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- Mellergård, Johan, et al.
(författare)
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Cerebrospinal fluid levels of neurofilament and tau correlate with brain atrophy in natalizumab-treated multiple sclerosis
- 2017
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Ingår i: European Journal of Neurology. - : Wiley. - 1351-5101 .- 1468-1331. ; 24:1, s. 112-121
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Tidskriftsartikel (refereegranskat)abstract
- Background and purpose: Brain atrophy is related to clinical deterioration in multiple sclerosis (MS) but its association with intrathecal markers of inflammation or neurodegeneration is unclear. Our aim was to investigate whether cerebrospinal fluid (CSF) markers of inflammation or neurodegeneration are associated with brain volume change in natalizumab-treated MS and whether this change is reflected in non-lesional white matter metabolites. Methods: About 25 patients with natalizumab-treated MS were followed for 3 years with assessment of percentage brain volume change (PBVC) and absolute quantification of metabolites with proton magnetic resonance spectroscopy (1 H MRS). Analyses of inflammatory [interleukin 1 beta (IL-1 beta), IL-6, C-X-C motif chemokine 8 (CXCL8), CXCL10, CXCL11, C-C motif chemokine 22] and neurodegenerative [neurofilament light protein (NFL), glial fibrillary acidic protein, myelin basic protein, tau proteins] markers were done at baseline and 1-year follow-up. Results: The mean decline in PBVC was 3% at the 3-year follow-up, although mean H-1 MRS metabolite levels in non-lesional white matter were unchanged. CSF levels of NFL and tau at baseline correlated negatively with PBVC over 3 years (r = -0.564, P = 0.012, and r = -0.592, P = 0.010, respectively). Conclusions: A significant 3-year whole-brain atrophy was not reflected in mean metabolite change of non-lesional white matter. In addition, our results suggest that CSF levels of NFL and tau correlate with brain atrophy development and may be used for evaluating treatment response in inflammatory active MS.
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| 2. |
- Bednarska, Olga, 1973-, et al.
(författare)
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Reduced excitatory neurotransmitter levels in anterior insulae are associated with abdominal pain in irritable bowel syndrome
- 2019
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Ingår i: Pain. - : Lippincott Williams & Wilkins. - 0304-3959 .- 1872-6623. ; 160:9, s. 2004-2012
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Tidskriftsartikel (refereegranskat)abstract
- Irritable bowel syndrome (IBS) is a visceral pain condition with psychological comorbidity. Brain imaging studies in IBS demonstratealtered function in anterior insula (aINS), a key hub for integration of interoceptive, affective, and cognitive processes. However,alterations in aINS excitatory and inhibitory neurotransmission as putative biochemical underpinnings of these functional changesremain elusive. Using quantitative magnetic resonance spectroscopy, we compared women with IBS and healthy women (healthycontrols [HC]) with respect to aINS glutamate 1 glutamine (Glx) and g-aminobutyric acid (GABA1) concentrations and addressedpossible associations with symptoms. Thirty-nine women with IBS and 21 HC underwent quantitative magnetic resonancespectroscopy of bilateral aINS to assess Glx and GABA1 concentrations. Questionnaire data from all participants and prospectivesymptom-diary data from patients were obtained for regression analyses of neurotransmitter concentrations with IBS-related andpsychological parameters. Concentrations of Glx were lower in IBS compared with HC (left aINS P , 0.05, right aINS P , 0.001),whereas no group differences were detected for GABA1concentrations. Lower right-lateralized Glx concentrations in patients weresubstantially predicted by longer pain duration, while less frequent use of adaptive pain‐coping predicted lower Glx in left aINS. Ourfindings provide first evidence for reduced excitatory but unaltered inhibitory neurotransmitter levels in aINS in IBS. The results alsoindicate a functional lateralization of aINS with a stronger involvement of the right hemisphere in perception of abdominal pain and ofthe left aINS in cognitive pain regulation. Our findings suggest that glutaminergic deficiency may play a role in pain processing in IBS.
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| 3. |
- Blystad, Ida, 1972-, et al.
