Neurology® Neuroimmunology & Neuroinflammation最新文献

{"title":"Abatacept Induces Long-Term Reconstitution of the B-Cell Niche in a Patient With CTLA-4 Haploinsufficiency: A Case Report.","authors":"Steffen Pfeuffer, Christopher Nelke, Marc Pawlitzki, Tobias Ruck, Christina B Schroeter, Christian Thomas, Guido Kobbe, Sascha Dietrich, Alexander A Zimprich, Heinz Wiendl, Sven G Meuth","doi":"10.1212/NXI.0000000000200351","DOIUrl":"10.1212/NXI.0000000000200351","url":null,"abstract":"<p><strong>Objectives: </strong>Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) haploinsufficiency is a rare genetic condition characterized by development of immune cytopenia, hypogammaglobulinemia, and/or lymphoproliferative disorder, as well as multiple autoimmunity. Treatment with abatacept was shown to alleviate autoimmune conditions, yet its long-lasting impact on bone marrow function remains undetermined.</p><p><strong>Methods: </strong>We here present the case of a now 39-year-old woman with CTLA-4 haploinsufficiency with predominant CNS affection, yet multiorgan autoimmunity and lymphopenia. We conducted single-cell RNA sequencing (scRNA-seq) of peripheral mononuclear blood cells before and after abatacept induction.</p><p><strong>Results: </strong>After several high-efficacy immunosuppressive treatments with little-to-no response, she started abatacept in 2017 and experienced ongoing remission including resolution of pre-existing immune cytopenia and hypogammaglobulinemia. Using scRNA-seq, we were able to demonstrate reconstitution of peripheral B cells accompanied by reduction of CD8⁺ T cells. CD4⁺ and CD8⁺ T cells were characterized by downregulation of pathways involved in activation of innate immune cells.</p><p><strong>Discussion: </strong>Our findings demonstrate long-lasting resolution of lymphopenia after abatacept treatment in CTLA-4 haploinsufficiency despite severity and duration of symptoms. Thus, abatacept should be considered throughout before stem cell transplantation also in CTLA-4 haploinsufficiency with severe symptoms.</p><p><strong>Classification of evidence: </strong>As a single report without controls, this report provides class IV evidence that abatacept might revert lymphopenia in patients with CTLA-4 haploinsufficiency.</p>","PeriodicalId":19472,"journal":{"name":"Neurology® Neuroimmunology & Neuroinflammation","volume":"12 2","pages":"e200351"},"PeriodicalIF":7.8,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11655169/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142847393","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":"Contribution of Blood Biomarkers to Multiple Sclerosis Diagnosis.","authors":"Manuel Comabella, Agustín Pappolla, Enric Monreal, Nicolás Fissolo, Augusto Cesaar Sao-Avilés, Georgina Arrambide, Pere Carbonell-Mirabent, Lucía Gutierrez, Álvaro Cobo-Calvo, Carmen Tur, Javier Villacieros-Álvarez, Ángela Vidal-Jordana, Joaquín Castilló, Ingrid Galán, Mercedes Espiño, Helena Ariño, Luca Bollo, Marta Rodríguez Barranco, Luciana Soledad Midaglia, René Carvajal, Noelia Villarrubia, José Ignacio Fernández Velasco, Breogán Rodríguez Acevedo, Lucienne F Costa Frossard, Andreu Vilaseca, Cristina Auger, Ana Zabalza, Susana Sainz De La Maza, Neus Mongay-Ochoa, Jordi Río, Jaume Sastre-Garriga, Àlex Rovira, Mar Tintoré, Luisa M Villar, Xavier Montalban","doi":"10.1212/NXI.0000000000200370","DOIUrl":"10.1212/NXI.0000000000200370","url":null,"abstract":"<p><strong>Background and objectives: </strong>Invasive procedures may delay the diagnostic process in multiple sclerosis (MS). We investigated the added value of serum neurofilament light chain (sNfL), glial fibrillary acidic protein (sGFAP), chitinase-3-like 1 (sCHI3L1), and the immune responses to the Epstein-Barr virus-encoded nuclear antigen 1 to current MS diagnostic criteria.