire (PSWQ) and Anxiety Sensitivity Index (ASI) were used as dependent variables.
Results
Overweight subjects (BMI ≥ 25) exhibited lower NAA levels in the hippocampus than normal-weight subjects (BMI < 25) (partial Eta-squared = 0.14) controlling for age, sex and psychiatric diagnosis, and the effect was significant for the right hippocampus in both GAD patients and control subjects. An inverse linear correlation was noted in all subjects between right hippocampal NAA and BMI. High scores on the PSWQ predicted low hippocampal NAA and CR. Both BMI and worry were independent inverse predictors of hippocampal NAA.
Conclusion
Overweight was associated with reduced NAA concentrations in the hippocampus with a strong effect size. Future mechanistic studies are warranted.
Highlights
•Overweight people show reduced concentrations of hippocampal N-acetylaspartate (NAA).•Reduced NAA reflects reduced neuronal viability.•There is an inverse relationship between BMI and hippocampal NAA.•Worry scores are independently associated with lower NAA.•Generalized anxiety disorder did not show low hippocampal NAA.
doi:10.1016/j.nicl.2013.12.014
PMCID: PMC3913836  PMID: 24501701
Body mass index; Generalized anxiety disorder; Penn State Worry Questionnaire; Neuronal integrity; Creatine (CR); Obesity
2.  METABOLIC SYNDROME AND NEUROMETABOLIC ASYMMETRY OF HIPPOCAMPUS IN ADULT BONNET MONKEYS 
Physiology & behavior  2011;103(5):535-539.
Objective
Obesity is associated with the insulin resistance metabolic syndrome, postulated to be mediated by stress-induced alterations within the hypothalamic-pituitary-adrenal (HPA) axis. In adult bonnet macaques we examined relationships between components of the metabolic syndrome, hippocampal neurometabolic asymmetry, an indicator of negative affect, and juvenile cerebrospinal fluid (csf) corticotropin-releasing factor (CRF) levels obtained after stress exposure associated with maternal food insecurity and in controls.
Methods
Eleven adult male monkeys (seven with early life stress) who had undergone csf-CRF analyses as juveniles had magnetic resonance spectroscopic imaging (MRSI) of bilateral hippocampus, morphometry (body mass index, BMI; sagittal abdominal diameter, SAD) and determination of fasting plasma glucose and insulin as adults. Neurometabolite ratios included N-acetyl-aspartate as numerator (NAA; a marker of neuronal integrity) and choline (Cho; cell turnover) and creatine (Cr; reference analyte) as denominators.
Results
Elevated juvenile csf-CRF levels positively predicted adult BMI and SAD and were associated with right > left shift of NAA ratio within the hippocampus. Adult visceral obesity and insulin level correlated with right > left shift in hippocampal NAA concentrations, controlling for age and denominator.
Conclusion
Juvenile csf-CRF levels, a neuropeptide associated with early life stress, predict adult visceral obesity and hippocampal asymmetry supporting the hypothesis that metabolic syndrome in adults may be related to early life stress. Furthermore, this study demonstrates asymmetrical hippocampal alterations related to obesity.
doi:10.1016/j.physbeh.2011.03.020
PMCID: PMC3107881  PMID: 21459102
Corticotropin releasing factor; hippocampus; stress; metabolic syndrome; food insecurity; obesity
3.  Reduced NAA in motor and non-motor brain regions in amyotrophic lateral sclerosis: a cross-sectional and longitudinal study 
OBJECTIVES
After replication of previous findings we aimed to: 1) determine if previously reported 1H MRSI differences between ALS patients and control subjects are limited to the motor cortex; and 2) determine the longitudinal metabolic changes corresponding to varying levels of diagnostic certainty.
METHODS
Twenty-one patients with possible/suspected ALS, 24 patients with probable/definite ALS and 17 control subjects underwent multislice 1H MRSI co-registered with tissue-segmented MRI to obtain concentrations of the brain metabolites N-acetylaspartate (NAA), creatine, and choline in the left and right motor cortex and in gray matter and white matter of non-motor regions in the brain.
RESULTS
In the more affected hemisphere, reductions in the ratios, NAA/Cho and NAA/Cre+Cho were observed both within (12.6% and 9.5% respectively) and outside (9.2% and 7.3% respectively) the motor cortex in probable/definite ALS. However, these reductions were significantly greater within the motor cortex (P<0.05 for NAA/Cho and P<0.005 for NAA/Cre+Cho). Longitudinal changes in NAA were observed at three months within the motor cortex of both possible/suspected ALS patients (P<0.005) and at nine months outside the motor cortex of probable/definite patients (P<0.005). However, there was no clear pattern of progressive change over time.
CONCLUSIONS
NAA ratios are reduced in the motor cortex and outside the motor cortex in ALS, suggesting widespread neuronal injury. Longitudinal changes of NAA are not reliable, suggesting that NAA may not be a useful surrogate marker for treatment trials. (ALS 2004; 5: 141–149)
doi:10.1080/14660820410017109
PMCID: PMC2744639  PMID: 15512902
amyotrophic lateral sclerosis; magnetic resonance spectroscopic imaging; magnetic resonance imaging
4.  Comprehensive Evaluation of Corticospinal Tract Metabolites in Amyotrophic Lateral Sclerosis Using Whole-Brain 1H MR Spectroscopy 
PLoS ONE  2012;7(4):e35607.