(författare)
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Quantitative MRI for analysis of peritumoral edema in malignant gliomas
- 2017
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Ingår i: PLOS ONE. - : Public Library of Science. - 1932-6203. ; 12:5
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Tidskriftsartikel (refereegranskat)abstract
- Background and purpose Damage to the blood-brain barrier with subsequent contrast enhancement is a hallmark of glioblastoma. Non-enhancing tumor invasion into the peritumoral edema is, however, not usually visible on conventional magnetic resonance imaging. New quantitative techniques using relaxometry offer additional information about tissue properties. The aim of this study was to evaluate longitudinal relaxation R-1, transverse relaxation R-2, and proton density in the peritumoral edema in a group of patients with malignant glioma before surgery to assess whether relaxometry can detect changes not visible on conventional images. Methods In a prospective study, 24 patients with suspected malignant glioma were examined before surgery. A standard MRI protocol was used with the addition of a quantitative MR method (MAGIC), which measured R-1, R-2, and proton density. The diagnosis of malignant glioma was confirmed after biopsy/surgery. In 19 patients synthetic MR images were then created from the MAGIC scan, and ROIs were placed in the peritumoral edema to obtain the quantitative values. Dynamic susceptibility contrast perfusion was used to obtain cerebral blood volume (rCBV) data of the peritumoral edema. Voxel-based statistical analysis was performed using a mixed linear model. Results R-1, R-2, and rCBV decrease with increasing distance from the contrast-enhancing part of the tumor. There is a significant increase in R1 gradient after contrast agent injection (P<.0001). There is a heterogeneous pattern of relaxation values in the peritumoral edema adjacent to the contrast-enhancing part of the tumor. Conclusion Quantitative analysis with relaxometry of peritumoral edema in malignant gliomas detects tissue changes not visualized on conventional MR images. The finding of decreasing R-1 and R-2 means shorter relaxation times closer to the tumor, which could reflect tumor invasion into the peritumoral edema. However, these findings need to be validated in the future.
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| 4. |
- Håkansson, Irene, et al.
(författare)
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Neurofilament light chain in cerebrospinal fluid and prediction of disease activity in clinically isolated syndrome and relapsing-remitting multiple sclerosis
- 2017
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Ingår i: European Journal of Neurology. - : Wiley. - 1351-5101 .- 1468-1331. ; 24:5, s. 703-712
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Tidskriftsartikel (refereegranskat)abstract
- Background and purpose: Improved biomarkers are needed to facilitate clinical decision-making and as surrogate endpoints in clinical trials in multiple sclerosis (MS). We assessed whether neurodegenerative and neuroinflammatory markers in cerebrospinal fluid (CSF) at initial sampling could predict disease activity during 2 years of follow-up in patients with clinically isolated syndrome (CIS) and relapsing-remitting MS. Methods: Using multiplex bead array and enzyme-linked immunosorbent assay, CXCL1, CXCL8, CXCL10, CXCL13, CCL20, CCL22, neurofilament light chain (NFL), neurofilament heavy chain, glial fibrillary acidic protein, chitinase-3-like-1, matrix metalloproteinase-9 and osteopontin were analysed in CSF from 41 patients with CIS or relapsing-remitting MS and 22 healthy controls. Disease activity (relapses, magnetic resonance imaging activity or disability worsening) in patients was recorded during 2 years of follow-up in this prospective longitudinal cohort study. Results: In a logistic regression analysis model, NFL in CSF at baseline emerged as the best predictive marker, correctly classifying 93% of patients who showed evidence of disease activity during 2 years of follow-up and 67% of patients who did not, with an overall proportion of 85% (33 of 39 patients) correctly classified. Combining NFL with either neurofilament heavy chain or osteopontin resulted in 87% overall correctly classified patients, whereas combining NFL with a chemokine did not improve results. Conclusions: This study demonstrates the potential prognostic value of NFL in baseline CSF in CIS and relapsing-remitting MS and supports its use as a predictive biomarker of disease activity.
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| 9. |
- Tapper, Sofie, et al.
(författare)
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How does motion affect GABA-measurements? Order statistic filtering compared to conventional analysis of MEGA-PRESS MRS
- 2017
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Ingår i: PLOS ONE. - : Public Library of Science. - 1932-6203. ; 12:5
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Tidskriftsartikel (refereegranskat)abstract
- Purpose The aim of this study was to evaluate two post-processing techniques applied to MRS MEGA-PRESS data influenced by motion-induced artifacts. In contrast to the conventional averaging technique, order statistic filtering (OSF) is a known method for artifact reduction. Therefore, this method may be suitable to incorporate in the GABA quantification. Methods Twelve healthy volunteers were scanned three times using a 3 T MR system. One measurement protocol consisted of two MEGA-PRESS measurements, one reference measurement and one measurement including head motions. The resulting datasets were analyzed with the standard averaging technique and with the OSF-technique in two schemes; filtering phase cycles RAW PC and filtering dynamics RAW Dyn. Results The datasets containing artifacts resulted in an underestimation of the concentrations. There was a trend for the OSF-technique to compensate for this reduction when quantifying SNR-intense signals. However, there was no indication that OSF improved the estimated GABA concentrations. Moreover, when only considering the reference measurements, the OSF technique was equally as effective as averaging, which suggests that the techniques are interchangeable. Conclusion OSF performed equally well as the conventional averaging technique for low-SNR signals. For high-SNR signals, OSF performed better and thus could be considered for routine usage.