</p><p><strong>Methods: </strong>In this multicentric study, we selected patients from 2 prospective cohorts presenting a clinically isolated syndrome (CIS). Patients were classified as (1) not presenting dissemination in space (DIS) nor dissemination in time (DIT) (noDIS and noDIT); (2) presenting DIS without DIT (DIS and noDIT); and (3) presenting both (DIS and DIT), which were used as a reference. sNfL, sGFAP, and sCHI3L1 levels were measured with single-molecule array immunoassays and EBNA1-specific IgG levels with ELISA. Biomarker levels were compared between groups using linear regression models. Receiver operating characteristic curve analyses and Youden Index were used to determine cutoff values associated with MS diagnosis during follow-up.</p><p><strong>Results: </strong>We included 181 patients (66.3% females, mean [SD] age of 35.0 [9.7] years). At baseline, 25 (13.8%) were classified as noDIS and noDIT, 62 (34.3%) as DIS and noDIT, and 94 (51.9%) as DIS and DIT. Only sNfL Z-scores discriminated between groups (DIS and DIT vs DIS and noDIT [<i>p</i> = 0.002], DIS and DIT vs noDIS and noDIT [<i>p</i> < 0.001], and DIS and noDIT vs noDIS and noDIT [<i>p</i> = 0.026]). In noDIS and noDIT patients (median interquartile range [IQR] follow-up of 8.1 [5.0-11.7] years), high sNfL Z-scores best predicted MS diagnosis (specificity [SP] and 95% CI of 93.3% [68.1-99.8] and positive predictive value [PPV] of 87.5% [47.3-99.7]). Among DIS and noDIT patients (median [IQR] follow-up of 6.8 [4.0-9.1] years), high sNfL Z-scores best predicted MS diagnosis (SP of 80% [28.4-99.5] and PPV of 97.3% [85.8-99.9]) without considering oligoclonal band (OB) status. In the subset of patients of this group with negative OBs, a combination of high sNfL Z-scores and sGFAP levels predicted MS diagnosis (SP of 100% [39.8-100] and PPV of 100% [54.1-100]).</p><p><strong>Discussion: </strong>These results suggest that sNfL and sGFAP may be incorporated in particular scenarios to diagnose MS in patients with CIS not fulfilling current diagnostic criteria.</p>","PeriodicalId":19472,"journal":{"name":"Neurology® Neuroimmunology & Neuroinflammation","volume":"12 2","pages":"e200370"},"PeriodicalIF":7.8,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11781269/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143067123","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":"Aberrant Complement Activation Is Associated With Structural Brain Damage in Multiple Sclerosis.","authors":"Johanna Oechtering, Sabine Anna Schaedelin, Kerstin Stein, Aleksandra Maleska Maceski, Lester Melie-Garcia, Pascal Benkert, Alessandro Cagol, Selina Leber, Riccardo Galbusera, Esther Ruberte, Wayne Hu, Ferhan Qureshi, Annette Orleth, Lilian Demuth, Eline Willemse, Ingmar Heijnen, Axel Regeniter, Tobias J Derfuss, Bettina Fischer-Barnicol, Lutz Achtnichts, Stefanie Mueller, Robert Hoepner, Patrice H Lalive, Claire Bridel, Marcus D'Souza, Caroline Pot, Renaud A Du Pasquier, Claudio Gobbi, Chiara Zecca, Heinz Wiendl, Johanna Maria Lieb, Christina Lamers, Ludwig Kappos, Marten Trendelenburg, David Leppert, Cristina Granziera, Jens Kuhle, Jan D Lünemann","doi":"10.1212/NXI.0000000000200361","DOIUrl":"https://doi.org/10.1212/NXI.0000000000200361","url":null,"abstract":"<p><strong>Background and objectives: </strong>Levels of activated complement proteins in the CSF are increased in people with multiple sclerosis (MS) and are associated with clinical disease severity. In this study, we determined whether complement activation profiles track with quantitative MRI metrics and liquid biomarkers indicative of disease activity and progression.