Mary A. McLean

Metabolic profiles of human brain tumors using quantitative in vivo 1H magnetic resonance spectroscopy

Proton spectroscopy can noninvasively provide useful information on brain tumor type and grade. Short‐ (30 ms) and long‐ (136 ms) echo time (TE) 1H spectra were acquired from normal white matter (NWM), meningiomas, grade II astrocytomas, anaplastic astrocytomas, glioblastomas, and metastases. Very low myo‐Inositol ([mI]) and creatine ([Cr]) were characteristic of meningiomas, and high [mI] characteristic of grade II astrocytomas. Tumor choline ([Cho]) was greater than NWM and increased with grade for grade II and anaplastic astrocytomas, but was highly variable for glioblastomas. Higher [Cho] and [Cr] correlated with low lipid and lactate (P < 0.05), indicating a dilution of metabolite concentrations due to necrosis in high‐grade tumors. Metabolite peak area ratios showed no correlation with lipids and mI/Cho (at TE = 30 ms), and Cr/Cho (at TE = 136 ms) best correlated with tumor grade. The quantified lipid, macromolecule, and lactate levels increased with grade of tumor, consistent with progression from hypoxia to necrosis. Quantification of lipids and macromolecules at short TE provided a good marker for tumor grade, and a scatter plot of the sum of alanine, lactate, and δ1.3 lipid signals vs. mI/Cho provided a simple way to separate most tumors by type and grade. Magn Reson Med 49:223–232, 2003.

Glutamate Dysfunction in People with Prodromal Symptoms of Psychosis: Relationship to Gray Matter Volume

BACKGROUND The glutamate model of schizophrenia proposes that altered glutamatergic neurotransmission is fundamental to the development of the disorder. In addition, its potential to mediate neurotoxicity raises the possibility that glutamate dysfunction could underlie neuroanatomic changes in schizophrenia. Here we determine whether changes in brain glutamate are present in subjects at ultra high risk of developing psychosis and whether these changes are related to reductions in cortical gray matter volume. METHODS Twenty-seven individuals with an at-risk mental state and a group of 27 healthy volunteers underwent proton magnetic resonance spectroscopy and volumetric proton magnetic resonance imaging using a 3-Tesla scanner. Glutamate and glutamine levels were measured in anterior cingulate, left hippocampus, and left thalamus. These measures were then related to cortical gray matter volume. RESULTS At-risk mental state (ARMS) subjects had significantly lower levels of glutamate than control subjects in the thalamus (p < .05) but higher glutamine in the anterior cingulate (p < .05). Within the ARMS group, the level of thalamic glutamate was directly correlated with gray matter volume in the medial temporal cortex and insula (p < .01). CONCLUSIONS This study provides the first evidence that brain glutamate function is perturbed in people with prodromal signs of schizophrenia and that glutamatergic dysfunction is associated with a reduction in gray matter volume in brain regions thought to be critical to the pathogenesis of the disorder. These findings support the hypothesis that drugs affecting the glutamate system may be of benefit in the early stages of psychotic illness.

Continuing Ischemic Damage After Acute Middle Cerebral Artery Infarction in Humans Demonstrated by Short-Echo Proton Spectroscopy

BACKGROUND AND PURPOSE Proton MR spectroscopy is a noninvasive method of monitoring in vivo metabolite concentration changes over time. The aim of this work was to study the ischemic penumbra in humans by measuring the metabolic changes that occur after a middle cerebral artery territory infarction. METHODS Diagnostic MRI and short-echo time MR spectroscopy were performed on a 1.5-T system. Localized proton MR spectroscopy was performed within the area of cerebral infarction and in a homologous area of the contralateral hemisphere. The residual water resonance in the spectra was removed with the use of the Hankel Lanczos singular value decomposition method, after which peak area estimates were obtained by means of the variable projection time domain fitting analysis. The unsuppressed water signal was used as an internal concentration standard. Ten patients with acute middle cerebral artery infarction were studied within 28 hours of stroke onset and followed up for a period of up to 3 months. RESULTS Significant changes were seen in the initial spectra from the infarct compared with the contralateral spectra. Lactate, a marker of anaerobic metabolism, was present within the infarct but not detected in the contralateral hemisphere. N-Acetyl aspartate, a neuronal marker, and total creatine were significantly reduced. The initial choline signal, arising from choline-containing compounds within the cell and cell membrane, remained unchanged in the infarct core compared with the contralateral hemisphere. Further reductions in N-acetyl aspartate and total creatine concentrations occurred within the first week. A fall in the lactate concentration was seen within the infarct core during the first 7 to 10 days. Similar reductions in the choline concentration were observed during this period. CONCLUSIONS The demonstration of the continuing loss of cerebral metabolites within an infarct region suggests that further cell loss occurs up to 10 days after infarction. The continuing loss of neurons may represent continued ischemic damage after middle cerebral artery infarction.

