Neurology® Neuroimmunology & Neuroinflammation最新文献

Objectives: The gut microbiota and altered intestinal physiology have been implicated in multiple sclerosis (MS). Enteric glial cells regulate enteric nervous and immune function and express glial fibrillary acidic protein (GFAP) and S100β. Serum GFAP and neurofilament light chain can predict disease worsening; however, no clear markers differentiate relapsing from progressive disease.

Methods: To investigate enteric glial function in MS, we measured stool GFAP (st-GFAP) using an enzyme-linked immunosorbent assay in 31 healthy controls (HCs), 77 patients with relapsing remitting MS (RRMS), and 53 patients with progressive MS (ProgMS). Participants underwent clinical follow-up at 2 and 5 years after stool donation.

Results: We found higher st-GFAP levels in patients with ProgMS compared with those with RRMS and HCs. St-GFAP was positively correlated with baseline Expanded Disability Status Scale (EDSS) score, 25-foot walk time, and an increased EDSS score at 2 and 5 years. We found enteric glial hyperplasia in the colonic mucosa of a patient with primary progressive MS, as indicated by GFAP and S100β immunoreactivity, an effect not observed in duodenum tissue in patients with RRMS from our Milan cohort. St-GFAP in patients with ProgMS was negatively associated with Eubacterium hallii.

Discussion: These exploratory data indicate an altered enteric glial phenotype in patients with ProgMS and suggest that st-GFAP may be a prognostic biomarker.

Objectives: The aim of this study was to characterize inflammatory cytokine profiles in women diagnosed with episodic migraine, endometriosis, or both conditions and to determine how these cytokine patterns relate to symptom severity and functional impact, to identify potential biological markers distinguishing comorbid cases from single-diagnosis cases.

Methods: Female patients with only episodic migraine, only endometriosis, or both conditions were enrolled. Plasma levels of proinflammatory cytokines were measured, and correlations with clinical parameters were analyzed.

Results: Women with episodic migraine had elevated levels of IL-1β, IL-6, and TNF-α compared with healthy controls, with even higher levels in those with both migraine and endometriosis, indicating a synergistic effect on systemic inflammation. IL-1β correlated with headache frequency and disability while IL-6 and TNF-α were linked to migraine severity and pain. Women with endometriosis alone did not show similar cytokine elevations, suggesting that inflammation is particularly amplified in comorbidity. Changes in leukocyte distribution further supported a unique immune activation profile in the comorbid group.

Discussion: These findings reveal novel biological evidence of a shared inflammatory endotype in women suffering from both conditions, which may contribute to the increased burden and comorbidity, highlighting the need for integrative diagnostic and management approaches.

Background and objectives: Paraneoplastic neurologic syndromes (PNS) are cancer-related neurologic disorders caused by an autoimmune response targeting both the tumor and the nervous system. Identifying new biomarkers for early cancer detection could improve treatment outcomes. Tumor-derived cells release extracellular vesicles (EVs) carrying tumor-specific molecular signatures, which can help distinguish patients with cancer even in early stages. The aim of this study was to assess the potential of EVs as biomarkers to enhance cancer detection in patients with PNS.

Methods: This observational and multicenter study included 27 patients with tumor-associated PNS, 26 with suspected PNS without a tumor, 35 with cancer, and 32 healthy controls. Subsequently, among the patients with PNS, individuals were subclassified according to the PNS-Care Score as definite, probable, possible, and non-PNS. Total EVs were isolated from blood by precipitation and from B cells, T cells, and neurons by immunoisolation. To identify a biomarker for diagnostic refinement and clinical stratification, EV levels, size, and protein content were compared across study groups. To find a tumor biomarker in intermediate-risk cases, the possible association between EV protein content and cancer detection in intermediate-risk syndromes was analyzed.

