Neurology® Neuroimmunology & Neuroinflammation最新文献

{"title":"Elevated ITGAX/CD11c in CSF-Derived Extracellular Vesicles Reflects Disability Progression in Multiple Sclerosis.","authors":"Naotoshi Iwahara, Satoshi Muraoka, Taro Saito, Masayo Hirano, Kazuki Yokokawa, Masanobu Tanemoto, Ryosuke Oda, Takayuki Nonaka, Shuuichirou Suzuki, Jun Adachi, Shin Hisahara","doi":"10.1212/NXI.0000000000200442","DOIUrl":"10.1212/NXI.0000000000200442","url":null,"abstract":"<p><strong>Background and objectives: </strong>Extracellular vesicles (EVs) are membrane-bound particles that are released into the extracellular space and are believed to play a role in the pathogenesis of neuroinflammation and neurodegeneration. Nevertheless, the precise role of these vesicles in the context of multiple sclerosis (MS) remains uncertain. The objective of this study was to identify the distinctive characteristics of EVs associated with MS.</p><p><strong>Methods: </strong>EVs were isolated from CSF using phosphatidylserine affinity methods. Mass spectrometry was used to analyze CSF samples and EVs isolated from those CSF samples collected from a discovery cohort of 10 patients with other neurologic diseases (ONDs) and 10 patients with MS. In addition, mass spectrometry was used to analyze EVs isolated from CSF samples in a validation cohort of 24 patients with ONDs, 38 patients with MS, and 14 patients with neuromyelitis optica spectrum disorders.</p><p><strong>Results: </strong>The results revealed notable increases in the levels of 33 proteins in the CSF samples and 100 proteins in the CSF-derived EVs from patients with MS in the validation cohort. Increases in the levels of ITGA4, ITGAX (CD11c), MS4A1 (CD20), CD3E, CD4, and CD8A, which are marker proteins of lymphocytes and myeloid cells, including activated microglia and dendritic cells, were observed in the CSF-derived EVs in the discovery cohort. The results of the validation cohort revealed that the levels of 4 proteins, ITGA4, ITGAX, MS4A1, and CD3E, were significantly greater in patients with MS than in patients with ONDs. Furthermore, the level of ITGAX was greater in the patients with confirmed disability worsening (CDW) than in those without CDW. The results of the receiver operating characteristic (ROC) and Kaplan-Meier analyses indicated that ITGAX levels in CSF-derived EVs may prove useful in predicting disease prognosis.</p><p><strong>Discussion: </strong>Our findings suggest that CSF-derived EVs reflect immunologic changes in MS and other neuroimmune diseases. In addition, these results raise the possibility that changing in myeloid cells and lymphocytes may also play a role in the pathogenesis of MS. CSF-derived EVs may serve as indicators of MS disease severity and could be used as biomarkers in the future.</p>","PeriodicalId":19472,"journal":{"name":"Neurology® Neuroimmunology & Neuroinflammation","volume":"12 5","pages":"e200442"},"PeriodicalIF":7.8,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12275904/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144663974","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Oral and Gut Dysbiosis in Migraine: Oral Microbial Signatures as Biomarkers of Migraine.","authors":"Soomi Cho, Yeonjae Jung, Hyun-Seok Oh, Jungyon Yum, Seungwon Song, JaeWook Jeong, Woo-Seok Ha, Kyung Min Kim, Won-Joo Kim, Min Kyung Chu","doi":"10.1212/NXI.0000000000200437","DOIUrl":"10.1212/NXI.0000000000200437","url":null,"abstract":"<p><strong>Background and objectives: </strong>Emerging evidence suggests that oral health conditions may exacerbate migraine, and saliva is a potential source of biomarkers for migraine. The 3-way interaction of the oral-gut-brain axis has been implicated in several neurologic disorders, but has rarely been studied in migraine. This study examined the oral and gut microbiomes simultaneously and identified several key oral microbes that may influence migraine.