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Experimental studies identified a role of neuroinflammation in the pathogenesis of neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). However, the role of inflammatory molecules as diagnostic and prognostic biomarkers in patients with ALS is unclear. In this cross-sectional study, the cerebrospinal fluid (CSF) levels of a set of inflammatory cytokines and chemokines were analyzed in 56 newly diagnosed ALS patients and in 47 age- and sex-matched control patients without inflammatory or degenerative neurological disorders. The molecules analyzed included: interleukin (IL)-1β, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-12, IL-13, IL-17, granulocyte colony stimulating factor (GCSF), macrophage inflammatory protein (MIP)-1a, MIP-1b, tumor necrosis factors (TNF), eotaxin. Principal component analysis (PCA) was used to explore possible associations between CSF molecules and ALS diagnosis. In addition, we analyzed the association between CSF cytokine profiles and clinical characteristics, including the disease progression rate score, and peripheral inflammation assessed using the Neutrophil-to-lymphocyte ratio (NLR). PCA identified six principal components (PCs) explaining 70.67% of the total variance in the CSF cytokine set. The principal component (PC1) explained 26.8% of variance and showed a positive load with CSF levels of IL-9, IL-4, GCSF, IL-7, IL-17, IL-13, IL-6, IL-1β, TNF, and IL-2. Logistic regression showed a significant association between PC1 and ALS diagnosis. In addition, in ALS patients, the same component was significantly associated with higher disease progression rate score and positively correlated with NLR. CSF inflammatory activation in present in ALS at the time of diagnosis and may characterize patients at higher risk for disease progression., (© 2024. The Author(s).)

(1) Multiple sclerosis (MS) is identified by a complex interaction between central inflammation and neurodegeneration. Genetic individual variability could play a significative role in clinical presentation. The interleukin-5 (IL-5) rs2069812 single-nucleotide polymorphism (SNP) seems to define the clinical course of Th2 autoimmune diseases, while its role in MS has never been investigated. (2) In a group of 230 patients diagnosed with relapsing-remitting MS (RR-MS) or progressive MS (P-MS) and controls (IC), rs2069812 polymorphism, cerebrospinal fluid (CSF) levels of inflammatory mediators, and clinical and demographic characteristics were determined. In RR-MS patients, No Evidence of Disease Activity (NEDA-3) at three years of follow-up was detected. (3) We identified higher levels of proinflammatory cytokines, particularly IL-2 (median [IQR], RR-MS = 0.2 [0-0.7]; P-MS = 0.1 [0-1.6]; IC = 0.1 [0.0-0.1]; p < 0.005), IL-6 (RR-MS = 0.9 [0.3-2.3]; P-MS = 0.8 [0.1-2.7]; IC = 0.1 [0.0-0.5]; p < 0.005), IL-12 (RR-MS = 0.5 [0-1.1]; P-MS = 0.5 [0-1.1]; IC = 0.0 [0.0-0.3]; p < 0.005), and GM-CSF (RR-MS = 15.6 [4.8-26.4]; P-MS = 14 [3.3-29.7]; IC = 8.9 [4.7-11.7]; p < 0.005) in MS patients compared with IC. Conversely, anti-inflammatory cytokines, specifically IL-5 (RR-MS = 0.65 [0-2.4]; P-MS = 0.1 [0-0.8]; IC = 1.7 [0.6-2.8]; p < 0.005) and IL-1ra (RR-MS = 14.7 [4.9-26.4]; P-MS = 13.1 [4.7-22.2]; IC = 27.8 [17.7-37.6]; p < 0.005) were higher in controls. According to rs2069812, in MS patients, the T-allele was associated with higher concentrations of proinflammatory mediators (IL-2, CT/TT = 0.2 [0.0-2.0]; CC = 0.1 [0.0-0.4], p = 0.015; IL-6, CT/TT = 1.2 [0.4-3.2] vs. CC = 0.7 [0.1-1.7], p = 0.007; IL-15, CT/TT = 0.1 [0.0-9.5] vs. CC = 0.0 [0.0-0.1], p = 0.019; and GM-CSF, CT/TT = 0.1 [0.0-0.6] vs. CC = 0.05 [0.0-0.1], p < 0.001), and CC was associated with anti-inflammatory mediators (IL-5, CT/TT = 0.03 [0.0-1.9] vs. CC = 1.28 [0.0-2.7], p = 0.001; IL-1ra, CT/TT = 12.1 [4.1-25.9] vs. CC = 18.1 [12.1-26.9], p = 0.006). We found the same differences in RR-MS patients (IL-2, T-allele median [IQR] = 0.3 [0.0-2.0] vs. C-allele, median [IQR] = 0.04 [0.0-0.3]; p = 0.005; IL-6, T-allele, median [IQR] = 1.3 [0.4-3.3] vs. C-allele, median [IQR] = 0.6 [0.03-1.5]; p = 0.001; IL-15, T-allele, median [IQR] = 0.1 [0.0-9.5] vs. C-allele, median [IQR] = 0.0 [0.0-0.1]; p = 0.008; GM-CSF, T-allele, median [IQR] = 0.1 [0.0-97.9] vs. C-allele, median [IQR] = 0.0 [0.0-0.001]; p < 0.001; IL-5, T-allele, median [IQR] = 0.02 [0.0-2.2] vs. C-allele, median [IQR] = 1.5 [0.0-2.9]; p = 0.016; and IL-1ra, T-allele, median [IQR] = 12.1 [4.3-26.4] vs. C-allele, median [IQR] = 18.5 [12.7-28.3]; p = 0.006) but not in P-MS, except for IL-5 (T-allele, median [IQR] = 0.1 [0-0.23] vs. C-allele, median [IQR] = 0.6 [0.0-2.5]; p = 0.022). Finally, we identified an association between CC in RR-MS patients and NEDA-3 after three years of follow-up ( p = 0.007). (4) We describe, for the first time, the role of an SNP of the IL-5 gene in regulating central neuroinflammation and influencing clinical course in MS patients.

