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Is Increased Normal White Matter Glutamate Concentration a Precursor of Gliosis and Disease Progression in Multiple Sclerosis?
Linköping University, Center for Medical Image Science and Visualization, CMIV. Linköping University, Department of Medicine and Health Sciences, Radiation Physics . Linköping University, Faculty of Health Sciences.
Linköping University, Department of Medicine and Health Sciences, Radiology . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Medical Imaging.
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(English)Manuscript (preprint) (Other academic)
Abstract [en]

Background: The multiple sclerosis (MS) severity scale (MSSS) is a new scoring procedure to clinically characterize the rate of disease progression in MS, rather than the disability of the patient. The latter is often characterized using the expanded disability status score (EDSS). The progress rate of the disease, magnetic resonance imaging (MRI)-based measures of ‘black hole lesions’, and atrophy have all been shown to be predicted well by MSSS. In this study we investigated possible relationships between brain metabolite concentrations, measured using proton (1H) magnetic resonance spectroscopy (MRS), and MSSS.

Purpose: Our aims were to quantitatively investigate the metabolite concentrations in normal appearing white matter (NAWM) in MS-patients, and also to investigate possible correlations between disease subtype, EDSS and MSSS and metabolite concentrations. To minimize the interference from lesion contamination in the MRS measurement, a refined novel analysis procedure had to be developed in order to correct for partial volume effects in tissues near plaques.

Materials and Methods: Forty eight patients with Clinically Definite MS (CDMS), and 18 normal control subjects (NC) were included retrospectively from several MRS studies. T1, T2, and proton density MRI, and four white matter 1H MRS single voxel PRESS (Point-REsolved SpectroScopy) spectra were acquired in each subject using echo time 35 ms and repetition time 6000 ms on a 1.5 T MR-scanner. A total of 108 examinations were acquired from patients and 18 from NC. Absolutely quantified NAWM metabolite concentrations were determined using a mixed linear model (MLM) analysis that included the degree of T2 lesion contamination in each voxel. The T2 lesion contamination of the MRS voxels was also used as an estimate of ‘lesion load’ at each exam. The corrected metabolite concentrations were then correlated with clinical measures of the patients’ status, including EDSS and MSSS.

Results: The axonal marker N-acetyl aspartate (NAA) did not correlate with either EDSS or MSSS. The glial cell markers creatine and myo-inositol correlated positively with EDSS. Creatine and glutamate correlated positively with MSSS. The ‘estimated lesion load’ correlated positively not only with EDSS, but also with the number of bouts since disease onset. Importantly, it did not correlate with MSSS.

Conclusion: The most interesting findings were the unchanged concentrations of NAA, and the concomitant increase of creatine and myo-inositol during the course of disease progression in MSpatients. These not only indicated a constant axonal density, but also that a simultaneous development of gliosis occurred. These processes are most likely linked to demyelination, as well as development of white matter atrophy, a process in which the demyelinated volume is replaced by the surrounding tissue leading to a net loss of white matter. As a consequence of this process, axons in NAWM are probably damaged, which leads to a higher concentration of glia cells relative to the axonal volume. The positive correlation that was found between MSSS, and the glutamate and creatine concentrations in NAWM, in combination with a complete lack of correlation between lesion load and MSSS, suggests that altered glutamate metabolism, and subsequent demyelination and gliosis, is an important pathophysiological mechanism in MS.

National Category
Medical and Health Sciences
URN: urn:nbn:se:liu:diva-54726OAI: diva2:309539
Available from: 2010-04-07 Created: 2010-04-07 Last updated: 2014-10-02Bibliographically approved
In thesis
1. Quantitative Magnetic Resonance in Diffuse Neurological and Liver Disease
Open this publication in new window or tab >>Quantitative Magnetic Resonance in Diffuse Neurological and Liver Disease
2010 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Introduction: Magnetic resonance (MR) imaging is one of the most important diagnostic tools in modern medicine. Compared to other imaging modalities, it provides superior soft tissue contrast of all parts of the body and it is considered to be safe for patients. Today almost all MR is performed in a nonquantitative manner, only comparing neighboring tissue in the search for pathology. It is possible to quantify MR-signals and relate them to their physical entities, but time consuming and complicated calibration procedures have prevented this being used in a practical manner for clinical routines. The aim of this work is to develop and improve quantification methods in MRspectroscopy (MRS) and MR-imaging (MRI). The techniques are intended to be applied to diffuse diseases, where conventional imaging methods are unable to perform accurate staging or to reveal metabolic changes associated with disease development.

Methods: Proton (1H) MRS was used to characterize the white matter in the brain of multiple sclerosis (MS) patients. Phosphorus (31P) MRS was used to evaluate the energy metabolism in patients with diffuse liver disease. A new quantitative MRI (qMRI) method was invented for accurate, rapid and simultaneous quantification of B1, T1, T2, and proton density. A method for automatic assessment of visceral adipose tissue volume based on an in- and out-ofphase imaging protocol was developed. Finally, a method for quantification of the hepatobiliary uptake of liver specific T1 enhancing contrast agents was demonstrated on healthy subjects.

Results: The 1H MRS investigations of white matter in MS-patients revealed a significant correlation between tissue concentrations of Glutamate and Creatine on the one hand and the disease progression rate on the other, as measured using the MSSS. High accuracy, both in vitro and in vivo, of the measured MR-parameters from the qMRI method was observed. 31P MRS showed lower concentrations of phosphodiesters, and a higher metabolic charge in patients with cirrhosis, compared to patients with mild fibrosis and to controls. The adipose tissue quantification method agreed with estimates obtained using manual segmentation, and enabled measurements which were insensitive to partial volume effects. The hepatobiliary uptake of Gd-EOB-DTPA and Gd-BOPTA was significantly correlated in healthy subjects.

Conclusion: In this work, new methods for accurate quantification of MR parameters in diffuse diseases in the liver and the brain were demonstrated. Several applications were shown where quantitative MR improves the interpretation of observed signal changes in MRI and MRS in relation to underlying differences in physiology and pathophysiology.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2010. 127 p.
Linköping Studies in Science and Technology. Dissertations, ISSN 0345-7524 ; 1184
National Category
Radiology, Nuclear Medicine and Medical Imaging
urn:nbn:se:liu:diva-54728 (URN)978-91-7393-390-2 (ISBN)
Public defence
2010-04-29, Elsa Brändströmsalen, Campus US, Linköpings universitet, Linköping, 13:15 (English)
Available from: 2010-04-07 Created: 2010-04-07 Last updated: 2014-10-02Bibliographically approved

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Dahlqvist Leinhard, OlofAalto, AnneSmedby, ÖrjanLandtblom, Anne-MarieLundberg, Peter
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Center for Medical Image Science and Visualization, CMIVRadiation Physics Faculty of Health SciencesRadiology Centre for Medical ImagingDepartment of Clinical and Experimental MedicineDepartment of NeurologyDepartment of Radiation Physics
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