</p><p><strong>Methods: </strong>In this cross-sectional case-control study, participants were divided into 3 groups: episodic migraine (n = 55), chronic migraine (n = 55), and healthy control (HC) (n = 55). Demographic and clinical characteristics; lifestyle factors; and biological samples including saliva, stool, and blood were collected. Composition, function, and community type of the oral and gut microbiomes were compared among the 3 groups.</p><p><strong>Results: </strong>Oral dysbiosis was more pronounced than gut dysbiosis in the migraine groups, with 13 oral genera significantly enriched or depleted compared with HCs. The migraine groups showed increased abundance of <i>Gemella</i>, <i>Streptococcus</i>, <i>Granulicatella</i>, and <i>Rothia</i> and decreased abundance of <i>Alloprevotella</i>, <i>Veillonella</i>, <i>Haemophilus</i>, <i>Selenomonas</i>, <i>Campylobacter</i>, <i>Cardiobacterium</i>, <i>Megasphaera</i>, and <i>Kingella</i> after adjustment for demographic and lifestyle factors including diet. The enriched oral genera within the migraine groups were associated with carbohydrate metabolic pathways, whereas the depleted oral genera were associated with pathways related to nitrogen. A significant proportion of the oral microbial signatures of migraine included genera capable of reducing nitrate and/or nitrite. Some of these oral microbial signatures of migraine had a relative abundance that was positively or negatively associated with the number of headache days per 30 days and formed distinct microbial clusters in both the oral cavity and gut. Machine learning classifiers using the oral microbiome effectively classified migraine status, with an area under the receiver-operating characteristic curve of 0.83-0.88.</p><p><strong>Discussion: </strong>Our findings suggest that oral dysbiosis may be involved in the development of migraine and highlight specific oral microbes as potential diagnostic biomarkers and therapeutic targets for migraine.</p>","PeriodicalId":19472,"journal":{"name":"Neurology® Neuroimmunology & Neuroinflammation","volume":"12 5","pages":"e200437"},"PeriodicalIF":7.5,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12221161/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144699181","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cerebrospinal 14-3-3 Protein Levels as a Neuroaxonal Biomarker in Aquaporin-4 Antibody-Positive Neuromyelitis Optica Spectrum Disorder.","authors":"Javier Villacieros-Álvarez, Maria Sepulveda, Adrián Valls-Carbó, Nicolas Fissolo, Alessandro Dinoto, Victoria Fernández, Andreu Vilaseca, Georgina Arrambide, Lucia Gutierrez, Mireia Castillo, Luca Bollo, Carmen Espejo, Sara Llufriu, Yolanda Blanco, Thais Armangue, Gary Álvarez Bravo, Ana Quiroga-Varela, Lluís Ramió Torrentà, Alvaro Cobo-Calvo, Mar Tintore, Jan D Lünemann, Albert Saiz, Sara Mariotto, Xavier Montalban, Manuel Comabella","doi":"10.1212/NXI.0000000000200432","DOIUrl":"10.1212/NXI.0000000000200432","url":null,"abstract":"<p><strong>Background and objectives: </strong>To investigate whether CSF 14-3-3 protein levels discriminate aquaporin-4 antibody-positive neuromyelitis optica spectrum disorder (AQP4-NMOSD) from myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) and multiple sclerosis (MS) and the association of CSF 14-3-3 protein levels with clinical features in patients with AQP4-NMOSD.</p><p><strong>Methods: </strong>This was a multicentric retrospective cohort study of patients with AQP4-NMOSD, MOGAD, and MS, with available CSF samples. 14-3-3 protein levels were quantified using ELISA and compared between the 3 conditions. In patients with AQP4-NMOSD, the association between CSF 14-3-3 protein levels and disability outcomes was explored.</p><p><strong>Results: </strong>A total of 134 patients were included (AQP4-NMOSD, n = 29; MOGAD, n = 43; MS, n = 62). Patients with AQP4-NMOSD had higher 14-3-3 protein levels (median [interquartile range] 4,441.37 [3,240.05-11526.41] arbitrary units (AU)/mL) compared with those with MS (3,169.86 [2,522.65-3,748.57], <i>p</i> = 0.001) and MOGAD (3,112.95 [2,367.37-3,889.43], <i>p</i> = 0.004). Patients with AQP4-NMOSD presenting with optic neuritis had lower 14-3-3 levels compared with those with other phenotypes (<i>p</i> < 0.001). In AQP4-NMOSD, 14-3-3 levels associated with Expanded Disability Status Scale (EDSS) at attack (β [95%CI] 0.33 [0.15-0.52], <i>p</i> = 0.003) and predicted final EDSS ≥ 6.0 (odds ratio 9.48 [1.69; 194.34]; <i>p</i> = 0.041) in patients with myelitis.