Substantial archaeocortical atrophy and neuronal loss in multiple sclerosis

Recent studies have revealed extensive neocortical pathology in multiple sclerosis (MS). The hippocampus is a unique archaeocortical structure understudied in MS. It plays a central role in episodic and anterograde memory—the most frequently impaired cognitive modalities in MS. This histopathological study aimed to investigate inflammatory demyelination and neurodegenerative changes in the MS archaeocortex. A detailed quantitative analysis was performed on hippocampal autopsy tissue from 45 progressive MS cases and seven controls. Forty-one lesions were identified in 28 of the 45 hippocampal MS-blocks examined, with percentage area of demyelination averaging 30.4%. The majority of lesions were chronic and subpially or subependymally located. Compared to controls, neuronal numbers were decreased by 27% in CA1 and 29.7% in CA3-2. Furthermore, the size of neurones was decreased by 17.4% in CA1. There was evidence of gross hippocampal atrophy with a 22.3% reduction in the average cross-sectional area, which correlated with neuronal loss. Our study provides evidence of substantial archaeocortical pathology largely resembling patterns seen in the neocortex and suggests that hippocampal involvement could contribute to memory impairments often seen in MS.     

State of the cervical section of the spinal cord in patients with remitting multiple sclerosis during immunomodulatory treatment

MRI scans were obtained of the cervical section of the spinal cords of 30 patients with remitting multiple sclerosis. During the study period, patients received immunomodulatory agents (seven received interferon β-1a, 13 received interferon β-1b, and 10 received glatiramer acetate). Total focus volume in brain matter was assessed before and after treatment, along with the linear size of the spinal cord on sagittal sections at the level of the inferior margin of the body of C2. There was a significant (p = 0.002) reduction in focus volume in the group overall, from 10993 mm³ (8098–13888 mm³, p < 0.05; Me = 9336) to 5630 mm³ (7400–3860 mm³, p < 0.05, Me = 4180). There were also significant decreases in focus volume on the background of treatment with interferon β-1b and glatiramer acetate (p = 0.026 and 0.027, respectively). Significant differences between groups were found in the magnitudes of increases in spinal cord atrophy: H (2, n = 30) = 8.06; p = 0.0178. Patients given glatiramer acetate showed a significantly smaller increase in atrophy as compared with those treated with interferon β (p < 0.02). Translated from Zhurnal Nevrologii i Psikhiatrii imeni S. S. Korsakova, Multiple Sclerosis, Supplement, No. 4, pp. 129–132, 2007.     

Axonal injury detected by in vivo diffusion tensor imaging correlates with neurological disability in a mouse model of multiple sclerosis

Recent studies have suggested that axonal damage, and not demyelination, is the primary cause of long-term neurological impairment in multiple sclerosis and its animal model, experimental autoimmune encephalomyelitis (EAE). The axial and radial diffusivities derived from diffusion tensor imaging have shown promise as non-invasive surrogate markers of axonal damage and demyelination, respectively. In this study, in vivo diffusion tensor imaging of the spinal cords from mice with chronic EAE was performed to determine if axial diffusivity correlated with neurological disability in EAE assessed by the commonly used clinical scoring system. Axial diffusivity in the ventrolateral white matter showed a significant negative correlation with EAE clinical score and was significantly lower in mice with severe EAE than in mice with moderate EAE. Furthermore, the greater decreases in axial diffusivity were associated with greater amounts of axonal damage, as confirmed by quantitative staining for non-phosphorylated neurofilaments (SMI32). Radial diffusivity and relative anisotropy could not distinguish between the groups of mice with moderate EAE and those with severe EAE. The results further the notion that axial diffusivity is a non-invasive marker of axonal damage in white matter and could provide the necessary link between pathology and neurological disability.     

The intelligent use and clinical benefits of electronic medical records in multiple sclerosis

Electronic medical records (EMRs) are being quickly adopted in clinics around the world. This advancement can greatly enhance the clinical care of patients with multiple sclerosis (MS) by providing formats that allow easier review of medical documents and more structured avenues to store relevant information. MS clinicians should be involved with implementing and updating EMRs at their institutions to ensure EMR formats that benefit MS clinics. EMRs also provide opportunities for research studies of MS to access detailed, longitudinal data of MS disease course that would otherwise be difficult to collect.     

