Abnormalities of NAWM tissue may cause demyelination

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Abnormalities in normal-appearing white matter from which multiple sclerosis lesions arise

https://academic.oup.com/braincomms/adv ... login=true



Abstract

Normal-appearing white matter (NAWM) is far from normal in multiple sclerosis; little is known about the precise pathology or spatial pattern of this alteration and its relation to subsequent lesion formation.

This study was undertaken to evaluate NAWM abnormalities in brain areas where multiple sclerosis lesions subsequently form, and to investigate the spatial distribution of NAWM abnormalities in persons with multiple sclerosis. Brain MRIs of pre-lesion NAWM were analyzed in participants with new T2 lesions, pooled from three clinical trials: SYNERGY (NCT01864148; n = 85 with relapsing multiple sclerosis) was the test data set; ASCEND (NCT01416181; n = 154 with secondary progressive multiple sclerosis) and ADVANCE (NCT00906399; n = 261 with relapsing-remitting multiple sclerosis) were used as validation data sets.

Focal NAWM tissue state was analyzed prior to lesion formation in areas where new T2 lesions later formed (pre-lesion NAWM) using normalized magnetization transfer ratio and T2-weighted (nT2) intensities, and compared with overall NAWM and spatially matched contralateral NAWM. Each outcome was analyzed using linear mixed-effects models.

Follow-up time (as a categorical variable), patient-level characteristics (including treatment group) and other baseline variables were treated as fixed effects. In SYNERGY, nT2 intensity was significantly higher, and normalized magnetization transfer ratio was lower in pre-lesion NAWM versus overall and contralateral NAWM at all time points up to 24 weeks before new T2 lesion onset. In ASCEND and ADVANCE (for which normalized magnetization transfer ratio was not available), nT2 intensity in pre-lesion NAWM was significantly higher compared to both overall and contralateral NAWM at all pre-lesion time points extending up to 2 years prior to lesion formation.

In all trials, nT2 intensity in the contralateral NAWM was also significantly higher at all pre-lesion time points compared to overall NAWM. Brain atlases of NAWM abnormalities were generated using measures of voxel-wise differences in normalized magnetization transfer ratio of NAWM in persons with multiple sclerosis compared to scanner-matched healthy controls.

We observed that overall spatial distribution of NAWM abnormalities in persons with multiple sclerosis largely recapitulated the anatomical distribution of probabilities of T2 hyperintense lesions.

Overall, these findings suggest that intrinsic spatial properties and/or longstanding precursory abnormalities of NAWM tissue may contribute to the risk of autoimmune acute demyelination in multiple sclerosis.

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More about the same.

Axon-Myelin Unit Blistering as Early Event in MS Normal Appearing White Matter

https://onlinelibrary.wiley.com/doi/ful ... /ana.26014

Abstract

Objective

Multiple sclerosis (MS) is a chronic neuroinflammatory and neurodegenerative disease of unknown etiology. Although the prevalent view regards a CD4+-lymphocyte autoimmune reaction against myelin at the root of the disease, recent studies propose autoimmunity as a secondary reaction to idiopathic brain damage. To gain knowledge about this possibility we investigated the presence of axonal and myelinic morphological alterations, which could implicate imbalance of axon-myelin units as primary event in MS pathogenesis.

Methods

Using high resolution imaging histological brain specimens from patients with MS and non-neurological/non-MS controls, we explored molecular changes underpinning imbalanced interaction between axon and myelin in normal appearing white matter (NAWM), a region characterized by normal myelination and absent inflammatory activity.

Results

In MS brains, we detected blister-like swellings formed by myelin detachment from axons, which were substantially less frequently retrieved in non-neurological/non-MS controls. Swellings in MS NAWM presented altered glutamate receptor expression, myelin associated glycoprotein (MAG) distribution, and lipid biochemical composition of myelin sheaths. Changes in tethering protein expression, widening of nodes of Ranvier and altered distribution of sodium channels in nodal regions of otherwise normally myelinated axons were also present in MS NAWM. Finally, we demonstrate a significant increase, compared with controls, in citrullinated proteins in myelin of MS cases, pointing toward biochemical modifications that may amplify the immunogenicity of MS myelin.

Interpretation

Collectively, the impaired interaction of myelin and axons potentially leads to myelin disintegration. Conceptually, the ensuing release of (post-translationally modified) myelin antigens may elicit a subsequent immune attack in MS.