Changes in the distribution of the proton magnetic resonance spectroscopy (MRS) observed metabolites N-acetyl aspartate (NAA), total-choline (Cho), and total-creatine (Cre) in the entire intracranial corticospinal tract (CST) including the primary motor cortex were evaluated in patients with amyotrophic lateral sclerosis (ALS). The study included 38 sporadic definite-ALS subjects and 70 age-matched control subjects. All received whole-brain MR imaging and spectroscopic imaging scans at 3T and clinical neurological assessments including percentage maximum forced vital capacity (FVC) and upper motor neuron (UMN) function. Differences in each individual metabolite and its ratio distributions were evaluated in the entire intracranial CST and in five segments along the length of the CST (at the levels of precentral gyrus (PCG), centrum semiovale (CS), corona radiata (CR), posterior limb of internal capsule (PLIC) and cerebral peduncle (CP)). Major findings included significantly decreased NAA and increased Cho and Cho/NAA in the entire intracranial CST, with the largest differences for Cho/NAA in all the groups. Significant correlations between Cho/NAA in the entire intracranial CST and the right finger tap rate were noted. Of the ten bilateral CST segments, significantly decreased NAA in 4 segments, increased Cho in 5 segments and increased Cho/NAA in all the segments were found. Significant left versus right CST asymmetries were found only in ALS for Cho/NAA in the CS. Among the significant correlations found between Cho/NAA and the clinical assessments included the left-PCG versus FVC and right finger tap rate, left -CR versus FVC and right finger tap rate, and left PLIC versus FVC and right foot tap rate. These results demonstrate that a significant and bilaterally asymmetric alteration of metabolites occurs along the length of the entire intracranial CST in ALS, and the MRS metrics in the segments correlate with measures of disease severity and UMN function.
doi:10.1371/journal.pone.0035607
PMCID: PMC3335096  PMID: 22539984
5.  Concussive brain injury from explosive blast 
Objective
Explosive blast mild traumatic brain injury (mTBI) is associated with a variety of symptoms including memory impairment and posttraumatic stress disorder (PTSD). Explosive shock waves can cause hippocampal injury in a large animal model. We recently reported a method for detecting brain injury in soldiers with explosive blast mTBI using magnetic resonance spectroscopic imaging (MRSI). This method is applied in the study of veterans exposed to blast.
Methods
The hippocampus of 25 veterans with explosive blast mTBI, 20 controls, and 12 subjects with PTSD but without exposure to explosive blast were studied using MRSI at 7 Tesla. Psychiatric and cognitive assessments were administered to characterize the neuropsychiatric deficits and compare with findings from MRSI.
Results
Significant reductions in the ratio of N-acetyl aspartate to choline (NAA/Ch) and N-acetyl aspartate to creatine (NAA/Cr) (P < 0.05) were found in the anterior portions of the hippocampus with explosive blast mTBI in comparison to control subjects and were more pronounced in the right hippocampus, which was 15% smaller in volume (P < 0.05). Decreased NAA/Ch and NAA/Cr were not influenced by comorbidities – PTSD, depression, or anxiety. Subjects with PTSD without blast had lesser injury, which tended to be in the posterior hippocampus. Explosive blast mTBI subjects had a reduction in visual memory compared to PTSD without blast.
Interpretation
The region of the hippocampus injured differentiates explosive blast mTBI from PTSD. MRSI is quite sensitive in detecting and localizing regions of neuronal injury from explosive blast associated with memory impairment.
doi:10.1002/acn3.98
PMCID: PMC4241796  PMID: 25493283
6.  Early detection and longitudinal changes in amyotrophic lateral sclerosis by 1H MRSI 
Neurology  2002;58(5):773-779.
Objective
To determine 1) the reproducibility of metabolite measurements by 1H MRS in the motor cortex; 2) the extent to which 1H MRS imaging (MRSI) detects abnormal concentrations of N-acetylaspartate (NAA)-, choline (Cho)-, and creatine (Cre)-containing compounds in early stages of ALS; and 3) the metabolite changes over time in ALS.
Methods
Sixteen patients with definite or probable ALS, 12 with possible or suspected ALS, and 12 healthy controls underwent structural MRI and multislice 1H MRSI. 1H MRSI data were coregistered with tissue-segmented MRI data to obtain concentrations of NAA, Cre, and Cho in the left and right motor cortex and in gray matter and white matter of nonmotor regions in the brain.
Results
The interclass correlation coefficient of NAA was 0.53 in the motor cortex tissue and 0.83 in nonmotor cortex tissue. When cross-sectional data for patients were compared with those for controls, the NAA/(Cre + Cho) ratio in the motor cortex region was significantly reduced, primarily due to increases in Cre and Cho and a decrease in NAA concentrations. A similar, although not significant, trend of increased Cho and Cre and reduced NAA levels was also observed for patients with possible or suspected ALS. Furthermore, in longitudinal studies, decreases in NAA, Cre, and Cho concentrations were detected in motor cortex but not in nonmotor regions in ALS.
Conclusion
Metabolite changes measured by 1H MRSI may provide a surrogate marker of ALS that can aid detection of early disease and monitor progression and treatment response.
PMCID: PMC2733360  PMID: 11889242
7.  Reduced medial temporal lobe N-acetylaspartate in cognitively impaired but nondemented patients 
Neurology  2005;64(2):282-289.
Background
N-acetylaspartate (NAA) in the medial temporal lobe (MTL) and parietal lobe gray matter (GM) is diminished in Alzheimer disease (AD). Because NAA is considered a marker of neuronal integrity, reduced medial temporal and parietal lobe NAA could be an early indication of dementia-related pathology in elderly individuals.
Objectives
1) To determine whether cognitively impaired but nondemented (CIND) elderly individuals exhibit a similar pattern of reduced medial temporal and parietal lobe NAA as AD patients. 2) To compare regional NAA patterns, hippocampal and neocortical gray matter (GM) volumes in CIND patients who remained cognitively stable and those who became demented over 3.6 years of follow-up. 3) To examine the relationship between memory performance, medial temporal lobe NAA, and hippocampal volume.
Methods
Seventeen CIND, 24 AD, and 24 cognitively normal subjects were studied using MRSI and MRI.
Results
Relative to controls, CIND patients had reduced MTL NAA (19 to 21%, p = 0.005), hippocampal (11 to 14%, p ≤ 0.04), and neocortical GM (5%, p = 0.05) volumes. CIND patients who later became demented had less MTL NAA (26%, p = 0.01), hippocampal (17 to 23%, p ≤ 0.05), and neocortical GM (13%, p = 0.02) volumes than controls, but there were no significant differences between stable CIND patients and controls. MTL NAA in combination with hippocampal volume improved discrimination of CIND and controls over hippocampal volume alone. In AD and CIND patients, decreased MTL NAA correlated significantly with impaired memory performance.