</p><p><strong>Methods: </strong>Complement components and activation products (Factor H and I, C1q, C3, C4, C5, Ba, Bb, C3a, C4a, C5a, and sC5b-9) and liquid biomarkers (neurofilament light chain, glial fibrillary acidic protein [GFAP], CXCL-13, CXCL-9, and IL-12b) were quantified in the CSF of 112 patients with clinically isolated syndromes and 127 patients with MS; longitudinal MRIs according to a standardized protocol of the Swiss MS cohort were assessed. We used multivariable models to analyze associations of the 12 complement parameters as individual independent variables and longitudinal brain volumes, T2-weighted (T2w) lesion volumes, contrast-enhancing (CELs) and paramagnetic rim lesions (PRLs), and molecular biomarkers as dependent variables, respectively.</p><p><strong>Results: </strong>Strongest associations with accelerated brain atrophy were found for C4a: doubling of C4a CSF levels was associated with an additional brain volume loss of -0.24% (95% CI -0.31% to -0.16%; <i>p</i> < 0.0001) per year, followed by Ba and C3a (-0.22% [-0.29% to -0.15%]) and -0.13% ([-0.21 to -0.06]; both <i>p</i> < 0.001). Doubling of C3a, Ba, and C4a levels correlated with 2.2- (1.6-3.0; <i>p</i> < 0.0001), 2.0- (1.3-3.1; <i>p</i> = 0.0038), and 1.8-fold (1.2-2.6; <i>p</i> = 0.0029) increased longitudinal T2w lesion volumes; C3a and Ba were associated with 2.5- (1.4-4.6; <i>p</i> = 0.0022) and 3.3-fold (1.5-7.2; <i>p</i> = 0.0024) higher odds for CELs and 2.6- (1.7-4.0; <i>p</i> < 0.0001) and 2.3-fold (1.3-4.3; <i>p</i> = 0.006) increased PRL incidence rates. C1q, C3a, and C4a were associated with higher GFAP levels, and CXCL-13, CXCL-9, and IL-12b analyses showed consistent patterns with strongest associations for C1q, followed by Ba, C3a, and C4a.</p><p><strong>Discussion: </strong>Intrathecal complement activation is consistently associated with MRI metrics and liquid biomarkers indicative for MS disease activity and progression. Our results demonstrate that aberrant complement activation is strongly associated with structural brain damage in MS. Therapeutic targeting of the complement system might limit disability accumulation due to MS.</p>","PeriodicalId":19472,"journal":{"name":"Neurology® Neuroimmunology & Neuroinflammation","volume":"12 2","pages":"e200361"},"PeriodicalIF":7.8,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142927652","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Novel Approaches to Treatment of Immune-Mediated Chronic Intestinal Pseudo-Obstruction.","authors":"Andreu Vilaseca, Paula Arranz, Arnau Llaurado, Ana Zabalza, Elianet Gisell Fonseca, Inmaculada Medina, Maria Amelia Gómez Lorente, Luis Alcalá-González, Natalia Borruel, José Luis Fernández-Forcelledo, Helena Ariño, Thais Armangue, Xavier Montalban, Francesc Graus, Carolina Malagelada","doi":"10.1212/NXI.0000000000200369","DOIUrl":"10.1212/NXI.0000000000200369","url":null,"abstract":"<p><strong>Background and objectives: </strong>The optimal immunosuppressive treatment for autoimmune chronic intestinal pseudo-obstruction (CIPO) is unknown due to lack of clinical trials. Even less data exist on treatment recommendations for patients who do not respond to first-line immunotherapy.</p><p><strong>Methods: </strong>We describe 4 patients with autoimmune CIPO treated with vedolizumab (3/4), a monoclonal antibody that interferes the lymphocyte trafficking to the gastrointestinal tract, or rituximab (1/4) who did not respond to steroids or IV immunoglobulins. We made a systematic review of previously published cases of CIPO treated with these biological agents.</p><p><strong>Results: </strong>Vedolizumab was effective in 2 of 3 patients but failed in a child with nonparaneoplastic anti-Hu-associated CIPO, who had generalized dysautonomia. The 2 patients who responded to vedolizumab had an isolated CIPO, and they did not present neuronal antibodies. Rituximab was prescribed in a case of anti-Hu-associated, nonparaneoplastic CIPO, who showed a complete clinical response after this treatment. Our review of the literature retrieved 4 previous cases of autoimmune CIPO treated with rituximab but none treated with vedolizumab. All patients treated with rituximab had Hu antibodies. Two patients showed a clinical response to the treatment with rituximab.