Glutamate gene polymorphisms predict brain volumes in multiple sclerosis

Strijbis, Eva; Inkster, Becky; Vounou, Maria; Naegelin, Yvonne; Kappos, Ludwig; Radue, Ernst‐Wilhelm; Matthews, Paul M.; Uitdehaag, Bernard M. J.; Barkhof, Frederik; Polman, Chris H.; Montana, Giovanni; Geurts, Jeroen J. G.

doi:10.1177/1352458512454345

Cited by 19 publications

(14 citation statements)

References 45 publications

(59 reference statements)

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“…The MRI imaging parameters T1‐hypo‐intense lesion volume, T2‐hyper‐intense lesion volume (T2‐lesion volume), and percentage brain volume change (PBVC) were used as outcome parameters based on the similarities in imaging protocols between centers according to the GeneMSA protocol as previously published . Briefly, participants underwent MRI scanning upon entry, using 1.5 Tesla MR scanners, using common MR sequences and protocols .…”

Section: Methodsmentioning

confidence: 99%

“…T1‐hypo‐intense lesions and T2‐lesions were centrally measured using the AMIRA software . Delta T1‐hypo‐intense lesion volume and delta T2‐lesion volume were used for statistical analyses by subtraction of T1‐hypo‐intense lesion and T2‐lesion follow‐up values by T1‐hypo‐intense lesion and T2‐lesion baseline values . Volumetric analyses for all patients were performed in Amsterdam .…”

Section: Methodsmentioning

confidence: 99%

“…Delta T1‐hypo‐intense lesion volume and delta T2‐lesion volume were used for statistical analyses by subtraction of T1‐hypo‐intense lesion and T2‐lesion follow‐up values by T1‐hypo‐intense lesion and T2‐lesion baseline values . Volumetric analyses for all patients were performed in Amsterdam . We had access to PBVC data of 62 MS patients with 2 years of follow‐up from the GeneMSA cohort.…”

Section: Methodsmentioning

confidence: 99%

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Plasma proteome in multiple sclerosis disease progression

Malekzadeh¹,

Leurs

Wieringen³

et al. 2019

Ann Clin Transl Neurol

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Background: The pathophysiology of multiple sclerosis disease progression remains undetermined. The aim of this study was to identify differences in plasma proteome during different stages of MS disease progression. Methods:We used a multiplex aptamer proteomics platform (Somalogic) for sensitive detection of 1129 proteins in plasma. MS patients were selected and categorized based on baseline and a 4-year follow-up EDSS (delta EDSS) scores; relapseonset (RO) slow progression (n = 31), RO with rapid progression (n = 29), primary progressive (n = 30), and healthy controls (n = 20). The relation of baseline plasma protein levels with delta EDSS and different MRI progression parameters were assessed using linear regression models. Results: Regression analyses of plasma proteins with delta EDSS showed six significant associations. Strong associations were found for the proteins LGLAS8 (P = 7.64 9 10 À5 , q = 0.06), CCL3 (P = 0.0001, q = 0.06), and RGMA (P = 0.0005, q = 0.09). In addition, associations of plasma proteins were found with percentage brain volume for C3 (P = 2,08 9 10 À9 , q = 1,70 9 10 À6 ), FGF9 (P = 3,42 9 10 À9 , q = 1,70 9 10 À6 ), and EHMT2 (P = 0.0007, q = 0.01). Most of the significant markers were associated with cell-cell and cell-extracellular matrix adhesion, immune system communication, immune system activation, and complement pathways. Conclusions: Our results revealed eight novel biomarkers related to clinical and radiological progression in MS. These results indicate that changes in immune system, complement pathway and ECM remodeling proteins contribute to MS progression and may therefore be further explored for use in prognosis of MS. 1582

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Plasma proteome in multiple sclerosis disease progression

Malekzadeh¹,

Leurs

Wieringen³

et al. 2019

Ann Clin Transl Neurol

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“…The significance of this association is uncertain at this time. An even more recent study found that after selecting MS patients for greater atrophy (and thus presumably for a greater degenerative undertone), this was associated with 5 single nucleotide polymorphisms of the GRIN2A gene that codes for the GluN2A subunit of the NMDA receptor [34]. This suggests a role for deregulation of glutamatergic signaling in the degenerative aspects of progressive MS.…”

Section: Nagging Discrepancies With This Picturementioning

confidence: 99%

Pathoetiology of multiple sclerosis: are we barking up the wrong tree?

