N-acetylaspartate/creatine Research Articles

Brain flexibility and balance and gait performances mark morphological and metabolic abnormalities in the elderly

Although previous studies have found that cerebral white matter hyperintensities are associated with balance–gait disorders, no proton magnetic resonance spectroscopy data at the plane of the basal ganglia have been published. We investigated a possible relationship between balance performance and brain metabolite ratios or structural MRI measurements. We also included neuropsychological tests to determine whether such tests are related to structural or metabolic findings. All 80 participants were taken from the cohort of the Three-City study (Dijon–Bordeaux–Montpellier, France). The ratios of N-acetyl-aspartate to creatine (NAA/Cr) and choline to creatine (Cho/Cr) were calculated in the basal ganglia, thalami and insular cortex. We used univariate regression to identify which variables predicted changes in NAA/Cr and Cho/Cr, and completed the analysis with a multiple linear or logistic regression. After the multivariate analysis including hypertension, age, balance–gait, sex, white matter lesions, brain atrophy and body mass index, only balance–gait performance remained statistically significant for NAA/Cr ( p = 0.01) and for deep white-matter lesions ( p = 0.02). The Trail-Making Test is independently associated with brain atrophy and periventricular white-matter hyperintensities. Neuronal and axonal integrity at the plane of the basal ganglia is associated with balance and gait in the elderly, whereas brain flexibility is associated with structural MRI brain abnormalities.

Hippocampal Metabolite Abnormalities in Fibromyalgia: Correlation With Clinical Features

Although the pathology of fibromyalgia is poorly understood, a growing body of evidence suggests involvement of the central nervous system. The hippocampus is a brain center that is sensitive to the effects of stress exposure and has been demonstrated to be affected in a variety of disorders whose onset, like fibromyalgia, are associated with stressful experience. We therefore interrogated the bilateral hippocampus of 16 female fibromyalgia patients in comparison to 8 age- and gender-matched healthy control subjects using single voxel proton magnetic resonance spectroscopy. Our results demonstrate a significant reduction in the ratio of N-acetylaspartate to creatine (NAA/Cr) in fibromyalgia patients versus matched control subjects specifically in the right temporal lobe from a voxel centered on the right hippocampus (patient vs control, mean +/- standard deviation: 1.20 +/- 0.13 vs 1.34 +/- 0.10, P = .03). Moreover, correlation analysis demonstrated a significant negative correlation between patient scores on the Fibromyalgia Impact Questionnaire and NAA/Cr ratio within the right hippocampus (Spearman rank correlation, rho = -0.681, P = .018). Our results indicate that fibromyalgia is associated with brain metabolite abnormalities within the right hippocampus that correlate with patient symptoms. We have demonstrated an abnormality in hippocampal brain metabolites in premenopausal female fibromyalgia patients with no psychiatric comorbidity. A significant negative correlation between patient subjective experience of symptoms and a reduced NAA/Cr ratio suggests a role for hippocampal pathology in fibromyalgia.

IC-P2-108: MRI and 1H MRS markers are complementary in predicting risk of future dementia in mild cognitive impairment

Hippocampal volume and N-acetylaspartate/creatine (NAA/Cr) on 1HMR spectroscopy (1HMRS) are predictors of the risk of future progression to dementia in mild cognitive impairment (MCI). The effect of various categories of cerebrovascular disease on the risk of progression to dementia is less clear. We investigated whether hippocampal atrophy, decreased neuronal integrity marker NAA/Cr and cerebrovascular disease have independent effects on the risk of progression to dementia in MCI and if the effects are additive. We identified 126 MCI subjects (59 amnestic and 15 non-amnestic MCI) who underwent MRI and 1HMRS studies at baseline and were followed with annual clinical examinations. Subjects were censored when they progressed to dementia, died, or lost to follow-up. Hippocampal volumes were expressed as age and gender adjusted W-scores. Proportional hazards models were used to determine if hippocampal W-scores, posterior cingulate gyrus NAA/Cr, white matter hyperintensity load, cortical and subcortical infarctions alone and in combination predict the risk of progression to dementia in MCI. Fifty-four MCI subjects progressed to dementia by last follow-up, and the median time to progression was 3.3 years. The dementia diagnoses were AD in 41 subjects, dementia with Lewy bodies in 10 subjects, and other dementia in three subjects. After adjusting for age and sex, the significant and independent predictors of progression to dementia were hippocampal W-score (p=0.023), NAA/Cr (p=0.014) and cortical infarctions (p=0.03). White matter hyperintensity load and subcortical infarctions were not associated with the future risk of dementia in MCI (p>0.11). Kaplan-Meier analysis estimated that by 3 years, 41% of patients with hippocampal atrophy (W-score < -1), 56% of patients with both hippocampal atrophy and low NAA/Cr (< 25th percentile), and 85% of patients with hippocampal atrophy, low NAA/Cr and cortical infarctions will progress to dementia (Figure). Hippocampal atrophy, low NAA/Cr and cortical infarctions at baseline independently increase risk of progression to dementia in MCI. Multiple MR markers may improve the ability to identify patients with prodromal dementia over a single MR marker. These results also support the concept that individuals with multiple brain pathologies have increased odds of dementia compared to individuals with a single pathology.

