Neurology® Neuroimmunology & Neuroinflammation最新文献

{"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":"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":"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}

{"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":7.5,"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":"Immune Checkpoint Inhibitors Trigger and Exacerbate Anti-CV2/CRMP5 Paraneoplastic Neurologic Syndromes.","authors":"Giulia Sofia Cereda, Macarena Villagrán-García, Antonio Farina, Marie Benaiteau, Cristina Birzu, Arnaud Sautereau, Melih Bayrak, Géraldine Picard, Dimitri Psimaras, Véronique Rogemond, Bastien Joubert, Jérôme Honnorat","doi":"10.1212/NXI.0000000000200446","DOIUrl":"10.1212/NXI.0000000000200446","url":null,"abstract":"<p><strong>Background and objectives: </strong>Immune checkpoint inhibitors (ICIs) are oncologic treatments that may trigger or worsen paraneoplastic neurologic syndromes (PNSs). This study describes patients with CV2/CRMP5-PNS treated by ICI, compares the post-ICI group with ICI-naïve patients with CV2/CRMP5-PNS, and estimates the overall survival of ICI-treated patients with CV2/CRMP5-PNS, Hu-PNS, and Ma2-PNS.</p><p><strong>Methods: </strong>The medical records of patients positive for anti-CV2/CRMP5 antibodies were retrospectively reviewed at the French Reference Centre to identify those treated with ICI (2016-2024). Patients with a preexisting PNS were described separately from those with post-ICI PNS; the latter were then compared with ICI-naïve patients with CV2/CRMP5-PNS diagnosed in the same study period. An overall survival analysis between ICI-treated patients with CV2/CRMP5-PNS, Hu-PNS, and Ma2-PNS was performed.</p><p><strong>Results: </strong>Fourteen patients with CV2/CRMP5-PNS treated with ICIs were included. Eight patients [median age, 73 years (range: 60-87); 87.5% men] developed post-ICI PNS after a median of 3.5 ICI cycles (range: 1-7). The frequency and distribution of clinical phenotypes (isolated neuropathy [n = 3] or a multifocal neurologic involvement [encephalopathy, limbic syndrome, brainstem syndrome, cerebellar syndrome, ocular syndrome, neuropathy, and/or dysautonomia; n = 5]) were similar to those of ICI-naïve CV2/CRMP5-PNS (n = 48). The frequency of severe presentations (modified Rankin Scale [mRS] score > 3) at diagnosis was similar between post-ICI patients and ICI-naïve patients with CV2/CRMP5-PNS (63% vs 48%, <i>p</i> = 0.7) and slightly higher at last visit in post-ICI patients (88% vs 54%, <i>p</i> = 0.12). Anti-CV2/CRMP5 antibodies were undetectable in the only patient with a pre-ICI serum sample. Among the 6 patients with preexisting CV2/CRMP5-PNS [median age, 66 years (range: 54-79); 50% men] who received ICIs, PNS symptoms worsened in 5 (83%) [median mRS increase of 1.5 points (range: 1-3)]. The median overall survival (22 months) was significantly longer in the ICI-treated patients with CV2/CRMP5-PNS compared with the Hu-PNS and Ma2-PNS groups (4 months and 8 months, respectively, <i>p</i> = 0.0069).</p><p><strong>Discussion: </strong>ICIs may trigger the onset and exacerbate the progression of CV2/CRMP5-PNS. Post-ICI forms are clinically undistinguishable but possibly more severe than their ICI-naïve counterparts. Increased surveillance is needed in identifying preexisting PNSs, with extreme caution when considering ICI treatment. Post-ICI-induced PNSs have variable prognosis according to the associated onconeural autoantibodies.</p>","PeriodicalId":19472,"journal":{"name":"Neurology® Neuroimmunology & Neuroinflammation","volume":"12 5","pages":"e200446"},"PeriodicalIF":7.8,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12275902/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144663975","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":"Serum Levels of Aryl Hydrocarbon Receptor Plasma Agonist Activity Are Reduced in Patients With NMOSD and Correlate With Disease Activity.","authors":"Thanos Tsaktanis, Leander Ammon, Lena Lößlein, Anne Peter, Oliver Vandrey, Ulrike J Naumann, Megan Behne, Lawrence J Cook, Michael Levy, Michael R Yeaman, Jeffrey L Bennett, Veit Rothhammer","doi":"10.1212/NXI.0000000000200457","DOIUrl":"10.1212/NXI.0000000000200457","url":null,"abstract":"<p><strong>Background and objectives: </strong>Neuromyelitis optica spectrum disorders (NMOSDs) are severe autoimmune diseases characterized by recurrent CNS inflammation and high risk of persistent disability. Effective disease monitoring is essential for timely intervention and relapse prevention. While biomarkers such