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Activation of Bruton's tyrosine kinase (BTK) has been shown to play a crucial role in the proinflammatory response of B cells and myeloid cells upon engagement with B cell, Fc, Toll-like receptor, and distinct chemokine receptors. Previous reports suggest BTK actively contributes to the pathogenesis of multiple sclerosis (MS). The BTK inhibitor Evobrutinib has been shown to reduce the numbers of gadolinium-enhancing lesions and relapses in relapsing-remitting MS patients. In vitro, BTK inhibition resulted in reduced phagocytic activity and modulated BTK-dependent inflammatory signaling of microglia and macrophages. Here, we investigated the protein expression of BTK and CD68 as well as iron accumulation in postmortem control (n = 10) and MS (n = 23) brain tissue, focusing on microglia and macrophages. MS cases encompassed active, chronic active, and inactive lesions. BTK + and iron + cells positively correlated across all regions of interests and, along with CD68, revealed highest numbers in the center of active and at the rim of chronic active lesions. We then studied the effect of BTK inhibition in the human immortalized microglia-like HMC3 cell line in vitro. In particular, we loaded HMC3 cells with iron-dextran and subsequently administered the BTK inhibitor Evobrutinib. Iron treatment alone induced a proinflammatory phenotype and increased the expression of iron importers as well as the intracellular iron storage protein ferritin light chain (FTL). BTK inhibition of iron-laden cells dampened the expression of microglia-related inflammatory genes as well as iron-importers, whereas the iron-exporter ferroportin was upregulated. Our data suggest that BTK inhibition not only dampens the proinflammatory response but also reduces iron import and storage in activated microglia and macrophages with possible implications on microglial iron accumulation in chronic active lesions in MS., (© 2024 The Authors. Brain Pathology published by John Wiley & Sons Ltd on behalf of International Society of Neuropathology.)

Background and Purpose: Rituximab (RTX) is frequently used off-label in multiple sclerosis. However, studies on the risk-benefit profile of RTX in pediatric-onset multiple sclerosis are scarce., Methods: In this multicenter retrospective cohort study, patients with pediatric-onset multiple sclerosis from Sweden, Austria and Germany, who received RTX treatment were identified by chart review. Annualized relapse rates, Expanded Disability Status Scale scores and magnetic resonance imaging parameters (new T2 lesions and contrast-enhancing lesions) were assessed before and during RTX treatment. The proportion of patients who remained free from clinical and disease activity (NEDA-3) during RTX treatment was calculated. Side effects such as infusion-related reactions, infections and laboratory abnormalities were assessed., Results: Sixty-one patients received RTX during a median (interquartile range) follow-up period of 20.9 (35.6) months. The annualized relapse rate decreased from 0.6 (95% confidence interval [CI] 0.38-0.92) to 0.03 (95% CI 0.02-0.14). The annual rate of new T2 lesions decreased from 1.25 (95% CI 0.70-2.48) to 0.08 (95% CI 0.03-0.25) and annual rates of new contrast-enhancing lesions decreased from 0.86 (95% CI 0.30-3.96) to 0. Overall, 70% of patients displayed no evidence of disease activity (NEDA-3). Adverse events were observed in 67% of patients. Six patients discontinued treatment due to ongoing disease activity or adverse events., Conclusion: Our study provides class IV evidence that RTX reduces clinical and radiological activity in pediatric-onset multiple sclerosis., (© 2024 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Magnetic resonance imaging (MRI) of focal or diffuse myelin damage or remyelination may provide important insights into disease progression and potential treatment efficacy in multiple sclerosis (MS). We performed post-mortem MRI and histopathological myelin measurements in seven progressive MS cases to evaluate the ability of three myelin-sensitive MRI scans to distinguish different stages of MS pathology, particularly chronic demyelinated and remyelinated lesions. At 3 Tesla, we acquired two different myelin water imaging (MWI) scans and magnetisation transfer ratio (MTR) data. Histopathology included histochemical stainings for myelin phospholipids (LFB) and iron as well as immunohistochemistry for myelin proteolipid protein (PLP), CD68 (phagocytosing microglia/macrophages) and BCAS1 (remyelinating oligodendrocytes). Mixed-effects modelling determined which histopathological metric best predicted MWF and MTR in normal-appearing and diffusely abnormal white matter, active/inactive, inactive, remyelinated and ischemic lesions. Both MWI measures correlated well with each other and histology across regions, reflecting the different stages of MS pathology. MTR data showed a considerable influence of components other than myelin and a strong dependency on tissue storage duration. Both MRI and histology revealed increased myelin densities in inactive compared with active/inactive lesions. Chronic inactive lesions harboured single scattered myelin fibres indicative of low-level remyelination. Mixed-effects modelling showed that smaller differences between white matter areas were linked to PLP densities and only to a small extent confounded by iron. MWI reflects differences in myelin lipids and proteins across various levels of myelin densities encountered in MS, including low-level remyelination in chronic inactive lesions., (© 2023 The Authors. Brain Pathology published by John Wiley & Sons Ltd on behalf of International Society of Neuropathology.)

Background and Objectives: Although the diagnosis of myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) is based on serum MOG antibodies (MOG-Abs) positivity, patients with coexisting or restricted MOG-Abs in the CSF have been reported. The aim of this study is to characterize the relevance of CSF MOG-Abs positivity in clinical practice., Methods: Eleven medical centers retrospectively collected clinical and laboratory data of adult and pediatric patients with suspected inflammatory CNS disease and MOG-Abs positivity in serum and/or CSF using live cell-based assays. Comparisons were performed using parametric or nonparametric tests, as appropriate. Potential factors of unfavorable outcomes were explored by Cox proportional hazard models and logistic regression., Results: The cohort included 255 patients: 139 (55%) women and 132 (52%) children (i.e., <18-year-old). Among them, 145 patients (56.8%) had MOG-Abs in both serum and CSF (MOG-Abs seropositive and CSF positive), 79 (31%) only in serum (MOG-Abs seropositive and CSF negative), and 31 (12%) only in CSF (MOG-Abs seronegative and CSF positive). MOG-Abs seronegative and CSF positive predominated in adults (22% vs 3% of children), presented more commonly with motor (n = 14, 45%) and sensory symptoms (n = 13, 42%), and all but 4 (2 multiple sclerosis, 1 polyradiculoneuritis, and 1 Susac syndrome) had a final diagnosis compatible with MOGAD. When comparing seropositive patients according to MOG-Abs CSF status, MOG-Abs seropositive and CSF positive patients had a higher Expanded Disability Status Scale (EDSS) at nadir during the index event (median 4.5, interquartile range [IQR] 3.0-7.5 vs 3.0, IQR 2.0-6.8, p = 0.007) and presented more commonly with sensory (45.5% vs 24%, p = 0.002), motor (33.6% vs 19%, p = 0.021), and sphincter symptoms (26.9% vs 7.8%, p = 0.001) than MOG-Abs seropositive and CSF negative. At the last follow-up, MOG-Abs seropositive and CSF positive cases had more often persistent sphincter dysfunction (17.3% vs 4.3%, p = 0.008) . Compared with seropositive patients, those MOG-Abs seronegative and CSF positive had higher disability at the last follow-up ( p ≤ 0.001), and MOG-Abs seronegative and CSF positive status were independently associated with an EDSS ≥3.0., Discussion: Paired serum and CSF MOG-Abs positivity are common in MOGAD and are associated with a more severe clinical presentation. CSF-only MOG-Abs positivity can occur in patients with a phenotype suggestive of MOGAD and is associated with a worse outcome. Taken together, these data suggest a clinical interest in assessing CSF MOG-Abs in patients with a phenotype suggestive of MOGAD, regardless of the MOG-Abs serostatus., (© 2022 American Academy of Neurology.)