3T MR with diffusion tensor imaging and single-voxel spectroscopy in giant axonal neuropathy

Magnetic resonance imaging (MRI), diffusion tensor imaging (DTI), and MR spectroscopy (MRS) data were obtained in a patient with giant axonal neuropathy (GAN) and compared to a control group. Fractional anisotropy (FA) and apparent coefficient diffusion (ADC) data were obtained from specific white matter tracts including the corticospinal tracts (CST), corpus callosum (CC), optic radiations (OR), and middle cerebellar peduncle (MCP). Analysis of the MRS was performed. DTI parameters and MRS results were correlated with the neuropathological findings described for GAN. No significant difference between the FA of the CC of the patient and the control group was found. However, there was a significant difference between the FA of the CST, OR, and MCP of the patient and the control group. The ADC values for all tracts of the patient were significantly increased. N-acetylaspartate to creatine (NAA/Cr) and N-acetylaspartate to choline (NAA-Cho) (choline) metabolite ratios were slightly decreased and choline to creatine (Cho/Cr) and myo-inositol to creatine (Ins/Cr) metabolite ratios were increased in the parietal gray and white matter of the patient as compared to the control group. Cerebellar involvement was less evident. The DTI and MRS findings suggest myelin and axonal damage.

Reproducibility over a 1-month period of 1H-MR spectroscopic imaging NAA/Cr ratios in clinically stable multiple sclerosis patients

N-acetylaspartate/creatine (NAA/Cr) ratios, assessed with proton magnetic resonance spectroscopy, are increasingly used as a surrogate marker for axonal dysfunction and degeneration in multiple sclerosis (MS). The purpose of this study was to test short-time reproducibility of NAA/Cr ratios in patients with clinically stable MS. In 35 MS patients we analysed NAA/Cr ratios obtained with 1H-MR spectroscopic imaging at the centrum semiovale either with lateral ventricles partially included (group 1; n=15) or more cranially with no ventricles included (group 2; n=20). To test short-term reproducibility of the NAA/Cr measurements, patients were scanned twice 4 weeks apart. We determined mean NAA/Cr and Cho/Cr ratios of 12 grey matter and 24 white matter voxels. Mean NAA/Cr ratios of both the white and grey matter did not change after 4 weeks. Overall 4-week reproducibility of the NAA/Cr ratio, expressed as coefficient of variation, was 4.8% for grey matter and 3.5% for white matter. Reproducibility of cranial scanning of the ventricles was slightly better than with cerebrospinal fluid included. Our study shows good short-term reproducibility of NAA/Cr ratio measurements in the centrum semiovale, which supports the reliability of this technique for longitudinal studies.

Brain N-acetylaspartate is Reduced in Parkinson Disease With Dementia

Persons with Parkinson disease (PD) are at risk of developing dementia. Of the dementias affecting patients with PD, PD with dementia (PDD) is not well understood, although brain imaging studies to date have observed characteristic patterns of brain atrophy. Metabolic differences have been observed in magnetic resonance spectroscopy (MRS) studies comparing patients with PDD to nondemented PD patients, although it is unclear whether PDD patients have abnormally low MRS ratios compared with healthy age-matched adults. In this study, 12 patients with PDD, 12 patients with PD and no dementia, and 12 age-matched healthy older adults underwent MRS of the posterior cingulate gyrus. Patients with PDD showed lower N-acetylaspartate/creatine (NAA/Cr) compared with controls (P=0.004) and compared with nondemented PD patients (P=0.003). No abnormalities were observed in choline/Cr or myo-Inositol/Cr. NAA/Cr was correlated with mental status in patients with PD and in patients with PDD (r=0.56; P=0.029). The findings suggest that reduced NAA/Cr of the posterior cingulate could be used as a marker for dementia in patients with PD. Future studies investigating the utility of brain MRS as a predictor of dementia in PD and comparing brain metabolism in PDD with other dementias seem warranted.

