scholarly journals The influence of HLA‐DRB1*15 on the relationship between microglia and neurons in multiple sclerosis normal appearing cortical grey matter

2021 ◽  
Author(s):  
Richard L. Yates ◽  
Jonathan Pansieri ◽  
Qizhu Li ◽  
Jack S. Bell ◽  
Sydney A. Yee ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Grey Matter ◽  
Cortical Grey Matter ◽  
The Relationship

scholarly journals Neuron-specific activation of necroptosis signaling in multiple sclerosis cortical grey matter

2021 ◽  
Vol 141 (4) ◽  
pp. 585-604 ◽  
Author(s):  
Carmen Picon ◽  
Anusha Jayaraman ◽  
Rachel James ◽  
Catriona Beck ◽  
Patricia Gallego ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Signaling Pathway ◽  
Cortical Neurons ◽  
Grey Matter ◽  
Molecular Mechanisms ◽  
Fold Increase ◽  
Cell Types ◽  
Meningeal Inflammation ◽  
Cortical Grey Matter

AbstractSustained exposure to pro-inflammatory cytokines in the leptomeninges is thought to play a major role in the pathogenetic mechanisms leading to cortical pathology in multiple sclerosis (MS). Although the molecular mechanisms underlying neurodegeneration in the grey matter remain unclear, several lines of evidence suggest a prominent role for tumour necrosis factor (TNF). Using cortical grey matter tissue blocks from post-mortem brains from 28 secondary progressive MS subjects and ten non-neurological controls, we describe an increase in expression of multiple steps in the TNF/TNF receptor 1 signaling pathway leading to necroptosis, including the key proteins TNFR1, FADD, RIPK1, RIPK3 and MLKL. Activation of this pathway was indicated by the phosphorylation of RIPK3 and MLKL and the formation of protein oligomers characteristic of necrosomes. In contrast, caspase-8 dependent apoptotic signaling was decreased. Upregulation of necroptotic signaling occurred predominantly in macroneurons in cortical layers II–III, with little expression in other cell types. The presence of activated necroptotic proteins in neurons was increased in MS cases with prominent meningeal inflammation, with a 30-fold increase in phosphoMLKL+ neurons in layers I–III. The density of phosphoMLKL+ neurons correlated inversely with age at death, age at progression and disease duration. In vivo induction of chronically elevated TNF and INFγ levels in the CSF in a rat model via lentiviral transduction in the meninges, triggered inflammation and neurodegeneration in the underlying cortical grey matter that was associated with increased neuronal expression of TNFR1 and activated necroptotic signaling proteins. Exposure of cultured primary rat cortical neurons to TNF induced necroptosis when apoptosis was inhibited. Our data suggest that neurons in the MS cortex are dying via TNF/TNFR1 stimulated necroptosis rather than apoptosis, possibly initiated in part by chronic meningeal inflammation. Neuronal necroptosis represents a pathogenetic mechanism that is amenable to therapeutic intervention at several points in the signaling pathway.

MULTI-MODAL MRI AT 7T TO DETECT AND QUANTIFY MULTIPLE SCLEROSIS CORTICAL GREY MATTER PATHOLOGY

2012 ◽  
Vol 83 (Suppl 2) ◽  
pp. A37.2-A37
Author(s):  
OE Mougin ◽  
N Mistry ◽  
MM Papachatzaki ◽  
P Gowland ◽  
N Evangelou ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Grey Matter ◽  
Cortical Grey Matter

Different white matter lesion characteristics correlate with distinct grey matter abnormalities on magnetic resonance imaging in secondary progressive multiple sclerosis

2009 ◽  
Vol 15 (6) ◽  
pp. 687-694 ◽  
Author(s):  
J Furby ◽  
T Hayton ◽  
D Altmann ◽  
R Brenner ◽  
J Chataway ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
White Matter ◽  
Grey Matter ◽  
Progressive Multiple Sclerosis ◽  
Secondary Progressive Multiple Sclerosis ◽  
Lesion Volume ◽  
Secondary Degeneration ◽  
Secondary Progressive ◽  
Demyelinating Lesions ◽  
The Relationship