Proinflammatory cytokines are implicated in promoting neurodegeneration in multiple sclerosis (MS) by affecting excitatory and inhibitory transmission at central synapses. Conversely, the synaptic effects of anti-inflammatory molecules remain underexplored, despite their potential neuroprotective properties and their presence in the cerebrospinal fluid (CSF) of patients. In a study involving 184 newly diagnosed relapsing-remitting (RR)-MS patients, we investigated whether CSF levels of the anti-inflammatory interleukin (IL)-10 were linked to disease severity and neurodegeneration measures. Additionally, we examined IL-10 impact on synaptic transmission in striatal medium spiny neurons and its role in counteracting inflammatory synaptopathy induced by IL-1β in female C57BL/6 mice with experimental autoimmune encephalomyelitis (EAE). Our findings revealed a significant positive correlation between IL-10 CSF levels and changes in EDSS (Expanded Disability Status Scale) scores one year after MS diagnosis. Moreover, IL-10 levels in the CSF were positively correlated with volumes of specific subcortical brain structures, such as the nucleus caudate. In both MS patients' CSF and EAE mice striatum, IL-10 and IL-1β expressions were upregulated, suggesting possible antagonistic effects of these cytokines. Notably, IL-10 exhibited the ability to decrease glutamate transmission, increase GABA transmission in the striatum, and reverse IL-1β-induced abnormal synaptic transmission in EAE. In conclusion, our data suggest that IL-10 exerts direct neuroprotective effects in MS patients by modulating both excitatory and inhibitory transmission and attenuating IL-1β-induced inflammatory synaptopathy. These findings underscore the potential therapeutic significance of IL-10 in mitigating neurodegeneration in MS., Competing Interests: DC is an Advisory Board member of Almirall, Bayer Schering, Biogen, GW Pharmaceuticals, Merck Serono, Novartis, Roche, Sanofi-Genzyme, and Teva and received honoraria for speaking or consultation fees from Almirall, Bayer Schering, Biogen, GW Pharmaceuticals, Merck Serono, Novartis, Roche, Sanofi-Genzyme, and Teva. He is also the principal investigator in clinical trials for Bayer Schering, Biogen, Merck Serono, Mitsubishi, Novartis, Roche, Sanofi-Genzyme, and Teva. His preclinical and clinical research was supported by grants from Bayer Schering, Biogen Idec, Celgene, Merck Serono, Novartis, Roche, Sanofi-Genzyme and Teva. FB acted as Advisory Board members of Teva and Roche and received honoraria for speaking or consultation fees from Merck Serono, Teva, Biogen Idec, Sanofi, and Novartis and non-financial support from Merck Serono, Teva, Biogen Idec, and Sanofi. RFu received honoraria for serving on scientific advisory boards or as a speaker from Biogen, Novartis, Roche, and Merck and funding for research from Merck. 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 author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Gilio, Fresegna, Stampanoni Bassi, Musella, De Vito, Balletta, Sanna, Caioli, Pavone, Galifi, Simonelli, Guadalupi, Vanni, Buttari, Dolcetti, Bruno, Azzolini, Borrelli, Fantozzi, Finardi, Furlan, Centonze and Mandolesi.)