</p><p><strong>Discussion: </strong>The study suggests a potential role of CSF 14-3-3 protein levels as a biomarker of neuroaxonal damage in AQP4-NMOSD, because of its ability to correlate with disease severity and predict poor clinical recovery.</p><p><strong>Classification of evidence: </strong>This study provides Class IV evidence that in individuals presenting with acute myelitis, CSF 14-3-3 differentiates AQP4-NMOSD from MS or MOGAD with a sensitivity of 0.60 (0.30-0.80) and specificity of 0.95 (0.84-1.00).</p>","PeriodicalId":19472,"journal":{"name":"Neurology® Neuroimmunology & Neuroinflammation","volume":"12 5","pages":"e200432"},"PeriodicalIF":7.8,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12221159/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144529041","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Neuronal Autoantibodies in Adults After Community-Acquired Bacterial Meningitis.","authors":"Steven L Staal, Liora Ter Horst, Juliette Brenner, Diederik van de Beek, Maarten J Titulaer, Matthijs C Brouwer","doi":"10.1212/NXI.0000000000200454","DOIUrl":"10.1212/NXI.0000000000200454","url":null,"abstract":"<p><strong>Background and objectives: </strong>Long-term cognitive impairment is observed in 14%-32% of patients surviving community-acquired bacterial meningitis. We hypothesized that the impairment might be linked to secondary immune activation due to the development of neuronal autoantibodies, similar to postinfectious autoimmune encephalitis after viral encephalitis.</p><p><strong>Methods: </strong>In this cross-sectional observational study, we included adult patients from a prospective, nationwide cohort study of community-acquired bacterial meningitis in the Netherlands, the MeninGene study. The presence of neuronal autoantibodies was evaluated in follow-up serum samples at 7 days, at 3 months, or over a year. Immunohistochemistry on complete rat brain slices was performed for the initial screening. If positive or ambiguous, immunocytochemistry using live primary rat hippocampal neurons and cell-based assays expressing extracellular targets were performed; immunoblots were used for intracellular targets.</p><p><strong>Results: </strong>In total, 118 patients were included, of whom 24 of 100 (24%) had cognitive impairment and 14 of 109 (13%) had focal neurologic deficits at discharge. Causative pathogens were <i>Streptococcus pneumoniae</i> in 98 patients (83%), <i>Neisseria meningitidis</i> in 4 (3%), and other pathogens in 6 (5%); in 10 patients (9%), no causative pathogen was identified. Two of 118 patients (2%) had neuronal autoantibodies in follow-up serum: 1 had leucine-rich glioma inactivated 1 antibodies, and 1 had unspecified antibodies. None of the patients was positive for NMDA receptor antibodies.</p><p><strong>Discussion: </strong>There was no clear evidence of postinfectious autoimmune encephalitis after bacterial meningitis. Therefore, acute brain damage caused by the infection itself seems to be the most plausible explanation for long-term cognitive impairment and neurologic disabilities.</p>","PeriodicalId":19472,"journal":{"name":"Neurology® Neuroimmunology & Neuroinflammation","volume":"12 5","pages":"e200454"},"PeriodicalIF":7.8,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12270495/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144650035","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Synaptic Density in Multiple Sclerosis: An In Vivo Study Using [¹¹C]UCB-J-PET Imaging.","authors":"Amelie Luoma, Markus Matilainen, Jouni Mikael Tuisku, Richard Aarnio, Taru Nikkilä, Sini Laaksonen, Mikko Koivumäki, Eveliina Honkonen, Marjo Nylund, Saara Wahlroos, Olof Solin, Ming-Kai Chen, Takuya Toyonaga, Jussi Lehto, Anniina Snellman, Juha O Rinne, Laura M Airas","doi":"10.1212/NXI.0000000000200435","DOIUrl":"10.1212/NXI.0000000000200435","url":null,"abstract":"<p><strong>Background and objectives: </strong>Multiple sclerosis (MS) is a chronic inflammatory disease coupled with neurodegenerative processes affecting both the white matter and gray matter (GM) in the CNS. Several histopathologic studies have reported a reduction in synaptic density in various areas of the brain. However, this pathologic feature is yet an unexplored entity among people with MS (pwMS). Therefore, we sought to investigate synaptic loss in vivo by quantifying the synaptic vesicle glycoprotein 2A using [¹¹C]UCB-J-PET imaging and to explore associations with clinical and cognitive measures.