Results: Patients with tumor-associated PNS showed significantly higher circulating EV levels compared with those with suspected PNS without evidence of a tumor (p = 0.028). Moreover, total EV levels, along with B cell-derived EVs, effectively differentiated patients with definite PNS from those with probable (p = 0.05) and possible (p = 0.006) PNS. A cutoff value of 2.10 × 10¹⁰ particles/mL EVs was identified, above which diagnosis of PNS was definite, with 86% sensitivity and 81% specificity. Proteomic analysis identified specific proteins, including ACADM, HPT, ACTBL, and CCAR2, as markers of definite PNS, differentiating such patients from those with probable and possible PNS, contributing to diagnostic refinement for clinical stratification. It is important to note that increased levels of EVs and CD44 distinguished intermediate-risk cases with tumors from those without.

Discussion: EVs may act as tumor biomarkers in patients with PNS, even in intermediate-risk cases.

Classification of evidence: This study provides Class IV evidence that higher circulating blood levels of EVs can distinguish between tumor-associated PNS from suspected PNS without tumor.

Background and objectives: Optical coherence tomography (OCT) allows evaluation of inter-eye differences (IEDs) in macular ganglion cell-inner plexiform layer (GCIPL) and peripapillary retinal nerve fiber layer (pRNFL) thicknesses to identify unilateral optic nerve involvement (UONI). UONI supports dissemination in space (DIS) as part of the 2024 revised McDonald diagnostic criteria for multiple sclerosis (MS). The OSCAR-IB quality control (QC) criteria identify suboptimal-quality OCT scans, which could potentially result in false-positive or false-negative UONI identification. We aimed to determine the influence of scans fulfilling OSCAR-IB criteria (SFO) and not fulfilling (SNFO) on test-retest reliability of pRNFL and GCIPL thicknesses/IEDs, with a commonly used OCT platform (Cirrus HD-OCT).

Methods: A total of 509 participants, including 397 people with MS, underwent Cirrus HD-OCT, with acquisition of 2 macular and optic disc scans per eye. Each scan was classified as either SFO or SNFO. There were no clinical or demographic exclusions in order to reflect a real-world clinical setting. Reproducibility was evaluated with intravisit intraclass correlation coefficients (ICCs) and coefficients of variation (COVs). IED consistency was assessed with difference-in-differences (DiDs) and probabilities of agreement (POA) for specific IED thresholds (GCIPL

Results: A total of 1,143 macular scan pairs (1,100 SFO and 42 SNFO) for GCIPL and 1,108 optic disc scan pairs (1,003 SFO and 105 SNFO) for pRNFL were analyzed. SFO demonstrated superior reliability, as compared to SNFO for GCIPL (SFO: ICC = 0.998, COV = 0.40%; SNFO: ICC 0.353, COV 10.14%) and pRNFL (SFO: ICC = 0.989, COV = 1.18%; SNFO: ICC = 0.852, COV = 3.94%) thicknesses. DiDs were lower for SFO (GCIPL 0.64 ± 0.67 μm, pRNFL: 2.00 ± 1.72 μm), as compared to SNFO (GCIPL: 10.17 ± 13.87 μm, pRNFL: 4.78 ± 5.51 μm). POA of IED thresholds (GCIPL:

Discussion: GCIPL and pRNFL thicknesses/IEDs demonstrated markedly inferior reliability in SNFO, relative to SFO. Failure to fulfill OSCAR-IB criteria influenced pRNFL measurements and, in particular, GCIPL measurements, highlighting the importance of thorough QC in the interpretation of OCT to correctly identify UONI and accurately support DIS for the diagnosis of MS.

Objectives: Amaurosis fugax (AF) is typically vascular but can rarely be associated with optic neuritis (ON). We describe AF preceding myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) ON.

Methods: We retrospectively reviewed our MOGAD cohort (July 2024-April 2024). Inclusion criteria were (1) AF-defined as transient visual loss <24 hours without retinal ischemic lesions-before first ON and (2) fulfilled international MOGAD 2023 diagnostic criteria. Demographics, symptoms/signs, MRI, and optical coherence tomography (OCT) data were collected. Descriptive statistics summarized the findings.

