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The Non-Invasive Brain Biopsy: Implementation and Application of Quantitative Magnetic Resonance Spectroscopy on Healthy and Diseased Human Brain
Linköping University, Center for Medical Image Science and Visualization, CMIV. Linköping University, Department of Medical and Health Sciences, Radiation Physics. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Surgery, Orthopaedics and Cancer Treatment, Department of Radiation Physics UHL.
2012 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Introduction: In this thesis, one of the major objectives was to implement a method for (absolute) quantitative magnetic resonance spectroscopy (qMRS) of the human brain, intended for clinical use. The implemented method was based on standard spatially selective MRS sequences. The tissue water was used as an internal reference, which was calibrated using whole brain quantitative magnetic resonance imaging (qMRI). The second objective was to apply the method in clinical neuroimaging investigation, of different disease processes in the human brain.

Materials and Methods: In total, 158 subjects were included and 507 MRS measurements (330 in white matter and 177 in the thalamus) were acquired.

In a cross-sectional study of multiple sclerosis (MS), 35 ‘clinically definite MS’ (CDMS) patients were included, of which 15 were atypical CDMS patients with a very low number of white matter lesions (two or fewer), and 20 were typical CDMS patients with white matter lesions (three or more) were included. The metabolite concentrations in normal appearing white matter (NAWM) and the thalamus were assessed using the qMRS method developed in this thesis, and the brain parenchymal fraction (BPF) was calculated from the qMRI data. A cohort of 27 CDMS patients were then treated with Natalizumab and examined both at baseline, and after one year of treatment. Both qMRS and CSF samples for the purpose of assessing intrathecal inflammation were obtained. In addition, the frontal deep white matter (FDWM) and the thalamus were investigated in 20 idiopathic normal pressure hydrocephalus (iNPH) patients using qMRS. Finally, the left thalamus of 14 Kleine-Levin Syndrome (KLS) patients were examined using both qMRS and functional MRI (fMRI) of neurological activation of the left thalamus during a working memory test. Moreover, 63 healthy subjects were included as controls for this work.

Results: A quantitative MRS method based on water referencing was successfully developed, implemented, and evaluated at 1.5 T. Both healthy subjects and MS patients showed a positive correlation between the concentrations of total Creatine (tCr) and myo Inositol (mIns) and age, and also a negative correlation with BPF were observed. Glutamate and Glutamine (Glx) levels were elevated for all MS patient groups compared to healthy controls. In contrast, lower concentrations of total N-acetyl aspartate and N-acetyl aspartate glutamate (tNA) and higher mIns concentrations in NAWM were only observed in MS patients that had developed white matter lesions. Moreover, the change in concentrations of tCr and total Choline (tCho) in MS patients during Natalizumab-treatment were positively correlated with markers of intrathecal inflammation. The iNPH patients had lower tNA and N-acetyl aspartate (NAA) concentrations in the thalamus compared to the controls. In addition, the NAA concentrations in the left thalamus were inversely correlated to the fMRI activation in the left thalamus during the working memory test in KLS patients.

Discussion: The calculated calibration factors were in good agreement with the results found in the literature, indicating that the calibration factors were accurate.

The observed elevated Glx concentration in MS could be due to increased concentrations of glutamate (Glu), which is neurotoxic at high concentrations, thus the elevated Glx could be linked to the clinically observed neurodegeneration in MS both in patients that have developed lesions and in atypical patients that do not develop any (or extremely few) lesions.

Both tCr and mIns can be used as glia markers, thus the correlations of tCr and mIns concentrations with both age and BPF indicates that the local glia cell density, or tissue fraction, increases with age and atrophy. Moreover, the higher mIns concentrations in the NAWM of MS patients with a substantial white matter lesion load indicate that the glia tissue amount in NAWM is increased in MS patients that develop lesions. NAA is neuronal-specific, thus the lower tNA concentrations indicate that the neurone concentration is lower in the NAWM of MS patients that develop MS lesions. The lack of correlation between tNA with age and BPF in combination with the presence of correlation between tCr and mIns with both age and BPF, might be explained using a model for neurodegeneration. In which, there is a higher neurone loss compared to the glia loss. However, the lost tissue is compensated by compression of the tissue, which keeps the density of neurones more or less constant and the density of glia increased.

The low concentration levels of the neuronal marker NAA in the thalamus of the iNPH patients indicates that the basal ganglia-thalamic-subcortical frontal circuits are damage or at least strongly modulated in the thalamus.