</p><p><strong>Methods: </strong>Ten pwMS and 8 healthy controls (HCs) underwent high-resolution [¹¹C]UCB-J-PET imaging and MRI. SV2A availability was determined using the tissue-to-plasma concentration ratio at equilibrium (distribution volume; V_T). We furthermore explored associations between PET imaging results and clinical and cognitive measures in pwMS (assessed with the Expanded Disability Status Scale (EDSS) and Symbol Digit Modalities Test [SDMT]). In addition, we considered volumetric, clinical, and cognitive measures during a 5-year period before PET imaging.</p><p><strong>Results: </strong>Ten pwMS (7 women [70%], median [interquartile range] age, 53 [50-56]) years were compared with 8 HCs (6 women [75%]; age, 51 [50-70] years). PwMS had a significantly lower SV2A availability in the cortical GM (pwMS: mean [SD], V_T = 15.65 mL/cm³ [2.26]; HCs: V_T = 18.14 mL/cm³ [2.09]; <i>p =</i> 0.029, <i>t</i> test), as well as in several subcortical regions. Moreover, a lower SV2A availability in cortical GM correlated significantly with reduced SDMT values in pwMS (<i>r</i> = 0.071, <i>p</i> = 0.021; Spearman correlation coefficient). No association between physical disability (measured using EDSS) and SV2A availability was found.</p><p><strong>Discussion: </strong>Using in vivo [¹¹C]UCB-J PET imaging, we provide evidence of reduced synaptic density in pwMS. Furthermore, the results reveal a link between synaptic loss and cognitive impairment. These findings highlight the potential of [¹¹C]UCB-J PET imaging as a promising tool for assessing clinically relevant aspects of GM pathology in MS.</p>","PeriodicalId":19472,"journal":{"name":"Neurology® Neuroimmunology & Neuroinflammation","volume":"12 5","pages":"e200435"},"PeriodicalIF":7.8,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12227148/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144560689","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"N-Glycan-Dependent Proinflammatory Effects of IgM in Anti-MAG Neuropathy.","authors":"Jean Neil, François Fenaille, Arnaud Bruneel, Tanya Stojkovic, Sophie Cholet, Emilien Delmont, Pauline Ober, Alexandre Raynor, Quentin Amiot, Karim Dorgham, Karine Viala, Pascale Ghillani-Dalbin, Guy Gorochov, Delphine Sterlin","doi":"10.1212/NXI.0000000000200440","DOIUrl":"10.1212/NXI.0000000000200440","url":null,"abstract":"<p><strong>Background and objectives: </strong>Anti-myelin-associated glycoprotein (anti-MAG) neuropathy is a chronic demyelinating neuropathy with deposits of IgM and sural nerve fiber demyelination. While growing evidence supports the critical role of IgG glycosylation in autoimmune diseases, IgM glycosylation profiles markedly differ from those of IgG but are largely neglected. The aim of this study was to characterize IgM N-glycosylation in patients with anti-MAG neuropathy and its involvement in anti-MAG pathogenicity.</p><p><strong>Methods: </strong>IgM antibodies were isolated from patients with anti-MAG neuropathy (n = 17), asymptomatic patients with monoclonal gammopathy of undetermined significance (n = 8), and healthy donors ([HDs], n = 6). N-glycan analysis was performed using mass spectrometry. Binding to myelin-associated glycoprotein (MAG), complement (C1q), and IgM Fc receptors (Fcα/μR and DC-SIGN) was compared using ELISA between anti-MAG and MGUS IgM, before and after N-deglycosylation/desialylation. Finally, we assessed how IgM N-glycosylation influences cytokine production by monocyte-derived macrophages by measuring cytokine levels in culture supernatants.