Varan Govind

Mapping of brain metabolite distributions by volumetric proton MR spectroscopic imaging (MRSI).

Distributions of proton MR‐detected metabolites have been mapped throughout the brain in a group of normal subjects using a volumetric MR spectroscopic imaging (MRSI) acquisition with an interleaved water reference. Data were processed with intensity and spatial normalization to enable voxel‐based analysis methods to be applied across a group of subjects. Results demonstrate significant regional, tissue, and gender‐dependent variations of brain metabolite concentrations, and variations of these distributions with normal aging. The greatest alteration of metabolites with age was observed for white‐matter choline and creatine. An example of the utility of the normative metabolic reference information is then demonstrated for analysis of data acquired from a subject who suffered a traumatic brain injury. This study demonstrates the ability to obtain proton spectra from a wide region of the brain and to apply fully automated processing methods. The resultant data provide a normative reference for subsequent utilization for studies of brain injury and disease. Magn Reson Med, 2009.

Neuroimaging in amyotrophic lateral sclerosis

The catastrophic system failure in amyotrophic lateral sclerosis is characterized by progressive neurodegeneration within the corticospinal tracts, brainstem nuclei and spinal cord anterior horns, with an extra-motor pathology that has overlap with frontotemporal dementia. The development of computed tomography and, even more so, MRI has brought insights into neurological disease, previously only available through post-mortem study. Although largely research-based, radionuclide imaging has continued to provide mechanistic insights into neurodegenerative disorders. The evolution of MRI to use advanced sequences highly sensitive to cortical and white matter structure, parenchymal metabolites and blood flow, many of which are now applicable to the spinal cord as well as the brain, make it a uniquely valuable tool for the study of a multisystem disorder such as amyotrophic lateral sclerosis. This comprehensive review considers the full range of neuroimaging techniques applied to amyotrophic lateral sclerosis over the last 25 years, the biomarkers they have revealed and future developments.

Whole-Brain Proton MR Spectroscopic Imaging of Mild-to-Moderate Traumatic Brain Injury and Correlation with Neuropsychological Deficits

Changes in the distribution of the magnetic resonance (MR)-observable brain metabolites N-acetyl aspartate (NAA), total choline (Cho), and total creatine (Cre), following mild-to-moderate closed-head traumatic brain injury (mTBI) were evaluated using volumetric proton MR spectroscopic imaging (MRSI). Studies were carried out during the subacute time period following injury, and associations of metabolite indices with neuropsychological test (NPT) results were evaluated. Twenty-nine subjects with mTBI and Glasgow Coma Scale (GCS) scores of 10-15 were included. Differences in individual metabolite and metabolite ratio distributions relative to those of age-matched control subjects were evaluated, as well as analyses by hemispheric lobes and tissue types. Primary findings included a widespread decrease of NAA and NAA/Cre, and increases of Cho and Cho/NAA, within all lobes of the TBI subject group, and with the largest differences seen in white matter. Examination of the association between all of the metabolite measures and the NPT scores found the strongest negative correlations to occur in the frontal lobe and for Cho/NAA. No significant correlations were found between any of the MRSI or NPT measures and the GCS. These results demonstrate that significant and widespread alterations of brain metabolites occur as a result of mild-to-moderate TBI, and that these measures correlate with measures of cognitive performance.

A large-scale multicentre cerebral diffusion tensor imaging study in amyotrophic lateral sclerosis

Objective Damage to the cerebral tissue structural connectivity associated with amyotrophic lateral sclerosis (ALS), which extends beyond the motor pathways, can be visualised by diffusion tensor imaging (DTI). The effective translation of DTI metrics as biomarker requires its application across multiple MRI scanners and patient cohorts. A multicentre study was undertaken to assess structural connectivity in ALS within a large sample size. Methods 442 DTI data sets from patients with ALS (N=253) and controls (N=189) were collected for this retrospective study, from eight international ALS-specialist clinic sites. Equipment and DTI protocols varied across the centres. Fractional anisotropy (FA) maps of the control participants were used to establish correction matrices to pool data, and correction algorithms were applied to the FA maps of the control and ALS patient groups. Results Analysis of data pooled from all centres, using whole-brain-based statistical analysis of FA maps, confirmed the most significant alterations in the corticospinal tracts, and captured additional significant white matter tract changes in the frontal lobe, brainstem and hippocampal regions of the ALS group that coincided with postmortem neuropathological stages. Stratification of the ALS group for disease severity (ALS functional rating scale) confirmed these findings. Interpretation This large-scale study overcomes the challenges associated with processing and analysis of multiplatform, multicentre DTI data, and effectively demonstrates the anatomical fingerprint patterns of changes in a DTI metric that reflect distinct ALS disease stages. This success paves the way for the use of DTI-based metrics as read-out in natural history, prognostic stratification and multisite disease-modifying studies in ALS.