In Parkinson's disease (PD), neuroinflammation may be involved in the pathogenesis of mood disorders, contributing to the clinical heterogeneity of the disease. The cerebrospinal fluid (CSF) levels of interleukin (IL)-1β, IL-2, IL-6, IL-7, IL-8, IL-9, IL-12, IL-17, interferon (IFN)γ, macrophage inflammatory protein 1-alpha (MIP-1a), MIP-1b, granulocyte colony stimulating factor (GCSF), eotaxin, tumor necrosis factor (TNF), and monocyte chemoattractant protein 1 (MCP-1), were assessed in 45 newly diagnosed and untreated PD patients and in 44 control patients. Spearman's correlations were used to explore possible associations between CSF cytokines and clinical variables including mood. Benjamini-Hochberg (B-H) correction for multiple comparisons was applied. Linear regression was used to test significant associations correcting for other clinical variables. In PD patients, higher CSF concentrations of the inflammatory molecules IL-6, IL-9, IFNγ, and GCSF were found (all B-H corrected p < 0.02). Significant associations were found between BDI-II and the levels of IL-6 (Beta = 0.438; 95%CI 1.313-5.889; p = 0.003) and IL-8 (Beta = 0.471; 95%CI 0.185-0.743; p = 0.002). Positive associations were also observed between STAI-Y state and both IL-6 (Beta = 0.452; 95%CI 1.649-7.366; p = 0.003), and IL-12 (Beta = 0.417; 95%CI 2.238-13.379; p = 0.007), and between STAI-Y trait and IL-2 (Beta = 0.354; 95%CI 1.923-14.796; p = 0.012), IL-6 (Beta = 0.362; 95%CI 0.990-6.734; p = 0.01), IL-8 (Beta = 0.341; 95%CI 0.076-0.796; p = 0.019), IL-12 (Beta = 0.328; 95%CI 0.975-12.135; p = 0.023), and IL-17 (Beta = 0.334; 95CI 0.315-4.455; p = 0.025). An inflammatory CSF milieu may be associated with depression and anxiety in the early phases of PD, supporting a role of neuroinflammation in the pathogenesis of mood disturbances., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Diego Centonze is an Advisory Board member of Almirall, Bayer Schering, Biogen, GW Pharmaceuticals, Merck Serono, Novartis, Roche, Sanofi-Genzyme, and Teva and received honoraria for speaking or consultation fees from Almirall, Bayer Schering, Biogen, GW Pharmaceuticals, Merck Serono, Novartis, Roche, Sanofi-Genzyme, and Teva. He is also the principal investigator in clinical trials for Bayer Schering, Biogen, Merck Serono, Mitsubishi, Novartis, Roche, Sanofi-Genzyme, and Teva. His preclinical and clinical research was supported by grants from Bayer Schering, Biogen Idec, Celgene, Merck Serono, Novartis, Roche, Sanofi- Genzyme and Teva. The other 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., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background and Purpose: Loss of long-term potentiation (LTP) expression has been associated with a worse disease course in relapsing-remitting multiple sclerosis (RR-MS) and represents a pathophysiological hallmark of progressive multiple sclerosis (PMS). Exercise and physical rehabilitation are the most prominent therapeutic approaches to promote synaptic plasticity. We aimed to explore whether physical exercise is able to improve the expression of LTP-like plasticity in patients with multiple sclerosis (MS)., Methods: In 46 newly diagnosed RR-MS patients, we explored the impact of preventive exercise on LTP-like plasticity as assessed by intermittent theta-burst stimulation. Patients were divided into sedentary or active, based on physical activity performed during the 6 months prior to diagnosis. Furthermore, in 18 patients with PMS, we evaluated the impact of an 8-week inpatient neurorehabilitation program on clinical scores and LTP-like plasticity explored using paired associative stimulation (PAS). Synaptic plasticity expression was compared in patients and healthy subjects., Results: Reduced LTP expression was found in RR-MS patients compared with controls. Exercising RR-MS patients showed a greater amount of LTP expression compared with sedentary patients. In PMS patients, LTP expression was reduced compared with controls and increased after 8 weeks of rehabilitation. In this group of patients, LTP magnitude at baseline predicted the improvement in hand dexterity., Conclusions: Both preventive exercise and physical rehabilitation may enhance the expression of LTP-like synaptic plasticity in MS, with potential beneficial effects on disability accumulation., (© 2023 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Introduction: The visual system is a prominent site of damage in MS since the earliest phases of the disease. Altered low-contrast visual acuity (LCVA) test has been associated with visual impairment and retinal degeneration, predicting medium- and long-term disability. However, it is unclear whether LCVA may also represent a reliable measure of neuroinflammation and a predictor of disease evolution in the very early stages of MS., Methods: We explored in a group of 76 consecutive newly diagnosed relapsing-remitting MS (RR-MS) patients without visual impairment or altered visual evoked potentials, the association between LCVA scores at 2.5% and 