1H Magnetic resonance spectroscopy in dementia

Present data support the concept that (1)H magnetic resonance spectroscopy ((1)H MRS) may become an adjunct to clinical evaluation for differential diagnosis of dementia in the future. The value of (1)H MRS in monitoring the disease progression in dementia is expected to be in areas where group effects are sought such as monitoring effectiveness of therapies in drug trials. Elevation of myoinositol to creatine (mI/Cr) and choline to creatine (Cho/Cr) and reduction in the neuronal integrity marker N-acetylaspartate to creatine (NAA/Cr) levels in individuals with mild cognitive impairment and pre-symptomatic Alzheimer's disease suggests that (1)H MRS may also be valuable in predicting future development of dementia and monitoring early disease progression for preventive therapies. Investigations of in vivo (1)H MRS as a marker for differential diagnosis and progression of dementia, however, has been limited to clinically confirmed cohorts and remains to be validated by histopathology at autopsy. Overall, MRS is a promising investigational technique in ageing and dementia at this time. The potential clinical application of MRS in ageing and dementia, however, is growing with technical advances in the field.

Metabolic Findings on 3T 1H-MR Spectroscopy in Peritumoral Brain Edema

Little is known about the metabolic properties of brain edema associated with tumors. This work was conducted on the basis of the assumption that, in the presence of intra-axial and extra-axial brain tumors, the white matter involved by the edema is a site of metabolic change that involves the structure of the myelin sheath. Thirteen patients comprised our cohort affected by intra-axial and extra-axial cerebral tumors with a peritumoral T2-weighted MR signal hyperintensity as a result of edema, where MR spectroscopy showed no increase in choline-containing compounds. Measurements on proton MR spectroscopy (1H-MR spectroscopy) were performed with a 3T whole-body scanner with use of a point-resolved spectroscopy sequence for localization (TR, 2000 ms; TE, 35 ms), and the metabolites were quantified with the SAGE method. Peak intensities of the main metabolites were expressed as ratios of one another and were compared with values obtained in the white matter of the left frontal region in a control group of 16 healthy volunteers. Choline-to-creatine (Cho/Cr) and myo-inositol-to-creatine (mIns/Cr) signal intensity ratios were normal in all patients. N-acetylaspartate-to-creatine (NAA/Cr) and N-acetylaspartate-to-choline (NAA/Cho) ratios decreased in 4 patients. Glutamate plus glutamine-to-creatine (Glx/Cr) was increased in 10 patients. A resonance peak at 3.44 ppm, strongly suggesting the presence of glucose, was detected in all but 1 patient. Lactate was detected in 12 patients and lipids in 5. Moreover, the resonances that pertained to the aliphatic amino acids valine, leucine, and isoleucine were present in 12 patients. Our findings on MR spectroscopy confirmed the hypothesis that in the edema surrounding brain tumors, an energy-linked metabolic alteration was associated with injury to the myelin sheath.

Multivoxel proton MR spectroscopy in malformations of cortical development.