Conclusion
Reduced medial temporal lobe N-acetylaspartate, together with reduced hippocampal and neocortical gray matter volumes, may be early indications of dementia-related pathology in subjects at high risk for developing dementia.
doi:10.1212/01.WNL.0000149638.45635.FF
PMCID: PMC1851679  PMID: 15668426
8.  Increased glutamate concentration in the auditory cortex of persons with autism and first-degree relatives: A 1H-MRS study 
Lay Abstract
We investigated brain chemistry of the primary region of the brain involved in auditory processing in adults with autism spectrum disorder (ASD). Due to the highly heritable nature of ASD and the lack of prior brain chemistry data on unaffected first-degree relatives, we also enrolled parents of children with ASD (pASD), comparing both groups to a healthy adult control group. The technique used to quantify chemical signals was magnetic resonance spectroscopy (MRS), which we used to assess the concentration of auditory glutamate, the primary excitatory brain neurotransmitter, as well as other metabolites that assess neuronal integrity and metabolism. We found significantly higher levels of auditory glutamate in persons with ASD. In addition, increases in two other metabolites, n-acetyl-aspartate (NAA), and creatine (Cr), were observed in the ASD group. No differences were observed in the pASD group in any MRS measurement. We interpret the glutamate finding as suggestive of an increase in brain excitability, and the NAA and Cr findings as indicative of a change in brain energy metabolism in ASD.
Scientific Abstract
Increased glutamate levels have been reported in the hippocampal and frontal regions of persons with autism using proton magnetic resonance spectroscopy (1H-MRS). Although autism spectrum disorders (ASD) are highly heritable, MRS studies have not included relatives of persons with ASD. We therefore conducted a study to determine if glutamate levels are elevated in people with autism and parents of children with autism.
Single-voxel, point resolved spectroscopy (PRESS) data were acquired at 3T for left and right hemisphere auditory cortical voxels in 13 adults with autism, 15 parents of children with autism, and 15 adult control subjects. The primary measure was Glx. Additional measures included n-acetyl-aspartate (NAA), choline (Cho), myoinositol (mI) and creatine (Cr).
The autism group had significantly higher Glx, NAA and Cr concentrations than the control subjects. Parents did not differ from control subjects on any measures. No significant differences in Cho or mI levels were seen among groups. No reliable correlations between autism symptom measures and MRS variables were seen after Bonferroni correction for multiple comparisons.
The elevation in Glx in autism is consistent with prior MRS data in the hippocampus and frontal lobe and may suggest increased cortical excitability. Increased NAA and Cr may indicate brain metabolism disturbances in autism. In the current study, we found no reliable evidence of a familial effect for any spectroscopy measure. This may indicate that these metabolites have no heritable component in autism, the presence of a compensatory factor in parents, or sample specific limitations such the participation of singleton families.
doi:10.1002/aur.1260
PMCID: PMC3580156  PMID: 23166003
glutamate; n-acetyl-aspartate; creatine; spectroscopy; auditory cortex
9.  Correlation of Diffusion and Metabolic Alterations in Different Clinical Forms of Multiple Sclerosis 
PLoS ONE  2012;7(3):e32525.
Diffusion tensor imaging (DTI) and MR spectroscopic imaging (MRSI) provide greater sensitivity than conventional MRI to detect diffuse alterations in normal appearing white matter (NAWM) of Multiple Sclerosis (MS) patients with different clinical forms. Therefore, the goal of this study is to combine DTI and MRSI measurements to analyze the relation between diffusion and metabolic markers, T2-weighted lesion load (T2-LL) and the patients clinical status. The sensitivity and specificity of both methods were then compared in terms of MS clinical forms differentiation. MR examination was performed on 71 MS patients (27 relapsing remitting (RR), 26 secondary progressive (SP) and 18 primary progressive (PP)) and 24 control subjects. DTI and MRSI measurements were obtained from two identical regions of interest selected in left and right centrum semioval (CSO) WM. DTI metrics and metabolic contents were significantly altered in MS patients with the exception of N-acetyl-aspartate (NAA) and NAA/Choline (Cho) ratio in RR patients. Significant correlations were observed between diffusion and metabolic measures to various degrees in every MS patients group. Most DTI metrics were significantly correlated with the T2-LL while only NAA/Cr ratio was correlated in RR patients. A comparison analysis of MR methods efficiency demonstrated a better sensitivity/specificity of DTI over MRSI. Nevertheless, NAA/Cr ratio could distinguish all MS and SP patients groups from controls, while NAA/Cho ratio differentiated PP patients from controls. This study demonstrated that diffusivity changes related to microstructural alterations were correlated with metabolic changes and provided a better sensitivity to detect early changes, particularly in RR patients who are more subject to inflammatory processes. In contrast, the better specificity of metabolic ratios to detect axonal damage and demyelination may provide a better index for identification of PP patients.
doi:10.1371/journal.pone.0032525
PMCID: PMC3316537  PMID: 22479330
10.  Early life stress and macaque amygdala hypertrophy: preliminary evidence for a role for the serotonin transporter gene 
Background: Children exposed to early life stress (ELS) exhibit enlarged amygdala volume in comparison to controls. The primary goal of this study was to examine amygdala volumes in bonnet macaques subjected to maternal variable foraging demand (VFD) rearing, a well-established model of ELS. Preliminary analyses examined the interaction of ELS and the serotonin transporter gene on amygdala volume. Secondary analyses were conducted to examine the association between amygdala volume and other stress-related variables previously found to distinguish VFD and non-VFD reared animals.
Methods: Twelve VFD-reared and nine normally reared monkeys completed MRI scans on a 3T system (mean age = 5.2 years).