1.25% and clinical characteristics, including prospective disability evaluated after 1- and 2 years of follow-up. Associations between LCVA and the CSF levels of IL-10 at diagnosis were also analyzed., Results: A negative correlation was found between LCVA at 2.5% and Expanded Disability Status Scale (EDSS) evaluated at first (Spearman's Rho = -0.349, p = 0.005, n = 62) and second year (Spearman's Rho = -0.418, p < 0.001, n = 62) of follow-up, and negative correlations were found with Multiple Sclerosis Severity Score (MSSS) at first (Spearman's Rho = -0.359, p = 0.004, n = 62) and second year (Spearman's Rho = -0.472, p < 0.001, n = 62). All the data were confirmed by a mixed effect model, considering other clinical variables. A positive correlation was found between the CSF concentrations of IL-10 and LCVA at 2.5% (Spearman's Rho = 0.272, p = 0.020, n = 76), and 1.25% (Spearman's Rho, = 0.276, p = 0.018, n = 76), also evidenced in a linear regression., Discussion: In MS patients at diagnosis, altered LCVA may be associated with CSF inflammation and represent a useful parameter to identify patients with worse disease course., Competing Interests: FB acted as Advisory Board members of Teva and Roche and received honoraria for speaking or consultation fees from Merck Serono, Teva, Biogen Idec, Sanofi, and Novartis and non-financial support from Merck Serono, Teva, Biogen Idec, and Sanofi. RF received honoraria for serving on scientific advisory boards or as a speaker from Biogen, Novartis, Roche, and Merck and funding for research from Merck. DC is an Advisory Board member of Almirall, Bayer Schering, Biogen, GW Pharmaceuticals, Merck Serono, Novartis, Roche, Sanofi-Genzyme, and Teva and received honoraria for speaking or consultation fees from Almirall, Bayer Schering, Biogen, GW Pharmaceuticals, Merck Serono, Novartis, Roche, Sanofi-Genzyme, and Teva. He is also the principal investigator in clinical trials for Bayer Schering, Biogen, Merck Serono, Mitsubishi, Novartis, Roche, Sanofi-Genzyme, and Teva. His preclinical and clinical research was supported by grants from Bayer Schering, Biogen Idec, Celgene, Merck Serono, Novartis, Roche, Sanofi-Genzyme, and Teva. 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 author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Dolcetti, Buttari, Bruno, Azzolini, Gilio, Di Caprio, Lauritano, Borrelli, Galifi, Furlan, Finardi, Musella, Guadalupi, Mandolesi, Rovella, Centonze and Stampanoni Bassi.)

Background: The role of vaccine-mediated inflammation in exacerbating multiple sclerosis (MS) is a matter of debate., Objective: In this cross-sectional study, we compared the cerebrospinal fluid (CSF) inflammation associated with MS relapses or anti-COVID-19 mRNA vaccinations in relapsing-remitting multiple sclerosis (RRMS)., Methods: We dosed CSF cytokines in 97 unvaccinated RRMS patients with clinical relapse within the last 100 days. In addition, we enrolled 29 stable RRMS and 24 control patients receiving COVID-19 vaccine within the last 100 days., Results: In RRMS patients, a negative association was found between relapse distance and the CSF concentrations of the pro-inflammatory cytokines interleukin (IL)-2 (beta = -0.265, p = 0.016), IL-6 (beta = -0.284, p = 0.01), and IL-17 (beta = -0.224, p = 0.044). Conversely, vaccine distance positively correlated with a different set of cytokines including IL-12 (beta = 0.576, p = 0.002), IL-13 (beta = 0.432, p = 0.027), and IL-1ra (beta = 0.387, p = 0.05). These associations were significant also considering other clinical characteristics. No significant associations emerged between vaccine distance and CSF molecules in the control group., Conclusion: Vaccine for COVID-19 induces a central inflammatory response in RRMS patients that is qualitatively different from that associated with disease relapse., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: F.B. acted as Advisory Board members of Teva and Roche and received honoraria for speaking or consultation fees from Merck Serono, Teva, Biogen Idec, Sanofi, and Novartis and non-financial support from Merck Serono, Teva, Biogen Idec, and Sanofi. R.F. received honoraria for serving on scientific advisory boards or as a speaker from Biogen, Novartis, Roche, and Merck and funding for research from Merck. D.C. is an Advisory Board member of Almirall, Bayer Schering, Biogen, GW Pharmaceuticals, Merck Serono, Novartis, Roche, Sanofi-Genzyme, and Teva and received honoraria for speaking or consultation fees from Almirall, Bayer Schering, Biogen, GW Pharmaceuticals, Merck Serono, Novartis, Roche, Sanofi-Genzyme, and Teva. He is also the principal investigator in clinical trials for Bayer Schering, Biogen, Merck Serono, Mitsubishi, Novartis, Roche, Sanofi-Genzyme, and Teva. His preclinical and clinical research was supported by grants from Bayer Schering, Biogen Idec, Celgene, Merck Serono, Novartis, Roche, Sanofi-Genzyme, and Teva. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results. The remaining authors had nothing to disclose.