Autoantibody-associated demyelinating diseases of the central nervous system such as myelin oligodendrocyte glycoprotein-antibody associated disease (MOGAD) and aquaporin 4-antibody positive neuromyelitis optica spectrum disorders (AQP4+ NMOSD) are rare diseases but can cause severe disability. In both diseases, associated neuroinflammation is accompanied by blood and cerebrospinal fluid cytokine and chemokine signatures, which were shown to be distinct from those observed in patients with multiple sclerosis (MS). In this study, we aimed to confirm and extend these findings by analyzing a larger number of serum cytokines, chemokines and related molecules in patients with MOGAD or AQP4+ NMOSD in comparison to MS, to better understand the pathophysiology and to identify biomarkers potentially useful in clinical practice for diagnostic and treatment purposes. A total of 65 serum cytokines, chemokines and related molecules like growth factors and soluble receptors were measured by Procartaplex multiplex immunoassays in 40 MOGAD, 40 AQP4+ NMOSD and 54 MS patients at baseline. Furthermore, follow-up samples of 25 AQP4+ NMOSD and 40 MOGAD patients were measured after 6-12 months. Selected analytes were validated in a subgroup of samples using other bead-based assays and ELISA. At baseline, 36 analytes in MOGAD and 30 in AQP4+ NMOSD were significantly increased compared to MS. K-means cluster analysis of all significantly altered molecules revealed three distinct groups: Cluster I, including 12 MOGAD, 2 AQP4+ NMOSD and 3 MS patients, had a specific association with 11 IL-6/IL-17A associated cytokines. In this cluster, 9/17 (53%) patients were children. Cluster II with 13 MOGAD, 24 AQP4+ NMOSD and 1 MS patient was associated with 31 upregulated analytes. Cluster III contained 15 MOGAD, 14 AQP4+ NMOSD and 50 MS patients. In cluster II and III the majority were adults (82% and 92%). Most measured analytes remained stable over time. Validation of selected cytokines and chemokines using other analytical methods revealed moderate to high correlation coefficients, but absolute values differed between assays. In conclusion, these results obtained by bead-based multiplex assays highlight a significant association of biomarkers of peripheral inflammation in patients with antibody-associated demyelinating diseases in comparison with MS., Competing Interests: AB is an employee of VASCage – Research Centre on Vascular Ageing and Stroke and has participated in meetings sponsored by or received travel funding from Novartis, Sanofi Genenzyme, Merck, Almirall and Biogen. KB has participated in meetings sponsored by and received travel funding from Roche, Biogen and Teva. HH has participated in meetings sponsored by, received speaker honoraria or travel funding from Bayer, Biogen, Celgene, Merck, Novartis, Sanofi-Genzyme, Siemens and Teva, and received honoraria for consulting Biogen, Celgene, Novartis and Teva. FD has participated in meetings sponsored by or received honoraria for acting as an advisor/speaker for Alexion, Almirall, Biogen, Celgene, Janssen, Merck, Novartis, Roche and Sanofi-Genzyme. His institution received scientific grants from Biogen and Sanofi-Genzyme.TB has participated in meetings sponsored by and received honoraria lectures, advisory boards, consultations from pharmaceutical companies marketing treatments for MS: Allergan, Bayer, Biogen, Bionorica, BMS/Celgene, GSK, GW/Jazz Pharma, Horizon, Janssen-Cilag, MedDay, Merck, Novartis, Octapharma, Roche, Sandoz, Sanofi-Genzyme, Teva and UCB. His institution has received financial support in the past 12 months by unrestricted research grants Biogen, Bayer, BMS/Celgene, Merck, Novartis, Roche, Sanofi-Genzyme, Teva and for participation in clinical trials in multiple sclerosis sponsored by Alexion, Bayer, Biogen, Merck, Novartis, Octapharma, Roche, Sanofi-Genzyme, Teva. RH has received honoraria for lectures from Novartis and Biogen. KR has served as consultant for the PARADIGM Study/Novartis without payment. SM received speaker honoraria from Novartis and Biogen. MR was supported by a research support from Euroimmun and Roche. The University Hospital and Medical University of Innsbruck Austria, employer of MR receives payments for antibody assays MOG, AQP4, and other autoantibodies and for MOG and AQP4 antibody validation experiments organized by Euroimmun Lübeck, Germany. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.​ The authors declare that this study received funding from Roche Austria. The funder was involved in the study design and critical revision of the article for important intellectual content., (Copyright © 2022 Bauer, Rudzki, Berek, Dinoto, Lechner, Wendel, Hegen, Deisenhammer, Berger, Höftberger, Rostasy, Mariotto and Reindl.)

The role of autoantibodies in multiple sclerosis (MS) has been enigmatic since the first description, many decades ago, of intrathecal immunoglobulin production in people with this condition. Some studies have indicated that MS pathology is heterogeneous, with an antibody-associated subtype - characterized by B cells (in varying quantities), antibodies and complement - existing alongside other subtypes with different pathologies. However, subsequent evidence suggested that some cases originally diagnosed as MS with autoantibody-mediated demyelination were more likely to be neuromyelitis optica spectrum disorder or myelin oligodendrocyte glycoprotein antibody-associated disease. These findings raise the important question of whether an autoantibody-mediated MS subtype exists and whether pathogenic MS-associated autoantibodies remain to be identified. Potential roles of autoantibodies in MS could range from specific antibodies defining the disease to a non-disease-specific amplification of cellular immune responses and other pathophysiological processes. In this Perspective, we review studies that have attempted to identify MS-associated autoantibodies and provide our opinions on their possible roles in the pathophysiology of MS., (© 2022. Springer Nature Limited.)