Malformations of cortical development (MCD) are traditionally considered as a cause of epilepsy. Our aim was to study patients with focal MCD, by using multivoxel proton MR spectroscopy; we focused not only on the lesion but also on the normal-appearing contralateral side (NACS). Our hypothesis was that the metabolic abnormality extends to the NACS; therefore, it would be inadequate to consider NACS as an internal control. We studied 16 patients with focal MCD. MR spectroscopy was performed by using a point-resolved spectroscopy sequence technique, including the MCD area and the NACS. In each volume of interest, a smaller volume of interest of 2.25 cm(3) centered on the MCD was selected to study the N-acetylaspartate/creatine (NAA/Cr) ratio. In NACS, this ratio was studied by placing a symmetric voxel in comparison with the smaller MCD volume of interest. A control group (n=30) was also studied to evaluate both white and gray matter by using the same MR spectroscopy protocol. From 16 analyzed volumes of interest with MCD, 9 were composed of gray matter heterotopia and 7 of cortical dysplasia. MR spectroscopy of both MCD lesions and NACS (n=10) showed decreased NAA/Cr compared with that of the control group. NACS in these patients did not present significant differences regarding NAA/Cr in comparison with the affected side. MR spectroscopy demonstrated abnormal NAA/Cr in both MCD lesions and NACS in patients harboring focal MCD, giving support to the hypothesis that in MCD metabolic abnormalities extend far away from the limits of the lesion, reaching the contralateral side.

Differentiation of SCA2 from MSA‐C using proton magnetic resonance spectroscopic imaging

To assess and compare biochemical and volumetric features of the cerebellum in patients with spinocerebellar ataxia type 2 (SCA2) and patients with the cerebellar variant of multiple system atrophy (MSA-C). Nine genetically assigned SCA2 patients and six MSA-C patients who met the clinical criteria of MSA-C underwent a clinical and neuroradiological workup with respect to cerebellar features. The MR protocol consisted of a sagittal T1-weighted three-dimensional fast low-angle shot (3D FLASH) sequence and a transversal T2- and spin-density-weighted turbo spin-echo sequence. The proton magnetic resonance spectroscopic imaging ((1)H-MRSI) protocol consisted of two chemical shift imaging (CSI) sequences (echo time (TE) = 20 and 135 msec). Both short- and long-TE MR spectroscopy (MRS) images showed significant decreases in values for N-acetylaspartate to creatine (NAA/Cr), and choline to creatine (Cho/Cr) ratios in MSA-C and SCA2 compared to normal controls, though there was no difference between the two patient groups. In contrast, distinct cerebellar lactate (Lac) peaks were detected in seven SCA2 patients, and small peaks were detected in two. However, we did not detect any definite Lac peak in MSA-C or control subjects. MRSI revealed Lac pathology in SCA2 but not in MSA-C. Whether this indicates distinct pathogenetic mechanisms of cerebellar degeneration remains to be established.

Glycogen Synthase Kinase 3 Beta (GSK-3β) as a Therapeutic Target in NeuroAIDS

Highly active antiretroviral therapy (HAART) has made a significant impact on the lives of people living with HIV-1 infection. The incidence of neurologic disease associated with HIV-1 infection of the CNS plummeted between 1996-2000, but unfortunately the number of people currently HIV-1 infected (i.e., prevalence) with associated cognitive impairment has been steadily rising. While the reasons for this may be multifactorial, the implication is clear: there is a pressing need for adjunctive therapy directed at reversing or preventing damage to vulnerable pathways in the central nervous system (CNS) from HIV-1 infection. Using a team of preclinical and clinical investigators, we have focused our efforts on defining how proinflammatory mediators and secretory neurotoxins from HIV-1 disrupt signaling of the survival-regulating enzyme, glycogen synthase kinase 3 beta (GSK-3beta). In a series of studies initiated using in vitro, then in vivo models of HIV-1-associated dementia (HAD), we have demonstrated the ability of the mood stabilizing and anticonvulsant drug, sodium valproate (VPA), that inhibits GSK-3beta activity and other downstream mediators, to reverse HIV-1-induced damage to synaptic pathways in the CNS. Based on these results, we successfully performed pharmacokinetic and safety and tolerability trials with VPA in a cohort of HIV-1-infected patients with neurologic disease. VPA was well tolerated in this population and secondary measures of brain metabolism, as evidenced by an increase in N-acetyl aspartate/creatine (NAA/Cr), further suggested that VPA may improve gray matter integrity in brain regions damaged by HIV-1. These findings highlight the therapeutic potential of GSK-3beta blockade.