Background Although MRI measures of grey matter abnormality correlate with clinical disability in multiple sclerosis, it is uncertain whether grey matter abnormality measured on MRI is entirely due to a primary grey matter process or whether it is partly related to disease in the white matter. Methods To explore potential mechanisms of grey matter damage we assessed the relationship of white matter T2 lesion volume, T1 lesion volume, and mean lesion magnetisation transfer ratio (MTR), with MRI measures of tissue atrophy and MTR in the grey matter in 117 subjects with secondary progressive multiple sclerosis. Results Grey matter fraction and mean grey matter MTR were strongly associated with lesion volumes and lesion MTR mean ( r = ±0.63–0.72). In contrast, only weak to moderate correlations existed between white matter and lesion measures. In a stepwise regression model, T1 lesion volume was the only independent lesion correlate of grey matter fraction and accounted for 52% of the variance. Lesion MTR mean and T2 lesion volume were independent correlates of mean grey matter MTR, accounting for 57% of the variance. Conclusions Axonal transection within lesions with secondary degeneration into the grey matter may explain the relationship between T1 lesions and grey matter fraction. A parallel accumulation of demyelinating lesions in white and grey matter may contribute to the association of T2 lesion volume and lesion MTR with grey matter MTR.

scholarly journals A longitudinal study of cortical grey matter lesion subtypes in relapse-onset multiple sclerosis

2015 ◽  
Vol 87 (7) ◽  
pp. 750-753 ◽  
Author(s):  
Varun Sethi ◽  
Tarek Yousry ◽  
Nils Muhlert ◽  
Daniel J Tozer ◽  
Daniel Altmann ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Longitudinal Study ◽  
Grey Matter ◽  
Cortical Grey Matter

scholarly journals Complement is activated in progressive multiple sclerosis cortical grey matter lesions

2016 ◽  
Vol 13 (1) ◽  
Author(s):  
Lewis M. Watkins ◽  
James W. Neal ◽  
Sam Loveless ◽  
Iliana Michailidou ◽  
Valeria Ramaglia ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Grey Matter ◽  
Progressive Multiple Sclerosis ◽  
Cortical Grey Matter

scholarly journals Meningeal and cortical grey matter pathology in multiple sclerosis

BMC Neurology ◽  
2012 ◽  
Vol 12 (1) ◽  
Author(s):  
Bogdan F Gh Popescu ◽  
Claudia F Lucchinetti
Keyword(s):  
Multiple Sclerosis ◽  
Grey Matter ◽  
Cortical Grey Matter

scholarly journals Cortical grey matter sodium accumulation is associated with disability and secondary progressive disease course in relapse-onset multiple sclerosis

2019 ◽  
Vol 90 (7) ◽  
pp. 755-760 ◽  
Author(s):  
Wallace J Brownlee ◽  
Bhavana Solanky ◽  
Ferran Prados ◽  
Marios Yiannakas ◽  
Patricia Da Mota ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Grey Matter ◽  
Disease Onset ◽  
Healthy Controls ◽  
Disease Course ◽  
Cross Sectional ◽  
Sodium Accumulation ◽  
Secondary Progressive ◽  
Cortical Grey Matter

ObjectiveSodium (23Na)-MRI is an emerging imaging technique to investigate in vivo changes in tissue viability, reflecting neuroaxonal integrity and metabolism. Using an optimised 23Na-MRI protocol with smaller voxel sizes and improved tissue contrast, we wanted to investigate whether brain total sodium concentration (TSC) is a biomarker for long-term disease outcomes in a cohort of patients with relapse-onset multiple sclerosis (MS), followed from disease onset.MethodsWe performed a cross-sectional study in 96 patients followed up ~ 15 years after a clinically isolated syndrome (CIS) and 34 healthy controls. Disease course was classified as CIS, relapsing-remitting MS or secondary progressive MS (SPMS). We acquired 1H-MRI and 23Na-MRI and calculated the TSC in cortical grey matter (CGM), deep grey matter, normal-appearing white matter (WM) and WM lesions. Multivariable linear regression was used to identify independent associations of tissue-specific TSC with physical disability and cognition, with adjustment for tissue volumes.ResultsTSC in all tissues was higher in patients with MS compared with healthy controls and patients who remained CIS, with differences driven by patients with SPMS. Higher CGM TSC was independently associated with Expanded Disability Status Scale (R2=0.26), timed 25-foot walk test (R2=0.23), 9-hole peg test (R2=0.23), Paced Auditory Serial Addition Test (R2=0.29), Symbol Digit Modalities Test (R2=0.31) and executive function (R2=0.36) test scores, independent of grey matter atrophy.ConclusionsSodium accumulation in CGM reflects underlying neuroaxonal metabolic abnormalities relevant to disease course heterogeneity and disability in relapse-onset MS. TSC and should be considered as an outcome measure in future neuroprotection trials.

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