Tissue Damage In Multiple Sclerosis Research Articles

Methylprednisolone Modulates the Tfr/Tfh ratio in EAE-Induced Neuroinflammation through the PI3K/AKT/FoxO1 and PI3K/AKT/mTOR Signalling Pathways.

Methylprednisolone (MP) is a potent glucocorticoid that can effectively inhibit immune system inflammation and brain tissue damage in Multiple sclerosis (MS) patients. T follicular helper (Tfh) cells are a subpopulation of activated CD4 + T cells, while T follicular regulatory (Tfr) cells, a novel subset of Treg cells, possess specialized abilities to suppress the Tfh-GC response and inhibit antibody production. Dysregulation of either Tfh or Tfr cells has been implicated in the pathogenesis of MS. However, the molecular mechanism underlying the anti-inflammatory effects of MP therapy on experimental autoimmune encephalomyelitis (EAE), a representative model for MS, remains unclear. This study aimed to investigate the effects of MP treatment on EAE and elucidate the possible underlying molecular mechanisms involed. We evaluated the effects of MP on disease progression, CNS inflammatory cell infiltration and myelination, microglia and astrocyte activation, as well as Tfr/Tfh ratio and related molecules/inflammatory factors in EAE mice. Additionally, Western blotting was used to assess the expression of proteins associated with the PI3K/AKT pathway. Our findings demonstrated that MP treatment ameliorated clinical symptoms, inflammatory cell infiltration, and myelination. Furthermore, it reduced microglial and astrocytic activation. MP may increase the number of Tfr cells and the levels of cytokine TGF-β1, while reducing the number of Tfh cells and the levels of cytokine IL-21, as well as regulate the imbalanced Tfr/Tfh ratio in EAE mice. The PI3K/AKT/FoxO1 and PI3K/AKT/mTOR pathways were found to be involved in EAE development. However, MP treatment inhibited their activation. MP reduced neuroinflammation in EAE by regulating the balance between Tfr/Tfh cells via inhibition of the PI3K/AKT/FoxO1 and PI3K/AKT/mTOR signalling pathways.

Complement Activation Is Associated With Disease Severity in Multiple Sclerosis.

Histopathologic studies have identified immunoglobulin (Ig) deposition and complement activation as contributors of CNS tissue damage in multiple sclerosis (MS). Intrathecal IgM synthesis is associated with higher MS disease activity and severity, and IgM is the strongest complement-activating immunoglobulin. In this study, we investigated whether complement components (CCs) and complement activation products (CAPs) are increased in persons with MS, especially in those with an intrathecal IgM synthesis, and whether they are associated with disease severity and progression. CC and CAP levels were quantified in plasma and CSF of 112 patients with clinically isolated syndrome (CIS), 127 patients with MS (90 relapsing-remitting, 14 primary progressive, and 23 secondary progressive), 31 inflammatory neurologic disease, and 44 symptomatic controls from the Basel CSF databank study. Patients with CIS/MS were followed in the Swiss MS cohort study (median 6.3 years). Levels of CC/CAP between diagnosis groups were compared; in CIS/MS, associations of CC/CAP levels with intrathecal Ig synthesis, baseline Expanded Disability Status Scale (EDSS) scores, MS Severity Score (MSSS), and neurofilament light chain (NfL) levels were investigated by linear regression, adjusted for age, sex, and albumin quotient. CSF (but not plasma) levels of C3a, C4a, Ba, and Bb were increased in patients with CIS/MS, being most pronounced in those with an additional intrathecal IgM production. In CIS, doubling of C3a and C4a in CSF was associated with 0.31 (CI 0.06-0.56; p = 0.016) and 0.32 (0.02-0.62; p = 0.041) increased EDSS scores at lumbar puncture. Similarly, doubling of C3a and Ba in CIS/MS was associated with 0.61 (0.19-1.03; p < 0.01) and 0.74 (0.18-1.31; p = 0.016) increased future MSSS. In CIS/MS, CSF levels of C3a, C4a, Ba, and Bb were associated with increased CSF NfL levels, e.g., doubling of C3a was associated with an increase of 58% (Est. 1.58; CI 1.37-1.81; p < 0.0001). CNS-compartmentalized activation of the classical and alternative pathways of complement is increased in CIS/MS and associated with the presence of an intrathecal IgM production. Increased complement activation within the CSF correlates with EDSS, future MSSS, and NfL levels, supporting the concept that complement activation contributes to MS pathology and disease progression. Complement inhibition should be explored as therapeutic target to attenuate disease severity and progression in MS.

