Gray Matter Lesions In Multiple Sclerosis Research Articles

Detection of Cortical and Deep Gray Matter Lesions in Multiple Sclerosis Using DIR and FLAIR at 3T.

The comparative detection rates of deep gray matter (GM) multiple sclerosis (MS) lesions using double inversion recovery (DIR) and fluid-attenuated inversion-recovery (FLAIR) on 3T MR imaging remain unknown. We aimed to assess the detectability of cortical and deep GM MS lesions using DIR and FLAIR on 3T clinical exams and evaluate the relationship between deep GM lesions and brain atrophy. One hundred fifty consecutive MS patients underwent routine brain MRI that included 3D DIR and 2D T2 FLAIR on the same 3T scanner. Three neuroradiologists independently reviewed all exams for cortical and deep GM lesions. Statistical parametric mapping (SPM) and FMRIB software library (FSL)-FIRST pipelines were used to determine normalized whole brain and deep GM volumes. A total of 65 cortical and 98 deep lesions were detected on DIR versus 24 and 20, respectively, on FLAIR. Among all 150 patients, the number and percentage of patients with GM lesions on DIR and FLAIR were as follows: cortical 43 (28.7%) versus 24 (16.0%) (P < .001), thalamus 47 (31.3%) versus 20 (13.3%) (P<.001), putamen 10 (6.7%) versus 3 (2.0%) (P = .02), globus pallidus 9 (6.0%) versus 3 (1.3%) (P = .02), and caudate 5 (3.3%) versus 1 (0.7%) (P = .125). Presence of deep GM lesions weakly correlated with deep GM volume fractions. Deep GM MS lesions can be detected using routine clinical brain MRI including DIR and FLAIR at 3T. Future studies to optimize these sequences may improve the detection rates of cortical and deep GM lesions. The presence of GM lesions showed weak correlation with GM atrophy.

Regulation of microglial TMEM119 and P2RY12 immunoreactivity in multiple sclerosis white and grey matter lesions is dependent on their inflammatory environment

Multiple Sclerosis (MS) is the most common cause of acquired neurological disability in young adults, pathologically characterized by leukocyte infiltration of the central nervous system, demyelination of the white and grey matter, and subsequent axonal loss. Microglia are proposed to play a role in MS lesion formation, however previous literature has not been able to distinguish infiltrated macrophages from microglia. Therefore, in this study we utilize the microglia-specific, homeostatic markers TMEM119 and P2RY12 to characterize their immunoreactivity in MS grey matter lesions in comparison to white matter lesions. Furthermore, we assessed the immunological status of the white and grey matter lesions, as well as the responsivity of human white and grey matter derived microglia to inflammatory mediators. We are the first to show that white and grey matter lesions in post-mortem human material differ in their immunoreactivity for the homeostatic microglia-specific markers TMEM119 and P2RY12. In particular, whereas immunoreactivity for TMEM119 and P2RY12 is decreased in the center of WMLs, immunoreactivity for both markers is not altered in GMLs. Based on data from post-mortem human microglia cultures, treated with IL-4 or IFNγ+LPS and on counts of CD3+ or CD20+ lymphocytes in lesions, we show that downregulation of TMEM119 and P2RY12 immunoreactivity in MS lesions corresponds with the presence of lymphocytes and lymphocyte-derived cytokines within the parenchyma but not in the meninges. Furthermore, the presence of TMEM119+ and partly P2RY12+ microglia in pre-active lesions as well as in the rim of active white and grey matter lesions, in addition to TMEM119+ and P2RY12+ rod-like microglia in subpial grey matter lesions suggest that blocking the entrance of lymphocytes into the CNS of MS patients may not interfere with all possible effects of TMEM119+ and P2RY12+ microglia in both white and grey matter MS lesions.

PECAM-1 Stabilizes Blood-Brain Barrier Integrity and Favors Paracellular T-Cell Diapedesis Across the Blood-Brain Barrier During Neuroinflammation.