Single voxel proton magnetic resonance spectroscopy in post-stroke depression

Mood disorders are associated with structural, metabolic and spectroscopic changes in prefrontal regions. In the case of depression associated with stroke, there is little information about the biochemical profile of these regions, as assessed by proton magnetic resonance spectroscopy ( 1H-MRS). In a group of first-ever stroke patients, we studied the association between post-stroke depression and 1H-MRS measurements in unaffected frontal lobes. Twenty-six patients with a first ischemic stroke located outside the frontal lobes were included in the study. Single voxel proton magnetic resonance spectroscopy ( 1H-MRS) was performed to assess N-acetylaspartate/creatine (NAA)/Cr, glutamate + glutamine (Glx)/Cr, choline (Cho)/Cr and myo-inositol (mI)/Cr ratios. Patients were assessed within the first 10 days after stroke and again four months later. The diagnosis of depression was made on the basis of clinical observation, interview and Hamilton Depression Rating Scale scores. In a group of 26 patients, eight (31%) met criteria for depression at the first assessment, and nine (35%) met criteria for depression at follow-up. Patients with depression in the immediate post-stroke phase had significantly higher Glx/Cr ratios in the contralesional hemisphere than non-depressive patients. No biochemical differences were found between the groups at 4-month follow-up. These findings suggest that post-stroke depression is accompanied by changes in frontal lobe glutamate/glutamine levels, perhaps reflecting abnormalities in glutamatergic transmission in the immediate post-stroke period.

Chronic intermittent but not constant hypoxia decreases NAA/Cr ratios in neonatal mouse hippocampus and thalamus

Chronic constant hypoxia (CCH) and chronic intermittent hypoxia (CIH) are known to have deleterious effects on the central nervous system. Because of the difference in the pattern of hypoxic exposure, it is possible that the pathological outcome would vary. The N-acetyl aspartate/creatine (NAA/Cr) ratio is a reliable marker of neuronal integrity, and this can be noninvasively measured by proton nuclear magnetic resonance spectroscopy. P2 CD1 mouse pups with their dams were exposed to either CCH, where the Fi(O(2)) was maintained at 11% continuously or to CIH, where the Fi(O(2)) was varied between 21 and 11% every 4 min. P30 mice exposed to intermittent hypoxia for 4 wk demonstrated a significant decrease in the NAA/Cr ratio in the hippocampus and thalamus, which was reversed by a subsequent exposure to 4 wk of normoxia. Meanwhile, mice exposed to 4 wk of constant hypoxia did not demonstrate any differences in their NAA/Cr ratios from controls in these brain regions. These results indicate that an intermittent pattern of hypoxic exposure may have a more adverse effect on neuronal function and integrity than a continuous one. The reversal of NAA/Cr levels to baseline during the return to normoxia indicates that therapeutic strategies targeted at alleviating the intermittent hypoxic stress in diseases, such as obstructive sleep apnea, have the potential for inducing significant neurocognitive recovery in these patients.

Magnetic resonance spectroscopic characteristics of glutaric aciduria type II

Magnetic resonance spectroscopy (MRS) of a 12‐year‐old female patient with glutaric aciduria type II was compared with data obtained from four healthy age‐ and sex‐matched volunteers. In the clinically active phase, conventional magnetic resonance imaging showed mild ventricular dilatation. Frontal lobe choline/creatine (Cho/Cr) ratio (1.98) was higher than the ratios reported for the comparison participants (1.64 [SD 0.21]). The N‐acetylaspartate/creatine (NAA/Cr) ratio (1.95) was lower than normal limits (2.66 [SD 0.23]). After successful riboflavin treatment and dietary restriction for proteins, the NAA/Cr ratio was within the normal range (2.44) and Cho/Cr ratio was below the normal range (1.15), suggesting riboflavin‐responsive multiple acyl‐coA dehydrogenase deficiency. An elevated Cho/Cr ratio and decreased NAA/Cr ratio is consistent with a demyelinating process in the active phase of glutaric aciduria type II. MRS helps to monitor the progress of the disease and the efficacy of treatment by revealing changes in NAA/Cr and Cho/Cr ratios.

Bilateral wallerian degeneration of the middle cerebellar peduncles due to unilateral pontine infarction: A morphologic and spectroscopic study

We report the case of a patient with bilateral and symmetrical T2 hyperintensities of the middle cerebellar peduncles. She had a history of left pontine infarction 8 months before. This was attributed to bilateral Wallerian degeneration. MR Spectroscopy showed decreased N-acetyl aspartate/Creatine (NAA/Cr) ratio in the cerebellar peduncles as well as in the whole cerebellum. We hypothesize that this could reflect neuronal degeneration following a stroke.