Catalytic autoantibodies in multiple sclerosis: Pathogenetic and clinical aspects

The significance of catalytic autoantibodies abzymes in the pathogenesis of multiple sclerosis was evaluated in patients with different disease patterns and severity of disability.__________This revised version was published online in July 2005 with the addition of the issue titleTranslated from Byulleten’ Eksperimental’noi Biologii i Meditsiny, Vol. 139, No. 1, pp. 98–101, January, 2005     

Low-level laser therapy ameliorates disease progression in a mouse model of multiple sclerosis

Multiple sclerosis (MS) is an autoimmune demyelinating inflammatory disease characterized by recurrent episodes of T cell-mediated immune attack on central nervous system (CNS) myelin, leading to axon damage and progressive disability. The existing therapies for MS are only partially effective and are associated with undesirable side effects. Low-level laser therapy (LLLT) has been clinically used to treat inflammation, and to induce tissue healing and repair processes. However, there are no reports about the effects and mechanisms of LLLT in experimental autoimmune encephalomyelitis (EAE), an established model of MS. Here, we report the effects and underlying mechanisms of action of LLLT (AlGaInP, 660?nm and GaAs, 904?nm) irradiated on the spinal cord during EAE development. EAE was induced in female C57BL/6 mice by immunization with MOG_35–55 peptide emulsified in complete Freund’s adjuvant. Our results showed that LLLT consistently reduced the clinical score of EAE and delayed the disease onset, and also prevented weight loss induced by immunization. Furthermore, these beneficial effects of LLLT seem to be associated with the down-regulation of NO levels in the CNS, although the treatment with LLLT failed to inhibit lipid peroxidation and restore antioxidant defense during EAE. Finally, histological analysis showed that LLLT blocked neuroinflammation through a reduction of inflammatory cells in the CNS, especially lymphocytes, as well as preventing demyelination in the spinal cord after EAE induction. Together, our results suggest the use of LLLT as a therapeutic application during autoimmune neuroinflammatory responses, such as MS.     

Risk factors in the development of multiple sclerosis

Multiple sclerosis (MS) is a T-cell-mediated demyelinating disease of the CNS with no known cure or cause. However, it is widely believed that MS is caused by an environmental trigger(s) in genetically susceptible individuals. Several lines of evidence suggest that infection with Epstein–Barr virus and cigarette smoking increase the risk of MS, whereas vitamin D plays a protective role. This review discusses the current evidence supporting a link between these factors and MS.     

B-cell subsets: cellular interactions and relevance in multiple sclerosis

There has been longstanding interest in how B-cell responses may contribute to the pathology of neurological diseases. Traditionally, the premise has been that any such contribution relates to the potential of B cells to produce autopathogenic antibodies. Targeting autoantibodies continues to be an important therapeutic approach, particularly in disorders where the role of antibodies is relatively well established, such as in certain inflammatory disorders of peripheral nerves or the neuromuscular junction. In other conditions, such as multiple sclerosis, the role of circulating antibodies targeting the CNS has been less clear, although pathologic studies continue to implicate CNS-reactive antibodies, as well as B cells within the CNS compartment. Recently, new insights into fundamental properties of B cells have suggested that these cells may contribute in an antibody-independent fashion, both to normal immune responses, and in the context of immune mediated diseases. Here, we will consider the potential roles of antibody-dependent as well as antibody-independent B-cell involvement in multiple sclerosis. The topic is of particular interest at a time that B-cell-directed therapies are being evaluated for this and other autoimmune diseases.     

Possible mechanisms of the formation of chronic fatigue syndrome in the clinical picture of multiple sclerosis

A frequent manifestation of multiple sclerosis (MS) is chronic fatigue syndrome, which can be defined as a subjective decrease in the level of physical and/or mental energy. Chronic fatigue syndrome can be divided into asthenia (fatigue at rest), pathological fatigability (fatigue on physical loading), and fatigue on the background of deterioration of other symptoms (exacerbation of MS). There are both central and peripheral mechanisms for the formation of fatigue. The combination of fatigue and affective disturbances, especially depression and sleep disorders (insomnia, restless legs syndrome) is common in MS and may provide evidence that they share common mechanisms — decreases in the activity of the serotoninergic and noradrenergic systems. An important component in the formation of chronic fatigue syndrome consists of endocrine and autoimmune factors, the latter having a greater effect on asthenia than on pathological fatigue. Further studies of the pathogenetic mechanisms of the formation of asthenia and pathological fatigue and clarification of their differential diagnostic signs should allow not only a better understanding of the nature of this syndrome, but also better selection of individual treatment. __________ Translated from Zhurnal Nevrologii i Psikhiatrii imeni S. S. Korsakova, Multiple Sclerosis, Supplement, No. 3, pp. 87–91, 2006.     