Diffusion basis spectrum imaging and diffusion tensor imaging predict persistent black hole formation in multiple sclerosis

Background and objectivesDiffusion basis spectrum imaging (DBSI) extracts multiple anisotropic and isotropic diffusion tensors, providing greater histopathologic specificity than diffusion tensor imaging (DTI). Persistent black holes (PBH) represent areas of severe tissue damage in multiple sclerosis (MS), and a high PBH burden is associated with worse MS disability. This study evaluated the ability of DBSI and DTI to predict which acute contrast-enhancing lesions (CELs) would persist as T1 hypointensities (i.e. PBHs) 12 months later. We expected that a higher radial diffusivity (RD), representing demyelination, and higher DBSI-derived isotropic non-restricted fraction, representing edema and increased extracellular space, of the acute CEL would increase the likelihood of future PBH development. MethodsIn this prospective cohort study, relapsing MS patients with ≥1 CEL(s) underwent monthly MRI scans for 4 to 6 months until gadolinium resolution. DBSI and DTI metrics were quantified when the CEL was most conspicuous during the monthly scans. To determine whether the CEL became a PBH, a follow-up MRI was performed at least 12 months after the final monthly scan. ResultsThe cohort included 20 MS participants (median age 33 years; 13 women) with 164 CELs. Of these, 59 (36 %) CELs evolved into PBHs. At Gd-max, DTI RD and AD of all CELs increased, and both metrics were significantly elevated for CELs which became PBHs, as compared to non-black holes (NBHs). DTI RD above 0.74 conferred an odds ratio (OR) of 7.76 (CI 3.77–15.98) for a CEL becoming a PBH (AUC 0.80, CI 0.73–0.87); DTI axial diffusivity (AD) above 1.22 conferred an OR of 7.32 (CI 3.38–15.86) for becoming a PBH (AUC 0.75, CI 0.66–0.83). DBSI RD and AD did not predict PBH development in a multivariable model. At Gd-max, DBSI restricted fraction decreased and DBSI non-restricted fraction increased in all CELs, and both metrics were significantly different for CELs which became PBHs, as compared to NBHs. A CEL with a DBSI non-restricted fraction above 0.45 had an OR of 4.77 (CI 2.35–9.66) for becoming a PBH (AUC 0.74, CI 0.66–0.81); a CEL with a DBSI restricted fraction below 0.07 had an OR of 9.58 (CI 4.59–20.02) for becoming a PBH (AUC 0.80, 0.72–0.87). ConclusionOur findings suggest that greater degree of edema/extracellular space in a CEL is a predictor of tissue destruction, as evidenced by PBH evolution.

Quantitative magnetic resonance imaging biomarkers for cortical pathology in multiple sclerosis at 7 T.

Substantial cortical gray matter tissue damage, which correlates with clinical disease severity, has been revealed in multiple sclerosis (MS) using advanced magnetic resonance imaging (MRI) methods at 3T and the use of ultra-high field, as well as in histopathology studies. While clinical assessment mainly focuses on lesions using - and -weighted MRI, quantitative MRI (qMRI) methods are capable of uncovering subtle microstructural changes. The aim of this ultra-high field study is to extract possible future MR biomarkers for the quantitative evaluation of regional cortical pathology. Because of their sensitivity to iron, myelin, and in part specifically to cortical demyelination, , , , and susceptibility mapping were performed including two novel susceptibility markers; in addition, cortical thickness as well as the volumes of 34 cortical regions were computed. Data were acquired in 20 patients and 16 age- and sex-matched healthy controls. In 18 cortical regions, large to very large effect sizes (Cohen's d ≥1) and statistically significant differences in qMRI values between patients and controls were revealed compared with only four regions when using more standard MR measures, namely, volume and cortical thickness. Moreover, a decrease in all susceptibility contrasts ( , , and values indicates that the role of cortical demyelination might outweigh inflammatory processes in the form of iron accumulation in cortical MS pathology, and might also indicate iron loss. A significant association between susceptibility contrasts as well as of the caudal middle frontal gyrus and disease duration was found (adjusted R2 : 0.602, p= 0.0011). Quantitative MRI parameters might be more sensitive towards regional cortical pathology compared with the use of conventional markers only and therefore may play a role in early detection of tissue damage in MS in the future.