The correlation between strong activation in left thalamus during a working memory test with the neuronal marker NAA indicate that the KLS patients that have low neuronal concentration also needed to utilise the working memory circuitry more heavily in order to perform the task as healthy subjects.

Conclusion: It is possible to use qMRI for accurate and robust determination of qMRS in clinical practice, even at 1.5 T field strength. The tGlx concentration may be an important marker for pathology in the nonlesional white matter of MS-patients. The increased glia and loss of neurones in the NAWM are associated with the formation of white matter lesions.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2012. , 69 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1328
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-85929ISBN: 978-91-7519-795-1 (print)OAI: oai:DiVA.org:liu-85929DiVA: diva2:573840
Public defence
2012-12-21, Elsa Brändströmsalen, Campus US, Linköpings universitet, Linköping, 13:00 (Swedish)
Opponent
Supervisors
Available from: 2012-12-03 Created: 2012-12-03 Last updated: 2014-10-02Bibliographically approved
List of papers
1. Procedure for Quantitative 1H Magnetic Resonance Spectroscopy and Tissue Characterization of Human Brain Tissue Based on the Use of Quantitative Magnetic Resonance Imaging
Open this publication in new window or tab >>Procedure for Quantitative 1H Magnetic Resonance Spectroscopy and Tissue Characterization of Human Brain Tissue Based on the Use of Quantitative Magnetic Resonance Imaging
2013 (English)In: Magnetic Resonance in Medicine, ISSN 0740-3194, E-ISSN 1522-2594, Vol. 70, no 4, 905-915 p.Article in journal (Refereed) Published
Abstract [en]

PurposeExisting methods for quantitative magnetic resonance spectroscopy are not widely used for magnetic resonance spectroscopy examinations in clinical practice due to the lengthy and difficult workflow. In this report, we aimed to investigate whether metabolite concentrations show co-variation with relaxation parameters (R-1,R-H2O,R-2,R-H2O), water concentration (C-H2O), and age, using a quantitative magnetic resonance spectroscopy method, which is suitable for a clinical setting. MethodsWe performed 166 single voxel magnetic resonance spectroscopy measurements in the white matter and thalamus in 47 healthy subjects, aged 18-72 years. Whole brain R-1,R-H2O, R-2,R-H2O, and C-H2O maps were determined for each subject using quantitative magnetic resonance imaging. Absolute metabolite concentrations were calculated by calibrating the water-scaled magnetic resonance spectroscopy, using the quantitative magnetic resonance imaging maps of R-1,R-H2O, R-2,R-H2O, and C-H2O. ResultsAbsolute concentrations in white matter of total Creatine and myo-Inositol were correlated with age (total Creatine: 12 4 M/year, P < 0.01; myo-Inositol: 23 +/- 9 M/year, P < 0.05), suggesting a process of increased glia density in aging white matter. Moreover, total Creatine and total N-acetylaspartate were inversely correlated with the R-1,R-H2O and positively correlated with the C-H2O of white matter. In addition, the Cramer-Rao lower bound was biased regarding the metabolite concentration, suggesting that should not be used as a quality assessment. ConclusionThe implemented method was fast, robust, and user-independent.

Keyword
1H-MRS, qMRI, LCModel, White matter, Thalamus, Age
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-85921 (URN)10.1002/mrm.24554 (DOI)000325136300002 ()
Available from: 2012-12-03 Created: 2012-12-03 Last updated: 2017-12-07
2. Increased Concentrations of Glutamate and Glutamine in Normal Appearing White Matter of Patients with Multiple Sclerosis and Normal MR Imaging Brain Scans
Open this publication in new window or tab >>Increased Concentrations of Glutamate and Glutamine in Normal Appearing White Matter of Patients with Multiple Sclerosis and Normal MR Imaging Brain Scans
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2013 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 4Article in journal (Refereed) Published
Abstract [en]