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| 10. |
- Tapper, Sofie, 1989-
(författare)
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Neurotransmitter Imaging of the Human Brain : Detecting γ-Aminobutyric Acid (GABA) Using Magnetic Resonance Spectroscopy
- 2019
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Introduction: In this thesis, MEGA-edited Magnetic Resonance Spectroscopy (MRS) has been used for the purpose of non-invasive detection of !- aminobutyric acid (GABA) within the brain. GABA is the main inhibitory neurotransmitter in the human central nervous system, and glutamate is the corresponding main excitatory neurotransmitter. A balance between GABA and glutamate is crucial for healthy neurotransmission within the brain, and regional altered concentrations have been linked to certain neurological disorders. However, it is challenging to measure GABA, and special editing approaches are needed in order to allow reliable quantification. In addition, the GABA measurement is further complicated due to disturbances such as movements during the acquisition that may lead to artifacts in the resulting spectrum. This thesis can be divided into two sections, where the first section focuses on three clinical applications (narcolepsy, irritable bowel syndrome (IBS), and essential tremor (ET)), which were all investigated using MEGA-edited single- voxel spectroscopy (SVS). The second section focuses on method development, where two statistical retrospective approaches were investigated for the purpose of improving MEGA-edited data. In addition, a new MRS imaging (MRSI) pulse sequence with the purpose of GABA detection using a high spatial resolution, short acquisition time, and full brain coverage was also investigated.Materials and Methods: In total, 164 participants were included and 272 MRS measurements were performed with the voxel placed in the medial prefrontal cortex (mPFC, 136), thalamus (32), and cerebellum (104) using two different but “identical” MR systems. Nineteen narcolepsy patients and 21 matched healthy controls performed an fMRI working memory task using a simultaneous EEG followed by an mPFC GABA-edited MRS measurement. Sixty-four IBS patients and 32 matched healthy controls underwent an mPFC GABA-edited MRS measurement followed by resting state fMRI. In addition, psychological symptoms were assessed using questionnaires. Ten ET patients and six matched healthy controls underwent four GABA-edited MRS measurements with the voxels placed in the thalamus and cerebellum. In this study, the symptom severity was investigated using the essential tremor rating scale (ETRS). All clinical MRS datasets were analyzed using conventional methods for post-processing and quantification. Furthermore, 12 volunteers were recruited for the purpose of investigating statistical retrospective approaches for artifact detection and elimination of MRS data. Each participant underwent three reference measurements and three measurements with induced head movements conducted according to a movement paradigm. Order statistic filtering (OSF) and jackknife correlation (JKC) were investigated as regards to the elimination of artifact-influenced spectra and reliability of the resulting concentrations. Finally, phantom measurements were performed for the purpose of investigating MEGA-edited MRSI.Results: In narcolepsy, a trend-level association was observed between the mPFC MRS concentrations and increased deactivation within the default mode network during the working memory task. A significantly higher mPFC GABA+ concentration was observed in IBS patients with a high severity of comorbid anxiety. In ET, a positive correlation was observed between cerebellar GABA+/Glx ratios and tremor severity. Moreover, movements during the measurement decreased the concentration estimates due to signal loss in the spectra. Both OSF and JKC resulted in trend-level improvement of the signal- intense metabolites in spectrum when artifacts were present in the data, while performing equally as well as conventional analysis methodology when no intentional movements were present in the data. Finally, using the fast MEGA- edited multi-voxel sequence developed for a conventional clinical scanner, our phantom measurements showed that GABA was detectable using a 1:45 min acquisition time and an MRSI voxel size of 1 mL.Discussion: Several challenges such as time constraints, large voxel sizes, and protocol design were encountered when performing SVS MEGA-PRESS in the clinical research settings. In addition, artifacts in the MRS data originating for example, from motions, negatively impacted the resulting averaged spectra, which was evident in both data from clinical populations and healthy controls. In the presence of artifacts in the data, both OSF and JKC improved the SVS MEGA-edited spectra. In addition, the implemented JKC method can be used not only for artifact detection, but also as a generally applicable retrospective technique for the quality control of a dataset, or as an indication of whether a shift in voxel placement occurred during the measurement. Using the MEGA-edited MRSI pulse sequence, there are many technical challenges, including detrimental effects from eddy currents, spurious echoes, and field inhomogeneities. Even though there are many technical challenges when using MEGA-edited MRSI, an optimized version of the MRSI sequence would be extremely valuable in clinical research applications where high spatial resolution and short acquisition times are highly desired.Conclusions: OSF and JKC improved the metabolite quantification when artifacts were present in the data, and JKC was preferable. Although there are many technical challenges, MEGA-edited MRSI with full brain coverage in combination with a minimal voxel size for the purpose of GABA detection, would be extremely useful in clinical research applications where disorders such as narcolepsy, IBS, or ET, are investigated.
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