Magnetic resonance spectroscopic characteristics of glutaric aciduria type II

Magnetic resonance spectroscopy (MRS) of a 12-year-old female patient with glutaric aciduria type II was compared with data obtained from four healthy age- and sex-matched volunteers. In the clinically active phase, conventional magnetic resonance imaging showed mild ventricular dilatation. Frontal lobe choline/creatine (Cho/Cr) ratio (1.98) was higher than the ratios reported for the comparison participants (1.64 [SD 0.21]). The N-acetylaspartate/creatine (NAA/Cr) ratio (1.95) was lower than normal limits (2.66 [SD 0.23]). After successful riboflavin treatment and dietary restriction for proteins, the NAA/Cr ratio was within the normal range (2.44) and Cho/Cr ratio was below the normal range (1.15), suggesting riboflavin-responsive multiple acyl-coA dehydrogenase deficiency. An elevated Cho/Cr ratio and decreased NAA/Cr ratio is consistent with a demyelinating process in the active phase of glutaric aciduria type II. MRS helps to monitor the progress of the disease and the efficacy of treatment by revealing changes in NAA/Cr and Cho/Cr ratios.

Magnetic resonance and spectroscopic imaging in prenatal alcohol-exposed children: Preliminary findings in the caudate nucleus

Magnetic resonance imaging (MRI) and magnetic resonance spectroscopic imaging (MRSI) offer unique, noninvasive methods of measuring, respectively, in vivo quantitative neuroanatomy and neurochemistry. The main purpose of the present study was to identify and compare the neuroanatomical and neurochemical abnormalities that are associated with prenatal exposure to alcohol in both fetal alcohol syndrome (FAS)-diagnosed children and those diagnosed with fetal alcohol effects (FAE). MR data of three age-, gender- and race-balanced groups of children, FAS-diagnosed, FAE-diagnosed and non-exposed controls, were compared. Effects of prenatal alcohol exposure, regardless of diagnosis, were found in the caudate nucleus. Specifically, a significantly smaller caudate nucleus was found for the FAS and FAE participants compared to the controls. In addition, the metabolite ratio of N-acetyl-aspartate to creatine (NAA/Cr), an indicator of neuronal function, in left caudate nucleus of both the FAS and FAE participants was elevated compared to the control group. Analysis of absolute concentrations revealed that the increase in the ratio of NAA/Cr was due to an increase in NAA alone. Although its exact function in the CNS is unknown, NAA is believed to be a neuronal marker due to its exclusive localization to neurons. Some also speculate a role for NAA in myelination. Elevated NAA in the prenatal alcohol-exposed participants could indicate a lack of normal program cell death, dendritic pruning and/or myelination during development. The present study demonstrates that prenatal alcohol-exposed children, with or without facial dysmorphology, have abnormal brain anatomy and chemistry.

Assessment with Magnetic Resonance Imaging and Spectroscopy in Lhermitte-Duclos Disease

Lhermitte-Duclos disease (LDD) is a rare benign lesion of uncertain pathogenesis characterized by distortion of the normal cerebellar laminar cytoarchitecture. We report a 22-year-old man admitted for injury sustained in a traffic accident with the incidental finding of a cerebellar mass. Magnetic resonance imaging (MRI) revealed a mass lesion within the right cerebellar hemisphere. The final diagnosis of LDD was made by obtaining a surgical specimen and identifying the characteristic appearance of the lesion by MRI study. The images showed the typical striated pattern of hyperintensity on T2-weighted images and corresponding hypointensity on T1-weighted images, as well as the typical absence of enhancement following gadolinium-diethylenetriaminepentaacetic acid (Gd-DTPA) administration. In addition, no disturbance of water diffusion on diffusion-weighted MRI, and associations of decreases in the N-acetylaspartate/creatine (NAA/Cr) and NAA/Choline (Cho) ratios with near normal values of Cho/Cr, as well as an obvious lactate peak gave supplemental information for diagnosis.