Assessing the differential sensitivities of wave-CAIPI ViSTa myelin water fraction and magnetization transfer saturation for efficiently quantifying tissue damage in MS

BackgroundWave-CAIPI Visualization of Short Transverse relaxation time component (ViSTa) is a recently developed, short-T1-sensitized MRI method for fast quantification of myelin water fraction (MWF) in the human brain. It represents a promising technique for the evaluation of subtle, early signals of demyelination in the cerebral white matter of multiple sclerosis (MS) patients. Currently however, few studies exist that robustly assess the utility of ViSTa MWF measures of myelin compared to more conventional MRI measures of myelin in the brain of MS patients. Moreover, there are no previous studies evaluating the sensitivity of ViSTa MWF for the non-invasive detection of subtle tissue damage in both normal-appearing white matter (NAWM) and white matter lesions of MS patients. As a result, a central purpose of this study was to systematically evaluate the relationship between myelin sensitivity of T1-based ViSTa MWF mapping and a more generally recognized metric, Magnetization Transfer Saturation (MTsat), in healthy control and MS brain white matter. MethodsViSTa MWF and MTsat values were evaluated in automatically-classified normal appearing white matter (NAWM), white matter (WM) lesion tissue, cortical gray matter, and deep gray matter of 29 MS patients and 10 healthy controls using 3T MRI. MWF and MT sat were also assessed in a tract-specific manner using the Johns Hopkins University WM atlas. MRI-derived measures of cerebral myelin content were uniquely compared by employing non-normal distribution-specific measures of median, interquartile range and skewness. Separate analyses of variance were applied to test tissue-specific differences in MTsat and ViSTa MWF distribution metrics. Non-parametric tests were utilized when appropriate. All tests were corrected for multiple comparisons using the False Discovery Rate method at the level, α=0.05. ResultsDifferences in whole NAWM MS tissue damage were detected with a higher effect size when using ViSTa MWF (q = 0.0008; ƞ2 = 0.34) compared to MTsat (q = 0.02; ƞ2= 0.24). We also observed that, as a possible measure of WM pathology, ViSTa-derived NAWM MWF voxel distributions of MS subjects were consistently skewed towards lower MWF values, while MTsat voxel distributions showed reduced skewness values. We further identified tract-specific reductions in mean ViSTa MWF of MS patients compared to controls that were not observed with MTsat. However, MTsat (q = 1.4 × 10−21; ƞ2 = 0.88) displayed higher effect sizes when differentiating NAWM and MS lesion tissue. Using regression analysis at the group level, we identified a linear relationship between MTsat and ViSTa MWF in NAWM (R2 = 0.46; p = 7.8 × 10−4) lesions (R2 = 0.30; p = 0.004), and with all tissue types combined (R2 = 0.71; p = 8.4 × 10−45). The linear relationship was also observed in most of the WM tracts we investigated. ViSTa MWF in NAWM of MS patients correlated with both disease duration (p = 0.02; R2 = 0.27) and WM lesion volume (p = 0.002; R2 = 0.34). ConclusionBecause ViSTa MWF and MTsat metrics exhibit differential sensitivities to tissue damage in MS white matter, they can be collected in combination to provide an efficient, comprehensive measure of myelin water and macromolecular pool proton signals. These complementary measures may offer a more sensitive, non-invasive biopsy of early precursor signals in NAWM that occur prior to lesion formation. They may also aid in monitoring the efficacy of remyelination therapies.

Multi-layer analysis of quantitative 7 T magnetic resonance imaging in the cortex of multiple sclerosis patients reveals pathology associated with disability

Background: Cortical demyelination is a relevant aspect of tissue damage in multiple sclerosis (MS). Microstructural changes may affect each layer in the cortex differently. Objectives: To evaluate the sensitivity of quantitative magnetic resonance imaging (qMRI) measurements on cortical layers as clinically accessible biomarkers of grey matter (GM) pathology. Methods: Forty-five participants with MS underwent 7 T magnetic resonance imaging (MRI) of the brain. Magnetization prepared two rapid acquisition gradient echoes (MP2RAGE) was processed for T1-weighted images and a T1 map. Multi-echo gradient echo images were processed for quantitative susceptibility and R2* maps. Cortical GM volumes were segmented into four cortical layers, and relaxometry metrics were calculated within and between these layers. Results: Significant correlations were found for disability scales and multi-layer metrics, for example, Expanded Disability Status Scale (EDSS) and peak height (PH) in the subpial (T1: ρ = −0.372, p < 0.050) and inner (R2*: ρ = −0.359, p < 0.050) cortical layers. Multivariate regression showed interdependency between atrophy and cortical metrics in some instances, but an independent relationship between cortical metrics and disability in others. Conclusion: Cortical layer 7 T qMRI analyses reveal layer-specific relationships with disability in MS and allow emergence of clinically relevant associations that are hidden when analysing the full cortex.