</p><p><strong>Discussion: </strong>Our findings underscore the potential efficacy of rituximab and vedolizumab in the management of autoimmune CIPO refractory to first-line treatments.</p>","PeriodicalId":19472,"journal":{"name":"Neurology® Neuroimmunology & Neuroinflammation","volume":"12 2","pages":"e200369"},"PeriodicalIF":7.8,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143256306","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Fluorescein Angiography as a Surrogate Marker of Disease Activity in Susac Syndrome.","authors":"Laura Guttieres, Lea Vannelli, Sarah Demortiere, Marine Perriguey, Maya Elziere, Pierre Durozard, Clemence Boutiere, Audrey Rico, Frederic Hilezian, Jan-Patrick Stellmann, Jean Pelletier, Adil Maarouf, Natacha Stolowy, Bertrand Audoin","doi":"10.1212/NXI.0000000000200379","DOIUrl":"10.1212/NXI.0000000000200379","url":null,"abstract":"<p><strong>Objectives: </strong>To evaluate the sensitivity of fluorescein angiography (FA) in detecting disease activity in Susac syndrome.</p><p><strong>Methods: </strong>We conducted a blinded analysis of all FA, brain MRI, and audiogram examinations performed throughout the follow-up of patients with Susac syndrome.</p><p><strong>Results: </strong>A total of 79 FA examinations, 85 brain MRI scans, and 49 audiograms were analyzed from 9 patients followed for a mean (SD) period of 6 (4) years. Disease activity was detected in 41.5% of FA examinations, 10.5% of MRI scans, and 25% of audiograms (FA vs MRI, <i>p</i> < 0.0001; FA vs audiogram, <i>p</i> = 0.06; audiogram vs MRI, <i>p</i> < 0.05). Within 3 months of clinical relapses, activity was observed in 57%, 24%, and 27% of FA, MRI, and audiogram examinations, respectively (FA vs MRI, <i>p</i> < 0.05; FA vs audiogram, <i>p</i> = 0.09; audiogram vs MRI, <i>p</i> = 1). Quantitative analysis of FA showed a mean (SD) of 2.5 (2.5) leakages (both eyes) during relapses compared with 1.2 (1.4) during remission (<i>p</i> < 0.05).</p><p><strong>Discussion: </strong>FA, particularly arterial leakage, demonstrated the highest sensitivity in detecting disease activity and may be a valuable tool for treatment management in Susac syndrome. Future studies with larger samples should aim to identify the optimal threshold of FA changes associated with an increased risk of relapse.</p>","PeriodicalId":19472,"journal":{"name":"Neurology® Neuroimmunology & Neuroinflammation","volume":"12 2","pages":"e200379"},"PeriodicalIF":7.8,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143256299","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Impaired Presynaptic Function Contributes Significantly to the Pathology of Glycine Receptor Autoantibodies.","authors":"Anna-Lena Wiessler, Fang Zheng, Christian Werner, Margarita Habib, Erdem Tuzun, Christian Alzheimer, Claudia Sommer, Carmen Villmann","doi":"10.1212/NXI.0000000000200364","DOIUrl":"https://doi.org/10.1212/NXI.0000000000200364","url":null,"abstract":"<p><strong>Background and objectives: </strong>Autoantibodies (aAbs) against glycine receptors (GlyRs) are mainly associated with the rare neurologic diseases stiff person syndrome (SPS) and progressive encephalomyelitis with rigidity and myoclonus (PERM). GlyR aAbs are also found in other neurologic diseases such as epilepsy. The aAbs bind to different GlyR α-subunits and, more rarely, also to the GlyR β-subunit. So far, studies on the pathogenic effects of the aAbs have focused on postsynaptic, heteromeric GlyRs, reporting a loss of ion channel function and receptor internalization upon aAb binding. We asked whether the aAbs also affect expression and functionality of presynaptic homomeric GlyRs.