as soluble glial fibrillary acidic protein and neurofilament light chain indicate astrocytic and neuronal damage, additional markers are needed to improve disease monitoring and treatment strategies. The ligand-activated transcription factor aryl hydrocarbon receptor (AHR) is a key immune regulator in autoimmune diseases such as multiple sclerosis, where its ligands correlate with disease activity. Given overlapping immunologic pathways, AHR signaling may also influence NMOSD pathophysiology. In this context, this study examines serum levels of AHR ligand in NMOSD, assessing their regulation and association with disease activity. Elucidating the role of AHR signaling may pave the way to explore novel markers of disease activity and therapeutic intervention in NMOSD.</p><p><strong>Methods: </strong>AHR agonistic activity was assessed in the serum of 102 patients with aquaporin-4 antibody-positive NMOSD across various stages of the disease. As control, serum samples from 36 patients with noninflammatory diseases were evaluated for AHR agonistic activity. In addition, we measured AHR activity longitudinally in 10 individuals at 3 distinct time points-during a quiescent phase preceding relapse, at relapse, and during a postrelapse quiescent phase-to evaluate the dynamic changes in AHR activity over time.</p><p><strong>Results: </strong>Serum AHR agonistic activity was globally decreased in the NMOSD cohort compared with the control group. AHR agonistic activity was further reduced during or near relapses. Finally, we conducted longitudinal analyses on individual serum samples obtained from patients with NMOSD. Our findings reveal that AHR activity significantly decreases during the relapse phase compared with the quiescent phase, with a subsequent recovery after relapse.</p><p><strong>Discussion: </strong>Serum AHR agonistic activity is reduced in patients with NMOSD compared with controls and further modulated in temporal vicinity to a relapse. Furthermore, our longitudinal analysis confirmed that AHR activity is markedly reduced during relapse, underscoring its dynamic modulation in relation to disease activity. AHR agonist activity might represent a potential tool to monitor disease activity and develop novel therapeutic strategies.</p><p><strong>Classification of evidence: </strong>This study provides Class III evidence that serum levels of AHR agonistic activity are reduced in patients with NMOSD compared with noninflammatory controls, and that these levels are further modulated across different stages of the disease.</p>","PeriodicalId":19472,"journal":{"name":"Neurology® Neuroimmunology & Neuroinflammation","volume":"12 5","pages":"e200457"},"PeriodicalIF":7.5,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12363339/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144789567","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":"Real-Life Evaluation of the MOGAD Diagnostic Criteria: Application Challenges and Discrepancies.","authors":"Sara Carta, Elia Sechi, Alessandro Dinoto, Chiara Mancinelli, Giacomo Greco, Giorgia Teresa Maniscalco, Sara Cornacchini, Maria Pia Giannoccaro, Francesca Calabria, Alessandro Marziali, Stefano Masciocchi, Mario Risi, Alberto Cossu, Irene Volonghi, Gaetano Cantalupo, Marco Zoccarato, Riccardo Orlandi, Elisabetta Del Zotto, Diana Ferraro, Milena Trentinaglia, Stefano De Biase, Luisa Grazian, Francesca Caleri, Maria Rachele Bianchi, Patrizia Rossi, Eleonora Virgilio, Marco Capobianco, Rosa Cortese, Carla Tortorella, Francesca Rossi, Giovanna De Luca, Anna Perelli, Silvia Bozzetti, Luigi Zuliani, Margherita Nosadini, Stefano Sartori, Laura Brambilla, Alberto Gajofatto, Alberto Vogrig, Luca Massacesi, Valentina Damato, Matteo Gastaldi, Sara Mariotto","doi":"10.1212/NXI.0000000000200456","DOIUrl":"10.1212/NXI.0000000000200456","url":null,"abstract":"<p><strong>Background and objectives: </strong>Myelin oligodendrocyte glycoprotein (MOG) antibody-associated disease (MOGAD) international panel criteria have been recently proposed to guide MOGAD diagnosis. The aim of this study was to evaluate the criteria performance and assess the discrepancies in their application in the clinical practice in an Italian multicenter cohort and to discuss some challenging aspects.