Extracellular Vesicles as Pro- and Anti-inflammatory Mediators, Biomarkers and Potential Therapeutic Agents in Multiple Sclerosis.

Multiple sclerosis (MS) is an autoimmune neurodegenerative disease of the central nervous system (CNS) characterized by multiple demyelinating lesions in the spinal cord and brain. Neuronal disruption caused by myelin loss or demyelination, which may accompany axonal changes, leads to multiple neurological symptoms. They may transiently appear for weeks during periods of disease worsening (relapse) in relapsing-remitting form of MS (RRMS). Although a number of genetic, metabolic and environmental factors influencing the development of MS have been identified, the precise mechanisms involved in the CNS tissue damage in MS are still poorly understood. Recent studies have revealed a significant role of circulating extracellular vesicles (EVs) in many diseases. EVs are known to serve as a cellular communication tool between two cell types either in close proximity or in different parts of the body. During the recent development in understanding of the pathogenesis of MS, studies have revealed the possible role of EVs in MS. Furthermore, circulating EVs can be used as a biomarker for monitoring disease progression and activity of MS, and they can also be therapeutic reagents or targets of therapy. In this review we overview and discuss in detail about generation of EVs and their diversified roles in MS.

Connecting Immune Cell Infiltration to the Multitasking Microglia Response and TNF Receptor 2 Induction in the Multiple Sclerosis Brain.

Signaling from central nervous system (CNS)-infiltrating lymphocytes and macrophages is critical to activate microglia and cause tissue damage in multiple sclerosis (MS). We combined laser microdissection with high-throughput real time RT-PCR to investigate separately the CNS exogenous and endogenous inflammatory components in postmortem brain tissue of progressive MS cases. A previous analysis of immune infiltrates isolated from the white matter (WM) and the meninges revealed predominant expression of genes involved in antiviral and cytotoxic immunity, including IFNγ and TNF. Here, we assessed the expression of 71 genes linked to IFN and TNF signaling and microglia/macrophage activation in the parenchyma surrounding perivascular cuffs at different stages of WM lesion evolution and in gray matter (GM) lesions underlying meningeal infiltrates. WM and GM from non-neurological subjects were used as controls. Transcriptional changes in the WM indicate activation of a classical IFNγ-induced macrophage defense response already in the normal-appearing WM, amplification of detrimental (proinflammatory/pro-oxidant) and protective (anti-inflammatory/anti-oxidant) responses in actively demyelinating WM lesions and persistence of these dual features at the border of chronic active WM lesions. Transcriptional changes in chronic subpial GM lesions indicate skewing toward a proinflammatory microglia phenotype. TNF receptor 2 (TNFR2) mediating TNF neuroprotective functions was one of the genes upregulated in the MS WM. Using immunohistochemistry we show that TNFR2 is highly expressed in activated microglia in the normal-appearing WM, at the border of chronic active WM lesions, and in foamy macrophages in actively demyelinating WM and GM lesions. In lysolecithin-treated mouse cerebellar slices, a model of demyelination and remyelination, TNFR2 RNA and soluble protein increased immediately after toxin-induced demyelination along with transcripts for microglia/macrophage-derived pro- and anti-inflammatory cytokines. TNFR2 and IL10 RNA and soluble TNFR2 protein remained elevated during remyelination. Furthermore, myelin basic protein expression was increased after selective activation of TNFR2 with an agonistic antibody. This study highlights the key role of cytotoxic adaptive immunity in driving detrimental microglia activation and the concomitant healing response. It also shows that TNFR2 is an early marker of microglia activation and promotes myelin synthesis, suggesting that microglial TNFR2 activation can be exploited therapeutically to stimulate CNS repair.