Preliminary evidence for neuronal damage in cortical grey matter and normal appearing white matter in short duration relapsing-remitting multiple sclerosis: a quantitative MR spectroscopic imaging study

Abstract Neuronal damage and loss is likely to underlie irreversible disability in multiple sclerosis (MS). The time of onset, location and extent of neuronal damage in early disease are all uncertain. To explore this issue 16 patients with short duration, mild relapsing-remitting disease (mean disease duration 1.8 years, median EDSS 1) were studied using short echo time proton magnetic resonance spectroscopic imaging (1H-MRSI) to quantify the concentration of the neuronal marker N-acetyl-aspartate (NAA). The data were compared with those from 12 age-matched controls. 1H-MRSI was obtained from a 1.5-cm-thick slice just above the lateral ventricles. The Linear Combination (LC) Model combined with locally developed software allowed automated measurement of absolute metabolite concentrations from lesions, normal-appearing white matter (NAWM) and cortical grey matter (CGM). MS CGM exhibited significantly lower NAA (P=0.01) and myo-inositol (P=0.04) than control CGM. MS NAWM exhibited a lower concentration of NAA (P=0.01) and increased myo-inositol (P=0.03) than control white matter. More marked reductions in NAA and increases in myo-inositol were seen in lesions. The reduced NAA in MS CGM and NAWM suggest that mild but widespread neuronal dysfunction or loss occurs early in the course of relapsing-remitting MS. This preliminary finding should be confirmed in a larger cohort, and follow-up studies are also needed to determine the prognostic and pathophysiological significance of these early changes

Short echo time single-voxel 1H magnetic resonance spectroscopy in magnetic resonance imaging-negative temporal lobe epilepsy : Different biochemical profile compared with hippocampal sclerosis

Single‐voxel proton magnetic resonance spectroscopy (1H MRS) has shown abnormalities in patients with temporal lobe epilepsy (TLE) and hippocampal sclerosis (HS). Many TLE patients, however, do not have HS or other lesions on quantitative magnetic resonance imaging (MRI) (MRI‐negative). Fifteen control subjects, 15 patients with unilateral HS, and 15 MRI‐negative TLE patients underwent 1H MRS at an echo time of 30 msec on a 1.5‐T GE Signa scanner. Voxels were tailored to the individual hippocampi. N‐Acetylaspartate (NAA), creatine, choline, total glutamate plus glutamine (Glx), and myo‐inositol (Ins) were quantitated by using an external standard and LCModel, a user‐independent quantitation method. Normal ranges were defined as the control mean ± 2.5 SD. In HS patients, 12 of 15 had abnormally low NAA in sclerotic hippocampi; 3 of these 12 also had abnormally low NAA contralaterally. Abnormally low NAA/Ins ratios lateralized the side affected by HS in 7 of 15 patients, without any bilateral abnormalities. In 15 MRI‐negative TLE patients, 4 had abnormally low hippocampal NAA ipsilateral to seizure onset, 1 of whom had abnormally low NAA bilaterally. Analysis of groups of subjects showed a bilateral decrease in NAA, most marked in patients with HS and on the side of seizure onset. The mean NAA/Ins ratio was lower in patients with HS than in control subjects and in MRI‐negative patients. The concentration of Glx was higher ipsilateral to seizure onset in MRI‐negative patients than in HS patients. Quantitative short echo time 1H MRS identified abnormalities in 87% of patients with HS and 27% of MRI‐negative TLE patients in concordance with other lateralizing data. In individual and group comparisons, 1H MRS described a metabolite profile in the hippocampi of MRI‐negative TLE patients that was different from patients with HS, with an increase in Glx and a less marked decrease in NAA than was seen in HS. Ann Neurol 1999;45:369–376