</p><p><strong>Methods: </strong>We applied the 2023 MOGAD criteria to patients who tested MOG-Abs positive on cell-based assays and were retrospectively recruited from 29 centers. Detailed clinical and paraclinical data were collected. Patients were classified as true positive/negative (TP/TN) in case of concordance between MOGAD criteria application and enrolling center final diagnosis, as false positive (FP) when MOGAD criteria were fulfilled but final diagnosis was different from MOGAD, and as false negative (FN) when MOGAD criteria were not fulfilled and final diagnosis of MOGAD was confirmed. Central revision of FN and FP cases was performed.</p><p><strong>Results: </strong>We included 214 patients (median age at onset 38.2 years [interquartile range 25.2-50.7], 60.3% female, 23 pediatric patients). Of these, 168 (78.5%) were classified as TP, 9 (4.2%) as FP, 23 (10.7%) as FN, and 14 (6.5%) as TN. The sensitivity of MOGAD criteria was 87.96% (CI 82.5%-92.2%), specificity 60.9% (CI 38.5%-80.3%), positive predictive value 94.9% (CI 91.8%-96.9%), negative predictive value 37.8% (CI 26.7%-50.2%), and accuracy 85.1% (CI 79.6%-89.5%). In 11 of 32 revised cases, available information did not allow a proper diagnosis. Independent revision changed the diagnosis in 17 of 21 remaining cases, increasing the performance of the MOGAD criteria. Of note, in 3 cases, diagnostic criteria were satisfied only at follow-up. The sensitivity and specificity after independent revision were 98.9% (CI 96%-99.9%) and 91.7% (CI 73%-98.9%), respectively. Moreover, 29 of 214 patients (13.6%) had 1 or more asymptomatic radiologic supportive features, and in 50% (3/6) of FP cases, independent revision did not confirm the presence of supportive features. Patients with clear positive serum titer or CSF-only MOG-Abs were those who received more commonly a MOGAD diagnosis.</p><p><strong>Discussion: </strong>MOGAD criteria demonstrate a good performance across different centers; however, controversial cases might benefit from collegial discussion and reassessment of MOGAD criteria during the follow-up. Main challenges include availability of proper radiologic data and interpretation of radiologic supportive features.</p>","PeriodicalId":19472,"journal":{"name":"Neurology® Neuroimmunology & Neuroinflammation","volume":"12 5","pages":"e200456"},"PeriodicalIF":7.5,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12366032/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144883377","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":"Multiple Sclerosis in the Emergency Department: A Retrospective Case-Control Study in a Large US Center.","authors":"Siddharth Satish, Amrapali Patel, Maya Latey Mastick, Seungwon Lee, Gladia C Hotan, Andrew Siyoon Ham, Farrah Jasmine Mateen","doi":"10.1212/NXI.0000000000200445","DOIUrl":"10.1212/NXI.0000000000200445","url":null,"abstract":"<p><strong>Background and objectives: </strong>The reasons for people with multiple sclerosis (MS) to access emergency services are understudied in the era of high-efficacy disease-modifying therapies (DMTs). Many people with MS live with multiple comorbidities and/or experience social determinants of health, which may affect their emergency department (ED) use. The aim of this study was to identify the reasons and risk factors for ED visits among patients with known MS, including sociodemographic characteristics, comorbidity burden, and DMT efficacy category.</p><p><strong>Methods: </strong>A retrospective case-control study was conducted at the Massachusetts General Hospital, Boston. Patients with MS were analyzed in a 1:2 ratio of cases (patients with at least one ED visit) and controls (no ED visits) during the study time frame June 2019-December 2023. Regression models were constructed to assess the association of predefined variables-sex, age, race, insurance type, comorbidities as a Charlson Comorbidity Index (CCI), and DMT efficacy category-with the likelihood of an ED visit.</p><p><strong>Results: </strong>Of 1,462 evaluated people with MS, 900 were randomly selected and included: 300 cases and 600 controls. Most patients were female (70.7% cases, 74.7% controls) and White (79.0% cases, 87.2% controls). Cases had a higher mean CCI score (0.83 points) compared with controls (0.05 points). Many people with MS were not taking a DMT (64.3% cases, 39.5% controls). ED utilization showed that 52.0% of patients had a single visit, with COVID-19 being the most common diagnosis (4.2%). 10.3% of people with MS who went to the ED had more than 5 visits during the study time frame. In a multivariable model, higher CCI score was the strongest predictor of ED visits (odds ratio [OR] = 4.23, <i>p</i> < 0.001). No DMT use (OR = 2.56, <i>p</i> < 0.001) and having public or no insurance (OR = 1.99, <i>p</i> < 0.001) each increased the likelihood of an ED visit while identifying as a racial minority led to a lower likelihood of an ED visit (OR = 0.48, <i>p</i> = 0.006).