</p><p><strong>Results: </strong>Anti-MAG IgM exhibited a unique glycosylation pattern, dominated by fucosylated, monosialylated N-glycan with a bisecting N-acetyl glucosamine (N-glycan 12), representing 48.5% of the total N-glycan pool, compared with 27.3% in MGUS IgM and 35.6% in HD IgM. We showed that deglycosylation and desialylation significantly reduced anti-MAG activity and C1q binding (average % of decrease 58.3 ± 18.8, <i>p</i> < 0.01, and 40.0 ± 19.9%, <i>p</i> < 0.05, respectively). Furthermore, anti-MAG IgM binding to C1q was significantly higher than that of MGUS IgM and HD IgM (<i>p</i> < 0.0001 and <i>p</i> < 0.001, respectively). Compared with MGUS IgM, anti-MAG IgM also significantly increased the production of proinflammatory cytokines IL-1, IL-6, IL-8, TNF-α, and IFN-Υ by macrophages, in a glycan-dependent manner (<i>p</i> < 0.01 to <i>p</i> < 0.001), with IL-8 being particularly elevated. Finally, we found that anti-MAG IgM bound more strongly Fcα/μ receptor and DC-SIGN compared with MGUS IgM (<i>p</i> < 0.05 and <i>p</i> = 0.06).</p><p><strong>Discussion: </strong>This study uncovered a unique N-glycosylation pattern of anti-MAG IgM, crucial for its interaction with MAG and binding to C1q. Moreover, anti-MAG IgM increased the macrophage cytokine production, driven by their glycosylation. The increased IL-8 expression and anti-MAG IgM binding to C1q might open 2 potential therapeutic avenues: inhibiting IL-8 activity or targeting the complement pathway. In addition, the glycosylation and C1q binding of anti-MAG IgM could serve as biomarkers for monitoring this neuropathy.</p>","PeriodicalId":19472,"journal":{"name":"Neurology® Neuroimmunology & Neuroinflammation","volume":"12 5","pages":"e200440"},"PeriodicalIF":7.5,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12316464/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144760652","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Unraveling Microstructural and Macrostructural Brain Age Dynamics in Multiple Sclerosis.","authors":"Xinjie Chen, Po-Jui Lu, Mario Ocampo-Pineda, Alessandro Cagol, Sabine Anna Schaedelin, Esther Ruberte, Matthias Weigel, Federico Spagnolo, Pascal Benkert, Johanna Maria Lieb, David Leppert, Özgür Yaldizli, Johanna Oechtering, Marcus D'Souza, Bettina Fischer-Barnicol, Tobias J Derfuss, Clara Ekerdt, Willeke M Menks, Kwok-Shing Chan, Marcel Zwiers, Andrew Chan, Robert Hoepner, Franca Wagner, Caroline Pot, Renaud A Du Pasquier, Sebastian Finkener, Michael Diepers, Claire Bridel, Patrice H Lalive, Marjolaine Uginet, Claudio Gobbi, Chiara Zecca, Emanuele Pravatà, Giulio Disanto, Patrick Roth, Jochen Vehoff, Stefanie Mueller, Olaf Chan-Hi Kim, Ludwig Kappos, Jens Kuhle, Lester Melie-Garcia, José P Marques, Cristina Granziera","doi":"10.1212/NXI.0000000000200459","DOIUrl":"10.1212/NXI.0000000000200459","url":null,"abstract":"<p><strong>Background and objectives: </strong>In multiple sclerosis (MS), neurodegeneration results from the interplay between disease-specific pathology and normal aging. Conventional MRI captures morphologic changes in neurodegeneration, while quantitative MRI (qMRI) provides biophysical measures of microstructural alterations. Combining these modalities may reveal how aging and pathology interact and contribute to disability progression in people with MS.</p><p><strong>Methods: </strong>We analyzed cross-sectional and longitudinal morphometry data from 1,353 patients with MS and 3,462 healthy controls (HCs). In addition, cross-sectional qMRI data, available for 378 HCs and 169 patients with MS, were analyzed separately. Morphometric measures and quantitative metrics were used to estimate brain-predicted age differences (brain-PADs) with machine learning. We assessed the added value of quantitative metrics over a model based exclusively on morphometric measures in brain age prediction. We also investigated the associations of brain-PADs derived from conventional and qMRI-based predictive models with clinical disability, serum inflammatory biomarkers of neuroaxonal and astrocytic injury, and lesion burden.