Quantitative analysis of short echo time 1H-MRSI of cerebral gray and white matter

Quantitative analysis of 1H‐magnetic resonance spectroscopic imaging (MRSI) data was developed using the user‐independent spectral analysis routine LCModel. Tissue segmentation was performed using statistical parametric mapping software (SPM 96), and the results were used to correct for cerebrospinal fluid contamination. A correction was developed for the imperfections in the spectroscopic excitation profile in order to improve the uniformity of metabolite images. After validation in phantoms, these techniques were applied to study differences in metabolite concentrations between gray and white matter in normal volunteers (n = 13). A positive correlation was found between concentration and gray matter content for most metabolites studied. The estimated ratios of metabolite concentration in gray vs. white matter were: N‐acetyl aspartate + N‐acetyl aspartyl glutamate (NAc) = 1.16 ± 0.11; creatine = 1.7 ± 0.3; glutamate + glutamine = 2.4 ± 0.5; myo‐inositol = 1.6 ± 0.3; choline = 0.9 ± 0.2. The ratio of NAc/Cr was negatively correlated with gray matter content: gray/white = 0.69 ± 0.08. These methods will be useful in the evaluation of metabolite concentrations in MRSI voxels with mixed tissue composition in patient groups. Magn Reson Med 44:401–411, 2000.

Thalamic glutamate levels as a predictor of cortical response during executive functioning in subjects at high risk for psychosis.

CONTEXT Alterations in glutamatergic neurotransmission and cerebral cortical dysfunction are thought to be central to the pathophysiology of psychosis, but the relationship between these 2 factors is unclear. OBJECTIVE To investigate the relationship between brain glutamate levels and cortical response during executive functioning in people at high risk for psychosis (ie, with an at-risk mental state [ARMS]). DESIGN Subjects were studied using functional magnetic resonance imaging while they performed a verbal fluency task, and proton magnetic resonance spectroscopy was used to measure their brain regional glutamate levels. SETTING Maudsley Hospital, London, England. PATIENTS AND OTHER PARTICIPANTS A total of 41 subjects: 24 subjects with an ARMS and 17 healthy volunteers (controls). MAIN OUTCOME MEASURES Regional brain activation (blood oxygen level-dependent response); levels of glutamate in the anterior cingulate, left thalamus, and left hippocampus; and psychopathology ratings at the time of scanning. RESULTS During the verbal fluency task, subjects with an ARMS showed greater activation than did controls in the middle frontal gyrus bilaterally. Thalamic glutamate levels were lower in the ARMS group than in control group. Within the ARMS group, thalamic glutamate levels were negatively associated with activation in the right dorsolateral prefrontal and left orbitofrontal cortex, but positively associated with activation in the right hippocampus and in the temporal cortex bilaterally. There was also a significant group difference in the relationship between cortical activation and thalamic glutamate levels, with the control group showing correlations in the opposite direction to those in the ARMS group in the prefrontal cortex and in the right hippocampus and superior temporal gyrus. CONCLUSIONS Altered prefrontal, hippocampal, and temporal function in people with an ARMS is related to a reduction in thalamic glutamate levels, and this relationship is different from that in healthy controls.

Altered Relationship Between Hippocampal Glutamate Levels and Striatal Dopamine Function in Subjects at Ultra High Risk of Psychosis