Results: Left amygdala volume was larger in VFD vs. control macaques. Larger amygdala volume was associated with: “high” cerebrospinal fluid concentrations of corticotropin releasing-factor (CRF) determined when the animals were in adolescence (mean age = 2.7 years); reduced fractional anisotropy (FA) of the anterior limb of the internal capsule (ALIC) during young adulthood (mean age = 5.2 years) and timid anxiety-like responses to an intruder during full adulthood (mean age = 8.4 years). Right amygdala volume varied inversely with left hippocampal neurogenesis assessed in late adulthood (mean age = 8.7 years). Exploratory analyses also showed a gene-by-environment effect, with VFD-reared macaques with a single short allele of the serotonin transporter gene exhibiting larger amygdala volume compared to VFD-reared subjects with only the long allele and normally reared controls.
Conclusion: These data suggest that the left amygdala exhibits hypertrophy after ELS, particularly in association with the serotonin transporter gene, and that amygdala volume variation occurs in concert with other key stress-related behavioral and neurobiological parameters observed across the lifecycle. Future research is required to understand the mechanisms underlying these diverse and persistent changes associated with ELS and amygdala volume.
doi:10.3389/fnbeh.2014.00342
PMCID: PMC4186477  PMID: 25339875
amygdala; early life stress; non-human primates; MRI; stress; serotonin transporter gene
11.  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 
Biological psychiatry  2008;64(10):856-862.
Background
This study was conducted to corroborate prior evidence of an effect of the BDNF Val66Met polymorphism on measures of N-acetyl aspartate containing compounds (NAA) in healthy subjects.
Methods
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 3T.
Results
Val/Met subjects exhibited significantly reduced levels of left hippocampal NAA/Cre and NAA/Cho compared to 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.
Conclusions
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.
doi:10.1016/j.biopsych.2008.07.009
PMCID: PMC2586327  PMID: 18707679
12.  Value of Proton-MR-Spectroscopy in the Diagnosis of Temporal Lobe Epilepsy; Correlation of Metabolite Alterations With Electroencephalography 
Background
Epilepsy, a well-known mostly idiopathic neurologic disorder, has to be correctly diagnosed and properly treated. Up to now, several diagnostic approaches have been processed to determine the epileptic focus.
Objectives
The aim of this study was to discover whether proton-MR-spectroscopic imaging (MRSI) aids in the diagnosis of temporal lobe epilepsy in conjunction with classical electroencephalography (EEG) findings.
Patients and Methods
Totally, 70 mesial temporal zones consisting of 39 right hippocampi and 31 left hippocampi of 46 patients (25 male, 21 female) were analyzed by proton MRSI. All patients underwent a clinical neurologic examination, scalp EEG recording and prolonged video EEG monitoring. Partial seizures on the right, left or both sides were recorded in all patients. All patients were under medical treatment and none of the patients underwent amygdalohippocampectomy and similar surgical procedures.
Results
The normal average lactate (Lac), phosphocreatine, N-acetyl aspartate (NAA), creatine (Cr), choline (Cho), myo-inositol, glutamate and glutamine (Glx) peaks and Nacetyl aspartate/Cr, NAA/ Cho + Cr, Cho/Cr ratios were measured from the healthy opposite hippocampi or from the control subjects. The Lac, glutamate and glutamine (Glx), myo-inositol, phosphocreatine and NAA metabolites plus Cho/Cr ratio showed statistical difference between the normal and the epileptic hippocampi. Cho, Cr metabolites plus NAA/Cr, NAA/ Cho + Cr ratios were almost the same between the groups. The sensitivity of Proton-MR-Spectroscopy for lateralization of the epileptic foci in all patients was 96% and the specificity was 50%.
Conclusions
Proton-MRSI can easily be considered as an alternative modality of choice in the diagnosis of temporal lobe epilepsy and in the future; Proton-MR-Spectroscopy may become the most important technique used in epilepsy centers.
doi:10.5812/iranjradiol.6686
PMCID: PMC3522336  PMID: 23329953
Magnetic Resonance Spectroscopy; Epilepsy; Temporal Lobe; Electroencephalography
13.  Diffuse axonal injury in mild traumatic brain injury: a 3D multivoxel proton MR spectroscopy study 
Journal of neurology  2012;260(1):242-252.
Since mild traumatic brain injury (mTBI) often leads to neurological symptoms even without clinical MRI findings, our goal was to test whether diffuse axonal injury is quantifiable with multivoxel proton MR spectroscopic imaging (1H-MRSI). T1- and T2-weighted MRI and three dimensional 1H-MRSI (480 voxels over 360 cm3, ∼30% of the brain) were acquired at 3 Tesla from 26 mTBI patients (mean Glasgow Coma Scale score 14.7), 18–56 years old, 3–55 days post injury and 13 healthy matched contemporaries. The N-acetylaspartate (NAA), choline (Cho), creatine (Cr) and myo-inositol (mI) concentrations and gray-, white-matter (GM/WM) and cerebrospinal fluid fractions were obtained in each voxel. Global GM and WM absolute metabolic concentrations were estimated using linear regression, and patients were compared with controls using two-way analysis of variance. Patients' mean NAA, Cr, Cho and mI concentrations in GM (8.4±0.7, 6.9±0.6, 1.3±0.2, 5.5±0.6 mM) and Cr, Cho and mI in WM (4.8±0.5, 1.4±0.2, 4.6±0.7 mM) were not different from controls'. NAA, however, was significantly lower in patients' than controls' WM (7.2±0.8 versus 7.7±0.6 mM, p=0.0125). The Cho and Cr levels in patients' WM positively correlated with time from mTBI. This 1H-MRSI approach allowed us to ascertain that early mTBI sequelae are (i) diffuse (not merely local), (ii) neuronal (not glial) and (iii) in the global white (not gray) matter. These findings support the hypothesis that, similarly to more severe head trauma, mTBI also results in diffuse axonal injury, but that dysfunction, rather than cell death, dominates shortly after injury.