Aberrant T cell responses to myelin antigens during clinical exacerbation in patients with multiple sclerosis

Multiple sclerosis (MS) is a demyelinating disease of presumed T cell autoimmunity against self myelin. We hypothesized that if myelin-reactive T cells are associated with the disease processes, they may undergo activation and expansion during acute exacerbation. In this study, we examined the precursor frequency, epitope recognition and cytokine profile of myelin-reactive T cells in 14 relapsing/remitting MS patients during exacerbation and remission. The study revealed that T cells recognizing the immunodominant peptides of candidate myelin antigens, including myelin basic protein (MBP), proteolipid protein and myelin oligodendrocyte glycoprotein, occurred at increased precursor frequency during acute exacerbation. The T cell responses to MBP focused on the immunodominant regions (residues 83-99 and 151-170) during exacerbation and shifted toward other epitopes of MBP at the time of remission. Furthermore, there was a marked increase in the production of T(h)1 cytokines among T cell lines obtained during exacerbation compared to those obtained during remission. The study demonstrated that myelin-reactive T cells underwent selective activation and expansion during acute MS exacerbation. In contrast, myelin-reactive T cells found during remission in the same patients generally resembled those identified in healthy controls with some discrepancies. The findings suggest potential association of aberrant myelin-reactive T cell responses with acute exacerbation in MS, which may reflect transient activation of myelin-reactive T cell populations of pathogenic potential.     

HLA-DP-associated susceptibility to the optico-spinal form of multiple sclerosis in the Japanese

Abstract: We studied polymorphism of the HLA-DP gene in 46 patients with optico-spinal form (Asian type) multiple sclerosis (MS) showing recurrent opticomyelitis and 46 patients with Western type MS with disseminated central nervous system involvement. We previously reported a significant association between an HLA-DRB1 *1501- DRB5 * 0101 haplotype and susceptibility to Western type but not Asian type MS. In the present study, we found that the frequencies of DPAl * 0202 and DPB1 * 0501 alleles were significantly increased in patients with Asian type MS, as compared with findings in 92 healthy control subjects (91.3% vs 65.2%, P ^corr<0.05 and 89.1% vs 63.0%, P ^corr < 0.05 respectively), but not in Western type MS. Our data provide further evidence that Asian and Western type MS are distinct regarding the immunogenetic background.     

Preclinical models of multiple sclerosis in nonhuman primates

Biotechnology has enabled the development of specifically acting therapies for immune-mediated inflammatory disorders (IMIDs) based on biological molecules. The high species specificity precludes safety and effectivity testing in lower species (mice and rats), thus creating a need for valid experimental models in nonhuman primates (NHPs). Here, we review the creation of relevant NHP model(s) for multiple sclerosis (MS), an IMID of the human CNS. We will also discuss how the model(s) can help in the translation of a scientific principle developed in lower species into a therapy for MS.     

多发性硬化的病毒感染及发病机制研究进展

病毒感染在多发性硬化的病因及发病机制中起主要作用。近年研究证实,EB病毒、人类疱疹病毒6型(HHV-6)是触发带有易感基因个体发生多发性硬化的主要病因。此外,麻疹、水痘等病毒也可能与多发性硬化的发病密切相关。     

Anti-MOG autoantibodies in Italian multiple sclerosis patients: specificity, sensitivity and clinical association

There is considerable evidence that multiple sclerosis (MS) is an immune-mediated disease characterized by infiltration of inflammatory cells into the CNS and demyelination. Several myelin proteins may be encephalitogenic, including myelin basic protein, proteolipid protein and myelin oligodendrocyte glycoprotein (MOG), the latter being expressed on the external layer of myelin sheaths and hence accessible to antibody attack. We investigated MOG autoreactivity in serum and cerebrospinal fluid (CSF) by ELISA, employing the recombinant extracellular domain of MOG as antigen. We tested serum samples from 262 MS patients (175 relapsing-remitting, 43 primary progressive and 44 secondary progressive), 131 patients with other neurological diseases (OND) and 307 healthy controls. No patients or controls were receiving immunomodulating treatments. We found anti-MOG antibodies in the serum of 13.7% MS patients, mainly in those with secondary progressive MS (25%), in 13.7% of OND patients and in 6.2% of controls. We found a direct correlation (R(2) = 0.6, P = 0.002) between disease severity and anti-MOG titer only in patients with primary and secondary progressive MS. Anti-MOG antibodies were present in the CSF of 11.4% MS patients and 18.9% OND patients. Intrathecal synthesis of anti-MOG antibodies was demonstrated in four (4.5%) of MS patients and no OND patients. Anti-MOG antibodies are not specific for MS; however, they may characterize a subset of MS patients and this may be revealed by serial assays in relation to changing disease phase.     

