Inside-out model: supporting papers.

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frodo
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Inside-out model: supporting papers.

Post by frodo » Wed Jan 30, 2019 2:28 am

The inside-out model is an alternative theoretical model for MS that postulates that something within the neurons is the cause of the later autoimmune attack. I am collecting here some papers that support this model.

Biochemically altered myelin triggers autoimmune demyelination (2018)
http://www.pnas.org/content/early/2018/ ... 5115.short

Early axonal damage in normal appearing white matter in multiple sclerosis (2017)
https://ieeexplore.ieee.org/abstract/document/8037494

Myelin Basic Protein Citrullination in Multiple Sclerosis (2016)
https://link.springer.com/article/10.10 ... 016-1920-2
"This review describes the MBP citrullination and its consequence, as well as offering further support for the “inside-out” hypothesis that MS is primarily a neurodegenerative disease with secondary inflammatory demyelination"

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Re: Inside-out model: supporting papers.

Post by frodo » Sun Feb 03, 2019 1:38 am

New paper challenging the outside-in model

https://www.sciencedirect.com/science/a ... 821930049X

Evidence of early microstructural white matter abnormalities in multiple sclerosis from multi-shell diffusion MRI


We found a significant reduction in FR focally in WM lesions and widespread in the NAWM in MS patients relative to controls (corrected p < .05). Signal fraction changes in NAWM were not driven by perilesional tissue, nor were they influenced by proximity to the ventricles, challenging the hypothesis of an outside-in pathological process driven by CSF-mediated immune cytotoxic factors. No significant differences were found in conventional DTI parameters. In a cross-validated classification task, FR showed the largest effect size and outperformed all other diffusion imaging metrics in discerning lesions from contralateral NAWM.

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Oligodendrocytes differences between patients and controls

Post by frodo » Sun Feb 03, 2019 7:46 am

Altered human oligodendrocyte heterogeneity in multiple sclerosis

https://www.nature.com/articles/s41586-019-0903-2

Oligodendrocyte (OL) pathology is increasingly implicated in neurodegenerative diseases as OLs both myelinate and provide metabolic support to axons. In multiple sclerosis (MS), demyelination in the central nervous system (CNS) thus leads to neurodegeneration, but the severity of MS between patients is very variable. Disability does not correlate well with the extent of demyelination1, suggesting that other factors contribute to this variability. One such factor may be OL heterogeneity. Not all OLs are the same—mouse spinal cord OLs inherently produce longer myelin sheaths than cortical OLs2, and single-cell analysis of mouse CNS identified further differences3,4. However, the extent of human OL heterogeneity and its possible contribution to MS pathology remains unknown. Here we performed single nuclei RNA-sequencing (snRNA-seq) from white matter (WM) areas of post mortem human brain both in control (Ctr) and MS patients. We identified sub-clusters of oligodendroglia in Ctr human WM, some similar to mouse, and defined new markers for these cell states.

Strikingly, some sub-clusters were under-represented in MS tissue, while others were more prevalent. These differences in mature OL sub-clusters may indicate different functional states of OLs in MS lesions. Since this is similar in normal appearing white matter (NAWM), MS is a more diffuse disease than its focal demyelination suggests. Our findings of an altered oligodendroglial heterogeneity in MS may be important to understanding disease progression and developing therapeutic approaches.

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