Breakdown of the blood-brain barrier (BBB) and increased immune cell trafficking into the central nervous system (CNS) are hallmarks of the pathogenesis of multiple sclerosis (MS). Platelet endothelial cell adhesion molecule-1 (PECAM-1; CD31) is expressed on cells of the vascular compartment and regulates vascular integrity and immune cell trafficking. Involvement of PECAM-1 in MS pathogenesis has been suggested by the detection of increased levels of soluble PECAM-1 (sPECAM-1) in the serum and CSF of MS patients. Here, we report profound upregulation of cell-bound PECAM-1 in initial (pre-phagocytic) white matter as well as active cortical gray matter MS lesions. Using a human in vitro BBB model we observed that PECAM-1 is not essential for the transmigration of human CD4+ T-cell subsets (Th1, Th1*, Th2, and Th17) across the BBB. Employing an additional in vitro BBB model based on primary mouse brain microvascular endothelial cells (pMBMECs) we show that the lack of endothelial PECAM-1 impairs BBB properties as shown by reduced transendothelial electrical resistance (TEER) and increases permeability for small molecular tracers. Investigating T-cell migration across the BBB under physiological flow by in vitro live cell imaging revealed that absence of PECAM-1 in pMBMECs did not influence arrest, polarization, and crawling of effector/memory CD4+ T cells on the pMBMECs. Absence of endothelial PECAM-1 also did not affect the number of T cells able to cross the pMBMEC monolayer under flow, but surprisingly favored transcellular over paracellular T-cell diapedesis. Taken together, our data demonstrate that PECAM-1 is critically involved in regulating BBB permeability and although not required for T-cell diapedesis itself, its presence or absence influences the cellular route of T-cell diapedesis across the BBB. Upregulated expression of cell-bound PECAM-1 in human MS lesions may thus reflect vascular repair mechanisms aiming to restore BBB integrity and paracellular T-cell migration across the BBB as it occurs during CNS immune surveillance.

Characterization of gray-matter multiple sclerosis lesions using double inversion recovery, diffusion, contrast-enhanced, and volumetric MRI

PurposeTo investigate gray-matter (GM) lesions in relapsing-remitting multiple sclerosis (MS) using double-inversion recovery (DIR) MRI, determine GM lesions prevalence, spatial distribution and characterize their contrast-enhancement, diffusion characteristics and compare them to white-matter (WM) lesions. This is the first study, to our knowledge, to investigate GM MS lesions using double-inversion recovery MRI, to determine GM lesion prevalence and location, and characterize contrast-enhancement and diffusion characteristics, compared to WM lesion characteristics in the same patients. We also correlated GM lesion counts, volume and apparent diffusion coefficient (ADC) with total brain, WM, and GM volumes, as well as 25-foot walk test as a clinical disability. Materials and MethodsThis retrospective study included 44 relapsing-remitting MS patients (12M/32F, 41 ± 13 years) and 24 age-matched healthy controls (14M/10F, 36 ± 13 years). Lesions were segmented based on DIR and grouped into GM, subcortical WM, and periventricular WM lesions. ADC was tabulated for contrast-enhancing and non-enhancing lesions. Unpaired two sample t-tests were used for comparison between groups. Linear regression was used to evaluate the relationship between number of GM lesions, number of total lesions, total GM lesion volume, and total WM lesion volume with brain volumes and clinical data. ResultsGM MS lesions were present in the majority (86.4%, 38/44) of RRMS patients based on DIR, suggesting GM damage plays an important role in MS pathogenesis. The majority of the GM lesions were located in the frontal lobe. The percentage of lesions in GM that were contrast-enhanced was similar to those in WM, suggesting that blood-brain barrier integrity is likely affected similarly in GM and WM. Contrast-enhanced GM lesions showed higher ADC. GM lesion count and volume were correlated with global and regional brain atrophy, and with more severe disability group. ConclusionThis study characterized GM MS lesions using double-inversion recovery, contrast-enhanced and diffusion MRI. Understanding GM lesion pathophysiology using MRI in vivo, may prove useful for improving targeted therapy and monitoring disease progression.

Cuprizone-induced demyelination in the mouse hippocampus is alleviated by phytoestrogen genistein

One of the major female sex hormones, estrogen, can influence a variety of mental states. Individuals with multiple sclerosis (MS) often suffer from mental health issues, which are correlated with the pathology of gray matter. In this study, we aimed to elucidate the validity of phytoestrogen genistein (GEN) for treating the gray matter lesions in MS using the mouse model of cuprizone (CPZ)-induced demyelination. First, we confirmed that 5-week 0.2% CPZ intoxication induced demyelination in the hippocampus, and that myelination was successfully recovered by GEN. Loss of mature oligodendrocytes following CPZ intoxication was counteracted by GEN. Neither CPZ nor GEN affected the densities of oligodendrocyte precursor cells and astrocytes. CPZ-induced activation and proliferation of microglia were not inhibited by GEN. Upregulation of gene expression of the pro-inflammatory cytokine, interleukin-1β, in sorted microglia by CPZ was not inhibited by GEN either. However, the expression levels of genes related to phagocytosis, such as cluster of differentiation 68 and lysosomal-associated membrane protein 1, in sorted microglia were elevated by CPZ but lowered by GEN. Notably, physical contact of microglia with myelin was increased by CPZ but decreased by GEN. The expression levels of myelin-related genes, such as myelin basic protein and myelin oligodendrocyte glycoprotein, in the whole hippocampal tissue were decreased by CPZ but recovered by GEN. These results show that GEN may act on mature oligodendrocytes in the hippocampus by promoting their survival and myelin formation, and suggest the therapeutic potential of phytoestrogens for treating MS patients suffering from mental health issues.