Background: Third vaccination against SARS-CoV-2 is recommended for patients with multiple sclerosis (pwMS), usually six months after the last vaccination., Methods: In this prospective multicenter study on 292 pwMS and 46 healthy controls (HC), who had all received two vaccinations prior to study enrollment, SARS-CoV-2 IgG response was measured in the month before and 2-4 months after third vaccination. PwMS were categorized as follows: untreated (N-DMT, n = 32), receiving disease-modifying therapy (DMT) with expected humoral response (er-DMT: interferon-beta preparations, glatiramer acetate, dimethyl fumarate, teriflunomide, natalizumab, cladribine, alemtuzumab; n = 120) or no expected humoral response (nr-DMT: S1PMs, CD20mAb; n = 140)., Results: PwMS on nr-DMT had significantly lower median antibody levels before (12.1 U/ml [0.4-2500]) and after third vaccination (305 U/ml [0.4-2500]) in comparison to other groups (p<0.001). We did not find differences in antibody levels after homologous (n = 281; 2500 [0.4-2500]) and heterologous (n = 57; 2500 [0.4-2500]) vaccination regime regardless of the DMT group. The DMT group (β= -0.60; 95% CI -1195.73, -799.10; p<0.001) was associated with antibody levels after third vaccination, while time to revaccination (6 months [1-13]) was not. After third vaccination, seropositivity was reached in 75.8% and 82.2% of pwMS on anti-CD20 mAbs and S1PMs, respectively. Complete B-cell depletion significantly decreased the probability of seroconversion even after the third vaccination (OR 0.14; p = 0.021), whereas time interval to last DMT intake and time to revaccination did not. Twenty-two patients reported a SARS-CoV-2 infection (3 N-DMT, 9 er-DMT, 10 nr-DMT), one being asymptomatic and the rest having a mild course., Conclusion: Humoral response to SARS-CoV-2 third vaccination in pwMS is excellent. While reduced by S1PMs and CD20mAb, protective response is still expected in the majority of patients., (Copyright © 2022. Published by Elsevier B.V.)

Background and Purpose: SARS-CoV2 vaccination is recommended for patients with multiple sclerosis (pwMS), but response may be limited by disease-modifying-treatments (DMTs). The aim of this study was to compare the rates of humoral immune response and safety of SARS-CoV-2 vaccines in pwMS and healthy controls (HCs)., Methods: In this multicenter prospective study on 456 pwMS and 116 HCs, SARS-CoV-2-IgG response was measured 3 months after the first vaccine dose. The primary endpoint was defined as proportion of patients developing antibodies (seroconversion). Secondary endpoints included antibody level, safety and efficacy., Results: Compared to 97.4% in HCs, seroconversion occurred in 96.7% (88/91) untreated pwMS, 97.1% of patients (135/139) on immunomodulatory DMTs and 61.1% (138/226; p < 0.001) on immunosuppressive DMTs. Seroconversion was lowest in patients on antiCD20 monoclonal antibodies (CD20 mAbs; 52.6%) followed by sphingosine-1-phosphate-receptor-modulators (S1PMs; 63.6%). In the S1PM subgroup, seroconversion increased with lymphocyte count (odds ratio [OR] 1.31 per 0.1 G/L; p = 0.035). In pwMS on CD20 mAbs, B-cell depletion decreased seroconversion (OR 0.52; p = 0.038), whereas time since last DMT did not. Safety of SARS-CoV-2 vaccines in pwMS was excellent., Conclusions: Humoral response to SARS-CoV2 vaccines in pwMS is generally excellent. While reduced by immunosuppressive DMTs, most importantly by B-cell-depleting CD20 mAbs and S1PMs, seroconversion is still expected in the majority of patients. SARS-CoV2 vaccination should be offered to every MS patient., (© 2022 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Background: Knowledge on immunity after SARS-CoV-2 infection in patients with multiple sclerosis (pwMS) and the impact of disease-modifying treatment (DMT) is limited., Objective: To evaluate degree, duration and potential predictors of specific humoral immune response in pwMS with prior COVID-19., Methods: Anti-SARS-CoV-2 antibody testing was performed in pwMS with PCR-confirmed diagnosis of symptomatic COVID-19 from a nation-wide registry. Predictors of seropositivity were identified by multivariate regression models., Results: In 125 pwMS (mean age = 42.4 years (SD = 12.3 years), 70% female), anti-SARS-CoV-2 antibodies were detected in 76.0% after a median of 5.2 months from positive PCR. Seropositivity rate was significantly lower in patients on IS-DMT (61.4%, p  = 0.001) than without DMT or immunomodulatory DMT (80.6%; 86.0%, respectively). In multivariate analysis, IS-DMT was associated with reduced probability of seropositivity (odds ratio (OR): 0.51; 95% confidence interval (95% CI): 0.17-0.82; p  < 0.001). Predefined subgroup analyses showed marked reduction of seropositivity in pwMS on rituximab/ocrelizumab (OR 0.15; 95% CI: 0.05-0.56; p  < 0.001). Rate of seropositivity did not change significantly over 6 months., Conclusions: Humoral immunity is stable after SARS-CoV-2 infection in MS, but is reduced by immunosuppressive DMT, particularly anti-CD20 monoclonal antibodies. This provides important evidence for advising pwMS as well as for planning and prioritizing vaccination.

This review honors Kurt Jellinger on his 90th birthday as one of the most outstanding neuropathologists, who has contributed immensely to neuroscience due to his vast experience and collection of excellently documented autopsy cases. Two of his many insightful reports are highlighted here. One report focuses on the pathogenesis of inflammatory demyelinating diseases and investigates the neuropathology in autopsy tissue of a patient, who developed an MS-like disease after repeated treatment with lyophilized bovine brain cells in 1958. More than 60 years later, after reinvestigation of the historic samples in 2015 and subsequent mRNA isolation, next generation sequencing and reconstruction of the antibody, we succeeded in identifying myelin oligodendrocyte glycoprotein (MOG) as the target antigen and provided the missing element between the pathomechanisms in classic EAE animal models and transfer of this disease process into humans. A second significant example of Kurt Jellinger's contribution to neuroscience was a report on the role of MS in the development of Alzheimer's disease (AD), which found that AD pathology is present to the same extent in demyelinated and non-demyelinated cortical areas in MS and the incidence for AD pathology in elderly MS patients is comparable to the normal-aging population. This indicates that chronic inflammation in the MS cortex alone does not significantly predispose to the development of cortical AD pathology. These and other findings were only possible due to the broad collection of extremely well-defined material established by Kurt Jellinger, which ultimately continues to contribute to translational neuroscience, even decades later., (© 2021. The Author(s).)

Aim of our study was to identify the target auto-antigen in the central nervous system recognized by the immune system of a unique patient, who died more than 60 years ago from a disease with pathological changes closely resembling multiple sclerosis (MS), following a misguided immunization with lyophilized calf brain tissue. Total mRNA was isolated from formaldehyde fixed and paraffin embedded archival brain tissue containing chronic active inflammatory demyelinating lesions with inflammatory infiltrates rich in B-lymphocytes and plasma cells. Analysis of the transcriptome by next generation sequencing and reconstruction of the dominant antibody by bioinformatic tools revealed the presence of one strongly expanded B-cell clone, producing an autoantibody against a conformational epitope of myelin oligodendrocytes glycoprotein (MOG), similar to that recognized by the well characterized monoclonal anti-MOG antibody 8-18C5. The reconstructed antibody induced demyelination after systemic or intrathecal injection into animals with T-cell mediated encephalomyelitis. Our study suggests that immunization with bovine brain tissue in humans may-in a small subset of patients-induce a disease with an intermediate clinical and pathological presentation between MS and MOG-antibody associated inflammatory demyelinating disease (MOGAD).