</p><p><strong>Methods: </strong>We established interneuron cultures from mouse embryonic spinal cord neurons and used protein biochemistry and super-resolution microscopy to determine aAb binding to presynaptic GlyRs in a uniform neuronal subpopulation. Brainstem slice recordings were used to detect functional alterations.</p><p><strong>Results: </strong>Several days-long exposure of spinal cord cultures with GlyR aAbs did not change expression levels of proteins building a functional glycinergic synapse. A notable exception was the enhanced expression of presynaptic glycine transporter 2 (GlyT2), possibly reflecting an adaptation to altered synaptic properties. Super-resolution microscopy revealed rather similar binding of patient-derived aAbs to postsynaptic vs presynaptic sites with individual binding preferences. Although characterization of interneurons showed absence of GlyRα1 in some interneuron subpopulations, GlyRα2 and patient serum signals exhibited a significantly higher colocalization in samples with presynaptic preference. This finding identifies GlyRα2 as the hitherto unknown predominant presynaptic GlyR subunit in the spinal cord and a target of patient aAbs. Whole-cell recordings from glycinergic neurons in mouse brainstem slices underscored the functional relevance of presynaptic aAb binding demonstrated by a significant reduction in the frequency of spontaneous and miniature inhibitory postsynaptic potentials.</p><p><strong>Discussion: </strong>In summary, our study is the first to implicate presynaptic defects in the pathophysiology of autoimmune diseases such as SPS and PERM, which are associated with GlyR aAbs. Individually tuned binding preferences for presynaptic and postsynaptic targets thus underlie the rather diverse appearance of clinical symptoms and different therapeutic responses in patients suffering from GlyR autoimmunity.</p>","PeriodicalId":19472,"journal":{"name":"Neurology® Neuroimmunology & Neuroinflammation","volume":"12 2","pages":"e200364"},"PeriodicalIF":7.8,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11741293/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143009113","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":"Long-Term Clinical and Biological Prognostic Factors of Anti-NMDA Receptor Encephalitis in Children.","authors":"Maxime Mazowiecki, Lorraine Flet-Berliac, Julia Roux, Anne Lépine, Pascale Chretien, Salima Hacein-Bey-Abina, Laetitia Giorgi, Frederic Villega, Emmanuel Cheuret, Marie Benaiteau, Veronique Rogemond, Geraldine Picard, Sarah Baer, Pierre Cleuziou, Elodie Lametery, Isabelle Desguerre, Mélodie Aubart, Mathilde Chevignard, Roger Le Grand, Philippe Horellou, Carole Leroy, Bastien Joubert, Jerome Honnorat, Kumaran Deiva","doi":"10.1212/NXI.0000000000200346","DOIUrl":"10.1212/NXI.0000000000200346","url":null,"abstract":"<p><strong>Background and objectives: </strong>Anti-NMDAR encephalitis (NMDARE) is a severe neurologic condition, and recently, the NMDAR Encephalitis One-Year Functional Status (NEOS) score has emerged as a 1-year prognostic tool. This study aimed to evaluate NEOS score and biomarker (neurofilament light chains [NfL], total-Tau protein, glial fibrillary acidic protein, and serum cytokines) correlation with modified Rankin Scale (mRS), cognitive impairment, and clinical recovery in pediatric NMDARE over 2 years.</p><p><strong>Methods: </strong>In this French multicenter observational study, 104 pediatric patients with NMDARE were followed for a minimum of 2 years. Clinical data and serum/plasma samples were collected. Biomarker levels, measured using electroluminescence mesoscale discovery (MSD) S-PLEX, were compared between patients and controls and assessed for correlations with disease activity, mRS, cognitive/language impairment, and recovery status at 2 years.