doi:10.1007/s00415-012-6626-z
PMCID: PMC3729330  PMID: 22886061
Brain Injury; Diffuse Axonal Injury; Magnetic Resonance Spectroscopy
14.  Hippocampal MR spectroscopic abnormalities in a cohort of syphilitic patients with HIV and neurosyphilis infection 
Co-infection of human immunodeficiency virus (HIV) and neurosyphilis (NS) has become a rising trend, but the extent of brain damage associated with the concomitant infections remains unknown. Proton magnetic resonance spectroscopy (1H-MRS) can evaluate metabolic changes underlying early brain infections. 25 syphilitic patients (7 HIV-positive with NS; 6 HIV-positive without NS; 5 HIV-negative with NS; 7 non-HIV, non-NS) and 17 healthy controls (HC) underwent single-voxel 1H-MRS in the bilateral hippocampi. Absolute concentrations of major metabolites were measured using a 3T MRI scanner. No significant structural abnormality was detected in all patients. However, metabolic changes were found in the left hippocampus of both the HIV-positive and NS subgroups, showing significantly higher choline (Cho), creatine (Cr) and myo-inositol (mI) compared to HC. In the right hippocampus, HIV-positive subgroup showed significantly higher Cr and reduced NAA, while NS subgroup only showed significantly reduced NAA compared to HC. The non-HIV, non-NS syphilitic subgroup showed no significant difference compared to HC. Substantial metabolic changes occurred in bilateral hippocampi in HIV and NS co-infections. NAA reduction might represent early neuronal damage, while mI/Cho elevation reflects gliosis/inflammatory changes. 1H-MRS could serve as a non-invasive tool to triage patients suspected of NS for lumbar puncture in non-HIV syphilitic patients.
PMCID: PMC4299779  PMID: 25625030
HIV; neurosyphilis; co-infection; magnetic resonance spectroscopy; hippocampus
15.  Presymptomatic spinal cord neurometabolic findings in SOD1-positive people at risk for familial ALS 
Neurology  2011;77(14):1370-1375.
Objective:
It has been speculated that amyotrophic lateral sclerosis (ALS) is characterized by a premanifest period during which neurodegeneration precedes the appearance of clinical manifestations. Magnetic resonance spectroscopy (MRS) was used to measure ratios of neurometabolites in the cervical spine of asymptomatic individuals with a mutation in the SOD1 gene (SOD1+) and compare their neurometabolic ratios to patients with ALS and healthy controls.
Methods:
A cross-sectional study of 1H-MRS of the cervical spine was performed on 24 presymptomatic SOD1+ volunteers, 29 healthy controls, and 23 patients with ALS. All presymptomatic subjects had no symptoms of disease, normal forced vital capacity, and normal electromyographic examination. Relative concentrations of choline (Cho), creatine (Cr), myo-inositol (Myo), and N-acetylaspartate (NAA) were determined.
Results:
NAA/Cr and NAA/Myo ratios are reduced in both SOD1+ subjects (39.7%, p = 0.001 and 18.0%, p = 0.02) and patients with ALS (41.2%, p < 0.001 and 24.0%, p = 0.01) compared to controls. Myo/Cr is reduced (10.3%, p = 0.02) in SOD1+ subjects compared to controls, but no difference was found between patients with ALS and controls. By contrast, NAA/Cho is reduced in patients with ALS (24.0%, p = 0.002), but not in presymptomatic SOD1+ subjects compared to controls.
Conclusions:
Changes in neurometabolite ratios in the cervical spinal cord are evident in presymptomatic SOD1+ individuals in advance of symptoms and clinical or electromyographic signs of disease. These changes reflect a reduction in NAA/Cr and NAA/Myo. Neurometabolic changes in this population resemble changes observed in patients with clinically apparent ALS. This suggests that neurometabolic changes occur early in the course of the disease process.
doi:10.1212/WNL.0b013e318231526a
PMCID: PMC3182757  PMID: 21940617
16.  The Effect of Insulin Infusion on the Metabolites in Cerebral Tissues Assessed With Proton Magnetic Resonance Spectroscopy in Young Healthy Subjects With High and Low Insulin Sensitivity 
Diabetes Care  2013;36(9):2787-2793.
OBJECTIVE
Insulin may play important roles in brain metabolism. Proton magnetic resonance spectroscopy (1H-MRS) of the central nervous system gives information on neuronal viability, cellular energy, and membrane status. To elucidate the specific role of insulin action in the brain, we estimated neurometabolites with 1H-MRS and assessed their regulation by insulin infusion and their relationship with insulin sensitivity.
RESEARCH DESIGN AND METHODS
We studied 16 healthy young men. 1H-MRS was performed at baseline and after 240 min of euglycemic-hyperinsulinemic clamp. Voxels were positioned in the left frontal lobe, left temporal lobe, and left thalamus. The ratios of N-acetylaspartate (NAA), choline-containing compounds (Cho), myo-inositol, and glutamate/glutamine/γ-aminobutyric acid complex (Glx) to creatine (Cr) and nonsuppressed water signal were determined. The participants were divided into subgroups of high (high IS) and low (low IS) insulin sensitivity.
RESULTS
Baseline neurometabolic substrates were not different between the groups. Insulin infusion resulted in an increase in frontal NAA/Cr and NAA/H2O and frontal and temporal Glx/Cr and Glx/H2O and a decrease in frontal Cho/Cr and temporal Cho/H2O and myo-inositol/H2O (all P < 0.05, except temporal Glx/H2O, P = 0.054, NS) in the high-IS, but not in the low-IS, group. Insulin sensitivity correlated positively with frontal NAA/Cr and NAA/H2O and temporal Glx/H2O and negatively with temporal myo-inositol/Cr and myo-inositol/H2O assessed during the second 1H-MRS (all P < 0.05).