Mechanism of demyelination and remyelination in multiple sclerosis

AbstractRecent insights into its molecular neuropathology and immunology have provided a comprehensive overview of the pathology of multiple sclerosis (MS), including demyelination and axonal loss. To date, neuropathology in MS as the human autoimmune disease is considered to be mainly mediated by autoreactive leukocytes. By contrast, accumulating evidence has also suggested that the inflammation and tissue damage in MS and its animal model, experimental autoimmune encephalomyelitis, (EAE) is also critically regulated by glial cells in the central nervous system. However, the molecular mechanism of the glial cells‐mediated pathology of MS/EAE has not been fully understood. We examined the oligodendrocyte‐mediated demyelination and axonal injury. To address this issue, we established a new scanning electron microscopy analysis to observe ultrastructural myelin morphology. In addition, we focused on kallikrein 6, a serine protease, secreted by oligodendrocytes in the central nervous system and proposed a new molecular mechanism of kallikrein 6‐mediated demyelination. In this article, we discuss the pathological roles of oligodendrocytes in mouse models of EAE. We also highlight recent findings of abnormal myelin formation and axonal injury in EAE.

Standardization of T1w/T2w Ratio Improves Detection of Tissue Damage in Multiple Sclerosis.

Normal appearing white matter (NAWM) damage develops early in multiple sclerosis (MS) and continues in the absence of new lesions. The ratio of T1w and T2w (T1w/T2w ratio), a measure of white matter integrity, has previously shown reduced intensity values in MS NAWM. We evaluate the validity of a standardized T1w/T2w ratio (sT1w/T2w ratio) in MS and whether this method is sensitive in detecting MS-related differences in NAWM. T1w and T2w scans were acquired at 3 Tesla in 47 patients with relapsing-remitting MS and 47 matched controls (HC). T1w/T2w and sT1w/T2w ratios were then calculated. We compared between-group variability between T1w/T2w and sT1w/T2w ratio in HC and MS and assessed for group differences. We also evaluated the relationship between the T1w/T2w and sT1w/T2w ratios and clinically relevant variables. Compared to the classic T1w/T2w ratio, the between-subject variability in sT1w/T2w ratio showed a significant reduction in MS patients (p < 0.001) and HC (p < 0.001). However, only sT1w/T2w ratio values were reduced in patients compared to HC (p < 0.001). The sT1w/T2w ratio intensity values were significantly influenced by age, T2 lesion volume and group status (MS vs. HC) (adjusted R2 = 0.30, p < 0.001). We demonstrate the validity of the sT1w/T2w ratio in MS and that it is more sensitive to MS-related differences in NAWM compared to T1w/T2w ratio. The sT1w/T2w ratio shows promise as an easily-implemented measure of NAWM in MS using readily available scans and simple post-processing methods.

Peak width of skeletonized mean diffusivity (PSMD) as marker of widespread white matter tissue damage in multiple sclerosis

BackgroundPeak width of skeletonized mean diffusivity (PSMD) is a novel and fully automated, MRI biomarker, which has shown clinical relevance in cerebral small vessel diseases (SVD). We aimed here to assess PSMD levels across the brain of patients with multiple sclerosis (MS), in comparison to normal controls (NC) and patients with CADASIL, a genetically defined form of severe SVD. MethodsWe assessed PSMD in relapsing-remitting (RR) MS patients (n = 47) in comparison to age-matched CADASIL patients (n = 25) and NC (n = 28). Diffusion Tensor Imaging data were acquired on 1.5T MR clinical scanner to automatically compute PSMD through “skeletonization” of WM tracts and diffusion histograms. ResultsRRMS had lower WM lesion volume (LV) than CADASIL (8.6 ± 8.2 vs 24.4 ± 17.4 cm3, p < 0.001). After correction for LV, PSMD values in MS were higher than in CADASIL patients (adjusted mean values: 4.5 vs 3.9 × 10−4 mm2/s, p = 0.03) and in both patient groups were higher than in NC (2.8 ± 0.3 × 10−4 mm2/s, p < 0.001). PSMD values correlated with LV in both patient groups (r = 0.8, p < 0.001 in MS; r = 0.6, p = 0.002 in CADASIL). ConclusionsIn both patient groups, PSMD was higher than in NC and closely correlated with LV, suggesting sensitivity in assessing brain tissue damage in these disorders. In MS patients, PSMD levels were higher than in CADASIL patients, despite the lower LV. This might be related to more severe normal-appearing WM abnormalities occurring in the MS brains. This novel, fully automated, MRI metric may represent a useful marker for a robust quantification of the diffuse WM tissue damage in MS.

