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Background and Objectives: Cognitive impairment (CI) in multiple sclerosis (MS) is frequent and determined by a complex interplay between inflammatory and neurodegenerative processes. We aimed to investigate whether CSF parvalbumin (PVALB), measured at the time of diagnosis, may have a prognostic role in patients with MS., Methods: In this cohort study, CSF analysis of PVALB and Nf-L levels was performed on all patients at diagnosis (T0) and combined with physical, cognitive, and MRI assessment after an average of 4 years of follow-up (T4) from diagnosis. Cognitive performance was evaluated with a comprehensive neuropsychologic battery: both global (cognitively normal, CN, mildly CI, mCI, and severely CI, sCI) and domain cognitive status (normal/impaired in memory, attention/information processing speed, and executive functions) were considered. Cortical thickness and gray matter volume data were acquired using 3T MRI scanner., Results: A total of 72 patients with MS were included. At diagnosis, PVALB levels were higher in those patients who showed a worsening physical disability after 4 years of follow-up ( p = 0.011). CSF PVALB levels were higher in sCI patients than in CN ( p = 0.033). Moreover, higher PVALB levels significantly correlated with worse global cognitive ( p = 0.024) and memory functioning ( p = 0.044). A preliminary clinical threshold for PVALB levels at diagnosis was proposed (2.57 ng/mL), which maximizes the risk of showing CI (in particular, sCI) at follow-up, with a sensitivity of 91% (specificity 30%). No significant results were found for these associations with Nf-L. In addition, patients with higher levels of PVALB at diagnosis showed higher cognitive ( p = 0.024) and global fatigue ( p = 0.043) at follow-up. Finally, higher PVALB levels also correlated significantly with more pronounced CTh/volume at T4 in the inferior frontal gyrus ( p = 0.044), postcentral gyrus ( p = 0.025), frontal pole ( p = 0.042), transverse temporal gyrus ( p = 0.008), and cerebellar cortex ( p = 0.041) and higher atrophy (change T0-T4) in the right thalamus ( p = 0.038), pericalcarine cortex ( p = 0.009), lingual gyrus ( p = 0.045), and medial frontal gyrus ( p = 0.028)., Discussion: The significant association found between parvalbumin levels in the CSF at diagnosis and cognitive, clinical, and neuroradiologic worsening after 4 years of follow-up support the idea that parvalbumin, in addition to Nf-L, might represent a new potential prognostic biomarker, reflecting MS neurodegenerative processes occurring since early disease stages.

Background and Objectives: To evaluate CSF inflammatory markers with accumulation of cortical damage as well as disease activity in patients with early relapsing-remitting MS (RRMS)., Methods: CSF levels of osteopontin (OPN) and 66 inflammatory markers were assessed using an immune-assay multiplex technique in 107 patients with RRMS (82 F/25 M, mean age 35.7 ± 11.8 years). All patients underwent regular clinical assessment and yearly 3T MRI scans for 2 years while 39 patients had a 4-year follow-up. White matter lesion number and volume, cortical lesions (CLs) and volume, and global cortical thickness (CTh) were evaluated together with the 'no evidence of disease activity' (NEDA-3) status, defined by no relapses, no disability worsening, and no MRI activity, including CLs., Results: The random forest algorithm selected OPN, CXCL13, TWEAK, TNF, IL19, sCD30, sTNFR1, IL35, IL16, and sCD163 as significantly associated with changes in global CTh. OPN and CXCL13 were most related to accumulation of atrophy after 2 and 4 years. In a multivariate linear regression model on CSF markers, OPN ( p < 0.001), CXCL13 ( p = 0.001), and sTNFR1 ( p = 0.024) were increased in those patients with accumulating atrophy (adjusted R-squared 0.615). The 10 markers were added in a model that included all clinical, demographic, and MRI variables: OPN ( p = 0.002) and IL19 ( p = 0.022) levels were confirmed to be significantly increased in patients developing more CTh change over the follow-up (adjusted R-squared 0.619). CXCL13 and OPN also revealed the best association with NEDA-3 after 2 years, with OPN significantly linked to disability accumulation (OR 2.468 [1.46-5.034], p = 0.004) at the multivariate logistic regression model., Discussion: These data confirm and expand our knowledge on the prognostic role of the CSF inflammatory profile in predicting changes in cortical pathology and disease activity in early MS. The data emphasize a crucial role of OPN.