</p><p><strong>Results: </strong>At a median follow-up of 39.5 months, 68 percent of patients had unfavorable recovery and 54% had significant cognitive impairment. Both outcomes were strongly associated with younger age at diagnosis (OR 6.10 [1.91-27.3] <i>p</i> < 0.01 and 5.69 [1.46-27.7] <i>p</i> = 0.02, respectively). A higher NEOS score was significantly correlated with increased cognitive impairment (OR 2.53 [1.52-4.21], <i>p</i> < 0.001), higher mRS scores (OR 2.12 [1.34-3.57], <i>p</i> < 0.01), and unfavorable recovery at 2 years (OR 2.00 [1.30-3.06], <i>p</i> = 0.015). Elevated NfL levels were significantly associated with unfavorable recovery (OR 3.62 [1.29-10.9] <i>p</i> = 0.012) and severe cognitive impairment (OR 3.77 [1.38-10.9] <i>p</i> = 0.012) at 2 years. The combined area under the curve (AUC) for NfL and NEOS was significantly higher than the AUCs of NEOS and NfL alone <i>(p</i> = 0.01).</p><p><strong>Discussion: </strong>The NEOS score strongly predicts long-term outcomes in NMDARE, with its predictive value extending beyond the first-year mR prediction. NfL levels at disease onset seem to improve accuracy in predicting poor outcomes, providing valuable information for treatment decisions and future clinical trials.</p>","PeriodicalId":19472,"journal":{"name":"Neurology® Neuroimmunology & Neuroinflammation","volume":"12 2","pages":"e200346"},"PeriodicalIF":7.8,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142882632","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dysregulation of the Kynurenine Pathway in Relapsing Remitting Multiple Sclerosis and Its Correlations With Progressive Neurodegeneration.","authors":"Ananda Staats Pires, Shivani Krishnamurthy, Samridhi Sharma, Sharron Chow, Samuel Klistorner, Gilles J Guillemin, Alexander Klistorner, Yuyi You, Benjamin Heng","doi":"10.1212/NXI.0000000000200372","DOIUrl":"10.1212/NXI.0000000000200372","url":null,"abstract":"<p><strong>Background and objectives: </strong>Despite the absence of acute lesion activity in multiple sclerosis (MS), chronic neurodegeneration continues to progress, and a potential underlying mechanism could be the kynurenine pathway (KP). Prolonged activation of the KP from chronic inflammation is known to exacerbate the progression of neurodegenerative diseases through the production of neurotoxic metabolites. Among the 8 KP metabolites, six of them, namely kynurenine (KYN), 3-hydroxylkynurenine (3HK), anthranilic acid (AA), kynurenic acid (KYNA), and quinolinic acid (QUIN), have been associated with neurodegeneration.</p><p><strong>Methods: </strong>To gain insights into the links between the KP and neurodegeneration in MS, we investigated the KP metabolomics profile of relapsing remitting MS (RRMS) patients and their correlation with parameters of neurodegeneration in brain and retinal. Outpatients with a clinical diagnosis of RRMS (n = 98) or age-matched and sex-matched healthy controls (n = 39) were included. MS participants undertook yearly evaluation of MRI and optical coherence tomography scan to evaluate neuroaxonal loss. Blood samples were collected at the baseline from all participants for the biochemical analysis of KP metabolites.</p><p><strong>Results: </strong>We identified increased plasma levels of AA and 3HAA in the MS group, indicating an anti-inflammatory response alongside active neurodegeneration. By contrast, plasma levels of KYNA and 3HK were lower in the MS group than in healthy controls. Our analysis revealed a higher KYN:tryptophan (TRP) and QUIN:KYNA ratios in the MS cohort, suggesting activation of the pathway toward the production of neurotoxic QUIN. Another important finding was that KP metabolites were correlated with measures of axonal degeneration in patients with MS. Notably, central brain atrophy positively correlated with the TRP levels, but negatively correlated with KYN and level KYN:TRP ratio. Finally, the choroid plexus volume was inversely correlated with KYNA plasma levels.