Objective: To assess the prognostic value of MOG antibodies (abs) in the differential diagnosis of acquired demyelinating syndromes (ADS)., Methods: Clinical course, MRI, MOG-abs, AQP4-abs, and CSF cells and oligoclonal bands (OCB) in children with ADS and 24 months of follow-up were reviewed in this observational prospective multicenter hospital-based study., Results: Two hundred ten children with ADS were included and diagnosed with acute disseminated encephalomyelitis (ADEM) (n = 60), neuromyelitis optica spectrum disorder (NMOSD) (n = 12), clinically isolated syndrome (CIS) (n = 101), and multiple sclerosis (MS) (n = 37) after the first episode. MOG-abs were predominantly found in ADEM (57%) and less frequently in NMOSD (25%), CIS (25%), or MS (8%). Increased MOG-ab titers were associated with younger age ( p = 0.0001), diagnosis of ADEM ( p = 0.005), increased CSF cell counts ( p = 0.011), and negative OCB ( p = 0.012). At 24-month follow-up, 96 children had no further relapses. Thirty-five children developed recurrent non-MS episodes (63% MOG-, 17% AQP4-abs at onset). Seventy-nine children developed MS (4% MOG-abs at onset). Recurrent non-MS episodes were associated with high MOG-ab titers ( p = 0.0003) and older age at onset ( p = 0.024). MS was predicted by MS-like MRI ( p < 0.0001) and OCB ( p = 0.007). An MOG-ab cutoff titer ≥1:1,280 predicted a non-MS course with a sensitivity of 47% and a specificity of 100% and a recurrent non-MS course with a sensitivity of 46% and a specificity of 86%., Conclusions: Our results show that the presence of MOG-abs strongly depends on the age at disease onset and that high MOG-ab titers were associated with a recurrent non-MS disease course., (© 2017 American Academy of Neurology.)

Susceptibility-sensitive magnetic resonance imaging (MRI) has gained importance in multiple sclerosis (MS) research because of its versatility, high resolution and excellent sensitivity to changes in tissue structure and composition. In particular, mapping of the resonance frequency of the MR signal and quantitative susceptibility mapping (QSM) have been explored for the description of MS lesions. Many current studies utilizing these techniques attribute increases in the MR frequency or QSM to elevated tissue iron content, in addition to myelin loss. However, this common interpretation is inconsistent with recent histopathological studies. Here, we investigate the nature of MR frequency shifts related to MS lesions by comparing post-mortem MRI data with histology, and contrast them with numerical simulations of the MR signal. We demonstrate that iron accumulation is not the driving source of the MR frequency or QSM image contrast in our sample; rather, most chronic MS lesions are characterized by advanced loss of both myelin and iron. Moreover, our results suggest that the appearance of MS lesions on MR frequency maps and QSM depends on changes in the non-lesional white matter surrounding the lesions. Understanding and accounting for these changes is essential for the quantitative interpretation of MR frequency or QSM data in white matter., (Copyright © 2017 John Wiley & Sons, Ltd.)

In multiple sclerosis (MS), iron accumulates inside activated microglia/macrophages at edges of some chronic demyelinated lesions, forming rims. In susceptibility-based magnetic resonance imaging at 7 T, iron-laden microglia/macrophages induce a rim of decreased signal at lesion edges and have been associated with slowly expanding lesions. We aimed to determine (1) what lesion types and stages are associated with iron accumulation at their edges, (2) what cells at the lesion edges accumulate iron and what is their activation status, (3) how reliably can iron accumulation at the lesion edge be detected by 7 T magnetic resonance imaging (MRI), and (4) if lesions with rims enlarge over time in vivo, when compared to lesions without rims. Double-hemispheric brain sections of 28 MS cases were stained for iron, myelin, and microglia/macrophages. Prior to histology, 4 of these 28 cases were imaged at 7 T using post-mortem susceptibility-weighted imaging. In vivo, seven MS patients underwent annual neurological examinations and 7 T MRI for 3.5 years, using a fluid attenuated inversion recovery/susceptibility-weighted imaging fusion sequence. Pathologically, we found iron rims around slowly expanding and some inactive lesions but hardly around remyelinated shadow plaques. Iron in rims was mainly present in microglia/macrophages with a pro-inflammatory activation status, but only very rarely in astrocytes. Histological validation of post-mortem susceptibility-weighted imaging revealed a quantitative threshold of iron-laden microglia when a rim was visible. Slowly expanding lesions significantly exceeded this threshold, when compared with inactive lesions (p = 0.003). We show for the first time that rim lesions significantly expanded in vivo after 3.5 years, compared to lesions without rims (p = 0.003). Thus, slow expansion of MS lesions with rims, which reflects chronic lesion activity, may, in the future, become an MRI marker for disease activity in MS., Competing Interests: Compliance with ethical standards The institutional review board of the Medical University in Vienna approved the post-mortem study (EK number 535/2004). No institutional review board was necessary at Vanderbilt University for the post-mortem study. The in vivo study was conducted in Vienna upon local institutional review board approval (EK number: 154/2009). Written informed consent in accordance with the 1964 declaration of Helsinki and its later amendments was obtained from all individual participants included in the study. Conflict of interest The authors declare no conflict of interest with respect to the study and data presented in this paper. Funding This work was supported by funds of the Oesterreichische Nationalbank (Anniversary Fund, project number 16153 to GG and SH and 15680 to ST) and the Austrian Science Fund (FWF project P27744-B27).

Multiple sclerosis is a chronic inflammatory disease with primary demyelination and neurodegeneration in the central nervous system. In our study we analysed demyelination and neurodegeneration in a large series of multiple sclerosis brains and provide a map that displays the frequency of different brain areas to be affected by these processes. Demyelination in the cerebral cortex was related to inflammatory infiltrates in the meninges, which was pronounced in invaginations of the brain surface (sulci) and possibly promoted by low flow of the cerebrospinal fluid in these areas. Focal demyelinated lesions in the white matter occurred at sites with high venous density and additionally accumulated in watershed areas of low arterial blood supply. Two different patterns of neurodegeneration in the cortex were identified: oxidative injury of cortical neurons and retrograde neurodegeneration due to axonal injury in the white matter. While oxidative injury was related to the inflammatory process in the meninges and pronounced in actively demyelinating cortical lesions, retrograde degeneration was mainly related to demyelinated lesions and axonal loss in the white matter. Our data show that accumulation of lesions and neurodegeneration in the multiple sclerosis brain does not affect all brain regions equally and provides the pathological basis for the selection of brain areas for monitoring regional injury and atrophy development in future magnetic resonance imaging studies., (© The Author (2016). Published by Oxford University Press on behalf of the Guarantors of Brain.)