Tumor necrosis factor (TNF) is a pleiotropic cytokine regulating many physiological and pathological immune-mediated processes. Specifically, it has been recognized as an essential pro-inflammatory cytokine implicated in multiple sclerosis (MS) pathogenesis and progression. MS is a chronic immune-mediated disease of the central nervous system, characterized by multifocal acute and chronic inflammatory demyelination in white and grey matter, along with neuroaxonal loss. A recent concept in the field of MS research is disability resulting from Progression Independent of Relapse Activity (PIRA). PIRA recognizes that disability accumulation since the early phase of the disease can occur independently of relapse activity overcoming the traditional dualistic view of MS as either a relapsing-inflammatory or a progressive-neurodegenerative disease. Several studies have demonstrated an upregulation in TNF expression in both acute and chronic active MS brain lesions. Additionally, elevated TNF levels have been observed in the serum and cerebrospinal fluid of MS patients. TNF appears to play a significant role in maintaining chronic intrathecal inflammation, promoting axonal damage neurodegeneration, and consequently contributing to disease progression and disability accumulation. In summary, this review highlights the current understanding of TNF and its receptors in MS progression, specifically focusing on the relatively unexplored PIRA condition. Further research in this area holds promise for potential therapeutic interventions targeting TNF to mitigate disability in MS patients., (© 2024. The Author(s).)

Leucine-rich repeat kinase-2 ( LRRK2 ), a gene mutated in familial and sporadic Parkinson's disease (PD), controls multiple cellular processes important for GLIA physiology. Interestingly, emerging studies report that LRRK2 is highly expressed in oligodendrocyte precursor cells (OPCs) compared to the pathophysiology of other brain cells and oligodendrocytes (OLs) in PD. Altogether, these observations suggest crucial function(s) of LRRK2 in OPCs/Ols, which would be interesting to explore. In this study, we investigated the role of LRRK2 in OLs. We showed that LRRK2 knock-out (KO) OPC cultures displayed defects in the transition of OPCs into OLs, suggesting a role of LRRK2 in OL differentiation. Consistently, we found an alteration of myelin basic protein (MBP) striosomes in LRRK2 KO mouse brains and reduced levels of oligodendrocyte transcription factor 2 (Olig2) and Mbp in olig2:EGFP and mbp:RFP transgenic zebrafish embryos injected with lrrk2 morpholino (MO). Moreover, lrrk2 knock-down zebrafish exhibited a lower amount of nerve growth factor (Ngf) compared to control embryos, which represents a potent regulator of oligodendrogenesis and myelination. Overall, our findings indicate that LRRK2 controls OL differentiation, affecting the number of mature OLs.

Background: Cladribine has been introduced as a high-efficacy drug for treating relapsing-remitting multiple sclerosis (RRMS). Initial cohort studies showed early disease activity in the first year after drug initiation. Biomarkers that can predict early disease activity are needed., Aim: To estimate cerebrospinal fluid (CSF) markers of clinical and radiological responses after initiation of cladribine., Methods: Forty-two RRMS patients (30F/12M) treated with cladribine were included in a longitudinal prospective study. All patients underwent a CSF examination at treatment initiation, clinical follow-up including Expanded Disability Status Scale (EDSS) assessment, and a 3T MRI scan after 6,12 and 24 months, including the evaluation of white matter (WM) and cortical lesions (CLs). CSF levels of 67 inflammatory markers were assessed with immune-assay multiplex techniques. The 'no evidence of disease activity' (NEDA-3) status was assessed after two years and defined by no relapses, no disability worsening measured by EDSS and no MRI activity, including CLs., Results: Three patients were lost at follow-up. At the end of follow-up, 19 (48%) patients remained free from disease activity. IFNgamma, Chitinase3like1, IL32, Osteopontin, IL12(p40), IL34, IL28A, sTNFR2, IL20 and CCL2 showed the best association with disease activity. When added in a multivariate regression model including age, sex, and baseline EDSS, Chitinase 3 like1 (p = 0.049) significantly increased in those patients with disease activity. Finally, ROC analysis with Chitinase3like1 added to a model with EDSS, sex, age previous relapses, WM lesion number, CLs, number of Gad enhancing lesions and spinal cord lesions provided an AUC of 0.76 (95%CI 0.60-0.91)., Conclusions: CSF Chitinase 3 like1 might provide prognostic information for predicting disease activity in the first years after initiation of cladribine. The drug's effect on chronic macrophage and microglia activation deserves further evaluation., Competing Interests: DM received honoraria for research or speaking and funds for travel from Biogen Idec, Roche, Sanofi-Genzyme, Novartis. MC received honoraria for research or speaking and funds for travel from Roche, Sanofi-Genzyme, Merck Serono S.p.a Italy, Biogen Idec, Teva and Novartis. 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 © 2024 Marastoni, Foschi, Eccher, Crescenzo, Mazziotti, Tamanti, Bajrami, Camera, Ziccardi, Guandalini, Bosello, Anni, Virla, Turano, Romoli, Mariotti, Pizzini, Bonetti and Calabrese.)