The neuroinflammatory process characterizing multiple sclerosis (MS) is associated with changes in excitatory synaptic transmission and altered central concentrations of the primary excitatory amino acid, L-glutamate (L-Glu). Recent findings report that cerebrospinal fluid (CSF) levels of L-Glu positively correlate with pro-inflammatory cytokines in MS patients. However, to date, there is no evidence about the relationship between the other primary excitatory amino acid, L-aspartate (L-Asp), its derivative D-enantiomer, D-aspartate, and the levels of pro-inflammatory and anti-inflammatory cytokines in the CSF of MS. In the present study, we measured by HPLC the levels of these amino acids in the cortex, hippocampus, cerebellum, and spinal cord of mice affected by experimental autoimmune encephalomyelitis (EAE). Interestingly, in support of glutamatergic neurotransmission abnormalities in neuroinflammatory conditions, we showed reduced L-Asp levels in the cortex and spinal cord of EAE mice and increased D-aspartate/total aspartate ratio within the cerebellum and spinal cord of these animals. Additionally, we found significantly decreased CSF levels of L-Asp in both relapsing-remitting (n = 157) MS (RR-MS) and secondary progressive/primary progressive (n = 22) (SP/PP-MS) patients, compared to control subjects with other neurological diseases (n = 40). Importantly, in RR-MS patients, L-Asp levels were correlated with the CSF concentrations of the inflammatory biomarkers G-CSF, IL-1ra, MIP-1β, and Eotaxin, indicating that the central content of this excitatory amino acid, as previously reported for L-Glu, reflects a neuroinflammatory environment in MS. In keeping with this, we revealed that CSF L-Asp levels were positively correlated with those of L-Glu, highlighting the convergent variation of these two excitatory amino acids under inflammatory synaptopathy occurring in MS., (© 2023 The Authors. Journal of Neurochemistry published by John Wiley & Sons Ltd on behalf of International Society for Neurochemistry.)

Background: Individual genetic variability may influence the course of multiple sclerosis (MS). The interleukin (IL)-8C>T rs2227306 single nucleotide polymorphism (SNP) regulates IL-8 activity in other clinical conditions; however, its role in MS has never been investigated., Objectives: To explore the association between IL-8 SNP rs2227306, cerebrospinal fluid (CSF) IL-8 concentrations, clinical, and radiological characteristics in a group of newly diagnosed MS patients., Methods: In 141 relapsing-remitting (RR)-MS patients, rs2227306 polymorphism, CSF levels of IL-8, clinical, and demographical characteristics were determined. In 50 patients, structural magnetic resonance imaging (MRI) measures were also assessed., Results: An association between CSF IL-8 and Expanded Disability Status Scale (EDSS) at diagnosis was found in our set of patients ( r  = 0.207, p  = 0.014). CSF IL-8 concentrations were significantly higher in patients carrying the T variant of rs2227306 ( p  = 0.004). In the same group, a positive correlation emerged between IL-8 and EDSS ( r  = 0.273, p  = 0.019). Finally, a negative correlation between CSF levels of IL-8 and cortical thickness emerged in rs2227306T carriers ( r  = -0.498, p  = 0.005)., Conclusion: We describe for the first time a role of SNP rs2227306 of IL-8 gene in regulating the expression and the activity of this inflammatory cytokine in MS.