</p><p><strong>Results: </strong>Models combining morphometry and qMRI data achieved the best performance (mean absolute error: 5.73), outperforming those based on qMRI (6.62) or morphometry alone (8.00). Cross-sectional and longitudinal morphometry-based brain-PAD correlated with clinical disability, serum neurofilament light chain, and serum glial fibrillary acidic protein levels (all <i>p</i> < 0.01), with significant longitudinal interactions with time (all <i>p</i> < 0.05). Cross-sectional qMRI-based brain-PAD correlated with white matter lesion count (<i>p</i> = 0.042, <i>R</i>^<i>2</i> = 0.028) and paramagnetic rim lesion volume (<i>p</i> = 0.028, <i>R</i>^<i>2</i> = 0.020).</p><p><strong>Discussion: </strong>Integrating qMRI improves brain age predictions. Brain-PAD serves as an imaging biomarker to quantify MS-associated aging and track disability and neuroinflammation progression.</p>","PeriodicalId":19472,"journal":{"name":"Neurology® Neuroimmunology & Neuroinflammation","volume":"12 5","pages":"e200459"},"PeriodicalIF":7.5,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12366035/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144883378","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Comorbidities and Their Influence on Outcomes and Infectious Complications in Autoimmune Encephalitis: A Multicenter Cohort Study.","authors":"Amelie Bohn, Klemens Angstwurm, Christian G Bien, Kathrin Doppler, Lena Ehmke, Joachim Havla, Frank Hoffmann, Dominica Hudasch, Jaqueline Klausewitz, Franz Felix Konen, Mirjam Korporal-Kuhnke, Andrea Kraft, Tania Kümpfel, Frank Leypoldt, Marie Madlener, Lena K Pfeffer, Steffen Pfeuffer, Duygu Pul, Anna Rada, Sebastian Rauer, Christopher Sänger, Thomas Seifert-Held, Kurt-Wolfram Sühs, Franziska S Thaler, Thanos Tsaktanis, Benjamin Vlad, Klaus-Peter Wandinger, Jonathan Wickel, Simone C Tauber","doi":"10.1212/NXI.0000000000200434","DOIUrl":"10.1212/NXI.0000000000200434","url":null,"abstract":"<p><strong>Background and objectives: </strong>Comorbidities greatly influence the course of many diseases. However, systematic data on comorbidities in patients with autoimmune encephalitis (AE) are scarce. We aimed to characterize comorbidities in patients with common AE variants and assess their influence on outcome and occurrence of infectious complications.</p><p><strong>Methods: </strong>This multicenter, retrospective cohort study analyzed adult patients with definite anti-N-methyl-d-aspartate receptor (NMDAR), anti-leucine-rich glioma-inactivated-1 (LGI1), anti-contactin-associated protein-like-2 (CASPR2), and anti-immunoglobulin-like cell adhesion molecule-5 (IgLON5) AE registered by the GErman NEtwork for REsearch on AuToimmune Encephalitis between June 2004 and July 2023. Preexisting conditions (PECs), secondary diagnoses, and infectious complications documented during hospitalization were analyzed. Outcome was evaluated using a modified Rankin Scale (mRS), with unfavorable outcome defined as mRS >2 after a minimum of 12 months of follow-up.</p><p><strong>Results: </strong>Among 308 patients with AE (144 NMDAR-AE, 98 LGI1-AE, 47 CASPR2-AE, and 19 IgLON5-AE), nearly half had cardiovascular and metabolic/endocrine, one-third neurologic, and one-fifth psychiatric comorbidities. Accompanying autoimmunity was observed in 12.7%. Univariable analysis showed that the presence of ≥3 PECs (OR 2.80, 95% CI 1.57-4.92), especially cardiovascular (OR 1.93, 95% CI 1.09-3.30) and psychiatric PECs (OR 3.84, 95% CI 1.96-7.31), was associated with unfavorable outcome. Multivariable regression analysis confirmed psychiatric PECs as independent risk factors (OR 4.55, 95% CI 1.99-10.60). During hospitalization, 13.6% of patients developed severe infections, although these were not associated with unfavorable outcome (OR 1.94, 95% CI 0.97-3.89). AE disease severity (OR 5.41, 95% CI 1.38-27.67) and intensive care unit admission emerged as the only independent predictors of severe infections (OR 20.76, 95% CI 7.02-75.10).