</p><p><strong>Discussion: </strong>These findings highlight changes in the biosynthesis of KP during the progression of RRMS and its correlation with axonal loss. This study underscores the potential of targeting the KP in developing novel treatments for neuroaxonal damage in MS and warrants future research in greater depth.</p>","PeriodicalId":19472,"journal":{"name":"Neurology® Neuroimmunology & Neuroinflammation","volume":"12 2","pages":"e200372"},"PeriodicalIF":7.8,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11744609/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143009112","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 Manifestations and Treatment Responses in Pediatric Neurofascin 155-IgG4 Autoimmune Nodopathy.","authors":"Hebatallah R Rashed, Naveen Kumar Paramasivan, Duygu Selcen, P James B Dyck, Smathorn Thakolwiboon, Michelle L Mauermann, John Mills, Divyanshu Dubey","doi":"10.1212/NXI.0000000000200368","DOIUrl":"10.1212/NXI.0000000000200368","url":null,"abstract":"<p><strong>Background and objectives: </strong>While it is well characterized in adults, little is known about the clinical features of neurofascin 155-IgG4 autoimmune nodopathy (NF155-IgG4 AN) in the pediatric population. In this study, we aimed to describe the clinical features and treatment outcomes in children diagnosed with neurofascin 155-IgG4 autoimmune nodopathy (NF155-IgG4 AN).</p><p><strong>Methods: </strong>Pediatric and adult patients with NF155-IgG4 AN were identified retrospectively through the Mayo Clinic Neuroimmunology Laboratory database.</p><p><strong>Results: </strong>Eight pediatric and 20 adult patients with NF155-IgG4 AN were included with a median age at onset of 11 and 43 years, respectively. Pediatric patients (3/8) were often diagnosed initially with Guillain-Barre syndrome compared with adults (2/20) (<i>p</i> = 0.123). Six pediatric patients deteriorated beyond 2 months with rapid progression to disease nadir compared with adults (22 vs 52 weeks, <i>p</i> = 0.04). All had distal predominant weakness with paresthesias. Four patients had tremor, and one had cerebellar ataxia. Sensory ataxia was significantly less common in pediatric patients (4/8) compared with adults (18/20) (<i>p</i> = 0.038). Most pediatric patients (6/7) were IVIG refractory and responded to rituximab. Six patients had favorable outcomes after immunotherapy with improvement ≥1 in the Inflammatory Neuropathy Cause and Treatment disability score.</p><p><strong>Discussion: </strong>Pediatric patients with NF155-IgG4 AN display an aggressive disease course with rapid progression to disease nadir compared with adults. Sensory ataxia is less common in children, and they often respond to rituximab. It is crucial to consider autoimmune nodopathies in the differential diagnosis of pediatric patients with suspected inflammatory demyelinating polyneuropathy and to test for NF155-IgG4 antibodies because of their diagnostic and therapeutic implications.</p><p><strong>Classification of evidence: </strong>This study provides Class IV evidence that in pediatric patients with NF155-IgG4 AN who are refractory to IVIG, rituximab treatment provided some benefit.</p>","PeriodicalId":19472,"journal":{"name":"Neurology® Neuroimmunology & Neuroinflammation","volume":"12 2","pages":"e200368"},"PeriodicalIF":7.8,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11744604/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143009110","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":"Conformational Antibodies to Proteolipid Protein-1 and Its Peripheral Isoform DM20 in Patients With CNS Autoimmune Demyelinating Disorders.","authors":"Stefano Masciocchi, Pietro Businaro, Giacomo Greco, Silvia Scaranzin, Antonio Malvaso, Chiara Morandi, Elisabetta Zardini, Mario Risi, Elisa Vegezzi, Luca Diamanti, Paola Bini, Sabrina