Stys

2013

F1000Prime Rep

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Despite a century of intensive investigation, the underlying cause of multiple sclerosis has eluded us. It is clear that there exists a prominent progressive degenerative phenotype together with an important autoimmune inflammatory component, and careful histopathological examination always shows, to a greater or lesser degree, concomitant degeneration/demyelination and adaptive T cell-dependent immune responses. Given this picture, it is difficult, if not impossible, to definitively say whether degeneration or autoimmunity is the initiator of the disease. In this review, I put forward the evidence for and against both models and speculate that, in contrast to the accepted view, it is equally likely that multiple sclerosis may be a degenerative disease that secondarily elicits an autoimmune response, and suggest how this might influence therapeutic approaches.

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“…MS patients with single nucleotide polymorphisms of the glutamate NMDA receptor 2A subunit domain show more advanced brain atrophy. [ 18 ] Glutamate levels, as measured by 1 H magnetic resonance spectroscopy (MRS), are increased in acute demyelinated WM lesions. [ 19 ] Glutamate transport and metabolism are decreased in oligodendrocytes around WM lesions in MS. [ 20 ] Excitatory amino acid transporters, which typically protect neurons and oligodendrocytes from glutamate toxicity, are downregulated from the membranes of astrocytes in the demyelinated cortex containing activated microglia.…”

Section: Introductionmentioning

confidence: 99%

Effect of teriflunomide on cortex-basal ganglia-thalamus (CxBGTh) circuit glutamatergic dysregulation in the Theiler's Murine Encephalomyelitis Virus mouse model of multiple sclerosis

Modica

Schweser²,

Sudyn

et al. 2017

PLoS ONE

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BackgroundPathology of gray matter is associated with development of physical and cognitive disability in patients with multiple sclerosis. In particular, glutamatergic dysregulation in the cortex-basal ganglia-thalamus (CxBGTh) circuit could be associated with decline in these behaviors.ObjectivesTo investigate the effect of an immunomodulatory therapy (teriflunomide, Aubagio®) on changes of the CxBGTh loop in the Theiler’s Murine Encephalomyelitis Virus, (TMEV) mouse model of MS.MethodsForty-eight (48) mice were infected with TMEV, treated with teriflunomide (24) or control vehicle (24) and followed for 39 weeks. Mice were examined with MRS and volumetric MRI scans (0, 8, 26, and 39 weeks) in the cortex, basal ganglia and thalamus, using a 9.4T scanner, and with behavioral tests (0, 4, 8, 12, 17, 26, and 39 weeks). Within conditions, MRI measures were compared between two time points by paired samples t-test and across multiple time points by repeated measures ANOVA (rmANOVA), and between conditions by independent samples t-test and rmANOVA, respectively. Data were considered as significant at the p<0.01 level and as a trend at p<0.05 level.ResultsIn the thalamus, the teriflunomide arm exhibited trends toward decreased glutamate levels at 8 and 26 weeks compared to the control arm (p = 0.039 and p = 0.026), while the control arm exhibited a trend toward increased glutamate between 0 to 8 weeks (p = 0.045). In the basal ganglia, the teriflunomide arm exhibited a trend toward decreased glutamate earlier than the control arm, from 0 to 8 weeks (p = 0.011), resulting in decreased glutamate compared to the control arm at 8 weeks (p = 0.016).ConclusionsTeriflunomide may reduce possible excitotoxicity in the thalamus and basal ganglia by lowering glutamate levels.

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Glutamate gene polymorphisms predict brain volumes in multiple sclerosis

Abstract: Using a novel, multivariate regression model confirmed by two other statistical approaches we show associations between GRIN2A SNPs and phenotypic variation in NBV and NWMV in this first exploratory study. Replications in independent datasets are now necessary to validate these findings.

Cited by 19 publications

References 45 publications

Plasma proteome in multiple sclerosis disease progression

Plasma proteome in multiple sclerosis disease progression

Pathoetiology of multiple sclerosis: are we barking up the wrong tree?

Effect of teriflunomide on cortex-basal ganglia-thalamus (CxBGTh) circuit glutamatergic dysregulation in the Theiler's Murine Encephalomyelitis Virus mouse model of multiple sclerosis

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