1H MRS of basal ganglia and thalamus in amyotrophic lateral sclerosis.

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. Copyright

Associations of age, gender and body mass with 1H MR-observed brain metabolites and tissue distributions

Recent reports have indicated that a measure of adiposity, the body mass index (BMI), is associated with MR‐observed brain metabolite concentrations and tissue volume measures. In addition to indicating possible associations between brain metabolism, BMI and cognitive function, the inclusion of BMI as an additional subject selection criterion could potentially improve the detection of metabolic and structural differences between subjects and study groups. In this study, a retrospective analysis of 140 volumetric MRSI datasets was carried out to investigate the value of including BMI in the subject selection relative to age and gender. The findings replicate earlier reports of strong associations of N‐acetylaspartate, creatine, choline and gray matter with age and gender, with additional observations of slightly increased spectral linewidth with age and in female relative to male subjects. Associations of metabolite levels, linewidth and gray matter volume with BMI were also observed, although only in some regions. Using voxel‐based analyses, it was also observed that the patterns of the relative changes of metabolites with BMI matched those of linewidth with BMI or weight, and that residual magnetic field inhomogeneity and measures of spectral quality were influenced by body weight. It is concluded that, although associations of metabolite levels and tissue distributions with BMI occur, these may be attributable to issues associated with data acquisition and analysis; however, an organic origin for these findings cannot be specifically excluded. There is, however, sufficient evidence to warrant the inclusion of body weight as a subject selection parameter, secondary to age, and as a factor in data analysis for MRS studies of some brain regions. Copyright

Comprehensive Evaluation of Corticospinal Tract Metabolites in Amyotrophic Lateral Sclerosis Using Whole-Brain 1H MR Spectroscopy

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.

Corrigendum: proton NMR chemical shifts and coupling constants for brain metabolites. Govindaraju V, Young K, Maudsley AA, NMR Biomed. 2000; 13: 129-153.

γ-Aminobutyric acid CH2 2.2840 2.2828 t 7.755 2-3 6.173 2-3’ CH2 1.8890 1.8888 qu 7.432 2’-3 7.933 2’-3’ CH2 3.0128 3.0082 t 5.372 3-4 10.578 3-4’ 7.127 3’-4 6.982 3’-4’ 10.744 2-2’ 13.121 3-3’ 12.021 4-4’ Choline CH2 4.0540 4.0500 m 14.100 1-1’ CH2 3.5010 3.5060 m 14.070 2-2’ Ethanolamine CH2 3.8184 m 10.640 1-1’ CH2 3.1467 m 11.710 2-2’ Glycerophosphocholine Glycerol moiety CH2 3.605 dd 14.78 1-1’ 3.672 dd CH2 3.871 m 14.78 3-3’ 3.946 m Choline moiety CH2 4.312 m 9.32 7-7’ CH2 3.659 m 9.32 8-8’ Histamine CH2 3.2916 3.3148 t 8.147 α-β’ Phosphorylcholine CH2 4.2805 4.2851 m 14.890 1-1’ CH2 3.6410 3.6440 m 14.190 2-2’ N(CH3)3 3.2080 3.2100 s 6.249 1’-P Phosphorylethanolamine CH2 3.9765 3.9825 m 2.980 1’-2’ 14.560 1-1’ CH2 3.2160 3.2150 m 14.710 2-2’ Taurine CH2 3.4206 3.4190 t 6.792 1’-2’ 12.438 1-1’ CH2 3.2459 3.2473 t 12.930 2-2’

Whole-brain proton MR spectroscopic imaging in Parkinson's disease.

To examine the distributions of proton magnetic resonance spectroscopy (MRS) observed metabolites in Parkinsons disease (PD) throughout the whole brain.

Diffusion Tensor Imaging of Basal Ganglia and Thalamus in Amyotrophic Lateral Sclerosis

To assess the involvement of basal ganglia and thalamus in patients with amyotrophic lateral sclerosis (ALS) using diffusion tensor imaging (DTI) method.