Siquilini, Maria Pia Giannoccaro, Luana Morelli, Rocco Liguori, Francesco Patti, Valeria De Giuli, Emilio Portaccio, Chiara Zanetta, Stefania Bergamoni, Anna Maria Simone, Roberta Lanzillo, Giorgia Bruno, Antonio Gallo, Alvino Bisecco, Massimiliano Di Filippo, Flavia Pauri, Antonella Toriello, Paolo Barone, Francesco Tazza, Sebastiano Bucello, Paola Banfi, Martina Fabris, Irene Volonghi, Loredana Raciti, Maria Claudia Vigliani, Tommaso Bocci, Matteo Paoletti, Elena Colombo, Massimo Filippi, Anna Pichiecchio, Enrico Marchioni, Diego Franciotta, Matteo Gastaldi","doi":"10.1212/NXI.0000000000200359","DOIUrl":"10.1212/NXI.0000000000200359","url":null,"abstract":"<p><strong>Background and objectives: </strong>Antibodies to proteolipid protein-1 (PLP1-IgG), a major central myelin protein also expressed in the peripheral nervous system (PNS) as the isoform DM20, have been previously identified mostly in patients with multiple sclerosis (MS), with unclear clinical implications. However, most studies relied on nonconformational immunoassays and included few patients with non-MS CNS autoimmune demyelinating disorders (ADDs). We aimed to investigate conformational PLP1-IgG in the whole ADD spectrum.</p><p><strong>Methods: </strong>We devised a new live cell-based assay (CBA) for PLP1-IgG and used it to test 2 cohorts (retrospective exploratory, n = 284; prospective validation, n = 824) of patients with ADDs and controls (n = 177). Patients were classified as MS, neuromyelitis optica spectrum disorders (NMOSDs), myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD), and other ADDs. PLP1-IgG-positive samples were tested for IgG subclasses, DM20-IgG, and on rat brain tissue-based assay (TBA). Complement-dependent cytotoxicity (CDC) was assessed on a live CBA and antigen specificity and conformational binding through immunoadsorption/colocalization/fixation experiments.</p><p><strong>Results: </strong>PLP1-IgG were found in 0 of 177 controls and 42 of 1104 patients with ADDs mainly diagnosed as other ADDs (19/42) with frequent myelitis/encephalomyelitis (14/19) and coexisting PNS involvement (13/19). Four of 19 patients with other ADDs fulfilled the seronegative NMOSD criteria. PLP1-IgG were also found in patients with MOGAD (11/42), more frequently with PNS involvement (<i>p</i> = 0.01), and in patients with MS (12/42), more frequently with atypical features (<i>p</i> < 0.001). PLP1-IgG-positive MOGAD had higher EDSS scores (<i>p</i> < 0.001) and PLP1-IgG-positive MS had higher severity scores (MSSS, <i>p</i> < 0.001) compared with those PLP1-IgG-negative. Overall, PLP1-IgG were found in 24.1% of patients with CNS+PNS-ADD, 21.2% with atypical MS, 8.3% with MOGAD, 12.0% with seronegative NMOSD, and 1.4% with typical MS. Their frequency within each diagnostic subgroup was consistent between the exploratory and validation cohorts. PLP1-IgG a) colocalized with their target on CBA-TBA, where their binding was abolished after immunoadsorption and fixation-induced conformational epitope alteration; b) mostly pertained to the IgG1/IgG3 subclass (68.3%) and were able to induce CDC; and c) coreacted with DM20 in all 12 patients with PNS involvement tested.</p><p><strong>Discussion: </strong>Conformational PLP1-IgG predominantly identify patients with non-MS ADDs. They should be tested mainly in those with CNS + PNS ADD, coherently with DM20-IgG coreactivity. PLP1-IgG could also be investigated as disease modifiers and prognostic markers in MS and MOGAD. Preliminary evidence supports their pathogenic potential.</p>","PeriodicalId":19472,"journal":{"name":"Neurology® Neuroimmunology & Neuroinflammation","volume":"12 2","pages":"e200359"},"PeriodicalIF":7.8,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11744608/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143009111","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}