</p><p><strong>Discussion: </strong>As premorbid psychiatric conditions are main factors associated with unfavorable outcomes, these patients would highly benefit from integrated interdisciplinary treatment centers, or at least heightened awareness of these factors. Concomitant autoimmunity affecting other organs is frequent and should be sought. The risk of severe infections during the acute phase of AE is moderate and, given their lack of effect on outcome, should not justify withholding appropriate immunotherapy, even in elderly patients with comorbidities. Future prognostic models should incorporate comorbidities, particularly psychiatric ones, to enhance risk assessment and guide personalized care strategies.</p>","PeriodicalId":19472,"journal":{"name":"Neurology® Neuroimmunology & Neuroinflammation","volume":"12 5","pages":"e200434"},"PeriodicalIF":7.8,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12258818/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144584383","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"AChR Autoantibody Pathogenic Properties Are Heterogeneously Distributed and Undergo Temporal Changes Among Patients With Myasthenia Gravis.","authors":"Fatemeh Khani-Habibabadi, Bhaskar Roy, Minh C Pham, Abeer H Obaid, Beata Filipek, Richard J Nowak, Kevin C O'Connor","doi":"10.1212/NXI.0000000000200436","DOIUrl":"10.1212/NXI.0000000000200436","url":null,"abstract":"<p><strong>Background and objectives: </strong>Acetylcholine receptor (AChR) autoantibodies contribute to myasthenia gravis (MG) pathogenesis through 3 mechanisms: complement activation, receptor internalization, and acetylcholine (ACh) binding site blocking. Recently approved therapies target these autoantibodies by inhibiting the complement pathway or blocking the neonatal Fc receptor, reducing IgG autoantibody levels. However, these approaches have limitations: complement inhibitors do not address complement-independent mechanisms, and FcRn blockers only target IgG. Understanding how different pathogenic mechanisms, isotypes, and IgG subclasses are represented in the AChR autoantibody repertoire could lead to more precise application of therapeutics. To address this, we used advanced live cell-based assays to study autoantibody heterogeneity in longitudinally collected patient samples.</p><p><strong>Methods: </strong>Serum samples (N = 210) from 50 AChR IgG+ generalized MG patients collected longitudinally over 2 years were evaluated using a set of cell-based assays to measure complement activation, receptor internalization, ACh binding site blocking, and the frequency of the IgM and IgA isotypes and IgG subclasses.</p><p><strong>Results: </strong>In cross-sectional samples, IgA and IgM autoantibodies co-occurred with IgG in 10% and 12% of patients, respectively. In addition, 4% of patients had all 3 isotypes (IgA, IgM, and IgG) present simultaneously. AChR-IgG1 was found in 67.4%, followed by IgG3 (21.7%) and IgG2 (17.4%). Complement was active in 84.8%, followed by AChR internalization (63%) and blocking (30.4%). Complement and AChR internalization were simultaneously active in 45.6%, complement and blocking were active in 10.8%, and all 3 pathomechanisms were active in 17.4%. Blocking alone was active in only 2.1%; AChR internalization alone was not found. Autoantibody binding capacity was associated with the magnitude of complement activation and AChR internalization. Temporal fluctuations of autoantibody binding capacity and the associated pathogenic mechanisms were observed. Pathogenic mechanisms were not associated with disease severity in cross-sectional analyses. However, longitudinally, disease severity measures followed a similar trend to the AChR autoantibody repertoire and mediated pathogenic mechanisms in some individuals, but not others.</p><p><strong>Discussion: </strong>These findings highlight subsets of patients with MG with autoantibodies that can mediate pathogenic mechanisms or include isotypes that some therapeutics may not effectively target. Consequently, we suggest incorporating comprehensive autoantibody profiling into future MG clinical trials to further investigate potential associations with treatment outcomes.