Alemtuzumab for the treatment of relapsing-remitting multiple sclerosis: a review of its clinical pharmacology,efficacy and safety

Multiple sclerosis (MS) is an inflammatory condition of the CNS presumably induced by an environmental trigger(s) in a genetically susceptible individual. Inflammation is prominent and most susceptible to intervention early in MS, so early treatment with disease-modifying therapies is recommended to reduce relapses and new MRI activity (both markers of inflammation) with the goal of delaying disability progression. Unfortunately, the response to the disease-modifying therapies is variable and often falls short of stopping observable disease activity, so the search for more effective agents continues. Alemtuzumab is a monoclonal antibody against CD52 that has exhibited significant efficacy throughout its clinical trial program in MS; uniquely, some of the studies have demonstrated a sustained reduction in disability in MS patients. Countering this impressive efficacy is an associated high risk of autoimmune events (especially thyroid) and concerns for infection or malignancy given prolonged immunosuppression after treatment with alemtuzumab.     

HLA-DRB1 associations with disease susceptibility and clinical course in Australians with multiple sclerosis

Human leucocyte antigen (HLA)-DRB1*1501 and other class II alleles influence susceptibility to multiple sclerosis (MS), but their contribution if any to the clinical course of MS remains uncertain. Here, we have investigated DRB1 alleles in a large sample of 1230 Australian MS cases, with some enrichment for subjects with primary progressive (PPMS) disease ( n  = 246) and 1210 healthy controls. Using logistic regression, we found that DRB1*1501 was strongly associated with risk ( P  = 7 × 10⁻⁴⁵), as expected, and after adjusting for DRB1*1501, a predisposing effect was also observed for DRB1*03 ( P  = 5 × 10⁻⁷). Individuals homozygous for either DRB1*15 or DRB1*03 were considerably more at risk of MS than heterozygotes and non-carriers. Both the DRB1*04 and the DRB1*01/DRB1*15 genotype combination, respectively, protected against PPMS in comparison to subjects with relapsing disease. Together, these data provide further evidence of heterogeneity at the DRB1 locus and confirm the importance of HLA variants in the phenotypic expression of MS.     

Soluble HLA class I and class II antigens in patients with multiple sclerosis

Abstract: Soluble HLA class I (sHLA-I) and soluble HLA class II (sHLA-II) antigen levels during different stages of disease were investigated in paired serum and cerebrospinal fluid (CSF) samples from 37 patients with multiple sclerosis (MS) using ELISA and Western blot analysis. Soluble HLA-II antigens in the serum of untreated patients with the relapsing-remitting type of MS (RRMS) were found to be significantly elevated in acute relapse as compared to values obtained from patients under steroid treatment, in remission or healthy controls. No significant differences in circulating sHLA-I levels could be detected. In contrast, a trend towards increased intrathecal production of sHLA-I molecules in the CSF was observed in untreated RRMS patients in acute relapse, whereas the levels of soluble HLA-II antigens in the CSF were below the detection limit of the ELISA method. Our observations underline the presence of systemic immune activation in MS patients, as reflected in elevated serum sHLA-II antigen levels, and reveal a dichotomy between sHLA class I and II antigen production in the peripheral blood versus CSF in acute MS. Serial measurements of sHLA-II antigen levels might represent a non-invasive method to assess disease activity in MS patients.     

干细胞治疗多发性硬化及视神经脊髓炎谱系疾病的有效性和临床应用限制

背景:干细胞的自我更新及分化潜能使其成为医学领域中的研究热点,其免疫调节、神经保护等作用使干细胞在多发性硬化、视神经脊髓炎谱系疾病中的应用受到临床医生的青睐.目的:总结近几年来干细胞治疗多发性硬化及视神经脊髓炎谱系疾病的研究进展.方法:通过检索PubMed、Web of science数据库中近几年发表的与干细胞治疗多...