Intrathecal inflammation plays a key role in the pathogenesis of multiple sclerosis (MS). To better elucidate its relationship with peripheral inflammation, we investigated the correlation between cerebrospinal fluid (CSF) and serum levels of 61 inflammatory proteins. Paired CSF and serum samples were collected from 143 treatment-naïve MS patients at diagnosis. A customized panel of 61 inflammatory molecules was analyzed by a multiplex immunoassay. Correlations between serum and CSF expression levels for each molecule were performed by Spearman's method. The expression of sixteen CSF proteins correlated with their serum expression ( p -value < 0.001): only five molecules (CXCL9, sTNFR2, IFNα2, Pentraxin-3, and TSLP) showed a Rho value >0.40, suggesting moderate CSF/serum correlation. No correlation between inflammatory serum patterns and Q alb was observed. Correlation analysis of serum expression levels of these sixteen proteins with clinical and MRI parameters pinpointed a subset of five molecules (CXCL9, sTNFR2, IFNα2, IFNβ, and TSLP) negatively correlating with spinal cord lesion volume. However, following FDR correction, only the correlation of CXCL9 remained significant. Our data support the hypothesis that the intrathecal inflammation in MS only partially associates with the peripheral one, except for the expression of some immunomodulators that might have a key role in the initial MS immune response.

The impact of disease-modifying therapies (DMTs) on the immune response to coronavirus disease-2019 (COVID-19) vaccines in persons with multiple sclerosis (pwMS) needs further elucidation. We investigated BNT162b2 mRNA COVID-19 vaccine effects concerning antibody seroconversion, inflammatory mediators' level and immunophenotype assessment in pwMS treated with cladribine (c-pwMS, n = 29), fingolimod (f-pwMS, n = 15) and ocrelizumab (o-pwMS, n = 54). Anti-spike immunoglobulin (Ig)-G detection was performed by an enzyme immunoassay; molecular mediators (GrB, IFN-γ and TNF-α) were quantified using the ELLA platform, and immunophenotype was assessed by flow cytometry. ANCOVA, Student's t -test and Pearson correlation analyses were applied. Only one o-pwMS showed a mild COVID-19 infection despite most o-pwMS lacking seroconversion and showing lower anti-spike IgG titers than c-pwMS and f-pwMS. No significant difference in cytokine production and lymphocyte count was observed in c-pwMS and f-pwMS. In contrast, in o-pwMS, a significant increase in GrB levels was detected after vaccination. Considering non-seroconverted o-pwMS, a significant increase in GrB serum levels and CD4+ T lymphocyte count was found after vaccination, and a negative correlation was observed between anti-spike IgG production and CD4+ T cells count. Differences in inflammatory mediators' production after BNT162b2 vaccination in o-pwMS, specifically in those lacking anti-spike IgG, suggest a protective cellular immune response., Competing Interests: Massimiliano Calabrese received speaker honoraria from Biogen (Cambridge, USA), Bristol-Myers Squibb (New York, USA), Genzyme (Cambridge, USA), Merck Serono (Darmstadt, DEU), Novartis (Basel, CHE) and Roche (Basel, CHE) and receives research support from the Progressive MS Alliance (Laurence, UK) and Italian Minister of Health (Rome, ITA). Francesco Crescenzo received research support from Sanofi (Paris, FRA) Genzyme (Cambridge, USA) and/or travel expenses for scientific meetings from Sanofi (Paris, FRA), Genzyme (Cambridge, USA), Teva (Petah Tiqwa, ISR), Bristol-Myers Squibb (New York, USA), Roche (Basel, CHE). Damiano Marastoni received research support and/or honoraria for speaking and funds for travel from Roche (Basel, CHE), Sanofi (Paris, FRA), Genzyme (Cambridge, USA), Merck-Serono (Darmstadt, DEU), Biogen Idec (Cambridge, USA) and Novartis (Basel, CHE). Valentina Camera is funded by Roche (Basel, CHE), received grant from European Charcot Foundation (Brussels, BEL), received support for scientific meetings from Janssen (Beerse, BEL) and Novartis (Basel, CHE). The other authors have no financial conflict of interest.