Introduction: Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system. Immunological studies suggest that it is a T-cell mediated autoimmune disease, although an MS-specific target antigen for autoimmunity has so far not been identified. Models of experimental autoimmune encephalomyelitis in part reproduce features of MS, but none of the models so far covers the entire spectrum of pathology and immunology. Autoimmune disease of the nervous system has occasionally been observed in humans after active sensitization with brain tissue or brain cells, giving rise to acute demyelinating polyradiculoneuritis, acute disseminated encephalomyelitis and in rare cases reflecting an inflammatory demyelinating condition similar to acute multiple sclerosis. In this study we analyzed in detail the immunopathology in archival autopsy tissue of a patient who died with an MS like disease after repeated exposure to subcutaneous injections of lyophilized brain cells., Results: The pathology of this patient fulfilled all pathological diagnostic criteria of MS. Demyelination and tissue injury was associated with antibody (IgM) deposition at active lesion sites and complement activation. Major differences to classical EAE models were seen in the composition of inflammatory infiltrates, being dominated by B-cells, infiltration of IgM positive plasma cells, profound infiltration of the tissue by CD8(+) T-lymphocytes and a nearly complete absence of CD4(+) T-cells., Conclusions: Our study shows that auto-sensitization of humans with brain tissue can induce a disease, which closely reflects the pathology of MS, but that the mechanisms leading to demyelination and tissue injury differ from those, generally implicated in the pathophysiology of MS through studies in experimental autoimmune encephalomyelitis.

Cortical lesions constitute an important part of multiple sclerosis pathology. Although inflammation appears to play a role in their formation, the mechanisms leading to demyelination and neurodegeneration are poorly understood. We aimed to identify some of these mechanisms by combining gene expression studies with neuropathological analysis. In our study, we showed that the combination of inflammation, plaque-like primary demyelination and neurodegeneration in the cortex is specific for multiple sclerosis and is not seen in other chronic inflammatory diseases mediated by CD8-positive T cells (Rasmussen's encephalitis), B cells (B cell lymphoma) or complex chronic inflammation (tuberculous meningitis, luetic meningitis or chronic purulent meningitis). In addition, we performed genome-wide microarray analysis comparing micro-dissected active cortical multiple sclerosis lesions with those of tuberculous meningitis (inflammatory control), Alzheimer's disease (neurodegenerative control) and with cortices of age-matched controls. More than 80% of the identified multiple sclerosis-specific genes were related to T cell-mediated inflammation, microglia activation, oxidative injury, DNA damage and repair, remyelination and regenerative processes. Finally, we confirmed by immunohistochemistry that oxidative damage in cortical multiple sclerosis lesions is associated with oligodendrocyte and neuronal injury, the latter also affecting axons and dendrites. Our study provides new insights into the complex mechanisms of neurodegeneration and regeneration in the cortex of patients with multiple sclerosis.

Under certain conditions or at certain stages of the disease course, multiple sclerosis (MS) and mitochondrial disorder (MID) may be differential diagnoses and thus may be confused with each other. In a 30 years old female MS was diagnosed at age 16 year upon recurrent sensory disturbances of the right lower leg, an "inflammatory" cerebrospinal fluid, and a cerebral MRI with multiple non-enhancing white matter lesions. Steroids were repeatedly given but because of rapid deterioration treatment was switched to interferon and mitoxantrone, without improvement. Fourteen years after onset the patient additionally presented with a history of rhabdomyolysis, hypothyroidism, ophthalmoparesis, anarthria, tetraspasticity, tetraparesis, and joint contractures. After MID had been diagnosed in her mother she was re-evaluated and elevated resting lactate, axonal polyneuropathy, and empty sella were additionally found. Muscle biopsy revealed myophagy, fat deposition, and type-II predominance, and biochemical investigations showed a deficiency of complex I and IV of the respiratory chain. MID was diagnosed also in the index patient. It is concluded that even if CSF investigations or imaging studies suggest MS, differentials such as MIDs need to be excluded before prescribing medication possibly toxic to a MID. An "inflammatory CSF" may also occur in MIDs.

Multiple sclerosis is a chronic inflammatory disease of the central nervous system, associated with demyelination and neurodegeneration. The mechanisms of tissue injury are currently poorly understood, but recent data suggest that mitochondrial injury may play an important role in this process. Since mitochondrial injury can be triggered by reactive oxygen and nitric oxide species, we analysed by immunocytochemistry the presence and cellular location of oxidized lipids and oxidized DNA in lesions and in normal-appearing white matter of 30 patients with multiple sclerosis and 24 control patients without neurological disease or brain lesions. As reported before in biochemical studies, oxidized lipids and DNA were highly enriched in active multiple sclerosis plaques, predominantly in areas that are defined as initial or 'prephagocytic' lesions. Oxidized DNA was mainly seen in oligodendrocyte nuclei, which in part showed signs of apoptosis. In addition, a small number of reactive astrocytes revealed nuclear expression of 8-hydroxy-d-guanosine. Similarly, lipid peroxidation-derived structures (malondialdehyde and oxidized phospholipid epitopes) were seen in the cytoplasm of oligodendrocytes and some astrocytes. In addition, oxidized phospholipids were massively accumulated in a fraction of axonal spheroids with disturbed fast axonal transport as well as in neurons within grey matter lesions. Neurons stained for oxidized phospholipids frequently revealed signs of degeneration with fragmentation of their dendritic processes. The extent of lipid and DNA oxidation correlated significantly with inflammation, determined by the number of CD3 positive T cells and human leucocyte antigen-D expressing macrophages and microglia in the lesions. Our data suggest profound oxidative injury of oligodendrocytes and neurons to be associated with active demyelination and axonal or neuronal injury in multiple sclerosis.

Multiple sclerosis (MS) is an idiopathic chronic inflammatory demyelinating disease of the central nervous system with variable extent of remyelination. Remyelination originates from oligodendrocyte (OG) precursor cells, which migrate and differentiate into mature OG. Tubulin polymerization promoting protein (TPPP/p25) is located in mature OG and aggregates in oligodendroglial cytoplasmic inclusions in multiple system atrophy. We developed a novel monoclonal anti-TPPP/p25 antibody to quantify OG in different subtypes and disease stages of MS, and possible degenerative changes in OG. We evaluated autopsy material from 25 MS cases, including acute, primary progressive, secondary progressive, relapsing remitting MS, and five controls. Demyelinated lesions revealed loss of TPPP/p25-positive OG within the plaques. In remyelination, TPPP/p25 was first expressed in OG cytoplasms and later became positive in myelin sheaths. We observed increased numbers of TPPP/p25 immunoreactive OG in the normal appearing white matter (NAWM) in MS patients. In MS cases, the cytoplasmic area of TPPP/p25 immunoreactivity in the OG was higher in the periplaque area when compared with NAWM and the plaque, and TPPP/p25 immunoreactive OG cytoplasmic area inversely correlated with the disease duration. There was a lack of phospho-TDP-43, phospho-tau, α-synuclein, and ubiquitin immunoreactivity in OG with enlarged cytoplasm. Our data suggest impaired differentiation, migration, and activation capacity of OG in later disease stages of MS. Upregulation of TPPP/p25 in the periplaque white matter OG without evidence for inclusion body formation might reflect an activation state. Distinct and increased expression of TPPP/p25 in MS renders it a potential prognostic and diagnostic marker of MS., (© 2010 Wiley-Liss, Inc.)

