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The relationship between cortical lesions and periventricular NAWM abnormalities suggests a shared mechanism of injury in primary-progressive MS.

ABSTRACT: In subjects with multiple sclerosis (MS), pathology is more frequent near the inner and outer surfaces of the brain. Here, we sought to explore if in subjects with primary progressive MS (PPMS) cortical lesion load is selectively associated with the severity of periventricular normal appearing white matter (NAWM) damage, as assessed with diffusion weighted imaging. To this aim, twenty-four subjects with PPMS and twenty healthy controls were included in the study. Using diffusion data, skeletonized mean diffusivity (MD) NAWM maps were computed excluding WM lesions and a 2 mm-thick peri-lesional rim. The supra-tentorial voxels between 2 and 6 mm of distance from the lateral ventricles were included in the periventricular NAWM mask while the voxels between 6 and 10 mm from the lateral ventricles were included in the deep NAWM mask; mean MD values were then computed separately for these two masks. Lastly, cortical lesions were assessed on phase-sensitive inversion recovery (PSIR) images and cortical thickness was quantified on volumetric T1 images. Our main result was the observation in the PPMS group of a significant correlation between periventricular NAWM MD values and cortical lesion load, with a greater cortical lesion burden being associated with more abnormal periventricular NAWM MD. Conversely, there was no correlation between cortical lesion load and deep NAWM MD values or periventricular WM lesions. Our data thus suggest that a common - and relatively selective - factor plays a role in the development of both cortical lesion and periventricular NAWM abnormalities in PPMS.

SUBMITTER: Pardini M

PROVIDER: S-EPMC5537392 | biostudies-other | 2017

REPOSITORIES: biostudies-other

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Project description:The white matter (WM) represents approximately half the cerebrum volume and is profoundly affected in Alzheimer's disease (AD). However, both the WM responses to AD as well as potential influences of this compartment to dementia pathogenesis remain comparatively neglected. Neuroimaging studies have revealed WM alterations are commonly associated with AD and renewed interest in examining the pathologic basis and importance of these changes. In AD subjects, immunohistochemistry and electron microscopy revealed changes in astrocyte morphology and myelin loss as well as up to 30% axonal loss in areas of WM rarefaction when measured against non-demented control (NDC) tissue. Comparative proteomic analyses were performed on pooled samples of periventricular WM (PVWM) obtained from AD (n=4) and NDC (n=5) subjects with both groups having a mean age of death of 86 years. All subjects had an apolipoprotein E ε3/3 genotype with the exception of one NDC subject who was ε2/3. Urea-detergent homogenates were analyzed using two different separation techniques: 2-dimensional isoelectric focusing/reverse-phase chromatography and 2-dimensional difference gel electrophoresis (2D-DIGE). Proteins with different expression levels between the 2 diagnostic groups were identified using MALDI-Tof/Tof mass spectrometry. In addition, Western blots were used to quantify proteins of interest in individual AD and NDC cases. Our proteomic studies revealed that when WM protein pools were loaded at equal amounts of total protein for comparative analyses, there were quantitative differences between the 2 groups. Molecules related to cytoskeleton maintenance, calcium metabolism and cellular survival such as glial fibrillary acidic protein, vimentin, tropomyosin, collapsin response mediator protein-2, calmodulin, S100-P, annexin A1, α-internexin, α- and β-synuclein, α-B-crystalline, fascin-1, ubiquitin carboxyl-terminal esterase and thymosine were altered between AD and NDC pools. Our experiments suggest that WM activities become globally impaired during the course of AD with significant morphological, biochemical and functional consequential implications for gray matter function and cognitive deficits. These observations may endorse the hypothesis that WM dysfunction is not only a consequence of AD pathology, but that it may precipitate and/or potentiate AD dementia.

Project description:Hypoxic-ischemic brain damage presents a significant neurological challenge, often manifesting during the perinatal period. Specifically, periventricular leukomalacia (PVL) is emerging as a notable contributor to cerebral palsy and intellectual disabilities. It compromises cerebral microcirculation, resulting in insufficient oxygen or blood flow to the periventricular region of the brain. As widely documented, these pathological conditions can be caused by several factors encompassing preterm birth (4-5% of the total cases), as well single cotwin abortion and genetic variants such as those associated with GTPase pathways. Whole exome sequencing (WES) analysis identified a de novo causative variant within the pleckstrin homology domain-containing family G member 1 (PLEKHG1) gene in a patient presenting with PVL. The PLEKHG1 gene is ubiquitously expressed, showing high expression patterns in brain tissues. PLEKHG1 is part of a family of Rho guanine nucleotide exchange factors, and the protein is essential for cell division control protein 42 (CDC42) activation in the GTPase pathway. CDC42 is a key small GTPase of the Rho-subfamily, regulating various cellular functions such as cell morphology, migration, endocytosis, and cell cycle progression. The molecular mechanism involving PLEKHG1 and CDC42 has an intriguing role in the reorientation of cells in the vascular endothelium, thus suggesting that disruption responses to mechanical stress in endothelial cells may be involved in the formation of white matter lesions. Significantly, CDC42 association with white matter abnormalities is underscored by its MIM phenotype number. In contrast, although PLEKHG1 has been recently associated with patients showing white matter hyperintensities, it currently lacks a MIM phenotype number. Additionally, in silico analyses classified the identified variant as pathogenic. Although the patient was born prematurely and subsequently to dichorionic gestation, during which its cotwin died, we suggest that the variant described can strongly contribute to PVL. The aim of the current study is to establish a plausible association between the PLEKHG1 gene and PVL.

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The relationship between cortical lesions and periventricular NAWM abnormalities suggests a shared mechanism of injury in primary-progressive MS.

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