Neurodegenerative and inflammatory processes influence the clinical course of multiple sclerosis (MS). The β-site amyloid precursor protein cleaving enzyme 1 (BACE1) has been associated with cognitive dysfunction, amyloid deposition and neuroinflammation in Alzheimer's disease. We explored in a group of 50 patients with relapsing-remitting MS the association between the cerebrospinal fluid (CSF) levels of BACE1, clinical characteristics at the time of diagnosis and prospective disability after three-years follow-up. In addition, we assessed the correlations between the CSF levels of BACE 1, amyloid β (Aβ) 1-40 and 1-42, phosphorylated tau (pTau), lactate, and a set of inflammatory and anti-inflammatory molecules. BACE1 CSF levels were correlated positively with depression as measured with Beck Depression Inventory-Second Edition scale, and negatively with visuospatial memory performance evaluated by the Brief Visuospatial Memory Test-Revised. In addition, BACE CSF levels were positively correlated with Bayesian Risk Estimate for MS at onset, and with Expanded Disability Status Scale score assessed three years after diagnosis. Furthermore, a positive correlation was found between BACE1, amyloid β 42/40 ratio (Spearman's r = 0.334, p = 0.018, n = 50), pTau (Spearman's r = 0.304, p = 0.032, n = 50) and lactate concentrations (Spearman's r = 0.361, p = 0.01, n = 50). Finally, an association emerged between BACE1 CSF levels and a group of pro and anti-inflammatory molecules, including interleukin (IL)-4, IL-17, IL-13, IL-9 and interferon-γ. BACE1 may have a role in different key mechanisms such as neurodegeneration, oxidative stress and inflammation, influencing mood, cognitive disorders and disability progression in MS., Competing Interests: Declaration of Competing Interest The authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: F.B. (Fabio Buttari) acted as Advisory Board members of Teva and Roche and received honoraria for speaking or consultation fees from Merck Serono, Teva, Biogen Idec, Sanofi, and Novartis and non-financial support from Merck Serono, Teva, Biogen Idec, and Sanofi. R.F. received honoraria for serving on scientific advisory boards or as a speaker from Biogen, Novartis, Roche, and Merck and funding for research from Merck. D.C. (Diego Centonze) is an Advisory Board member of Almirall, Bayer Schering, Biogen, GW Pharmaceuticals, Merck Serono, Novartis, Roche, Sanofi-Genzyme, and Teva and received honoraria for speaking or consultation fees from Almirall, Bayer Schering, Biogen, GW Pharmaceuticals, Merck Serono, Novartis, Roche, Sanofi-Gen-zyme, and Teva. He is also the principal investigator in clinical trials for Bayer Schering, Biogen, Merck Serono, Mitsubishi, Novartis, Roche, Sanofi-Genzyme, and Teva. His preclinical and clinical research was supported by grants from Bayer Schering, Biogen Idec, Celgene, Merck Serono, Novartis, Roche, Sanofi-Genzyme, and Teva. G.M. (Giuseppe Matarese) reports receiving research grant support from Merck, Biogen, and Novartis and advisory board fees from Merck, Biogen, Novartis, and Roche. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results. A.B., E.D., F.A., L.G., E.I., G.G., A.Bo., R.F., A.F., F.C., F.DV., A.Mu., L.Gu., G.M, M.S.B.: nothing to report., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Osteopontin, an extracellular matrix protein involved in bone remodeling, tissue repair and inflammation, has previously been associated with increased inflammation and neurodegeneration in multiple sclerosis (MS), promoting a worse disease course. Osteopontin is also likely involved in acute MS relapses., Methods: In 47 patients with relapsing-remitting MS, we explored the correlation between the time elapsed between the last clinical relapse and lumbar puncture, and the cerebrospinal fluid (CSF) levels of osteopontin and a group of inflammatory cytokines and adipokines such as resistin, plasminogen activator inhibitor-1, osteoprotegerin, interleukin (IL)-1β, IL-2, IL-6 and IL-1 receptor antagonist (IL-1ra). We also analyzed the correlations between CSF levels of osteopontin and the other CSF molecules considered., Results: Osteopontin CSF concentrations were higher in patients with a shorter time interval between the last clinical relapse and CSF withdrawal. In addition, CSF levels of osteopontin were positively correlated with the proinflammatory cytokines IL-2 and IL-6 and negatively correlated with the anti-inflammatory molecule IL-1ra., Conclusions: Our results further suggest the role of osteopontin in acute MS relapses showing that, in proximity to relapses, osteopontin expression in CSF may be increased along with other proinflammatory mediators and correlated with decreased concentrations of anti-inflammatory molecules.