In Multiple Sclerosis (MS) the relationship between disease process in normal-appearing white matter (NAWM) and the development of white matter lesions is not well understood. In this study we used single voxel proton ‘Quantitative Magnetic Resonance Spectroscopy’ (qMRS) to characterize the NAWM and thalamus both in atypical ‘Clinically Definite MS’ (CDMS) patients, MRIneg (N = 15) with very few lesions (two or fewer lesions), and in typical CDMS patients, MRIpos (N = 20) with lesions, in comparison with healthy control subjects (N = 20). In addition, the metabolite concentrations were also correlated with extent of brain atrophy measured using Brain Parenchymal Fraction (BPF) and severity of the disease measured using ‘Multiple Sclerosis Severity Score’ (MSSS). Elevated concentrations of glutamate and glutamine (Glx) were observed in both MS groups (MRIneg 8.12 mM, p<0.001 and MRIpos 7.96 mM p<0.001) compared to controls, 6.76 mM. Linear regressions of Glx and total creatine (tCr) with MSSS were 0.16±0.06 mM/MSSS (p = 0.02) for Glx and 0.06±0.03 mM/MSSS (p = 0.04) for tCr, respectively. Moreover, linear regressions of tCr and myo-Inositol (mIns) with BPF were −6.22±1.63 mM/BPF (p<0.001) for tCr and −7.71±2.43 mM/BPF (p = 0.003) for mIns. Furthermore, the MRIpos patients had lower N-acetylaspartate and N-acetylaspartate-glutamate (tNA) and elevated mIns concentrations in NAWM compared to both controls (tNA: p = 0.04 mIns p<0.001) and MRIneg (tNA: p = 0.03 , mIns: p = 0.002). The results suggest that Glx may be an important marker for pathology in non-lesional white matter in MS. Moreover, Glx is related to the severity of MS independent of number of lesions in the patient. In contrast, increased glial density indicated by increased mIns and decreased neuronal density indicated by the decreased tNA, were only observed in NAWM of typical CDMS patients with white matter lesions.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-85924 (URN)10.1371/journal.pone.0061817 (DOI)000317907200090 ()23613944 (PubMedID)
Available from: 2012-12-03 Created: 2012-12-03 Last updated: 2017-12-07Bibliographically approved
3. Association between Change in Normal Appearing White Matter Metabolites and Intrathecal Inflammation in Natalizumab-Treated Multiple Sclerosis
Open this publication in new window or tab >>Association between Change in Normal Appearing White Matter Metabolites and Intrathecal Inflammation in Natalizumab-Treated Multiple Sclerosis
Show others...
2012 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, no 9, e44739- p.Article in journal (Refereed) Published
Abstract [en]

Background: Multiple sclerosis (MS) is associated not only with focal inflammatory lesions but also diffuse pathology in the central nervous system (CNS). Since there is no firm association between the amount of focal inflammatory lesions and disease severity, diffuse pathology in normal appearing white matter (NAWM) may be crucial for disease progression. Immunomodulating treatments for MS reduce the number of focal lesions, but possible effects on diffuse white matter pathology are less studied. Furthermore, it is not known whether intrathecal levels of inflammatory or neurodegenerative markers are associated with development of pathology in NAWM.

Methods: Quantitative proton magnetic resonance spectroscopy (1H-MRS) was used to investigate NAWM in 27 patients with relapsing MS before and after one year of treatment with natalizumab as well as NAWM in 20 healthy controls at baseline. Changes in 1H-MRS metabolite concentrations during treatment were also correlated with a panel of intrathecal markers of inflammation and neurodegeneration in 24 of these 27 patients.

Results: The group levels of 1H-MRS metabolite concentrations were unchanged pre-to posttreatment, but a pattern of high magnitude correlation coefficients (r = 0.43–0.67, p<0.0005–0.03) were found between changes in individual metabolite concentrations (total creatine and total choline) and levels of pro-inflammatory markers (IL-1β and CXCL8).

Conclusions: Despite a clinical improvement and a global decrease in levels of inflammatory markers in cerebrospinal fluid during treatment, high levels of pro-inflammatory CXCL8 and IL-1β were associated with an increase in 1H-MRS metabolites indicative of continued gliosis development and membrane turnover in NAWM.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-84270 (URN)10.1371/journal.pone.0044739 (DOI)000309742800016 ()
Note

funding agencies|Swedish Society of Neurologically Disabled||Swedish Society of Medicine||National Research Council (VR/NT)||University Hospital of Linkoping||County Council of Ostergotland||Teva||Biogen Idec||

Available from: 2012-10-03 Created: 2012-10-03 Last updated: 2017-12-07
4. Reduced thalamic N-acetylaspartate in idiopathic normal pressure hydrocephalus: a controlled (1)H-magnetic resonance spectroscopy study of frontal deep white matter and the thalamus using absolute quantification
Open this publication in new window or tab >>Reduced thalamic N-acetylaspartate in idiopathic normal pressure hydrocephalus: a controlled (1)H-magnetic resonance spectroscopy study of frontal deep white matter and the thalamus using absolute quantification
Show others...
2011 (English)In: Journal of Neurology, Neurosurgery and Psychiatry, ISSN 0022-3050, E-ISSN 1468-330X, Vol. 82, no 7, 772-778 p.Article in journal (Refereed) Published
Abstract [en]