Inhibition of Casein Kinase 2 Protects Oligodendrocytes From Excitotoxicity by Attenuating JNK/p53 Signaling Cascade.

Oligodendrocytes are highly vulnerable to glutamate excitotoxicity, a central mechanism involved in tissue damage in Multiple Sclerosis (MS). Sustained activation of AMPA receptors in rat oligodendrocytes induces cytosolic calcium overload, mitochondrial depolarization, increase of reactive oxygen species, and activation of intracelular pathways resulting in apoptotic cell death. Although many signals driven by excitotoxicity have been identified, some of the key players are still under investigation. Casein kinase 2 (CK2) is a serine/threonine kinase, constitutively expressed in all eukaryotic tissues, involved in cell proliferation, malignant transformation and apoptosis. In this study, we identify CK2 as a critical regulator of oligodendrocytic death pathways and elucidate its role as a signal inductor following excitotoxic insults. We provide evidence that CK2 activity is up-regulated in AMPA-treated oligodendrocytes and CK2 inhibition significantly diminished AMPA receptor-induced oligodendroglial death. In addition, we analyzed mitogen-activated protein kinase (MAPK) signaling after excitotoxic insult. We observed that AMPA receptor activation induced a rapid increase in c-Jun N-terminal kinase (JNK) and p38 phosphorylation that was reduced after CK2 inhibition. Moreover, blocking their phosphorylation, we enhanced oligodendrocyte survival after excitotoxic insult. Finally, we observed that the tumor suppressor p53 is activated during AMPA receptor-induced cell death and, interestingly, down-regulated by JNK or CK2 inhibition. Together, these data indicate that the increase in CK2 activity induced by excitotoxic insults regulates MAPKs, triggers p53 activation and mediates subsequent oligodendroglial loss. Therefore, targeting CK2 may be a useful strategy to prevent oligodendrocyte death in MS and other diseases involving central nervous system (CNS) white matter.

The Interleukin (IL)-23/T helper (Th)17 Axis in Experimental Autoimmune Encephalomyelitis and Multiple Sclerosis.

T helper (Th)17 cells are responsible for host defense against fungi and certain extracellular bacteria but have also been reported to play a role in a variety of autoimmune diseases. Th17 cells respond to environmental cues, are very plastic, and might also be involved in tissue homeostasis and regeneration. The imprinting of pathogenic properties in Th17 cells in autoimmunity seems highly dependent on interleukin (IL)-23. Since Th17 cells were first described in experimental autoimmune encephalomyelitis, they have been suggested to also promote tissue damage in multiple sclerosis (MS). Indeed, some studies linked Th17 cells to disease severity in MS, and the efficacy of anti-IL-17A therapy in MS supported this idea. In this review, we will summarize molecular features of Th17 cells and discuss the evidence for their function in experimental models of autoimmune diseases and MS.

Cerebrospinal fluid neurofilament light levels mark grey matter volume in clinically isolated syndrome suggestive of multiple sclerosis

Background: Brain atrophy is a known marker of irreversible tissue damage in multiple sclerosis (MS). Cerebrospinal fluid (CSF) osteopontin (OPN) and neurofilament light chain (NF-L) have been proposed as candidate surrogate markers of inflammatory and neurodegenerative processes in MS. Objective: To evaluate the relationship between CSF NF-L and OPN levels and brain grey and white matter volumes in patients with clinically isolated syndrome (CIS) suggestive of MS. Methods: A total of 41 CIS patients and 30 neurological controls (NCs) were included. CSF NF-L and OPN were measured by commercial ELISA. Measures of brain volume (normalized brain volume (NBV), normalized grey matter volume (NGV), peripheral grey matter volume (PGV), normalized white matter volume (WMV), and ventricular volume) were obtained by SIENAX. Corpus callosum index (CCI) was calculated. Brain volumes were categorized into ‘high’ and ‘low’ according to the median value. Results: CSF NF-L and OPN levels were higher in CIS patients in comparison with NCs. CIS patients with ‘low’ TGV, PGV, and TBV showed higher CSF NF-L levels than CIS patients with ‘high’ brain volumes. TGV and PGV correlated inversely with NF-L levels, whereas CCI was inversely related to OPN levels. CSF NF-L was the only independent predictor of TGV and PGV. Conclusion: CSF NF-L tracks mainly grey matter damage in patients with CIS suggestive of MS.

Role of dimethyl fumarate in oxidative stress of multiple sclerosis: A review.

