Dataset Information

Patterns of cortical grey matter thickness reduction in multiple sclerosis.

ABSTRACT:

Objective

To examine the patterns of cortical gray matter thickness in multiple sclerosis (MS) patients.

Methods

Seventy-four MS patients-clinically isolated syndrome (4%), relapsing-remitting MS (79%), and progressive MS (17%)-and 21 healthy controls (HCs) underwent 1.5 Tesla T1-weighted 3D MRI examinations to measure brain cortical thickness in a total of 68 regions of interest. Using hierarchical cluster analysis with multivariate cortical thickness data, cortical thickness reduction patterns were cross-sectionally investigated in MS patients.

Results

The MS patients were grouped into three major clusters (Clusters 1, 2, and 3). Most of the regional cortical thickness values were equivalent between the HCs and Cluster 1, but decreased in the order of Clusters 2 and 3. Only the thicknesses of the temporal lobe cortices (the bilateral superior and left middle temporal cortex, as well as the left fusiform cortex) were significantly different among Clusters 1, 2, and 3. In contrast, temporal pole thickness reduction was evident exclusively in Cluster 3, which was also characterized by increased lesion loads in the temporal pole and the adjacent juxtacortical white matter, dilatation of the inferior horn of the lateral ventricle, severe whole-brain volume reduction, and longer disease duration. Although cortical atrophy was significantly more common in the progressive phase, approximately half of the MS patients with the severe cortical atrophy pattern had relapsing-remitting disease.

Conclusion

Cortical thickness reduction patterns in MS are mostly characterized by the degree of temporal lobe cortical atrophy, which may start in the relapsing-remitting phase. Among the temporal lobe cortices, the neurodegenerative change may accelerate in the temporal pole in the progressive phase.

SUBMITTER: Fujimori J

PROVIDER: S-EPMC8035454 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Similar Datasets

Project description:Sustained 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.

Project description:BackgroundRecent studies of cortical pathology in secondary progressive multiple sclerosis have shown that a more severe clinical course and the presence of extended subpial grey matter lesions with significant neuronal/glial loss and microglial activation are associated with meningeal inflammation, including the presence of lymphoid-like structures in the subarachnoid space in a proportion of cases.MethodsTo investigate the molecular consequences of pro-inflammatory and cytotoxic molecules diffusing from the meninges into the underlying grey matter, we carried out gene expression profiling analysis of the motor cortex from 20 post-mortem multiple sclerosis brains with and without substantial meningeal inflammation and 10 non-neurological controls.ResultsGene expression profiling of grey matter lesions and normal appearing grey matter not only confirmed the substantial pathological cell changes, which were greatest in multiple sclerosis cases with increased meningeal inflammation, but also demonstrated the upregulation of multiple genes/pathways associated with the inflammatory response. In particular, genes involved in tumour necrosis factor (TNF) signalling were significantly deregulated in MS cases compared with controls. Increased meningeal inflammation was found to be associated with a shift in the balance of TNF signalling away from TNFR1/TNFR2 and NFkB-mediated anti-apoptotic pathways towards TNFR1- and RIPK3-mediated pro-apoptotic/pro-necroptotic signalling in the grey matter, which was confirmed by RT-PCR analysis. TNFR1 was found expressed preferentially on neurons and oligodendrocytes in MS cortical grey matter, whereas TNFR2 was predominantly expressed by astrocytes and microglia.ConclusionsWe suggest that the inflammatory milieu generated in the subarachnoid space of the multiple sclerosis meninges by infiltrating immune cells leads to increased demyelinating and neurodegenerative pathology in the underlying grey matter due to changes in the balance of TNF signalling.