CONCLUSIONS
Insulin might influence cerebral metabolites, and this action is impaired in subjects with low whole-body insulin sensitivity. Thus, our results provide a potential link between insulin resistance and altered metabolism of the central nervous system.
doi:10.2337/dc12-1437
PMCID: PMC3747869  PMID: 23596182
17.  Elevated cerebrospinal fluid 5-hydroxyindoleacetic acid in macaques following early life stress and inverse association with hippocampal volume: preliminary implications for serotonin-related function in mood and anxiety disorders 
Background: Early life stress (ELS) is cited as a risk for mood and anxiety disorders, potentially through altered serotonin neurotransmission. We examined the effects of ELS, utilizing the variable foraging demand (VFD) macaque model, on adolescent monoamine metabolites. We sought to replicate an increase in cerebrospinal fluid (CSF) 5-hydroxyindoleacetic acid (5-HIAA) observed in two previous VFD cohorts. We hypothesized that elevated cisternal 5-HIAA was associated with reduced neurotrophic effects, conceivably due to excessive negative feedback at somatodendritic 5-HT1A autoreceptors. A putatively decreased serotonin neurotransmission would be reflected by reductions in hippocampal volume and white matter (WM) fractional anisotropy (FA).
Methods: When infants were 2–6 months of age, bonnet macaque mothers were exposed to VFD. We employed cisternal CSF taps to measure monoamine metabolites in VFD (N = 22) and non-VFD (N = 14) offspring (mean age = 2.61 years). Metabolites were correlated with hippocampal volume obtained by MRI and WM FA by diffusion tensor imaging in young adulthood in 17 males [10 VFD (mean age = 4.57 years)].
Results: VFD subjects exhibited increased CSF 5-HIAA compared to non-VFD controls. An inverse correlation between right hippocampal volume and 5-HIAA was noted in VFD- but not controls. CSF HVA and MHPG correlated inversely with hippocampal volume only in VFD. CSF 5-HIAA correlated inversely with FA of the WM tracts of the anterior limb of the internal capsule (ALIC) only in VFD.
Conclusions: Elevated cisternal 5-HIAA in VFD may reflect increased dorsal raphe serotonin, potentially inducing excessive autoreceptor activation, inducing a putative serotonin deficit in terminal fields. Resultant reductions in neurotrophic activity are reflected by smaller right hippocampal volume. Convergent evidence of reduced neurotrophic activity in association with high CSF 5-HIAA in VFD was reflected by reduced FA of the ALIC.
doi:10.3389/fnbeh.2014.00440
PMCID: PMC4274982  PMID: 25566007
variable foraging demand; MRI; cisternal tap; serotonin metabolite; monoamine metabolites
18.  Proton Magnetic Resonance Spectroscopy and Thought Disorder in Childhood Schizophrenia 
Schizophrenia research  2011;133(1-3):82-90.
Objective
Although magnetic resonance spectroscopy has identified metabolic abnormalities in adult and childhood schizophrenia, no prior studies have investigated the relationship between neurometabolites and thought disorder. This study examined this association in language-related brain regions using proton magnetic resonance spectroscopic imaging (1H MRSI).
Method
MRSI was acquired bilaterally from 28 youth with childhood-onset schizophrenia and 34 healthy control subjects in inferior frontal, middle frontal, and superior temporal gyri at 1.5 T and short echo time (TR/TE=1500/30 ms). CSF-corrected “total NAA” (tNAA; N-acetyl-aspartate+N-acetyl-aspartyl-glutamate), glutamate+glutamine (Glx), creatine+phosphocreatine (Cr+PCr), choline compounds (Cho), and myo-inositol (mI) were assayed in manually drawn regions-of-interest partitioned into gray matter, white matter, and CSF and then coregistered with MRSI. Speech samples of all subjects were coded for thought disorder.
Results
In the schizophrenia group, the severity of formal thought disorder correlated significantly with tNAA in the left inferior frontal and superior temporal gyri and with Cr+PCr in left superior temporal gyrus.
Conclusions
Neurometabolite concentrations in language-related brain regions are associated with thought disorder in childhood-onset schizophrenia.
doi:10.1016/j.schres.2011.07.011
PMCID: PMC3229835  PMID: 21872444
Childhood-onset schizophrenia; Thought Disorder; Magnetic Resonance Spectroscopy; N-acetyl aspartate; Choline compounds
19.  Hippocampal abnormalities of glutamate/glutamine, N-acetylaspartate and choline in patients with depression are related to past illness burden 
Background
Smaller hippocampal volumes in major depressive disorder (MDD) have been linked with earlier onset, previous recurrences and treatment refractoriness. The aim of our study was to investigate metabolite abnormalities in the hippocampus associated with past depressive illness burden.
Methods
Glutamate/glutamine (Glx), N-acetylaspartate (NAA) and choline (Cho), potential markers of glial/neuronal integrity and membrane turnover, respectively, were measured in adults with depression and healthy controls using a 3 T magnetic resonance spectroscopy scanner. Voxels were placed in the head of the right and left hippocampus. We controlled for systematic differences resulting from volume-of-interest (VOI) tissue composition and total hippocampal volume.
Results
Our final sample comprised a total of 16 healthy controls and 52 adult patients with depression in different stages of the illness (20 treatment-resistant/chronic, 18 remitted-recurrent and 14 first-episode), comparable for age and sex distribution. Patients with treatment-resistant/chronic and remitted-recurrent depression had significantly lower levels of Glx and NAA than controls, especially in the right hippocampal region (p ≤ 0.025). Diminished levels of Glx were correlated with longer illness duration (left VOI r = −0.34, p = 0.01). By contrast, Cho levels were significantly higher in patients with treatment-resistant/chronic depression than those with first-episode depression or controls in the right and left hippocampus (up to 19% higher; all p ≤ 0.025) and were consistently related to longer illness duration (right VOI r = 0.30, p = 0.028; left VOI r = 0.38, p = 0.004) and more previous episodes (right VOI r = 0.46, p = 0.001; left VOI r = 0.44, p = 0.001).
Limitations
The cross-sectional design and the inclusion of treated patients are the main limitations of the study.