Introduction Patients with idiopathic normal pressure hydrocephalus (INPH) frequently have a reduction in cerebral blood flow in the subcortical frontal lobe/basal ganglia/thalamic areas. With magnetic resonance spectroscopy, the metabolism in the brain can be examined. The aim of this study was to investigate if there was a compromised metabolism in the thalamus and in the subcortical frontal areas in INPH patients. This was done by measuring total creatine, myo-inositol, total choline, N-acetylaspartate (NAA), total N-acetylaspartate (tNA), glutamate and lactate levels. A comparison was made with healthy individuals (HI). Subjects and methods 16 patients (nine males, seven females, mean age 74 years, range 49-83) diagnosed as INPH and 15 HI (nine males, six females, mean age 74 years, range 62-89) were examined. 1 H magnetic resonance spectroscopy (1.5 T, point-resolved spectroscopy, echo time/relaxation time 30/3000 ms, volume of interest 2.5-3 ml) was performed in frontal deep white matter and in the thalamus. Absolute quantification with internal water as a reference was used. Results INPH patients had lower NAA (p = 0.02) and lower tNA (p = 0.05) concentrations in the thalamus compared with HI. NAA and tNA in the frontal deep white matter did not differ between patients and HI. The absolute metabolic concentrations of total creatine, myoinositol total choline, tNA, lactate and Cr ratios in frontal deep white matter and in the thalamus were similar in INPH patients and HI. Conclusion Reduced thalamic NAA and tNA in INPH patients suggest a compromised metabolic neuronal function in these regions. Thus, the thalamus might have an important role in the pathogenesis of INPH.

Place, publisher, year, edition, pages
BMJ Publishing Group, 2011
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-69842 (URN)10.1136/jnnp.2010.223529 (DOI)000291429200016 ()
Note

Original Publication: Fredrik Lundin, Anders Tisell, Olof Dahlqvist Leinhard, M. Tullberg, C. Wikkelso, Peter Lundberg and Göran Leijon, Reduced thalamic N-acetylaspartate in idiopathic normal pressure hydrocephalus: a controlled (1)H-magnetic resonance spectroscopy study of frontal deep white matter and the thalamus using absolute quantification, 2011, Journal of Neurology, Neurosurgery and Psychiatry, (82), 7, 772-778. http://dx.doi.org/10.1136/jnnp.2010.223529 Copyright: BMJ Publishing Group http://group.bmj.com/

Available from: 2011-08-10 Created: 2011-08-08 Last updated: 2017-12-08
5. Low Thalamic NAA-Concentration Corresponds to Strong Neural Activation in Working Memory in Kleine-Levin Syndrome
Open this publication in new window or tab >>Low Thalamic NAA-Concentration Corresponds to Strong Neural Activation in Working Memory in Kleine-Levin Syndrome
Show others...
2013 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 2Article in journal (Refereed) Published
Abstract [en]

Background

Kleine Levin Syndrome (KLS) is a rare disorder of periodic hypersomnia and behavioural disturbances in young individuals. It has previously been shown to be associated with disturbances of working memory (WM), which, in turn, was associated with higher activation of the thalamus with increasing WM load, demonstrated with functional magnetic resonance imaging (fMRI). In this study we aimed to further elucidate how these findings are related to the metabolism of the thalamus.

Methods

fMRI and magnetic resonance spectroscopy were applied while performing a WM task. Standard metabolites were examined: n-acetylaspartate (NAA), myo-inositol, choline, creatine and glutamate-glutamine. Fourteen KLS-patients and 15 healthy controls participated in the study. The patients with active disease were examined in asymptomatic periods.

Results

There was a statistically significant negative correlation between thalamic fMRI-activation and thalamic NAA, i.e., high fMRI-activation corresponded to low NAA-levels. This correlation was not seen in healthy controls. Thalamic levels of NAA in patients and controls showed no significant differences between the groups. None of the other metabolites showed any co-variation with fMRI-activiation.

Conclusion

This study shows negative correlation between NAA-levels and fMRI-activity in the left thalamus of KLS-patients while performing a WM task. This correlation could not be found in healthy control subjects, primarily interpreted as an effect of increased effort in the patient group upon performing the task. It might indicate a disturbance in the neuronal networks responsible for WM in KLS patients, resulting in higher effort at lower WM load, compared with healthy subjects. The general relationship between NAA and BOLD-signal is also discussed in the article.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-85927 (URN)10.1371/journal.pone.0056279 (DOI)000316849500009 ()
Available from: 2012-12-03 Created: 2012-12-03 Last updated: 2017-12-07Bibliographically approved

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