</p>","PeriodicalId":19472,"journal":{"name":"Neurology® Neuroimmunology & Neuroinflammation","volume":"12 5","pages":"e200436"},"PeriodicalIF":7.8,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12275905/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144663972","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"COVID-19 Vaccine Boosters in People With Multiple Sclerosis: Improved SARS-CoV-2 Cross-Variant Antibody Response and Prediction of Protection.","authors":"Avani Yeola, Samuel Houston, Anupriya Aggarwal, Rashmi Gamage, Vicki E Maltby, Marzena J Fabis-Pedrini, Linh Le-Kavanagh, Vera Merheb, Kristy Nguyen, Fiona X Z Lee, Susan Walters, Marinda Taha, Annmaree O'Connell, Vilija G Jokubaitis, Angie Roldan, Mastura Monif, Helmut Butzkueven, Sandeep Sampangi, Louise Rath, Katherine Fazzolari, Todd A Hardy, Heidi N Beadnall, Michael H Barnett, Allan G Kermode, Christopher Dwyer, Tomas Kalincik, Simon A Broadley, Stuart G Turville, Stephen W Reddel, Sudarshini Ramanathan, Jeannette Lechner-Scott, Anneke Van Der Walt, Fabienne Brilot","doi":"10.1212/NXI.0000000000200443","DOIUrl":"10.1212/NXI.0000000000200443","url":null,"abstract":"<p><strong>Background and objectives: </strong>Although disease-modifying therapies (DMTs) may suppress coronavirus disease 2019 (COVID-19) vaccine responses in people with multiple sclerosis (pwMS), limited data are available on the cumulative effect of additional boosters. Maturation of Spike immunoglobulin G (IgG) to target a greater diversity of SARS-CoV-2 variants, especially past the BA.1 variant, has not been reported. In addition, the prediction of variant-specific protection, given that Spike antibody testing is not performed routinely, remains a challenge. We, therefore, evaluated whether additional vaccine doses improved the breadth of cross-variant recognition to target emerging SARS-CoV-2 variants. Machine learning-based models were designed to predict variant-specific protection status.</p><p><strong>Methods: </strong>In a prospective observational cohort (n = 442), Spike IgG titers and live virus neutralization against D614, BA.1, BA.2, BA.5, XBB.1.1, XBB.1.5, and EG.5.1 variants were determined in 1,011 serum samples (0-12 months after 2-4 doses). Predictive protection models were developed by K-fold cross-validation on training and test data sets (random split 70:30).</p><p><strong>Results: </strong>After primary vaccination, pwMS on immunosuppressive disease-modifying therapy (IMM-DMT) had 10-fold and 7.2-fold lower D614 Spike IgG titers than pwMS on low-efficacy (LE)-DMT and cladribine (<i>p</i> < 0.01). After 4 doses, pwMS on IMM-DMT had significantly lower Spike IgG titers, compared with pwMS on low-efficacy disease-modifying therapy, for D614 (<i>p</i> < 0.05), as well as BA.1, BA.2, BA.5, XBB.1, XBB.1.5, and EG.5.1(<i>p</i> < 0.01). The breadth of Spike IgG to recognize variants other than the cognate antigen increased after 4 doses of all DMTs. Although pwMS on IMM-DMT displayed reduced cross-variant recognition, a fourth dose resulted in a 2-4-fold increase in protection against newer variants and a reduction in two-thirds of pwMS without protective Spike IgG (<i>p</i> < 0.0001). Tixagevimab and cilgavimab did not induce additional cross-variant protection. Variant-specific predictive models of vaccine protection were influenced by treatment, time since primary vaccination, and age, with high sensitivity (99.4%, 95% CI 96.8-99.99) and specificity (72.0%, 95% CI 50.6-87.9) for XBB.1.5/EG.5.1 variants.</p><p><strong>Discussion: </strong>Despite not eliciting adequate antibody response in pwMS on IMM-DMT, COVID-19 boosters improve the breadth of the humoral response against SARS-CoV-2 emerging variants. Vaccine protection can be predicted by statistical modeling.</p>","PeriodicalId":19472,"journal":{"name":"Neurology® Neuroimmunology & Neuroinflammation","volume":"12 5","pages":"e200443"},"PeriodicalIF":7.8,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12285670/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144691133","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}