Conclusion
Our results support that metabolite alterations within the hippocampus are more pronounced in patients with a clinical evolution characterized by recurrences and/or chronicity and add further evidence to the potential deleterious effects of stress and depression on this region.
doi:10.1503/jpn.110185
PMCID: PMC3581591  PMID: 23425950
20.  Magnetic resonance spectroscopy of limbic structures displays metabolite differences in young unaffected relatives of schizophrenia probands 
Schizophrenia research  2011;131(1-3):4-10.
Imaging studies of schizophrenia patients showed fronto-temporal brain volume deficits, while magnetic resonance spectroscopy (MRS) studies of patients and unaffected biological relatives have found a decrement of the neuronal marker N-acetyl-aspartate (NAA) in the hippocampus and frontal lobes, and increased choline-containing phospholipids. Using a 3 T MR scanner, we determined the metabolite profile within limbic regions (anterior cingulate cortex (ACC) and left hippocampus) of 36 unaffected, adolescent/young adult relatives of schizophrenia probands (first-degree=16, second-degree=20) and 25 healthy controls with no family history of schizophrenia. Significant main effects of group were found on NAA/Cho ratios for both the left hippocampus (F=6.11, p≤0.02) and ACC (F=4.89, p≤0.03) as well as for the left hippocampus Cho/Cr ratio (F=5.55, p≤0.02). Compared to age and sex matched healthy controls without a family history of schizophrenia, first-degree relatives of probands had greater MRS metabolite deviations than second-degree relatives. Greater familial proximity to the schizophrenia proband (or higher schizophrenia susceptibility) among biological relatives was associated with stepwise lowering of NAA/Cho and elevations in Cho/Cr ratios. The observed limbic metabolite changes among young, nonpsychotic biological relatives are likely related to shared genetic vulnerability factors, and may assist in the early identification of schizophrenia for primary and secondary prevention.
doi:10.1016/j.schres.2011.05.024
PMCID: PMC3485075  PMID: 21705196
Adolescence; Endophenotype; Genetics; Magnetic resonance spectroscopy; Hippocampus; Anterior cingulate cortex
21.  MR Spectroscopy Indicates Diffuse Multiple Sclerosis Activity During Remission 
Objective
To test the hypothesis that diffuse abnormalities precede axonal damage and atrophy in the MRI normal-appearing tissue of relapsing-remitting (RR) multiple sclerosis (MS) patients, and that these processes continue during clinical remission.
Methods
Twenty-one recently diagnosed mildly disabled (mean disease duration 2.3 years, mean Expanded Disability Status Scale score of 1.4) RR MS patients and 15 healthy matched controls were scanned with MRI and proton MR spectroscopic imaging (1H-MRSI) at 3 T. Metabolite concentrations: N-acetylaspartate (NAA) for neuronal integrity; choline (Cho) for membrane turnover rate; creatine (Cr) and myo-inositol (mI) for glial status were obtained in a 360 cm3 volume-of-interest (VOI) with 3D multivoxel 1H-MRSI. They were converted into absolute amounts using phantom replacement and normalized into absolute concentrations by dividing by the VOI tissue volume fraction obtained from MRI segmentation.
Results
The patients’ mean VOI tissue volume fraction, 0.92 and NAA concentration, 9.6 mM, were not different from controls’ 0.94 and 9.6 mM. In contrast, the patients’ mean Cr, Cho and mI levels 7.7, 1.9, 4.1 mM were 9%, 14% and 20%, higher than the controls’ 7.1, 1.6 and 3.4 mM (p=0.0097, 0.003 and 0.0023).
Conclusions
The absence of early tissue atrophy and apparent axonal dysfunction (NAA loss) in these RR MS patients suggests that both are preceded by diffuse glial proliferation (astrogliosis), as well as possible inflammation, de- and re-myelination reflected by elevated mI, Cho and Cr, even during clinical remission and despite immunomodulatory treatment.
doi:10.1136/jnnp.2009.176263
PMCID: PMC2900785  PMID: 19546105
Multiple Sclerosis; normal-appearing tissue; MR Spectroscopy
22.  Sensitivity of quantitative 1H magnetic resonance spectroscopy of the brain in detecting early neuronal damage in systemic lupus erythematosus 
Annals of the Rheumatic Diseases  2001;60(2):106-111.
OBJECTIVE—To quantify N-acetylaspartate (NAA), total creatines (tCr), total cholines (tCho), and myo-inositol (mI) levels in normal and abnormal appearing white matter of patients with neuropsychiatric systemic lupus erythematosus (NPSLE) in order to determine the specific changes in metabolite concentrations.
METHODS—Axial proton density and T2 weighted magnetic resonance images, and short echo time (TE 30 ms) 1H spectra were acquired with a GE SIGNA 1.5 T magnetic resonance system. Concentrations of NAA, tCr, tCho, and mI were determined, using brain tissue water as a reference, from nine patients (seven female, mean age 40.3 years, range 16-65) with NPSLE and eight healthy women (mean age 43 years, range 31-65).
RESULTS—A significant rise of tCho (12.4%, p<0.05) and mI (31.4%, p<0.005) and a significant reduction in NAA (−12%, p<0.05) was found in normal appearing white matter compared with controls. Analysis according to severity of the clinical NPSLE features (subgrouped as major or minor) showed that SLE major had reduced NAA compared with SLE minor (−18.4%, p<0.05) and controls (−20%, p<0.005). The SLE major group showed a significant rise of mI (32%, p<0.01) and the SLE minor group a significant increase in tCho (18.6%, p<0.05) compared with controls. Longitudinal analysis of brain metabolites in normal appearing white matter showed consistent abnormalities in NAA, tCho, and mI in a patient with stable clinical features and a constant rise of tCho, but transient rise of mI was seen during a flare of disease in another patient.