Results: In total, 8 of 350 (2.3%) MOGAD patients with ON experienced AF. Most patients (7/8, 87.5%) were women, and all reported periocular pain. Transient visual episodes were typically brief (median, 15 minutes; range, 1-300 minutes) and usually less than 1 hour (6/8, 75.0%). Amaurosis fugax affected the right (n = 4), left (n = 3), or both (n = 1) eyes. Within 1 week, 7 developed ON. MRI showed optic nerve enhancement in involved eye in 8 of 8 (100%). OCT completed in 1 patient at the time of AF showed increased peripapillary retinal nerve fiber layer thickness. No alternative diagnoses emerged during follow-up.

Discussion: Painful AF is a previously unrecognized and specific prodrome of MOGAD-associated ON; identifying this rare presentation may enable earlier diagnosis and treatment.

Background and objectives: Understanding the immunologic changes induced by immune reconstitution therapies (IRTs) is key to optimizing multiple sclerosis (MS) treatment. We evaluate lymphocyte dynamics and their association with secondary autoimmune disease (SAD) and its recurrence after treatment with alemtuzumab (ALZ), autologous hematopoietic stem cell transplantation (AHSCT), and cladribine tablets (CladT).

Methods: People with MS (pwMS) initiating treatment with ALZ, AHSCT, and CladT were included in this cohort study. Blood samples were collected at baseline (BL) and at months (M) 6, 12, and 24 for flow cytometry analysis of lymphocyte subpopulation.

Results: A total of 130 pwMS (ALZ: n = 51; AHSCT: n = 20; CladT: n = 59) were included, with a mean (SD) age of 35.5 (±8.2) years. The median (IQR) Expanded Disability Status Scale (EDSS) score was 1.5 (1.0-2.5) at BL. The median follow-up duration was 4.7 (ALZ: 5.0; AHSCT: 4.2; CladT: 3.7) years. During follow-up, 29.2% (38/130; ALZ n = 29; AHSCT n = 3; CladT n = 6) received a SAD diagnosis and 43.1% (56/130; ALZ n = 15; AHSCT n = 13; CladT n = 28) showed no disease activity. The SAD cohort (n = 38) showed lower median BL ratios of CD4⁺ T-cell recent thymic emigrant (Trte):CD4 (0.26 [0.12-0.34], p = 0.04) and CD4⁺ Trte:CD8+ terminally differentiated effector memory (Temra) (1.73 [0.76-4.39], p = 0.02) compared with the non-SAD cohort (CD4⁺ Trte:CD4 = 0.31 [0.23-0.42]; CD4⁺ Trte:CD8+ Temra = 3.61 [1.47-7.24]). During follow-up, the SAD cohort exhibited a greater relative increase in CD4⁺ Trte:CD4, CD4⁺ Trte:CD8+ Temra, and CD4⁺ T regulatory cell (Treg):CD8+ Temra ratios at M12 and M24, compared with BL, relative to the non-SAD group. The difference at M24 was most pronounced for the CD4⁺ Trte:CD8+ Temra ratio (SAD: +100% vs non-SAD: -23%, p < 0.001), with this difference being confirmed in the ALZ cohort (SAD: +123% vs non-SAD: -21%, p = 0.03), but not in the CladT cohort (SAD: -62% vs non-SAD: -38%, p = 0.39). In a multivariable Cox analysis, BL CD8⁺ T-cell count (aHR 0.34, 95% CI 0.15-0.80, p = 0.01) was associated with a reduced hazard of evidence of disease activity.

Discussion: A low BL CD4⁺ Trte:CD8⁺ Temra ratio, accompanied by a sharp relative increase during follow-up, was associated with SAD development. While no definitive associations were found between BL lymphocyte subpopulations and disease activity, a lower CD8⁺ T-cell count may suggest an increased risk.

Background and objectives: Recent decades have witnessed the emergence of arbovirus infections, such as dengue, chikungunya, and Zika viruses, which are responsible for neurologic complications such as Guillain-Barré syndrome (GBS). To date, it has mainly been demonstrated that these neurologic complications occur concomitantly with infectious processes. We hypothesized that arbovirus infections may also influence the incidence of autoimmune diseases of the central or peripheral nervous system.

