Dataset Information

Cortical axonal loss is associated with both gray matter demyelination and white matter tract pathology in progressive multiple sclerosis: Evidence from a combined MRI-histopathology study.

ABSTRACT:

Background

Neuroaxonal degeneration is one of the hallmarks of clinical deterioration in progressive multiple sclerosis (PMS).

Objective

To elucidate the association between neuroaxonal degeneration and both local cortical and connected white matter (WM) tract pathology in PMS.

Methods

Post-mortem in situ 3T magnetic resonance imaging (MRI) and cortical tissue blocks were collected from 16 PMS donors and 10 controls. Cortical neuroaxonal, myelin, and microglia densities were quantified histopathologically. From diffusion tensor MRI, fractional anisotropy, axial diffusivity (AD), radial diffusivity (RD), and mean diffusivity (MD) were quantified in normal-appearing white matter (NAWM) and white matter lesions (WML) of WM tracts connected to dissected cortical regions. Between-group differences and within-group associations were investigated through linear mixed models.

Results

The PMS donors displayed significant axonal loss in both demyelinated and normal-appearing (NA) cortices (p?p?=?0.02) compared with controls. In PMS, cortical axonal density was associated with WML MD and AD (p?=?0.003; p?=?0.02, respectively), and NAWM MD and AD (p?=?0.04; p?=?0.049, respectively). NAWM AD and WML AD explained 12.6% and 22.6%, respectively, of axonal density variance in NA cortex. Additional axonal loss in demyelinated cortex was associated with cortical demyelination severity (p?=?0.002), explaining 34.4% of axonal loss variance.

Conclusion

Reduced integrity of connected WM tracts and cortical demyelination both contribute to cortical axonal loss in PMS.

SUBMITTER: Kiljan S

PROVIDER: S-EPMC7897796 | biostudies-literature | 2021 Mar

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Cortical axonal loss is associated with both gray matter demyelination and white matter tract pathology in progressive multiple sclerosis: Evidence from a combined MRI-histopathology study.

Kiljan Svenja S Preziosa Paolo P Jonkman Laura E LE van de Berg Wilma Dj WD Twisk Jos J Pouwels Petra Jw PJ Schenk Geert J GJ Rocca Maria A MA Filippi Massimo M Geurts Jeroen Jg JJ Steenwijk Martijn D MD

Multiple sclerosis (Houndmills, Basingstoke, England) 20200511 3

<h4>Background</h4>Neuroaxonal degeneration is one of the hallmarks of clinical deterioration in progressive multiple sclerosis (PMS).<h4>Objective</h4>To elucidate the association between neuroaxonal degeneration and both local cortical and connected white matter (WM) tract pathology in PMS.<h4>Methods</h4><i>Post-mortem in situ</i> 3T magnetic resonance imaging (MRI) and cortical tissue blocks were collected from 16 PMS donors and 10 controls. Cortical neuroaxonal, myelin, and microglia densit ...[more]

PMID: 32390507

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Project description:BackgroundBrain astroglia are activated preceding the onset of experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS). We characterized the effects of brain astroglia on spinal cord inflammation, focusing on astroglial connexin (Cx)43, because we recently reported that Cx43 has a critical role in regulating neuroinflammation.MethodsBecause glutamate aspartate transporter (GLAST)+ astroglia are enriched in the brain gray matter, we generated Cx43fl/fl;GLAST-CreERT2/+ mice that were brain gray matter astroglia-specific Cx43 conditional knockouts (Cx43 icKO). EAE was induced by immunization with myelin oligodendroglia glycoprotein (MOG) 35-55 peptide 10 days after tamoxifen injection. Cx43fl/fl mice were used as controls.ResultsAcute and chronic EAE signs were significantly milder in Cx43 icKO mice than in controls whereas splenocyte MOG-specific responses were unaltered. Histologically, Cx43 icKO mice showed significantly less demyelination and fewer CD45+ infiltrating immunocytes, including F4/80+ macrophages, and Iba1+ microglia in the spinal cord than controls. Microarray analysis of the whole cerebellum revealed marked upregulation of anti-inflammatory A2-specific astroglia gene sets in the pre-immunized phase and decreased proinflammatory A1-specific and pan-reactive astroglial gene expression in the onset phase in Cx43 icKO mice compared with controls. Astroglia expressing C3, a representative A1 marker, were significantly decreased in the cerebrum, cerebellum, and spinal cord of Cx43 icKO mice compared with controls in the peak phase. Isolated Cx43 icKO spinal microglia showed more anti-inflammatory and less proinflammatory gene expression than control microglia in the pre-immunized phase. In particular, microglial expression of Ccl2, Ccl5, Ccl7, and Ccl8 in the pre-immunized phase and of Cxcl9 at the peak phase was lower in Cx43 icKO than in controls. Spinal microglia circularity was significantly lower in Cx43 icKO than in controls in the peak phase. Significantly lower interleukin (IL)-6, interferon-γ, and IL-10 levels were present in cerebrospinal fluid from Cx43 icKO mice in the onset phase compared with controls.ConclusionsThe ablation of Cx43 in brain gray matter astroglia attenuates EAE by promoting astroglia toward an anti-inflammatory phenotype and suppressing proinflammatory activation of spinal microglia partly through depressed cerebrospinal fluid proinflammatory cytokine/chemokine levels. Brain astroglial Cx43 might be a novel therapeutic target for MS.

Dataset Information

Cortical axonal loss is associated with both gray matter demyelination and white matter tract pathology in progressive multiple sclerosis: Evidence from a combined MRI-histopathology study.

Background

Objective

Methods

Results

Conclusion

Publications

Cortical axonal loss is associated with both gray matter demyelination and white matter tract pathology in progressive multiple sclerosis: Evidence from a combined MRI-histopathology study.

Similar Datasets

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