Background: Reduced N-acetyl-aspartate (NAA) levels in magnetic resonance spectroscopy (MRS) may visualize axonal damage even in the normal appearing white matter (NAWM). Demyelination and axonal degeneration are a hallmark in multiple sclerosis (MS)., Objective: To define the extent of axonal degeneration in the NAWM in the remote from focal lesions in patients with relapsing-remitting (RRMS) and secondary progressive MS (SPMS)., Material and Methods: 37 patients with clinical definite MS (27 with RRMS, 10 with SPMS) and 8 controls were included. We used 2D (1)H-MR-chemical shift imaging (TR = 1500ms, TE = 135ms, nominal resolution 1ccm) operating at 3Tesla to assess the metabolic pattern in the fronto-parietal NAWM. Ratios of NAA to creatine (Cr) and choline (Cho) and absolute concentrations of the metabolites in the NAWM were measured in each voxel matching exclusively white matter on the anatomical T2 weighted MR images., Results: No significant difference of absolute concentrations for NAA, Cr and Cho or metabolite ratios were found between RRMS and controls. In SPMS, the NAA/Cr ratio and absolute concentrations for NAA and Cr were significantly reduced compared to RRMS and to controls., Conclusions: In our study SPMS patients, but not RRMS patients were characterized by low NAA levels. Reduced NAA-levels in the NAWM of patients with MS is a feature of progression.

Leber's hereditary optic neuropathy (LHON) is associated with point mutations in the mitochondrial DNA (mtDNA), coding for a mitochondrial respiratory chain complex I subunit. It is characterized by bilateral, usually sequential, optic neuropathy and may co-occur with multiple sclerosis-like white matter lesions. Despite repeated clinical reports including MRI and histopathological examination of the visual system, neuropathological descriptions of LHON associated with multiple sclerosis-like syndrome are lacking. We present here the case of a female patient with a point mutation at nucleotide position T14484C, who suffered from relapsing episodes of visual loss of both eyes and consecutively developed Hashimoto thyroiditis as well as widespread demyelinating CNS lesions outside the visual system. She died of bronchopneumonia at the age of 44 years, after a disease duration of 19 years, with progressive deterioration, epileptic seizures and immobility. Immunohistochemical analysis on formalin-fixed and paraffin-embedded tissue reveals a spectrum of neuropathological changes, including actively and inactively demyelinating plaques in the white matter and optic nerve, vacuolation and cystic necrosis with CD8-positive T cells in the frontal lobe, axonal damage, and vacuolation of white matter. Tissue destruction is associated with upregulation of mitochondrial manganese superoxide dismutase within the lesions and an increase in the expression of inducible nitric oxide synthase within macrophages and microglia. This variable phenotype of extraoptic LHON disease suggests that mtDNA mutations may affect the nervous system on a common metabolic basis and occasionally may aggravate or initiate autoimmune pathology.

Background: Knowledge on immunity after SARS-CoV-2 infection in patients with multiple sclerosis (pwMS) and the impact of disease-modifying treatment (DMT) is limited. Objective: To evaluate degree, duration and potential predictors of specific humoral immune response in pwMS with prior COVID-19. Methods: Anti-SARS-CoV-2 antibody testing was performed in pwMS with PCR-confirmed diagnosis of symptomatic COVID-19 from a nation-wide registry. Predictors of seropositivity were identified by multivariate regression models. Results: In 125 pwMS (mean age = 42.4 years (SD = 12.3 years), 70% female), anti-SARS-CoV-2 antibodies were detected in 76.0% after a median of 5.2 months from positive PCR. Seropositivity rate was significantly lower in patients on IS-DMT (61.4%, p = 0.001) than without DMT or immunomodulatory DMT (80.6%; 86.0%, respectively). In multivariate analysis, IS-DMT was associated with reduced probability of seropositivity (odds ratio (OR): 0.51; 95% confidence interval (95% CI): 0.17–0.82; p < 0.001). Predefined subgroup analyses showed marked reduction of seropositivity in pwMS on rituximab/ocrelizumab (OR 0.15; 95% CI: 0.05–0.56; p < 0.001). Rate of seropositivity did not change significantly over 6 months. Conclusions: Humoral immunity is stable after SARS-CoV-2 infection in MS, but is reduced by immunosuppressive DMT, particularly anti-CD20 monoclonal antibodies. This provides important evidence for advising pwMS as well as for planning and prioritizing vaccination. [ABSTRACT FROM AUTHOR]

Background: Demyelinating diseases of the central nervous system associated with autoantibodies against aquaporin-4 and myelin-oligodendrocyte-glycoprotein are mediated by different immunopathological mechanisms compared to multiple sclerosis. Objective: The purpose of this study was to evaluate serum and cerebrospinal fluid cytokine/chemokine profiles in patients with autoantibodies against aquaporin-4 or autoantibodies against myelinoligodendrocyte-glycoprotein-associated demyelination compared to multiple sclerosis and autoimmune encephalitis. Methods: Serum and cerebrospinal fluid cytokine/chemokine levels were analysed using Procartaplex Multiplex Immunoassays. First, we analysed a panel of 32 cytokines/chemokines in a discovery group (nine aquaporin-4-antibody seropositive, nine myelin oligodendrocyte glycoprotein-antibody seropositive, eight encephalitis, 10 multiple sclerosis). Significantly dysregulated cytokines/chemokines were validated in a second cohort (11 aquaporin-4-antibody seropositive, 18 myelin oligodendrocyte glycoprotein-antibody seropositive, 18 encephalitis, 33 multiple sclerosis). Results: We found 11 significantly altered cytokines/chemokines in cerebrospinal fluid and serum samples in the discovery group (a proliferation-inducing ligand, fractalkine=CX3CL1, growthregulated oncogene-α, interleukin-1 receptor antagonist, interleukin-6, interleukin-8=CXCL8, interleukin-10, interleukin-21, interferon-Ç-induced protein-10=CXCL10, monokine induced by interferon-Ç=CXCL9, macrophage inflammatory protein-1ß=CCL4). Most of these cytokines/chemokines were up-regulated in autoantibodies against aquaporin-4 or autoantibodies against myelinoligodendrocyte-glycoprotein positive patients compared to multiple sclerosis. We confirmed these results for cerebrospinal fluid interleukin-6 and serum interleukin-8, growth-regulated oncogene-α, a proliferation-inducing ligand and macrophage inflammatory protein-1b in the validation set. Receiveroperating characteristic analysis revealed increased levels of cerebrospinal fluid interleukin-6, serum interleukin-8 and growth-regulated oncogene-α in most patients with autoantibody-associated neurological diseases. Conclusion: This study suggests that distinctive cerebrospinal fluid and serum cytokine/chemokine profiles are associated with autoantibody-mediated demyelination, but not with multiple sclerosis. [ABSTRACT FROM AUTHOR]