Multiple sclerosis (MS) is a chronic inflammatory disease of the CNS affecting both white and grey matter. Inflammation and oxidative stress are also thought to promote tissue damage in multiple sclerosis. Recent data point at an important role of anti-oxidative pathways for tissue protection in chronic MS, particularly involving the transcription factor nuclear factor (erythroid-derived 2)-related factor 2 (Nrf2). Thus, novel therapeutics enhancing cellular resistance to free radicals could prove useful for MS treatment. Oxidative stress and anti-oxidative pathways are important players in MS pathophysiology and constitute a promising target for future MS therapy with dimethyl fumarate. The clinical utility of DMF in multiple sclerosis is being explored through phase III trials with BG-12, which is an oral therapeutic agent. Currently a wide research is going on to find out the exact mechanism of DMF, till date it is not clear. Based on strong signals of nephrotoxicity in non-humans and the theoretical risk of renal cell cancer from intracellular accumulation of fumarate, post-marketing study of a large population of patients will be necessary to fully assess the long-term safety of dimethyl fumarate. The current treatment goals are to shorten the duration and severity of relapses, prolong the time between relapses, and delay progression of disability. In this regard, dimethyl fumarate offers a promising alternative to orally administered fingolimod (GILENYA) or teriflunomide (AUBAGIO), which are currently marketed in the United States under FDA-mandated Risk Evaluation and Mitigation Strategy (REMS) programs because of serious safety concerns. More clinical experience with all three agents will be necessary to differentiate the tolerability of long-term therapy for patients diagnosed with multiple sclerosis. This write-up provides the detailed information of dimethyl fumarate in treating the neuro disease, multiple sclerosis and its mechanism involved via oxidative stress pathway. The rapid screening methods are also need to be developed to estimate DMF in biological samples to perform and proceed for further investigations.

Assessment of cortical damage in early multiple sclerosis with quantitative T2 relaxometry.

T2 relaxation time is a quantitative MRI in vivo surrogate of cerebral tissue damage in multiple sclerosis (MS) patients. Cortical T2 prolongation is a known feature in later disease stages, but has not been demonstrated in the cortical normal appearing gray matter (NAGM) in early MS. This study centers on the quantitative evaluation of the tissue parameter T2 in cortical NAGM in a collective of early MS and clinically isolated syndrome (CIS) patients, hypothesizing that T2 prolongation is already present at early disease stages and variable over space, in line with global and focal inflammatory processes in MS. Additionally, magnetization transfer ratio (MTR) mapping was performed for further characterization of the expected cortical T2 alteration. Quantitative T2 and MTR maps were acquired from 12 patients with CIS and early MS, and 12 matched healthy controls. The lesion-free part of the cortical volume was identified, and the mean T2 and MTR values and their standard deviations within the cortical volume were determined. For evaluation of spatial specificity, cortical lobar subregions were tested separately for differences of mean T2 and T2 standard deviation. We detected significantly prolonged T2 in cortical NAGM in patients. T2 prolongation was found across the whole cerebral cortex and in all individual lobar subregions. Significantly higher standard deviations across the respective region of interest were found for the whole cerebral cortex and all subregions, suggesting the occurrence of spatially inhomogeneous cortical damage in all regions studied. A trend was observed for MTR reduction and increased MTR variability across the whole cortex in the MS group, suggesting demyelination. In conclusion, our results suggest that cortical damage in early MS is evidenced by spatially inhomogeneous T2 prolongation which goes beyond demyelination. Iron deposition, which is known to decrease T2, seems less prominent.

Serum lipid antibodies are associated with cerebral tissue damage in multiple sclerosis

Objective:To determine whether peripheral immune responses as measured by serum antigen arrays are linked to cerebral MRI measures of disease severity in multiple sclerosis (MS).Methods:In this cross-sectional study, serum samples were obtained from patients with relapsing-remitting MS (n = 21) and assayed using antigen arrays that contained 420 antigens including CNS-related autoantigens, lipids, and heat shock proteins. Normalized compartment-specific global brain volumes were obtained from 3-tesla MRI as surrogates of atrophy, including gray matter fraction (GMF), white matter fraction (WMF), and total brain parenchymal fraction (BPF). Total brain T2 hyperintense lesion volume (T2LV) was quantified from fluid-attenuated inversion recovery images.Results:We found serum antibody patterns uniquely correlated with BPF, GMF, WMF, and T2LV. Furthermore, we identified immune signatures linked to MRI markers of neurodegeneration (BPF, GMF, WMF) that differentiated those linked to T2LV. Each MRI measure was correlated with a specific set of antibodies. Strikingly, immunoglobulin G (IgG) antibodies to lipids were linked to brain MRI measures. Based on the association between IgG antibody reactivity and each unique MRI measure, we developed a lipid index. This comprised the reactivity directed against all of the lipids associated with each specific MRI measure. We validated these findings in an additional independent set of patients with MS (n = 14) and detected a similar trend for the correlations between BPF, GMF, and T2LV vs their respective lipid indexes.Conclusions:We propose serum antibody repertoires that are associated with MRI measures of cerebral MS involvement. Such antibodies may serve as biomarkers for monitoring disease pathology and progression.