BACKGROUND Animal models of psychosis propose that striatal hyperdopaminergia is driven by abnormalities in hippocampal glutamatergic neurotransmission, but this has never been tested in humans. METHODS Sixteen individuals with an at-risk mental state for psychosis (ARMS) and 12 control subjects underwent proton magnetic resonance spectroscopy to estimate hippocampal glutamate and [18F]DOPA positron emission tomography to index striatal dopamine function. The relationship between hippocampal glutamate and striatal dopamine, as well as their relationship with prodromal symptoms, was determined using linear regression. RESULTS In ARMS subjects, but not controls, there was a significant negative relationship between hippocampal glutamate levels and striatal [18F]DOPA uptake (p = .03). Within the ARMS sample, striatal [18F]DOPA uptake was correlated with severity of abnormal beliefs (p = .03), there was a trend for hippocampal glutamate levels to be correlated with disordered speech (p = .06) and a trend for the interaction between hippocampal glutamate and [18F]DOPA uptake to predict later transition to psychosis (p = .07). CONCLUSIONS The relationship between hippocampal glutamate and striatal dopamine systems is altered in people at high risk of psychosis, and the degree to which it is changed may be related to the risk of transition to psychosis. Pharmacologic modulation of the glutamate system before the onset of psychosis might ameliorate this risk.

Proton MRS reveals frontal lobe metabolite abnormalities in idiopathic generalized epilepsy.

Objective: To assess γ-aminobutyric acid (GABA) plus homocarnosine (GABA+) and glutamate plus glutamine (GLX) concentrations in the frontal lobes of patients with idiopathic generalized epilepsy (IGE). Methods: Twenty-one patients and 17 healthy volunteers were studied. A single voxel was prescribed in each frontal lobe for each subject. Point-resolved spectroscopy (PRESS)-localized short echo time MR spectroscopy (MRS) was performed to measure GLX and the metabolites N-acetylaspartate plus N-acetylaspartylglutamate (NAAt), creatine and phosphocreatine (Cr), choline-containing compounds (Cho), and myo-inositol (Ins). A double quantum GABA filter was used to measure GABA+. Segmented T1-weighted images gave the tissue composition of the prescribed voxel. Results: Group comparisons showed elevation of GLX and reduction of NAAt in the patient group (p < 0.05). The metabolite ratios GLX/NAAt and GLX/Ins also showed elevation in IGE (p = 0.01). No group effect was observed for GABA+, Cr, or Cho. Ins concentrations were not significantly reduced in the patient group but were less in the subgroup of patients who were taking sodium valproate. Conclusions: IGE was associated with bilateral frontal lobe metabolite changes. Elevation in GLX was observed, which may imply increased neuronal excitability, whereas reduction in NAAt suggests reduced overall neuronal numbers or neuronal dysfunction.

Metabolite changes in early relapsing- remitting multiple sclerosis : A two year follow-up study

Previous in vivo proton magnetic resonance spectroscopic imaging (1H–MRSI) studies have found reduced levels of N–acetyl–aspartate (NAA) in multiple sclerosis (MS) lesions, the surrounding normal–appearing white matter (NAWM) and cortical grey matter (CGM), suggesting neuronal and axonal dysfunction and loss. Other metabolites, such as myoinositol (Ins), creatine (Cr), choline (Cho), and glutamate plus glutamine (Glx), can also be quantified by 1H–MRSI, and studies have indicated that concentrations of these metabolites may also be altered in MS. Relatively little is known about the time course of such metabolite changes. This preliminary study aimed to characterise changes in total NAA (tNAA, the sum of NAA and N–acetyl–aspartyl–glutamate), Cr, Cho, Ins and Glx concentrations in NAWM and in CGM, and their relationship with clinical outcome, in subjects with clinically early relapsing–remitting MS (RRMS). Twenty RRMS subjects and 10 healthy control subjects underwent 1H–MRSI examinations yearly for two years. Using the LCModel, tNAA, Cr, Cho, Ins and Glx concentrations were estimated both in NAWM and CGM.At baseline, the concentration of tNAA was significantly reduced in the NAWM of the MS patients compared to the control group (–7%, p = 0.003), as well as in the CGM (–8.7%, p = 0.009). NAWM tNAA concentrations tended to recover from baseline, but otherwise tissue metabolite profiles did not significantly change in the MS subjects, or relatively between MS and healthy control subjects. While neuronal and axonal damage is apparent from the early clinical stages of MS, this study suggests that initially it may be partly reversible. Compared with other MR imaging measures, serial 1H–MRSI may be relatively less sensitive to progressive pathological tissue changes in early RRMS.