Background: Elevated levels of specific proinflammatory molecules in the cerebrospinal fluid (CSF) have been associated with disability progression, enhanced neurodegeneration and higher incidence of mood disorders in people with multiple sclerosis (MS). Studies in animal models of MS suggest that preventive exercise may play an immunomodulatory activity, with beneficial effects on both motor deficits and behavioral alterations. Here we explored the impact of lifestyle physical activity on clinical presentation and associated central inflammation in a large group of newly diagnosed patients with MS. Furthermore, we addressed the causal link between exercise-mediated immunomodulation and mood symptoms in the animal setting., Methods: A cross-sectional study was conducted on 235 relapsing-remitting MS patients at the time of the diagnosis. Patients were divided into 3 groups ("sedentary", "lifestyle physical activity" and "exercise") according to the level of physical activity in the six months preceding the evaluation. Patients underwent clinical, neuropsychological and psychiatric evaluation, magnetic resonance imaging and lumbar puncture for diagnostic purposes. The CSF levels of proinflammatory and anti-inflammatory cytokines were analyzed and compared with a group of 80 individuals with non-inflammatory and non-degenerative diseases. Behavioral and electrophysiological studies were carried out in control mice receiving intracerebral injection of IL-2 or vehicle. Behavior was also assessed in mice with experimental autoimmune encephalomyelitis (EAE), animal model of MS, reared in standard (sedentary group) or running wheel-equipped (exercise group) cages., Results: In exercising MS patients, depression and anxiety were reduced compared to sedentary patients. The CSF levels of the interleukin-2 and 6 (IL-2, IL-6) were increased in MS patients compared with control individuals. In MS subjects exercise was associated with normalized CSF levels of IL-2. In EAE mice exercise started before disease onset reduced both behavioral alterations and striatal IL-2 expression. Notably, a causal role of IL-2 in mood disorders was shown. IL-2 administration in control healthy mice induced anxious- and depressive-like behaviors and impaired type-1 cannabinoid (CB1) receptor-mediated neurotransmission at GABAergic synapses, mimicking EAE-induced synaptic dysfunction., Conclusions: Our results indicate an immunomodulatory effect of exercise in MS patients, associated with reduced CSF expression of IL-2, which might result in reduced mood disorders. These data suggest that exercise in the early stages may act as a disease-modifying therapy in MS although further longitudinal studies are needed to clarify this issue., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

In multiple sclerosis (MS), fatigue is a frequent symptom that negatively affects quality of life. The pathogenesis of fatigue is multifactorial and inflammation may play a specific role. To explore the association between fatigue, central inflammation and disease course in MS in 106 relapsing-remitting (RR)-MS patients, clinical characteristics, including fatigue and mood, were explored at the time of diagnosis. NEDA (no evidence of disease activity)-3 status after one-year follow up was calculated. Cerebrospinal fluid (CSF) levels of a set of proinflammatory and anti-inflammatory molecules and peripheral blood markers of inflammation were also analyzed. MRI structural measures were explored in 35 patients. A significant negative correlation was found at diagnosis between fatigue measured with the Modified Fatigue Impact Scale (MFIS) and the CSF levels of interleukin (IL)-10. Conversely, no significant associations were found with peripheral markers of inflammation. Higher MFIS scores were associated with reduced probability to reach NEDA-3 status after 1-year follow up. Finally, T2 lesion load showed a positive correlation with MFIS scores and a negative correlation with CSF IL-10 levels at diagnosis. CSF inflammation, and particularly the reduced expression of the anti-inflammatory molecule IL-10, may exacerbate fatigue. Fatigue in MS may reflect subclinical CSF inflammation, predisposing to greater disease activity., Competing Interests: The authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: TP has been an advisor or speaker for Sanofi-Genzyme, Medis, Hemofarm, Merck, Teva, and Roche. JD has been an advisor or speaker for Bayer HealthCare, Sanofi-Genzyme, Medis, Merck, Teva, Novartis, Hemofarm, Biogen and Roche. FB acted as Advisory Board members of Teva and Roche and received honoraria for speaking or consultation fees from Merck Serono, Teva, Bio-gen Idec, Sanofi, and Novartis and non-financial support from Merck Serono, Teva, Biogen Idec, and Sanofi. RF received honoraria for serving on scientific advisory boards or as a speaker from Biogen, Novartis, Roche, and Merck and funding for research from Merck. DC is an Advisory Board member of Almirall, Bayer Schering, Biogen, GW Pharmaceuticals, Merck Serono, Novar-tis, Roche, Sanofi-Genzyme, and Teva and received honoraria for speaking or consultation fees from Almirall, Bayer Schering, Biogen, GW Pharmaceuticals, Merck Serono, Novartis, Roche, Sanofi-Genzyme, and Teva. He is also the principal investigator in clinical trials for Bayer Schering, Biogen, Merck Serono, Mitsubishi, Novartis, Roche, Sanofi-Genzyme, and Teva. His preclinical and clinical research was supported by grants from Bayer Schering, Biogen Idec, Celgene, Merck Serono, Novartis, Roche, Sanofi-Genzyme, and Teva. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results. LG, LP, EI, GG, ED, FA, ABr, ABo, MS, AF, GM, DF, VV, MSB: nothing to report.