Decreased choline and creatine concentrations in centrum semiovale in patients with generalized anxiety disorder: Relationship to IQ and early trauma

We have demonstrated, using proton magnetic resonance spectroscopy imaging ( 1H-MRSI), elevations of N-acetyl-aspartate/creatine (NAA/CR) in right dorsolateral prefrontal cortex (DLPFC) in patients with generalized anxiety disorder (GAD) in comparison to healthy volunteers. A recent study indicates that the volume of prefrontal cortical white matter may be disproportionately increased in man in comparison to other primate species, with evolutionary implications. We therefore re-analyzed the identical scans with a specific focus on the centrum semiovale (CSO) as a representative region of interest of cerebral white matter. The central hypothesis was, in accordance with our gray matter findings, that patients with GAD, in comparison to healthy controls, would exhibit either an increase in NAA in CSO, or alternatively demonstrate reductions in concentrations of choline (CHO)-containing compounds and/or creatine + phosphocreatine (CR). MRSI scans that were obtained from an earlier [Mathew, S.J., Mao, X., Coplan, J.D., Smith, E.L., Sackeim, H.A., Gorman, J.M., Shungu, D.C., 2004. Dorsolateral prefrontal cortical pathology in generalized anxiety disorder: a proton magnetic resonance spectroscopic imaging study. American Journal of Psychiatry 161, 1119–1121] sample of 15 patients with GAD [6 with early trauma (ET)] and 15 healthy age- and sex-matched volunteers were analyzed further for CSO metabolite alterations. Self-reported worry was scored using the Penn State Worry Questionnaire (PSWQ) and intelligence was assessed using the Wechsler Abbreviated Scale of Intelligence (WASI). Serial multislice/multivoxel MRSI scans had been performed on a 1.5-T MRI. Using absolute quantification methods for metabolite concentrations, we examined NAA, CHO and CR. GAD patients without ET exhibited bilaterally decreased concentrations of CHO and CR in CSO in comparison to healthy volunteers, whereas GAD patients with ET were indistinguishable from controls. In patients with GAD, high IQ was paired with greater worry, whereas in healthy volunteers, high IQ was associated with less worry. In all subjects, IQ inversely predicted left and right CSO CHO concentrations, independent of age, sex, group assignment and PSWQ scores. The CSO may therefore represent a neural substrate that exhibits reductions in CHO and CR metabolite concentrations that are inversely associated with GAD symptomatology and, in the case of CHO, with intelligence. These conclusions are deemed preliminary due to small sample size, with further study of cerebral WM in anxiety disorders suggested.

Proton Magnetic Resonance Spectroscopy of Mesial Temporal Sclerosis

To determine if change in voxel shape and position improves the lateralization of magnetic resonance (MR) spectroscopy to the side of the MR imaging and/or electroencephalography (EEG) abnormality in mesial temporal sclerosis. In 10 patients with unilateral mesial temporal sclerosis and 5 controls, MR spectroscopy was performed. Long echo time single-voxel spectroscopy was obtained in the right and left hippocampus. First, the standard 2-cm x 2-cm x 2-cm cubic voxels were placed bilaterally. Then, 1-cm x 2-cm x 4-cm rectangular voxels were used. With this rectangular voxel shape, more of the hippocampus and less of the adjacent medial temporal lobe were included in the interrogation voxel. N-acetylaspartate-to-creatine (NAA/Cr) ratios and choline-to-creatine (Cho/Cr) ratios were obtained. The difference between the affected and unaffected sides in the patients was calculated and compared with the controls. Additionally, the mean difference and standard deviation were determined. Predictive values and Student t tests were also performed. In all 10 patients, using the NAA/Cr ratios, the rectangular voxel correctly identified the abnormal side. The cubic voxel only identified the abnormal side in 6 of the 10 patients, however. Additionally, the mean difference between the affected and unaffected sides was 0.30 for the rectangular voxel but only 0.003 for the cubic voxel; that is, there was no overall significant difference when using the cubic voxel (P = 0.007). No significant correlation between the affected and unaffected sides was found using the Cho/Cr ratios. No significant difference between the right and left sides was found in the controls. Use of a 1-cm x 2-cm x 4-cm rectangular voxel places more of the hippocampus in the region of interrogation with less partial volume artifact from the adjacent brain parenchyma, which occurs with use of the standard 2-cm x 2-cm x 2-cm cubic voxel, resulting in improved correct lateralization of MR spectroscopy to the side of the MR imaging and/or EEG abnormality.