Methods: This was a retrospective, observational, single-center study conducted between January 2002 and January 2024 at the Cayenne Hospital in French Guiana including patients with autoimmune encephalitis, neuromyelitis optica spectrum disorders (NMOSDs), GBS, chronic inflammatory demyelinating polyneuropathy, and myasthenia gravis (MG). This series was compared with the incidence of arbovirus infections recorded by the French Public Health Agency during the same period.

Results: We observed a significant correlation between dengue infection and the incidence of NMOSD (Spearman rho = 0.88 [p = 0.03]) and MG (Spearman rho = 0.82 [p = 0.048]). GBS was significantly associated with chikungunya (Spearman rho = 0.97 [p = 0.01]), but not with other arbovirus infections. In addition, the mean estimated incidence of NMOSD was high at 5.08 (95% CI 3.03-7.13) per million person-year, approaching the world's highest incidence observed in the French West Indies.

Discussion: This study reports the epidemiology of neurologic autoimmune diseases in French Guiana. We found a high incidence of NMOSD, like that reported in the French West Indies. Multicenter studies involving countries in the tropical zone are needed to better elucidate the relationship between dengue outbreak and NMOSD and MG.

Background and objectives: Myelitis is a relatively common clinical entity for neurologists, with diverse underlying causes. The aim of this study was to describe the incidence of myelitis, its causes, clinical presentation, and factors predicting functional outcomes and relapses.

Methods: Using the Swedish National Patient Registry, we identified all adult patients in Stockholm County between 2008 and 2018 using International Classification of Diseases, 10th Edition (ICD-10) codes likely to include myelitis. We collected medical records and classified patients using a modification of the 2002 Transverse Myelitis Consortium Group criteria. Long-term follow-up data were collected for patients not diagnosed with multiple sclerosis (MS) or neuromyelitis optica spectrum disorder as a result of the initial myelitis.

Results: We identified 2,321 individuals, of whom 461 were patients with myelitis. The crude mean incidence of all-cause myelitis was 24.9 (95% CI 16.7-33.9) cases per million person-years, of which idiopathic myelitis had an incidence of 8.0 (95% CI 3.8-12.1) cases per million person-years. Partial myelitis was found in 80% of patients. Poor functional outcome was found in 11% of the cohort and correlated, in a multivariate logistic model, with age older than 50 years (OR 4.26, 95% CI 1.75-10.40), transverse spinal cord lesions (odds ratio [OR] 6.85, 95% CI 2.68-17.52), elevated CSF count of polymorphonuclear cells (OR 6.09, 95% CI 1.56-23.72), and elevated CSF/serum albumin ratio (OR 3.17, 95% CI 1.23-8.17). The median follow-up time was 5.4 years. Relapses occurred in 27% of patients with idiopathic myelitis and 72% of patients with unspecified demyelinating disease of the CNS. An increased relapse rate after idiopathic myelitis was found to be associated, in a multivariate model, with the presence of oligoclonal bands (incidence rate ratio [IRR] 4.47, 95% CI 1.70-11.73), transverse spinal cord lesions (IRR 2.81, 95% CI 1.11-7.12), and multifocal spinal cord lesions (IRR 2.82, 95% CI 1.03-7.69). Around half (48%) of all patients with myelitis received MS diagnosis during the study period.

Discussion: This large population-wide study describes a relatively high incidence of myelitis and low risk of relapses after idiopathic myelitis. A complete diagnostic workup of myelitis, including MRI of the entire CNS and collection of CSF, is essential in evaluating underlying causes and prognosis.

Background and objectives: Mesenchymal stem cells (MSCs) represent a potential cellular therapy for multiple sclerosis (MS). It has been suggested that MSCs from patients with MS have lower immunomodulatory properties than those from healthy controls (HCs). The aims of this study were to compare the immunomodulatory abilities of MSCs from patients with MS and HCs against autologous immune cells and to identify potential targets affecting this ability.

