Citations

Background: Smokers with multiple sclerosis (MS) experience worse disease, yet underlying mechanisms remain unknown. Smoking disrupts bile acid and tryptophan metabolism in non-MS populations; both pathways involve host–microbiome co-metabolism and have been linked to MS. Objective: Determine whether smoking perturbs these metabolic pathways in MS and whether such alterations statistically mediate smoking’s effect on MS severity. Methods: We analyzed serum bile acid, tryptophan, and tobacco-related metabolites across four independent MS cohorts ( N = 266) using discovery-replication analyses. Mixed-effects regression assessed replicating associations with current smoking and nicotine exposure. Mediation analyses tested if replicating metabolites were potential mediators between smoking and MS severity. Hypothesis-generating metagenomic analyses explored smoking-associated gut–microbial shifts and metabolite correlations. Results: Current smokers and nicotine-exposed MS subjects had reductions in bile acids and tryptophan metabolites, notably indolepropionate, a neuroprotective, anti-inflammatory gut–microbial metabolite. Lower indolepropionate statistically mediated ~20% of smoking’s adverse effect on MS severity. Metagenomic analyses identified potential smoking-enriched MS-linked taxa, and that indolepropionate broadly co-occurs with microbial networks (e.g. Lachnoclostridium appeared inversely associated with indolepropionate in smokers with MS). Conclusion: Tobacco exposure disrupts host–microbiome tryptophan and bile acid metabolism in persons with multiple sclerosis, with indolepropionate depletion partially mediating disease severity, highlighting a potential mechanistic pathway warranting further investigation in MS smokers.

Background Psychiatric comorbidities are increasingly recognised in demyelinating diseases, yet their frequency and timing in myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) are not well defined. We aimed to characterise the spectrum and temporal pattern of psychiatric illness in MOGAD and compare to multiple sclerosis (MS) and neuromyelitis optica spectrum disorder (NMOSD) with aquaporin-4 antibody (AQP4-IgG). Methods We conducted a cross-sectional study of patients with MOGAD (n=388), age-matched and sex-matched MS (n=257) and AQP4-IgG-positive NMOSD (n=58) evaluated at Mayo Clinic (1991–2025). Psychiatric diagnoses, timing relative to the first attack and patient-reported outcomes were extracted from electronic health records (EHRs). Complementary analyses were conducted using the NeuroBlu real-world EHR database. Results Among 388 patients with MOGAD, 54.8% had ≥1 psychiatric disorder, most commonly anxiety (47.7%), depression (36.6%) and attention-deficit/hyperactivity disorder (ADHD, 9%). After the first attack, 33.3% of patients with MOGAD developed a new psychiatric disorder, often within the first year. MOGAD showed a lower frequency of depression versus MS (36.6% vs 47.5%, p=0.02) but similar rates of anxiety and ADHD. Temporal patterns differed: psychiatric disorders often appeared years before onset in MS but clustered shortly after onset in MOGAD. NeuroBlu analyses supported high rates of psychiatric disorders across the three conditions. Conclusion Psychiatric comorbidities are common in MOGAD, particularly depression and anxiety, typically emerging close after onset, whereas in MS they often preceded onset by years. These findings underscore the need for routine psychiatric screening in MOGAD and highlight unresolved questions regarding whether, and to what extent, MOG-IgG-mediated inflammatory demyelination contributes to psychiatric vulnerability.

Abstract Description Background Glutamic acid decarboxylase 65 (GAD65) antibodies are found in patients with stiff-person syndrome (SPS), cerebellar ataxia (CA), epilepsy and type-I diabetes (T1D). Given the intracellular localization of the antigenic target, a direct pathogenic role for GAD65 antibody (GAD65Ab) is unlikely. Methods PBMC-derived dendritic cells (DCs) from GAD65Ab+ patients with SPS (n = 6), epilepsy (n = 4), CA (n = 5), or T1D (n = 4) were pulsed with full-length GAD65 proteins or with 15-mer peptides from GAD65. T cell activation, exhaustion, and cytotoxicity were measured via cytometric bead array, FluoroSpot, flow cytometry, and live cell imaging. Results CD8+ T cells from patients with GAD65Ab-associated neurological disorders (AD) were activated by exposure to DCs pulsed with full-length GAD65 (p < 0.01 vs unstimulated, Mann-Whitney test; n = 16). We found 3 peptides of interest that caused a 10-30% increase in activated CD8+ T cells in GAD65AbAD patients, as assessed by surface CD69+ labeling. Using NetMHCpan4.2, we identified 8 different 9-mer peptides with high predicted affinity for HLA-C*03:03/04 and HLA-C*07:01/02. Two of these peptides showed high binding to HLA-C and subsequently demonstrated tetramer labeling of CD8+ T cells in GAD65AbAD patients. Conclusions We demonstrated that both full-length GAD65 protein and specific GAD peptides activated CD8+ T cells derived from patients with GAD65AbAD, indicating a potential pathogenic role for these effectors in these disorders. Funding Sources Support from Aditxt Immune Health Project (EU CT number: 2023-504798-19-00) and the Center for MS and Autoimmune Neurology in Mayo Clinic. Topic Categories Neuroimmunology (NEUR)