Neuropsychology of Multiple Sclerosis: Looking Back and Moving Forward.

The neuropsychological aspects of multiple sclerosis (MS) have evolved over the past three decades. What was once thought to be a rare occurrence, cognitive dysfunction is now viewed as one of the most disabling symptoms of the disease, with devastating effects on patients' quality of life. This selective review will highlight major innovations and scientific discoveries in the areas of neuropathology, neuroimaging, diagnosis, and treatment that pertain to our understanding of the neuropsychological aspects of MS. Specifically, we focus on the recent discovery that MS produces pathogical lesions of gray matter (GM) that have consequences for cognitive functions. Methods for imaging these GM lesions in MS are discussed along with multimodal imaging studies that integrate structural and functional imaging methods to provide a better understanding of the relationship between cognitive test performance and functional reserve. Innovations in the screening and comprehensive assessment of cognitive disorders are presented along with recent research that examines cognitive dysfunction in pediatric MS. Results of innovative outcome studies in cognitive rehabilitation are discussed. Finally, we highlight trends for potential future innovations over the next decade. (JINS, 2017, 23, 832-842).

Pathological differences between white and grey matter multiple sclerosis lesions.

Multiple sclerosis (MS) is a debilitating disease characterized by demyelination of the central nervous system (CNS), resulting in widespread formation of white matter lesions (WMLs) and grey matter lesions (GMLs). WMLs are pathologically characterized by the presence of immune cells that infiltrate the CNS, whereas these immune cells are barely present in GMLs. This striking pathological difference between WMLs and GMLs raises questions about the underlying mechanism. It is known that infiltrating leukocytes contribute to the generation of WMLs; however, since GMLs show a paucity of infiltrating immune cells, their importance in GML formation remains to be determined. Here, we review pathological characteristics of WMLs and GMLs, and suggest some possible explanations for the observed pathological differences. In our view, cellular and molecular characteristics of WM and GM, and local differences within WMLs and GMLs (in particular, in glial cell populations and the molecules they express), determine the pathway to demyelination. Further understanding of GML pathogenesis, considered to contribute to chronic MS, may have a direct impact on the development of novel therapeutic targets to counteract this progressive neurological disorder.

Significance of gray matter brain lesions in multiple sclerosis and neuromyelitis optica.

Multiple sclerosis (MS) and neuromyelitis optica (NMO) are the two main autoimmune diseases of the CNS. In patients with NMO, the target antigen is aquaporin-4 (AQP4), the most abundant water channel protein in the CNS. AQP4 is mainly expressed on astrocytic endfoot processes at the blood-brain barrier and in subpial and subendymal regions. MS and NMO are distinct diseases, but they have some common clinical features: both have long been considered autoimmune diseases that primarily affect the white matter (WM). However, because WM demyelination by itself cannot explain the full extent of the clinical disabilities, including cognitive decline in patients with MS and NMO, renewed interest in gray matter (GM) pathology in MS and NMO is emerging. Important hallmarks of WM and GM lesions in MS and NMO may differentially influence neuronal degeneration and demyelination in the brain and spinal cord, given different detrimental effects, including cytokine diffusion, disruption of water homeostasis associated with or without AQP4 (the target antigen in NMO) dynamics, or other unidentified mechanisms. An increase in knowledge of the structure of GM and WM lesions in MS and NMO will result in more targeted therapeutic approaches to these two diseases.

Immunohistochemical detection of sphingosine‐1‐phosphate receptor 1 and 5 in human multiple sclerosis lesions

Sphingosine-1-phosphate receptor (S1PR) modulating therapies are currently in the clinic or undergoing investigation for multiple sclerosis (MS) treatment. However, the expression of S1PRs is still unclear in the central nervous system under normal conditions and during neuroinflammation. Using immunohistochemistry we examined tissues from both grey and white matter MS lesions for sphingosine-1-phosphate receptor 1 (S1P1 ) and 5 (S1P5 ) expression. Tissues from Alzheimer's disease (AD) cases were also examined. S1P1 expression was restricted to astrocytes and endothelial cells in control tissues and a decrease in endothelial cell expression was found in white matter MS lesions. In grey matter MS lesions, astrocyte expression was lost in active lesions, while in quiescent lesions it was restored to normal expression levels. CNPase colocalization studies demonstrated S1P5 expression on myelin and both were reduced in demyelinated lesions. In AD tissues we found no difference in S1P1 expression. These data demonstrate a differential modulation of S1PRs in MS lesions, which may have an impact on S1PR-directed therapies.