Methods: MSCs were obtained by bone marrow aspiration from 5 people with MS and 7 HCs. Autologous peripheral blood mononuclear cells (PBMCs) were stimulated in monoculture or co-culture with MSCs and tested for T-cell expression of IL-17, IFN-γ, and granulocyte-macrophage colony-stimulating factor (GM-CSF) by flow cytometry. Supernatants of monoculture unstimulated MSCs were tested for a panel of cytokines and chemokines using multiplex array or individual ELISA. Gene expression profiling in MSCs was studied using Lexogen QuantSeq RNA-seq platform and subsequent Ingenuity Pathway Analysis.

Results: The MSCs from HCs reduced the proportion of autologous T cells expressing IL-17 (Th17, p = 0.046), IFN-γ (Th1, p = 0.03), and GM-CSF (p = 0.012), whereas MSCs from patients with MS had an opposite effect, increasing both autologous Th17 cells (p = 0.01) and GM-CSF-expressing T cells (p = 0.03), with no changes in Th1 cell abundance. Unstimulated MSCs from patients with MS produced less IL-10 (p = 0.03) and more osteopontin (OPN) (p = 0.002) than those from HCs. Gene expression profiling suggested an increase of ADAM28 in the MS MSCs. This was further confirmed at mRNA (by quantitative polymerase chain reaction [qPCR]) and protein (by flow cytometry) levels. Co-cultures of MS MSCs and autologous PBMCs in the presence of natalizumab, a monoclonal antibody that binds α4β1 and blocks its interaction with both ADAM28 and OPN, resulted in a reduction of Th17 cells. In addition, adding IL-10 to the co-cultures abrogated the increase in Th17 cells, potentially interfering with MS MSC inflammatory effect.

Discussion: Our results suggest that blocking ADAM-28 and OPN interaction with cognate receptors or increasing IL-10 reduces the proinflammatory potential of MSCs from people with MS. Similar approaches could be used in clinical MSC treatments.

Background and objectives: Multiple sclerosis (MS) is a neuroinflammatory and neurodegenerative CNS disorder characterized by a state of "virtual hypoxia." Angiogenesis, one of the main homeostatic responses to hypoxia, has been implicated in the pathophysiology of MS. The study objective was to determine whether angiogenic and hypoxia-related molecules are dysregulated in the serum and CNS of patients with progressive multiple sclerosis (PMS).

Methods: Baseline serum samples were obtained from a phase II trial of Ibudilast in PMS (n = 203 analyzed) and matched to healthy controls (n = 53). Participants on previous therapeutics (interferons or glatiramer acetate) were excluded from analysis (n = 131). Angiogenic factors were measured using a commercially available bead-based multiplex assay, and hypoxia biomarkers were measured using a custom bead-based multiplex assay. To interrogate the expression of selected hypoxia and angiogenic markers in the CNS, we analyzed publicly available transcriptomic databases and in-house generated data from normal appearing white matter of 2 SPMS donors and 2 nonneurologic disease controls.

Results: Circulating markers of hypoxia (such as hypoxia inducible factor-1-a, heme oxygenase-1, and heat shock protein-90) were increased in serum. Conversely, markers of angiogenesis (such as vascular endothelial growth factor-A [VEGF-A], heparin-binding epidermal growth factor, and hepatocyte growth factor) were reduced suggesting a blunting of the angiogenic response. Several of these changes were confirmed in the PMS CNS transcriptome. Lower levels of VEGF-A were associated with disability worsening on the timed-25 foot-walk test at 24 (p = 0.02) and 48 (p = 0.02) weeks and predicted disability worsening (hazard ratio 0.31, 95% CI 0.14-0.69, p = 0.034). Conversely, higher leptin levels trended to predict cognitive worsening on the symbol digit modalities test.

Discussion: Hypoxia-angiogenesis signals are dysregulated in PMS. Increased hypoxia and an insufficient angiogenic adaptive response may play a role in PMS pathophysiology and be a relevant pathway, both in understanding disease mechanisms and as a possible therapeutic target.