Citations

Background: Tumefactive demyelination (TD) is a rare variant of multiple sclerosis (MS) characterized by tumor-like lesions that often require aggressive management. Genome-wide association studies (GWAS) identified variants associated with MS; similar analyses in TD are lacking. Objective: A GWAS was performed to identify variants associated with TD. Methods: The case–control study included 142 TD cases and 293 controls. TD patients were required to have a demyelinating event and magnetic resonance imaging (MRI) showing one or more lesions. Controls were patients without a neurologic or systemic inflammatory disease or cancer. Logistic regression was used to compare cases versus controls for each variant; age, sex, and principal components were included as covariates. A p -value threshold of 5 × 10 −8 was GWAS significant and 5 × 10 −6 nominally significant. A polygenic risk score (PRS) was compared across TD and controls. Results: Variants on chromosome 14 (rs117797734, p = 2.06 × 10 −11 , odds ratio (OR) = 13.14) and chromosome 6 (most significant rs6936540, p = 5.5 × 10 −7 , OR = 2.61) near DCBLD1 were significant. Seven non-MHC and two MHC variants associated with MS were associated with TD. The PRS was significantly higher in TD versus controls. Conclusion: We identified novel regions associated with TD, demonstrating the importance of performing GWAS in homogeneous subtypes of MS. Further validation and functional experiments are necessary.

ABSTRACT Objectives To investigate the value of cytokine, chemokine, and neurofilament light chain (NfL) concentrations in predicting relapse risk, chronic epilepsy, and functional impairment in LGI1 autoimmune encephalitis (AE). Methods Cytokines/chemokines (IL‐1‐beta, IL‐2, IL‐4, IL‐5, IL‐6, IL‐8/CXCL8, IL‐10, IL‐12p70, IL‐13, IL‐17A, GM‐CSF, TNF‐alpha, IFN‐gamma, CXCL9, CXCL10, CXCL13, BAFF) and NfL concentrations were measured in CSF and paired serum from LGI1‐AE patients evaluated at Mayo Clinic (01/2015–02/2024), using a multiplex immunoassay system (ELLA, Bio‐Techne) and correlated with clinical outcomes. A laboratory‐based cohort of LGI1‐IgG‐positive patients and control cohorts, including patients with mixed non‐inflammatory disorders (MNID), Alzheimer's disease (AD), and temporal lobe epilepsy (TLE) were analyzed. Results Forty‐four patients with LGI1‐AE were included; 29 (66%) were male, with a median age of 68.5 years (range, 8–85). Median time from symptom onset to CSF sampling was eight months (IQR, 3–17); 19/42 (45%) experienced a clinical relapse and 27% developed chronic epilepsy. Serum IL‐6, serum and CSF IL‐8/CXCL8, and IL‐17A were higher in LGI1‐IgG positive patients than MNID ( p < 0.05). TLE cytokine/chemokine profiles were similar to LGI1 AE; AD patients had lower serum IL‐6 and CSF IL‐8/CXCL8 ( p = 0.04; p = 0.01), and higher serum IL‐17A and GM‐CSF ( p = 0.004; p = 0.01) than LGI1‐AE. Higher CSF IL‐6 and IL‐8/CXCL8 in LGI1‐AE associated with clinical relapse ( p < 0.05) and higher CSF NfL associated with chronic epilepsy ( p = 0.01). Conclusion Elevations in IL‐6, IL‐8/CXCL8, and IL‐17A were identified in this LGI1‐AE cohort. CSF IL‐6, IL‐8/CXCL8, and NfL levels are potential prognostic biomarkers for risk of relapse and chronic epilepsy in LGI1‐AE.

Abstract Anti-IgLON5 disease is an autoimmune encephalitis that presents with a heterogenous clinical phenotype, including sleep disorders, movement abnormalities and bulbar involvement. It is characterized by autoantibodies against IgLON5, 85% association with HLA-DQB1*05:∼ and a brainstem-dominant tauopathy. Cellular and murine models report pathogenic effects of the autoantibodies, and neurodegenerative factors suggest progressive atrophy as a common sequela. However, evidence from in vivo patient data and long-term follow-up is limited, and the degree of progression remains elusive. In this multicentre study, clinical and brain MRI data were collected from 127 patients across 12 countries to investigate the relationships between clinical presentations and the development of distinct brain atrophy patterns. Our data show that most patients develop a complex multisystem phenotype as the disease progresses; however, neuromuscular manifestations rarely emerge at later disease stages. By comparison to healthy controls, this disease presents with severe substructure-specific atrophy, especially affecting the hypothalamus, brainstem, accumbens and basal ganglia, which, in age-independent analyses, show significant ventricular enlargement and also suggest progression of brainstem atrophy over the disease course. Moreover, the focality of atrophy was functionally linked to specific symptoms, with more severe involvement of the basal ganglia in patients with movement disorders, and greater atrophy in the hippocampus and thalamus in patients with cognitive impairment. Taken together, our results provide evidence of distinct atrophy patterns in anti-IgLON5 disease, which closely mirror sites of pathophysiologic processes, including autoantibody binding and tau deposition. Our data emphasize the brainstem as the pathophysiological hub of the disease and provide normative data for the incorporation of atrophy measurements into routine clinical assessments and future treatment studies to monitor disease trajectory and evaluate future treatment strategies.

Abstract Organoids, which are tiny, lab-grown 3D structures that mimic some organizational and functional properties of human organs, are slowly transforming the face of systems and developmental biology, biomedical research, pharmaceutical testing, environmental toxin testing, and healthcare. Significant investments are essential for the mass production, preservation, and distribution of organoids, with the aim to accelerate innovation and progress across multiple fields—much like the investments made in cell and biologics manufacturing over the past 2 decades.

Multiple sclerosis is characterized by CNS infiltration of autoreactive immune cells that drive both acute inflammatory demyelination and chronic progressive axonal and neuronal injury. Expanding evidence implicates CD8 + antineural T cells in the neurodegeneration that underlies irreversible clinical progression in multiple sclerosis, yet therapies specifically targeting this cell population are limited. CD8 + T cells from patients with MS exhibit increased engagement of the pentose phosphate pathway. Pharmacologic inhibition of the pentose phosphate pathway reduced glycolysis, glucose uptake, NADPH production, ATP production, proliferation, and proinflammatory cytokine secretion in CD8 + T cells activated by ligation of CD3 and CD28. Pentose phosphate pathway inhibition also prevented CD8 + T cell–mediated antigen-specific neuronal injury in vitro and in both an adoptive transfer–based cuprizone model of demyelination and in mice with experimental autoimmune encephalomyelitis. Notably, transcriptional profiling of CNS-infiltrating CD8 + T cells in patients with MS indicated increased pentose phosphate pathway engagement, suggesting that this pathway is involved in CD8 + T cell–mediated injury of axons and neurons in the demyelinated CNS. Inhibiting the pentose phosphate pathway disrupts CD8 + T cell metabolic reprogramming and effector functions, suggesting that such inhibition may serve as a therapeutic strategy to prevent neurodegeneration in patients with progressive MS.

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.