X-linked adrenoleukodystrophy is caused by ATP-binding cassette transporter D1 (ABCD1) mutations and manifests by default as slowly progressive spinal cord axonopathy with associated demyelination (adrenomyloneuropathy). In 60% of male cases, however, X-linked adrenoleukodystrophy converts to devastating cerebral inflammation and demyelination (cerebral adrenoleukodystrophy) with infiltrating blood-derived monocytes and macrophages and cytotoxic T cells that can only be stopped by allogeneic haematopoietic stem cell transplantation or gene therapy at an early stage of the disease. Recently, we identified monocytes/macrophages but not T cells to be severely affected metabolically by ABCD1 deficiency. Here we found by whole transcriptome analysis that, although monocytes of patients with X-linked adrenoleukodystrophy have normal capacity for macrophage differentiation and phagocytosis, they are pro-inflammatory skewed also in patients with adrenomyloneuropathy in the absence of cerebral inflammation. Following lipopolysaccharide activation, the ingestion of myelin debris, normally triggering anti-inflammatory polarization, did not fully reverse the pro-inflammatory status of X-linked adrenoleukodystrophy macrophages. Immunohistochemistry on post-mortem cerebral adrenoleukodystrophy lesions reflected the activation pattern by prominent presence of enlarged lipid-laden macrophages strongly positive for the pro-inflammatory marker co-stimulatory molecule CD86. Comparative analyses of lesions with matching macrophage density in cases of cerebral adrenoleukodystrophy and acute multiple sclerosis showed a similar extent of pro-inflammatory activation but a striking reduction of anti-inflammatory mannose receptor (CD206) and haemoglobin-haptoglobin receptor (CD163) expression on cerebral adrenoleukodystrophy macrophages. Accordingly, ABCD1-deficiency leads to an impaired plasticity of macrophages that is reflected in incomplete establishment of anti-inflammatory responses, thus possibly contributing to the devastating rapidly progressive demyelination in cerebral adrenoleukodystrophy that only in rare cases arrests spontaneously. These findings emphasize monocytes/macrophages as crucial therapeutic targets for preventing or stopping myelin destruction in patients with X-linked adrenoleukodystrophy. [ABSTRACT FROM AUTHOR]

Objective: Chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS) is a rare syndrome with relapsing brainstem/cerebellar symptoms. To examine the pathogenic processes and investigate potential biomarkers, we analyzed combined materials of brain and cerebrospinal fluid (CSF) by comprehensive methodologies. Materials and methods: To identify major pathways of perivascular inflammation in CLIPPERS, we first compared the CSF proteome (n = 5) to a neurodegenerative condition, Alzheimer's disease (AD, n = 5). Activation of complement was confirmed by immunohistochemistry (IHC) on CLIPPERS brain samples (n = 3) and by ELISA in the CSF. For potential biomarkers, we used biomarker arrays, and compared inflammatory and vessel-associated proteins in the CSF of CLIPPERS (n = 5) with another inflammatory relapsing CNS disease, multiple sclerosis (RMS, n = 9) and healthy subjects (HS, n = 7). Results: Two hundred and seven proteins in the CSF discriminated CLIPPERS from AD. The complement cascade, immunoglobulins, and matrix proteins were among the most frequently represented pathways. Pathway analysis of upstream regulators suggested the importance of vascular cell adhesion protein 1 (VCAM1), IFN-γ, interleukin (IL)-1, and IL-10. Differential regulation of more than 10 complement proteins of the 3 complement pathways in the CSF pointed to the role of complement activation. IHC on brain samples confirmed the perivascular complement activation, i.e., deposition of C3bc, C3d, and the terminal C5b-9 complement complex that partially overlapped with accumulation of IgG in the vessel wall. Besides endothelial cell damage, reactivity to smooth muscle actin was lost in the walls of inflamed vessels, but the glia limitans was preserved. The semi-quantitative array indicated that increased level of IL-8/CXCL8 (p < 0.05), eotaxin/CCL11 (p < 0.01), and granulocyte colony-stimulating factor (p < 0.05) in CSF could distinguish CLIPPERS from HS. The quantitative array confirmed elevated concentration of IL-8/CXCL8 and eotaxin/CCL11 compared to HS (p < 0.05, respectively) besides increased levels of ICAM-1 (p < 0.05) and VCAM-1 (p < 0.001). The increased concentration of VCAM-1 were able to differentiate CLIPPERS from RMS (p < 0.01), and a trend of elevated levels of ICAM-1 and IL-8/CXCL8 compared to RMS was also observed (p = 0.06, respectively). Conclusion: Complement activation, IgG deposition, and alterations of the extracellular matrix may contribute to inflammation in CLIPPERS. VCAM1, ICAM1, and IL-8 in the CSF may differentiate CLIPPERS from RMS. [ABSTRACT FROM AUTHOR]

Multiple sclerosis is a chronic inflammatory disease with primary demyelination and neurodegeneration in the central nervous system. In our study we analysed demyelination and neurodegeneration in a large series of multiple sclerosis brains and provide a map that displays the frequency of different brain areas to be affected by these processes. Demyelination in the cerebral cortex was related to inflammatory infiltrates in the meninges, which was pronounced in invaginations of the brain surface (sulci) and possibly promoted by low flow of the cerebrospinal fluid in these areas. Focal demyelinated lesions in the white matter occurred at sites with high venous density and additionally accumulated in watershed areas of low arterial blood supply. Two different patterns of neurodegeneration in the cortex were identified: oxidative injury of cortical neurons and retrograde neurodegeneration due to axonal injury in the white matter. While oxidative injury was related to the inflammatory process in the meninges and pronounced in actively demyelinating cortical lesions, retrograde degeneration was mainly related to demyelinated lesions and axonal loss in the white matter. Our data show that accumulation of lesions and neurodegeneration in the multiple sclerosis brain does not affect all brain regions equally and provides the pathological basis for the selection of brain areas for monitoring regional injury and atrophy development in future magnetic resonance imaging studies. [ABSTRACT FROM AUTHOR]