Relating multi-sequence longitudinal intensity profiles and clinical covariates in incident multiple sclerosis lesions.

The formation of multiple sclerosis (MS) lesions is a complex process involving inflammation, tissue damage, and tissue repair — all of which are visible on structural magnetic resonance imaging (MRI) and potentially modifiable by pharmacological therapy. In this paper, we introduce two statistical models for relating voxel-level, longitudinal, multi-sequence structural MRI intensities within MS lesions to clinical information and therapeutic interventions: (1) a principal component analysis (PCA) and regression model and (2) function-on-scalar regression models. To do so, we first characterize the post-lesion incidence repair process on longitudinal, multi-sequence structural MRI from 34 MS patients as voxel-level intensity profiles. For the PCA regression model, we perform PCA on the intensity profiles to develop a voxel-level biomarker for identifying slow and persistent, long-term intensity changes within lesion tissue voxels. The proposed biomarker's ability to identify such effects is validated by two experienced clinicians (a neuroradiologist and a neurologist). On a scale of 1 to 4, with 4 being the highest quality, the neuroradiologist gave the score on the first PC a median quality rating of 4 (95% CI: [4,4]), and the neurologist gave the score a median rating of 3 (95% CI: [3,3]). We then relate the biomarker to the clinical information in a mixed model framework. Treatment with disease-modifying therapies (p < 0.01), steroids (p < 0.01), and being closer to the boundary of abnormal signal intensity (p < 0.01) are all associated with return of a voxel to an intensity value closer to that of normal-appearing tissue. The function-on-scalar regression model allows for assessment of the post-incidence time points at which the covariates are associated with the profiles. In the function-on-scalar regression, both age and distance to the boundary were found to have a statistically significant association with the lesion intensities at some time point. The two models presented in this article show promise for understanding the mechanisms of tissue damage in MS and for evaluating the impact of treatments for the disease in clinical trials.

Success and failure in translation of findings from experimental autoimmune encephalomyelitis to multiple sclerosis

Despite the differences between multiple sclerosis (MS) and its animal model experimental autoimmune encephalomyelitis (EAE), most of the knowledge on immune-mediated tissue damage in MS is based on data from EAE. Immune response– modifying therapies such as TNFα inhibitors, glatiramer acetate (GA) or natalizumab have been studied in rodents and have been translated into treatment for patients with varying success. In humans treatment with an anti TNF monoclonal antibody or a recombinant TNF receptor Ig fusion protein resulted in enhanced inflammation. In contrast, findings from GA or natalizumab have been successful in human translation. Findings of EAE studies should be interpreted carefully and should be confirmed using substances (proof of principle). Only if successful, these substances should be studied in humans.

Advanced imaging tools to investigate multiple sclerosis pathology

Conventional MR imaging techniques still lack specificity for the underlying central nervous system tissue damage in multiple sclerosis (MS), impeding a comprehensive investigation of the key mechanisms responsible for neurological disability such as myelin damage and repair, neurodegeneration and neuroinflammation. A range of novel and advanced imaging tools, using quantitative magnetic resonance (MR) or positron emission tomography (PET) technologies are now emerging and open the perspective to obtain unique insights into the disease mechanisms. Both can be employed either in experimental models or in patients with MS, and they have already allowed to obtain imaging metrics that significantly correlate with clinical scores. In this review, we summarize the main evidence supporting the use of quantitative MR and PET as essential investigation tools to explore myelin changes, neuronal damage and compartmentalized inflammation in MS. The clinical translation of these imaging techniques has the potential to improve the design of future clinical trials and to allow the measurement of the effects of new drugs aimed at enhancing myelin repair and reducing neurodegeneration and neuroinflammation.