Gray matter lesions and cognitive impairment in multiple sclerosis

Multiple sclerosis (MS) has long been considered to be the autoimmune disease that primarily affects oligodendrocyte and myelin in the white matter (WM) of the CNS. However, renewed interest in the gray matter (GM) pathology including cortical and deep GM of MS is emerging. Radiological and pathological assessments demonstrate that substantial cortical demyelination is prominent in all stages or courses of MS, and cortical neurodegeneration is also present in even normal-appearing GM in MS. Patients with MS have cognitive impairment as represented by the latent start of impairment from the very early stage of the disease course, and not only WM lesions but also GM lesions might be good predictors for cognitive impairment in MS. Although the cause of the GM lesions in MS has not been fully determined, an increase in knowledge of the structure of GM lesions in MS brains will result in more targeted therapeutic approaches to the disease.

Autoinflammatory grey matter lesions in humans

In recent years, evidence has accumulated that grey matter abnormalities are common in many inflammatory central nervous system (CNS) disorders, such as multiple sclerosis (MS), which is by far the most frequent autoimmune-mediated CNS disease. A recent study described comprehensively the pathology of grey matter lesions in early MS. In this study, cortical demyelination together with inflammation was frequently observed in early MS cases. This study and others serve as a basis for a model of the development of cortical MS lesions in which several consecutive events may be involved. After the activation of T cells, which may open the blood-brain barrier, the humoral immune system may mediate the inflammatory process. The inflammation may become chronic through the involvement of activated glial cells and the persistence of immune cells in the meninges.Apart from MS, other grey matter CNS disorders exist in which antibodies against neuronal structures contribute to pathophysiological events such as in limbic encephalitis. Humoral and adaptive immunity mediates the pathophysiology of Rasmussen encephalitis. This review focuses on the difference between inflammatory grey matter and white matter lesions. New insights into inflammatory grey matter lesions in MS and other CNS inflammatory processes such as limbic encephalitis are discussed.

Complement and neuronal damage in deep grey matter multiple sclerosis lesions

Complement and neuronal damage in deep grey matter multiple sclerosis lesions

The histopathology of grey matter demyelination in multiple sclerosis

Multiple sclerosis (MS) is characterized by focal demyelinating lesions in white matter (WM) and grey matter (GM) of the central nervous system. Results of studies using quantitative magnetic resonance imaging techniques indicate that GM MS pathology has a significant impact on clinical symptoms and disability in MS, and may occur partly independently of WM pathology. Subpial cerebral and cerebellar cortexes are predilection sites for demyelination in MS. Significant neuronal and axonal pathology has been detected in GM MS lesions. The pathology of MS lesions is location-dependent; there is less pronounced inflammation in GM lesion areas than in WM lesions. The presence and extent of GM lesions has recently been correlated to meningeal inflammation, and cells infected with the Epstein-Barr virus have been detected in meningeal infiltrates, suggesting a role of meningeal inflammation in cortical lesion pathogenesis.

Grey matter pathology in multiple sclerosis

Although multiple sclerosis (MS) has been considered a white matter disease, MS lesions are known to occur in grey matter. Recent immunohistochemical studies have demonstrated extensive grey matter demyelination in chronic MS. The most common lesion type consists of purely cortical lesions extending inward from the surface of the brain, this lesion subgroup is grossly underestimated by standard histochemical myelin staining methods. Some MS patients have subpial demyelination in all cortical areas of the brain; this pattern has been termed ''general cortical subpial demyelination''. Extensive cortical demyelination is associated with the progressive phases of disease, as less cortical demyelination has been detected in relapsing-remitting MS. The pathology of grey matter lesions differs from that of white matter lesions; grey matter lesions are less inflammatory, with less macrophage and lymphocyte infiltration. In purely cortical lesions there is no significant increase in lymphocytes compared with non-demyelinated adjacent cortical areas in MS patients or cerebral cortex in control patients. Significant axonal transection and neuronal loss have been demonstrated in grey matter MS lesions. Current magnetic resonance imaging (MRI) methods are not sensitive for purely cortical MS lesions. The clinical significance of cortical MS lesions may not be characterised until more sensitive MRI methods are developed.