Abstract Purpose: Germ cell tumors (GCTs) pose significant diagnostic challenges due to the limited sensitivity and specificity of current tumor markers. Hereby we utilize phage immunoprecipitation sequencing (PhIP-Seq) technique to develop a unique immunosignature panel (iSIGN) with high sensitivity and specificity to improve the diagnosis and differentiation of GCTs. Patients and Methods: Serum samples from patients with confirmed gonadal or extragonadal GCTs and controls were collected from Mayo Clinic repositories. Controls included benign testicular lesions, autoimmune diseases, neurodegenerative disorders, and other cancers. Samples were randomized into development and validation cohorts. PhIP-Seq identified antigen-autoantibody interactions, and enrichment scores were calculated to develop a biomarker panel distinguishing GCT from non-GCT cases. A second biomarker panel was developed to predict seminoma from nonseminoma cases. Results: A total of 427 serum samples were analyzed, including 150 from GCT patients and 277 controls. For our primary model to distinguish GCT cases (GCT-iSIGN), 24 peptides from 16 antigens were identified based on significant differential autoantibody binding enrichment in GCT patients (p < 0.05), ≥2 peptides per antigen, and enrichment scores ≥ 2.5-fold. GCT-iSIGN was highly sensitive (93%) and specific (99%) for identifying GCT cases from controls with an area under curve (AUC) of 0.93 and 9% Unknown Case Rate (UCR). The secondary panel (Sem-iSIGN) included 17 peptides corresponding to 5 unique proteins with high specificity (93%), moderate sensitivity (65%) and AUC of 0.77 to distinguish seminoma from nonseminoma GCT cases. Conclusion: This study demonstrates the potential use of PhIP-Seq to identify unique immunosignature panels that can serve as reliable biomarkers for GCT. These panels address the limitations of traditional markers and other proteomic techniques. This immunosignature model represents a cost-effective, stable, and scalable approach to enhancing GCT diagnosis and management. Citation Format: M Bakri Hammami, Andrew Knight, Haidara Kherbek, Brian Costello, Silvana De Lorenzo, Bradley C. Leibovich, John C. Cheville, Yong Guo, Jessica Sagen, Janet E. Olson, Alicia Algeciras-Schimnich, Sean J. Pittock, John R. Mills, Surendra Dasari, Divyanshu Dubey. iSIGN panel identifies germ cell tumors via whole-proteome phage immunoprecipitation sequencing [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Mechanisms of Cancer Immunity and Cancer-related Autoimmunity; 2025 Sep 24-27; Montreal, QC, Canada. Philadelphia (PA): AACR; Cancer Immunol Res 2025;13(9 Suppl):Abstract nr B027.

Clonus is a disabling symptom of upper motor neuron dysfunction in patients with multiple sclerosis (MS). We report immediate termination of mechanically evoked clonus by epidural lumbosacral spinal cord stimulation (ES) in a 58-year-old man with secondary progressive MS. This observation was captured during training using video and skin surface electromyography of soleus muscle activity. ES immediately reduced mechanically evoked clonus duration and cycle count compared to trials without stimulation, as determined by a Kruskal–Wallis test ( p < 0.05, n = 2–3 trials), and reverted to baseline status when stimulation was off.

Background Falls in people with multiple sclerosis (pwMS) lead to morbidity and expense. Objective Identify clinical metrics associated with falls. Methods Eighty-six pwMS completed fall surveys, timed 25-foot walk (T25FW), and motion analysis with Clario Opal devices. Logistic regression models were created. Results Median age was 54.5 years (range 21–73), 62% (53) were female. The cohort included 58% with relapsing (50) and 42% with progressive MS (36). Those who reported falling in the last year were older (median age 58 vs 52.5, p = .03) and had a higher Patient Determined Disease Step (PDDS) score (median 3 vs 1, p < .0001). Falls were associated with worse balance metrics including sway area (median 2.3 degrees 2 vs 1.2, p = .01), jerk (median 3.3 m 2 /s 5 vs 1.6, p = .005), and slower T25FW (median 11.5 s vs 8; p < .0001). A multivariable regression model based on gait aid use and T25FW time >10.8 s (c = 0.80) was derived. Having both features portended a probability of falling of 0.97, while having neither, a probability of 0.26. Conclusions Falls in pwMS are more frequent in patients who are older, have higher PDDS, slower walking, and worse balance. Gait aid use and T25FW >10.8 s were strongly associated with falls in the past year.