(1) Background: The clinical course of multiple sclerosis (MS) is critically influenced by the expression of different pro-inflammatory and anti-inflammatory cytokines. Interleukin 6 (IL-6) represents a major inflammatory molecule previously associated with exacerbated disease activity in relapsing remitting MS (RR-MS); however, the role of single-nucleotide polymorphisms (SNPs) in the IL-6 gene has not been fully elucidated in MS. (2) Methods: We explored in a cohort of 171 RR-MS patients, at the time of diagnosis, the associations between four IL-6 SNPs ( rs1818879 , rs1554606, rs1800797 , and rs1474347 ), CSF inflammation, and clinical presentation. (3) Results: Using principal component analysis and logistic regression analysis we identified an association between rs1818879 , radiological activity, and a set of cytokines, including the IL-1 β , IL-9, IL-10, and IL-13. No significant associations were found between other SNPs and clinical or inflammatory parameters. (4) Conclusions: The association between the rs1818879 polymorphism and subclinical neuroinflammatory activity suggests that interindividual differences in the IL-6 gene might influence the immune activation profile in MS.

Excessive extracellular concentrations of L-glutamate (L-Glu) can be neurotoxic and contribute to neurodegenerative processes in multiple sclerosis (MS). The association between cerebrospinal fluid (CSF) L-Glu levels, clinical features, and inflammatory biomarkers in patients with MS remains unclear. In 179 MS patients (relapsing remitting, RR, N = 157; secondary progressive/primary progressive, SP/PP, N = 22), CSF levels of L-Glu at diagnosis were determined and compared with those obtained in a group of 40 patients with non-inflammatory/non-degenerative disorders. Disability at the time of diagnosis, and after 1 year follow-up, was assessed using the Expanded Disability Status Scale (EDSS). CSF concentrations of lactate and of a large set of pro-inflammatory and anti-inflammatory molecules were explored. CSF levels of L-Glu were slightly reduced in MS patients compared to controls. In RR-MS patients, L-Glu levels correlated with EDSS after 1 year follow-up. Moreover, in MS patients, significant correlations were found between L-Glu and both CSF levels of lactate and the inflammatory molecules interleukin (IL)-2, IL-6, and IL-1 receptor antagonist. Altered expression of L-Glu is associated with disability progression, oxidative stress, and inflammation. These findings identify CSF L-Glu as a candidate neurochemical marker of inflammatory neurodegeneration in MS., (© 2021 International Society for Neurochemistry.)

Age at onset is the main risk factor for disease progression in patients with relapsing-remitting multiple sclerosis (RR-MS). In this cross-sectional study, we explored whether older age is associated with specific disease features involved in the progression independent of relapse activity (PIRA). In 266 patients with RR-MS, the associations between age at onset, clinical characteristics, cerebrospinal fluid (CSF) levels of lactate, and that of several inflammatory molecules were analyzed. The long-term potentiation (LTP)-like plasticity was studied using transcranial magnetic stimulation (TMS). Older age was associated with a reduced prevalence of both clinical and radiological focal inflammatory disease activity. Older patients showed also increased CSF levels of lactate and that of the pro-inflammatory molecules monocyte chemoattractant protein 1 (MCP-1)/CCL2, macrophage inflammatory protein 1-alpha (MIP-1α)/CCL3, and interleukin (IL)-8. Finally, TMS evidenced a negative correlation between age and LTP-like plasticity. In newly diagnosed RR-MS, older age at onset is associated with reduced acute disease activity, increased oxidative stress, enhanced central inflammation, and altered synaptic plasticity. Independently of their age, patients with multiple sclerosis (MS) showing similar clinical, immunological, and neurophysiological characteristics may represent ideal candidates for early treatments effective against PIRA., Competing Interests: RFu received honoraria for serving on scientific advisory boards or as a speaker from Biogen, Novartis, Roche, and Merck and funding for research from Merck. DC is an Advisory Board member of Almirall, Bayer Schering, Biogen, GW Pharmaceuticals, Merck Serono, Novartis, Roche, Sanofi-Genzyme, and Teva and received honoraria for speaking or consultation fees from Almirall, Bayer Schering, Biogen, GW Pharmaceuticals, Merck Serono, Novartis, Roche, Sanofi-Genzyme, and Teva. He is also the principal investigator in clinical trials for Bayer Schering, Biogen, Merck Serono, Mitsubishi, Novartis, Roche, Sanofi-Genzyme, and Teva. His preclinical and clinical research was supported by grants from Bayer Schering, Biogen Idec, Celgene, Merck Serono, Novartis, Roche, Sanofi-Genzyme and Teva. FB acted as Advisory Board members of Teva and Roche and received honoraria for speaking or consultation fees from Merck Serono, Teva, Biogen Idec, Sanofi, and Novartis and non-financial support from Merck Serono, Teva, Biogen Idec, and Sanofi. 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., (Copyright © 2021 Stampanoni Bassi, Gilio, Iezzi, Moscatelli, Pekmezovic, Drulovic, Furlan, Finardi, Mandolesi, Musella, Galifi, Fantozzi, Bellantonio, Storto, Centonze and Buttari.)