Neurodegenerative diseases are characterised by neuronal loss and cerebral deposition of proteins with altered physicochemical properties. The major proteins are amyloid-β (Aβ), tau, α-synuclein, and TDP-43. Although neuropathological studies on elderly individuals have emphasised the importance of mixed pathologies, there have been few observations on the full spectrum of proteinopathies in the ageing brain. During a community-based study we performed comprehensive mapping of neurodegeneration-related proteins and vascular pathology in the brains of 233 individuals (age at death 77-87; 73 examined clinically in detail). While all brains (from individuals with and without dementia) showed some degree of neurofibrillary degeneration, Aβ deposits were observed only in 160 (68.7 %). Further pathologies included α-synucleinopathies (24.9 %), non-Alzheimer tauopathies (23.2 %; including novel forms), TDP-43 proteinopathy (13.3 %), vascular lesions (48.9 %), and others (15.1 %; inflammation, metabolic encephalopathy, and tumours). TDP-43 proteinopathy correlated with hippocampal sclerosis ( p < 0.001) and Alzheimer-related pathology (CERAD score and Braak and Braak stages, p = 0.001). The presence of one specific variable (cerebral amyloid angiopathy, Aβ parenchymal deposits, TDP-43 proteinopathy, α-synucleinopathy, vascular lesions, non-Alzheimer type tauopathy) did not increase the probability of the co-occurrence of others ( p = 0.24). The number of observed pathologies correlated with AD-neuropathologic change ( p < 0.0001). In addition to AD-neuropathologic change, tauopathies associated well with dementia, while TDP-43 pathology and α-synucleinopathy showed strong effects but lost significance when evaluated together with AD-neuropathologic change. Non-AD neurodegenerative pathologies and their combinations have been underestimated, but are frequent in reality as demonstrated here. This should be considered in diagnostic evaluation of biomarkers, and for better clinical stratification of patients. [ABSTRACT FROM AUTHOR]

Neuromyelitis optica (NMO) is an autoimmune disease targeting aquaporin 4 (AQP4), localized mainly at the astrocytic foot processes. Loss of AQP4 and glial fibrillary acidic protein (GFAP) was reported, but the pathological significance of astrocytopathy is still controversial. Here we show that active lesions in NMO display a wide spectrum of pathology even within a single tissue block of an individual patient. We have distinguished six different lesion types. The first reflects complement deposition at the surface of astrocytes, associated with granulocyte infiltration and astrocyte necrosis and followed by demyelination, global tissue destruction and the formation of cystic, necrotic lesions (lesion type 2). Such destructive lesions lead to Wallerian degeneration in lesion-related tracts (lesion type 3). Around active NMO lesions AQP4 may selectively be lost in the absence of aquaporin 1 (AQP1) loss or other structural damage (lesion type 4). Another pattern is characterized by clasmatodendrosis of astrocytes, defined by cytoplasmic swelling and vacuolation, beading and dissolution of their processes and nuclear alterations resembling apoptosis, which was associated with internalization of AQP4 and AQP1 and astrocyte apoptosis in the absence of complement activation. Such lesions give rise to extensive astrocyte loss, which may occur in part in the absence of any other tissue injury, such as demyelination or axonal degeneration (lesion type 5). Finally, lesions with a variable degree of astrocyte clasmatodendrosis are found, which show plaque-like primary demyelination that is associated with oligodendrocyte apoptosis, but with preservation of axons (lesion type 6). In active multiple sclerosis (MS) lesions astrocytes reveal changes of reactive protoplasmatic or fibrillary gliosis. Only in a subset of lesions, in patients with aggressive disease, loss of AQP4 is observed in the initial stage of their formation, which is associated with retraction of astrocyte processes in the absence of complement deposition, granulocyte infiltration or loss of AQP1 or astrocytes. Our data underline the primary assault of astrocytes in NMO lesions, but also indicate that different mechanisms of tissue injury operate in parallel in the same patient and even within the same lesion. [ABSTRACT FROM AUTHOR]

Cortical lesions constitute an important part of multiple sclerosis pathology. Although inflammation appears to play a role in their formation, the mechanisms leading to demyelination and neurodegeneration are poorly understood. We aimed to identify some of these mechanisms by combining gene expression studies with neuropathological analysis. In our study, we showed that the combination of inflammation, plaque-like primary demyelination and neurodegeneration in the cortex is specific for multiple sclerosis and is not seen in other chronic inflammatory diseases mediated by CD8-positive T cells (Rasmussen’s encephalitis), B cells (B cell lymphoma) or complex chronic inflammation (tuberculous meningitis, luetic meningitis or chronic purulent meningitis). In addition, we performed genome-wide microarray analysis comparing micro-dissected active cortical multiple sclerosis lesions with those of tuberculous meningitis (inflammatory control), Alzheimer’s disease (neurodegenerative control) and with cortices of age-matched controls. More than 80% of the identified multiple sclerosis-specific genes were related to T cell-mediated inflammation, microglia activation, oxidative injury, DNA damage and repair, remyelination and regenerative processes. Finally, we confirmed by immunohistochemistry that oxidative damage in cortical multiple sclerosis lesions is associated with oligodendrocyte and neuronal injury, the latter also affecting axons and dendrites. Our study provides new insights into the complex mechanisms of neurodegeneration and regeneration in the cortex of patients with multiple sclerosis. [ABSTRACT FROM AUTHOR]

Multiple sclerosis is a chronic inflammatory disease of the central nervous system, associated with demyelination and neurodegeneration. The mechanisms of tissue injury are currently poorly understood, but recent data suggest that mitochondrial injury may play an important role in this process. Since mitochondrial injury can be triggered by reactive oxygen and nitric oxide species, we analysed by immunocytochemistry the presence and cellular location of oxidized lipids and oxidized DNA in lesions and in normal-appearing white matter of 30 patients with multiple sclerosis and 24 control patients without neurological disease or brain lesions. As reported before in biochemical studies, oxidized lipids and DNA were highly enriched in active multiple sclerosis plaques, predominantly in areas that are defined as initial or ‘prephagocytic’ lesions. Oxidized DNA was mainly seen in oligodendrocyte nuclei, which in part showed signs of apoptosis. In addition, a small number of reactive astrocytes revealed nuclear expression of 8-hydroxy-d-guanosine. Similarly, lipid peroxidation-derived structures (malondialdehyde and oxidized phospholipid epitopes) were seen in the cytoplasm of oligodendrocytes and some astrocytes. In addition, oxidized phospholipids were massively accumulated in a fraction of axonal spheroids with disturbed fast axonal transport as well as in neurons within grey matter lesions. Neurons stained for oxidized phospholipids frequently revealed signs of degeneration with fragmentation of their dendritic processes. The extent of lipid and DNA oxidation correlated significantly with inflammation, determined by the number of CD3 positive T cells and human leucocyte antigen-D expressing macrophages and microglia in the lesions. Our data suggest profound oxidative injury of oligodendrocytes and neurons to be associated with active demyelination and axonal or neuronal injury in multiple sclerosis. [ABSTRACT FROM AUTHOR]

Due to an error in the final editing of our manuscript the injection volume of intrathecal antibody application (page 72) was stated as 100ml instead of 100microliter. [ABSTRACT FROM AUTHOR]