CONCLUSION—Quantitative 1H magnetic resonance spectroscopy (MRS) suggests a particular course of neurometabolite changes that precedes irreversible reductions in NAA and permanent neuronal loss. Initially, in patients with SLE minor, there is a significant rise in tCho and a trend (reversible) for mI also to be raised. In patients with SLE major the NAA is significantly and permanently reduced and mI is significantly raised, whereas the tCho levels are near normal. Further investigations are needed to determine how specific MRS is as a clinical marker for brain disturbance in SLE.


doi:10.1136/ard.60.2.106
PMCID: PMC1753471  PMID: 11156541
23.  Abnormal N-acetylaspartate in hippocampus and anterior cingulate in posttraumatic stress disorder 
Psychiatry research  2008;162(2):147-157.
Magnetic resonance spectroscopic imaging (MRSI) studies suggest hippocampal abnormalities in posttraumatic stress disorder (PTSD), whereas findings of volume deficits in the hippocampus, as revealed with magnetic resonance imaging (MRI), have been inconsistent. Co-morbidities of PTSD, notably alcohol abuse, may have contributed to the inconsistency. The objective was to determine whether volumetric and metabolic abnormalities in the hippocampus and other brain regions are present in PTSD, independent of alcohol abuse. Four groups of subjects, PTSD patients with (n=28) and without (n=27) alcohol abuse and subjects negative for PTSD with (n=23) and without (n=26) alcohol abuse, were enrolled in this observational MRI and MRSI study of structural and metabolic brain abnormalities in PTSD. PTSD was associated with reduced N-acetylaspartate (NAA) in both the left and right hippocampus, though only when normalized to creatine levels in the absence of significant hippocampal volume reduction. Furthermore, PTSD was associated with reduced NAA in the right anterior cingulate cortex regardless of creatine. NAA appears to be a more sensitive marker for neuronal abnormality in PTSD than brain volume. The alteration in the anterior cingulate cortex in PTSD has implications for fear conditioning and extinction.
doi:10.1016/j.pscychresns.2007.04.011
PMCID: PMC2443727  PMID: 18201876
Magnetic resonance imaging; Magnetic resonance spectroscopy; Brain metabolites; Brain atrophy; Alcoholism
24.  1H MRS of basal ganglia and thalamus in amyotrophic lateral sclerosis† 
Nmr in Biomedicine  2011;24(10):1270-1276.
Previous studies have evaluated motor and extramotor cerebral cortical regions in patients with amyotrophic lateral sclerosis (ALS) using 1H MRS, but none have evaluated the thalamus or basal ganglia. The objective of this exploratory study was to evaluate the subclinical involvement of the basal ganglia and thalamus in patients with ALS using 1H MRS. Fourteen patients (52 ± 7 years) with sporadic definite ALS and 17 age-matched controls were studied using volumetric MRSI on a 3-T scanner. The concentration of the metabolites N-acetylaspartate (NAA), choline (Cho) and their ratio (NAA/Cho) were obtained bilaterally from the basal ganglia (lentiform nucleus, caudate) and thalamus. The maximum rates of finger and foot tap and lip and tongue movements were obtained to assess extrapyramidal and pyramidal tract function. In patients with ALS, relative to controls, the NAA concentration was significantly lower (p < 0.02) in the basal ganglia and thalamus, and the Cho concentration was higher (p < 0.01) in these structures, except in the caudate (p = 0.04). Correspondingly, the NAA/Cho ratio was significantly lower (p < 0.01) in these structures, except in the caudate (p = 0.03), in patients than in controls. There were mild to strong correlations (r = 0.4–0.7) between the metabolites of the basal ganglia and finger tap, foot tap and lip and tongue movement rates. In conclusion, decreased NAA in the basal ganglia and thalamus and increased Cho and decreased NAA/Cho in the lentiform nucleus and thalamus are indicative of neuronal loss or dysfunction and alterations in choline-containing membranes in these structures.
doi:10.1002/nbm.1687
PMCID: PMC3210902  PMID: 21404355
amyotrophic lateral sclerosis; basal ganglia; MRS; extramotor; thalamus
25.  Proton MR Spectroscopy Correlates Diffuse Axonal Abnormalities with Post-Concussive Symptoms in Mild Traumatic Brain Injury 
Journal of Neurotrauma  2013;30(13):1200-1204.
Abstract
There are no established biomarkers for mild traumatic brain injury (mTBI), in part because post-concussive symptoms (PCS) are subjective and conventional imaging is typically unremarkable. To test whether diffuse axonal abnormalities quantified with three-dimensional (3D) proton magnetic resonance spectroscopic imaging (1H-MRSI) correlated with patients' PCS, we retrospectively studied 26 mTBI patients (mean Glasgow Coma Scale [GCS] score of 14.7), 18- to 56-year-olds and 13 controls three to 55 days post-injury. All were scanned at 3 Tesla with T1- and T2-weighted MRI and 3D 1H-MRSI (480 voxels over 360 cm3, ∼30% of the brain). On scan day, patients completed a symptom questionnaire, and those who indicated at least one of the most common subacute mTBI symptoms (headache, dizziness, sleep disturbance, memory deficits, blurred vision) were grouped as PCS-positive. Global gray matter and white matter (GM/WM) absolute concentrations of N-acetylaspartate (NAA), choline (Cho), creatine (Cr) and myo-inositol (mI) in PCS-positive and PCS-negative patients were compared to age- and gender-matched controls using two-way analysis of variance. The results showed that the PCS-negative group (n=11) and controls (n=8) did not differ in any GM or WM metabolite level. The PCS-positive patients (n=15) had lower WM NAA than the controls (n=12; 7.0±0.6 versus 7.9±0.5mM; p=0.0007). Global WM NAA, therefore, showed sensitivity to the TBI sequelae associated with common PCS in patients with mostly normal neuroimaging, as well as GCS scores. This suggests a potential biomarker role in a patient population in which objective measures of injury and symptomatology are currently lacking.
doi:10.1089/neu.2012.2696
PMCID: PMC3700460  PMID: 23339670
diffuse axonal injury; magnetic resonance spectroscopy; mild traumatic brain injury; N-acetyl-aspartate; post-concussive symptoms

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