Background: Disease activity in the first years after a diagnosis of relapsing-remitting multiple sclerosis (RRMS) is a negative prognostic factor for long-term disability. Markers of both clinical and radiological responses to disease-modifying therapies (DMTs) are advocated., Objective: The objective of this study is to estimate the value of cerebrospinal fluid (CSF) inflammatory markers at the time of diagnosis in predicting the disease activity in treatment-naïve multiple sclerosis (MS) patients exposed to dimethyl fumarate (DMF)., Methods: In total, 48 RRMS patients (31 females/17 males) treated with DMF after the diagnosis were included in this 2-year longitudinal study. All patients underwent a CSF examination, regular clinical and 3T magnetic resonance imaging (MRI) scans that included the assessment of white matter (WM) lesions, cortical lesions (CLs) and global cortical thickness. CSF levels of 10 pro-inflammatory markers - CXCL13 [chemokine (C-X-C motif) ligand 13 or B lymphocyte chemoattractant], CXCL12 (stromal cell-derived factor or C-X-C motif chemokine 12), tumour necrosis factor (TNF), APRIL (a proliferation-inducing ligand, or tumour necrosis factor ligand superfamily member 13), LIGHT (tumour necrosis factor ligand superfamily member 14 or tumour necrosis factor superfamily member 14), interferon (IFN) gamma, interleukin 12 (IL-12), osteopontin, sCD163 [soluble-CD163 (cluster of differentiation 163)] and Chitinase3-like1 - were assessed using immune-assay multiplex techniques. The combined three-domain status of 'no evidence of disease activity' (NEDA-3) was defined by no relapses, no disability worsening and no MRI activity, including CLs., Results: Twenty patients (42%) reached the NEDA-3 status; patients with disease activity showed higher CSF TNF ( p  = 0.009), osteopontin ( p  = 0.005), CXCL12 ( p  = 0.037), CXCL13 ( p  = 0.040) and IFN gamma levels ( p  = 0.019) compared with NEDA-3 patients. After applying a random forest approach, TNF and osteopontin revealed the most important variables associated with the NEDA-3 status. Six molecules that emerged at the random forest approach were added in a multivariate regression model with demographic, clinical and MRI measures of WM and grey matter damage as independent variables. TNF levels confirmed to be associated with the absence of disease activity: odds ratio (OR) = 0.25, CI% = 0.04-0.77., Conclusion: CSF inflammatory markers may provide prognostic information in predicting disease activity in the first years after DMF initiation. CSF TNF levels are a possible candidate in predicting treatment response, in addition to clinical, demographic and MRI variables., Competing Interests: Conflict of interest statement: The authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: DM received honoraria for research or speaking and funds for travel from Biogen Idec, Roche, Sanofi-Genzyme and Novartis. AIP, GMS, VM, MCas, AT, FB, FC, SM, FBP and GKR: no disclosures relevant to the manuscript. MC received honoraria for research or speaking and funds for travel from Roche, Sanofi-Genzyme, Merck-Serono, Biogen Idec, Teva and Novartis., (© The Author(s), 2022.)