</p><p><strong>Discussion: </strong>Specific risk factors for ED use occur in people with known MS. Comprehensive management of comorbidities and clinical pathways to reassess the high number of people with MS in the ED who do not take a DMT should be considered.</p>","PeriodicalId":19472,"journal":{"name":"Neurology® Neuroimmunology & Neuroinflammation","volume":"12 5","pages":"e200445"},"PeriodicalIF":7.8,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12273709/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144659785","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":"Clinical Characterization and Long-Term Outcome in Children and Adults With Anti-AMPA Receptor Encephalitis.","authors":"Chiara Milano, Ezgi Saylam, Claudia Papi, Laura Marmolejo, Alexandra Sankovic, Raphael Reinecke, Jeroen Kerstens, Chiara Pizzanelli, Mateus Mistieri Simabukuro, Marie Benaiteau, Bastien Joubert, Matteo Gastaldi, Lívia Almeida Dutra, Frank Leypoldt, Mareike Jansen, Izumi Kawachi, Hisanao Akiyama, Nikolas Boy, Silvia Bozzetti, Peter Broegger Christensen, Pietro Businaro, Alessandro Dinoto, Tal Friedman-Korn, Urara Fujiwara, Tatsuya Fukumoto, Kenshiro Fuse, Sam Ishmael Hooshmand, Lauren Hurst, Raffaele Iorio, Isabelle Korn-Lubetzki, André Filipe Lucchi Rodrigues, Sara Mariotto, Johannes Michael, Yuko Morimoto, Rinze Frederik Neuteboom, Amanda L Piquet, Andrea O Rossetti, Sabine Rumpler-Kreiner, Jonathan D Santoro, Florian Schwendinger, Brenda Shen, Steffen Syrbe, Johannes Troger, Ingrid Wagner, Christian G Bien, Eugenia Martinez-Hernandez, Thais Armangue, Romana Höftberger, Takahiro Iizuka, Maarten J Titulaer, Jerome Honnorat, Francesc Graus, Josep O Dalmau, Setty Magaña, Marianna Spatola","doi":"10.1212/NXI.0000000000200453","DOIUrl":"10.1212/NXI.0000000000200453","url":null,"abstract":"<p><strong>Background and objectives: </strong>Anti-alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptor (anti-AMPAR) encephalitis manifests as limbic encephalitis in adults and is often associated with cancer. Although some reports suggest that it may occur in children, the clinical features in this population, as well as the prognostic factors and long-term outcomes in children and adults, are unknown.</p><p><strong>Methods: </strong>We performed a retrospective, international collaborative study of patients with anti-AMPAR encephalitis. Clinical information was reviewed, together with data from published pediatric patients. Clinical features of children and adults were compared with nonparametric tests. Survival rates (Kaplan-Meier curves) were compared using log-rank tests. Prognostic factors of poor outcome (modified Rankin Scale score >2) were identified using logistic regression models.</p><p><strong>Results: </strong>A total of 115 patients were included, of whom 84 (71 adults, 13 children) had only AMPAR antibodies and 31 (27 adults, 4 children) had additional concurrent neural antibodies. Among patients with AMPAR antibodies alone, tumors were identified in 37 adults (56%) and none of the children (<i>p</i> < 0.0001). Children were more likely than adults to have behavioral/psychiatric symptoms (5/13, 39%, vs 8/71, 11%, <i>p</i> = 0.026) at onset, cerebellar dysfunction (6/13, 46%, vs 7/68, 10% <i>p</i> = 0.005) or movement disorders (5/13, 39%, vs 8/67, 12%, <i>p</i> = 0.032) during the disease course, and extratemporal brain MRI lesions (4/9, 44%, vs 5/44, 11%, <i>p</i> = 0.035). Among 34 patients with prolonged follow-up (>24 months), long-term neurocognitive sequelae were reported in 23 (68%), all adults. Failure to respond to first-line immunotherapy at multivariable analysis predicted a poor outcome (OR 8.0, 95% CI 1.1-59.2, <i>p</i> = 0.043). Among the 31 patients with concurrent neural autoantibodies, 22 (79%) had a tumor; those with high-risk antibodies had lower survival rates (<i>p</i> = 0.008).</p><p><strong>Discussion: </strong>Children and adults with anti-AMPAR encephalitis show distinct clinical-radiologic features. At long-term follow-up, 68% of patients, all adults, have neurologic sequelae, with failure to respond to first-line immunotherapy being associated with worse outcomes.</p>","PeriodicalId":19472,"journal":{"name":"Neurology® Neuroimmunology & Neuroinflammation","volume":"12 5","pages":"e200453"},"PeriodicalIF":7.8,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12275903/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144663973","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}