Introduction and Methods: In order to verify whether parvalbumin (PVALB), a protein specifically expressed by GABAergic interneurons, could be a MS-specific marker of grey matter neurodegeneration, we performed neuropathology/molecular analysis of PVALB expression in motor cortex of 40 post-mortem progressive MS cases, with/without meningeal inflammation, and 10 control cases, in combination with cerebrospinal fluid (CSF) assessment. Analysis of CSF PVALB and neurofilaments (Nf-L) levels combined with physical/cognitive/3TMRI assessment was performed in 110 naïve MS patients and in 32 controls at time of diagnosis., Results: PVALB gene expression was downregulated in MS (fold change = 3.7 ± 1.2, P < 0.001 compared to controls) reflecting the significant reduction of PVALB+ cell density in cortical lesions, to a greater extent in MS patients with high meningeal inflammation (51.8, P < 0.001). Likewise, post-mortem CSF-PVALB levels were higher in MS compared to controls (fold change = 196 ± 36, P < 0.001) and correlated with decreased PVALB+ cell density (r = -0.64, P < 0.001) and increased MHC-II+ microglia density (r = 0.74, P < 0.01), as well as with early age of onset (r = -0.69, P < 0.05), shorter time to wheelchair (r = -0.49, P < 0.05) and early age of death (r = -0.65, P < 0.01). Increased CSF-PVALB levels were detected in MS patients at diagnosis compared to controls (P = 0.002). Significant correlation was found between CSF-PVALB levels and cortical lesion number on MRI (R = 0.28, P = 0.006) and global cortical thickness (R = -0.46, P < 0.001), better than Nf-L levels. CSF-PVALB levels increased in MS patients with severe cognitive impairment (mean ± SEM:25.2 ± 7.5 ng/mL) compared to both cognitively normal (10.9 ± 2.4, P = 0.049) and mild cognitive impaired (10.1 ± 2.9, P = 0.024) patients., Conclusions: CSF-PVALB levels reflect loss of cortical interneurons in MS patients with more severe disease course and might represent an early, new MS-specific biomarker of cortical neurodegeneration, atrophy, and cognitive decline., (© 2021 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Background: Intrathecal immunoglobulin M (IgM) synthesis has been demonstrated in the early disease stages of multiple sclerosis (MS) as a predictor factor of a worsening disease course. Similarly, increased cerebrospinal fluid (CSF) molecules related to B-cell intrathecal activity have been associated with a more severe MS progression. However, whether CSF levels of IgM are linked to specific inflammatory and clinical profile in MS patients at the time of diagnosis remains to be elucidated., Methods: Using customized Bio-Plex assay, the protein levels of IgG, IgA, IgM, and of 34 other inflammatory molecules, related to B-cell, T-cell, and monocyte/macrophage activity, were analyzed in the CSF of 103 newly diagnosed relapsing-remitting MS patients and 36 patients with other neurological disorders. CSF IgM levels were also correlated with clinical and neuroradiological measures [advanced 3-T magnetic resonance imaging (MRI) parameters], at diagnosis and after 2 years of follow-up., Results: A 45.6% increase in CSF IgM levels was found in MS patients compared to controls ( p = 0.013). CSF IgM levels correlated with higher CSF levels of CXCL13 ( p = 0.039), CCL21 ( p = 0.023), interleukin 10 (IL-10) ( p = 0.025), IL-12p70 ( p = 0.020), CX3CL1 ( p = 0.036), and CHI3L1 ( p = 0.048) and were associated with earlier age of patients at diagnosis ( p = 0.008), white matter lesion (WML) number ( p = 0.039) and disease activity ( p = 0.033) after 2 years of follow-up., Conclusion: IgMs are the immunoglobulins mostly expressed in the CSF of naive MS patients compared to other neurological conditions at the time of diagnosis. The association between increased CSF IgM levels and molecules related to both B-cell immunity (IL-10) and recruitment (CXCL13 and CCL21) and to macrophage/microglia activity (IL-12p70, CX3CL1, and CHI3L1) suggests possible correlation between humoral and innate intrathecal immunity in early disease stage. Furthermore, the association of IgM levels with WMLs and MS clinical and MRI activity after 2 years supports the idea of key role of IgM in the disease course., (Copyright © 2020 Magliozzi, Mazziotti, Montibeller, Pisani, Marastoni, Tamanti, Rossi, Crescenzo and Calabrese.)

Objective: Intrathecal inflammation correlates with the grey matter damage since the early stages of multiple sclerosis (MS), but whether the cerebrospinal fluid (CSF) profile can help to identify patients at risk of disease activity is still unclear., Methods: We evaluated the association between CSF levels of 18 cytokines, previously found to be associated to grey matter damage, and the disease activity, among 99 patients with relapsing-remitting MS, who underwent blinded clinical and 3 T magnetic resonance imaging (MRI) evaluations for 4 years. Groups with evidence of disease activity (EDA) or no evidence of disease activity (NEDA; occurrence of relapses, new white matter lesions, and Expanded Disability Status Scale [EDSS] change) were identified. Cortical lesions and the annualized cortical thinning were also evaluated., Results: Forty-one patients experienced EDA and, compared to the NEDA group, had at diagnosis higher CSF levels of CXCL13, CXCL12, IFNγ, TNF, sCD163, LIGHT, and APRIL (p < 0.001). In the multivariate analysis, CXCL13 (hazard ratio [HR] = 1.35; p = 0.0002), LIGHT (HR = 1.22; p = 0.005) and APRIL (HR = 1.78; p = 0.0001) were the CSF molecules more strongly associated with the risk of EDA. The model, including CSF variables, predicted more accurately the occurrence of disease activity than the model with only clinical/MRI parameters (C-index at 4 years = 71% vs 44%). Finally, higher CSF levels of CXCL13 (β = 4.7*10 -4 ; p < 0.001), TNF (β = 3.1*10 -3 ; p = 0.004), LIGHT (β = 2.6*10 -4 ; p = 0.003), sCD163 (β = 4.3*10 -3 ; p = 0.009), and TWEAK (β = 3.4*10 -3 ; p = 0.024) were associated with more severe cortical thinning., Interpretation: A specific CSF profile, mainly characterized by elevated levels of B-cell related cytokines, distinguishes patients at high risk of disease activity and severe cortical damage. The CSF analysis may allow stratifications of patients at diagnosis for optimizing therapeutic approaches. ANN NEUROL 2020;88:562-573., (© 2020 American Neurological Association.)

Background: Multiple sclerosis (MS) is an immune-mediated, chronic inflammatory, and demyelinating disease of the central nervous system (CNS). Several cytokines are thought to be involved in the regulation of MS pathogenesis. We recently identified interleukin (IL)-9 as a cytokine reducing inflammation and protecting from neurodegeneration in relapsing-remitting MS patients. However, the expression of IL-9 in CNS, and the mechanisms underlying the effect of IL-9 on CNS infiltrating immune cells have never been investigated., Methods: To address this question, we first analyzed the expression levels of IL-9 in post-mortem cerebrospinal fluid of MS patients and the in situ expression of IL-9 in post-mortem MS brain samples by immunohistochemistry. A complementary investigation focused on identifying which immune cells express IL-9 receptor (IL-9R) by flow cytometry, western blot, and immunohistochemistry. Finally, we explored the effect of IL-9 on IL-9-responsive cells, analyzing the induced signaling pathways and functional properties., Results: We found that macrophages, microglia, and CD4 T lymphocytes were the cells expressing the highest levels of IL-9 in the MS brain. Of the immune cells circulating in the blood, monocytes/macrophages were the most responsive to IL-9. We validated the expression of IL-9R by macrophages/microglia in post-mortem brain sections of MS patients. IL-9 induced activation of signal transducer and activator of transcription (STAT)1, STAT3, and STAT5 and reduced the expression of activation markers, such as CD45, CD14, CD68, and CD11b in inflammatory macrophages stimulated in vitro with lipopolysaccharide and interferon (IFN)-γ. Similarly, in situ the number of activated CD68 + macrophages was significantly reduced in areas with high levels of IL-9. Moreover, in the same conditions, IL-9 increased the secretion of the anti-inflammatory cytokine, transforming growth factor (TGF)-β., Conclusions: These results reveal a new cytokine expressed in the CNS, with a role in the context of MS. We have demonstrated that IL-9 and its receptor are both expressed in CNS. Moreover, we found that IL-9 decreases the activation state and promotes the anti-inflammatory properties of human macrophages. This mechanism may contribute to the beneficial effects of IL-9 that are observed in MS, and may be therapeutically potentiated by modulating IL-9 expression in MS.

Fingolimod phosphate (FTY720), the first approved oral therapy for multiple sclerosis, primarily acts as an immunomodulator. Its concomitant effects in the central nervous system, however, indicate a potentially broader spectrum of activity in neurodegenerative diseases. In the present study, we investigated the possible effects of fingolimod in a mouse model of amyotrophic lateral sclerosis (ALS), a neurodegenerative disease characterized by a strong neuroinflammatory component. Fingolimod (0.1 and 1 mg/kg i.p.) was administered to mSOD1 G93A mice, a well-characterized mouse model of ALS, starting from the onset of motor symptoms to the end stage of the disease. The drug was able to improve the neurological phenotype (p < 0.05) and to extend the survival (p < 0.01) of ALS mice. The beneficial effect of fingolimod administration was associated with a significant modulation of neuroinflammatory and protective genes (CD11b, Foxp3, iNOS, Il1β, Il10, Arg1, and Bdnf) in motor cortex and spinal cord of animals. Our data show, for the first time, that fingolimod is protective in ALS mice and that its beneficial effects are accompanied by a modulation of microglial activation and innate immunity. Considering that the treatment was started in already symptomatic mice, our data strongly support fingolimod as a potential new therapeutic approach to ALS.