High throughput method for detecting murine brain atrophy using a clinical 3T MRI

Theiler's murine encephalomyelitis virus (TMEV) induces a demyelinating disease in susceptible SJL mice that has similarities to multiple sclerosis in humans. TMEV infection of susceptible mice leads to a persistent virus infection of the central nervous system (CNS), which promotes the development of demyelinating disease associated with an inflammatory immune response in the CNS. TMEV infection of resistant C57BL6 mice results in viral clearance without development of demyelinating disease. Interestingly, TMEV infection of resistant mice deficient in IFNγ leads to a persistent virus infection in the CNS and development of demyelinating disease. We have previously shown that the innate immune response affects development of TMEV- induced demyelinating disease, thus we wanted to determine the role of IFNγ during the innate immune response. TMEV-infected IFNγ-deficient mice had an altered innate immune response, including reduced expression of innate immune cytokines, especially type I interferons. Administration of type I interferons, IFNα and IFNß, to TMEV-infected IFNγ-deficient mice during the innate immune response restored the expression of innate immune cytokines. Most importantly, administration of type I interferons to IFNγ-deficient mice during the innate immune response decreased the virus load in the CNS and decreased development of demyelinating disease. Microglia are the CNS resident immune cells that express innate immune receptors. In TMEV-infected IFNγ-deficient mice, microglia had reduced expression of innate immune cytokines, and administration of type I interferons to these mice restored the innate immune response by microglia. In the absence of IFNγ, microglia from TMEV-infected mice had reduced expression of some innate immune receptors and signaling molecules, especially IRF1. These results suggest that IFNγ plays an important role in the innate immune response to TMEV by enhancing the expression of innate immune cytokines, especially type I interferons, which directly affects the development of demyelinating disease.

To perform a meta-analysis of randomized, blinded, multiple sclerosis (MS) clinical trials, to test the hypothesis that efficacy of immunomodulatory disease-modifying therapies (DMTs) on MS disability progression is strongly dependent on age. We performed a literature search with pre-defined criteria and extracted relevant features from 38 clinical trials that assessed efficacy of DMTs on disability progression. We fit a linear regression, weighted for trial sample size, and duration, to examine the hypothesis that age has a defining effect on the therapeutic efficacy of immunomodulatory DMTs. More than 28,000 MS subjects participating in trials of 13 categories of immunomodulatory drugs are included in the meta-analysis. The efficacy of immunomodulatory DMTs on MS disability strongly decreased with advancing age (R2 = 0.6757, p = 6.39e-09). Inclusion of baseline EDSS did not significantly improve the model. The regression predicts zero efficacy beyond approximately age 53 years. The comparative efficacy rank derived from the regression residuals differentiates high- and low-efficacy drugs. High-efficacy drugs outperform low-efficacy drugs in inhibiting MS disability only for patients younger than 40.5 years. The meta-analysis supports the notion that progressive MS is simply a later stage of the MS disease process and that age is an essential modifier of a drug efficacy. Higher efficacy treatments exert their benefit over lower efficacy treatments only during early stages of MS, and, after age 53, the model suggests that there is no predicted benefit to receiving immunomodulatory DMTs for the average MS patient.

Theiler's murine encephalomyelitis virus (TMEV) infection of susceptible mice leads to the development of demyelinating disease in the central nervous system (CNS) associated with an inflammatory immune response. The demyelinating disease in mice has similarities to multiple sclerosis in humans and is used as an experimental model for the human disease. The innate immune response initiates the immune response to TMEV through innate immune receptors on cells that recognize components of the virus and activate intracellular signaling that leads to the expression of innate immune cytokines, chemokines, and effector molecules. The innate immune response directly affects the development of the adaptive immune response, especially the T cell response, which mediates viral clearance. However, infection of Swiss Jim Laboratory (SJL) mice with TMEV leads to a persistent virus infection of the microglia/macrophage in the CNS which contributes to the development of demyelinating disease. Susceptibility to demyelinating disease has been linked to the T cell response against the virus. However, the current studies will examine the role of the innate immune response to TMEV and the affect it has on the adaptive immune response and development of demyelinating disease following TMEV infection. The innate immune cytokines, chemokines, and effector molecules as well as the innate immune cells, both CNS resident and infiltrating peripheral cells, all contribute to the innate immune response following TMEV and may affect susceptibility to demyelinating disease.

Disability in progressive MS is associated with T2 lesion changes

Upregulation of voltage-gated Ca2+ channels in mouse astrocytes infected with Theiler’s murine encephalomyelitis virus (TMEV)

Disability in multiple sclerosis is associated with vascular factors: An ultrasound study

Early prediction of disability progression in multiple sclerosis (MS) remains challenging despite its critical importance for therapeutic decision-making. We present the first systematic evaluation of personalized federated learning (PFL) for 2-year MS disability progression prediction, leveraging multi-center real-world data from over 26,000 patients. While conventional federated learning (FL) enables privacy-aware collaborative modeling, it remains vulnerable to institutional data heterogeneity. PFL overcomes this challenge by adapting shared models to local data distributions without compromising privacy. We evaluated two personalization strategies: a novel AdaptiveDualBranchNet architecture with selective parameter sharing, and personalized fine-tuning of global models, benchmarked against centralized and client-specific approaches. Baseline FL underperformed relative to personalized methods, whereas personalization significantly improved performance, with personalized FedProx and FedAVG achieving ROC-AUC scores of 0.8398 ± 0.0019 and 0.8384 ± 0.0014, respectively. These findings establish personalization as critical for scalable, privacy-aware clinical prediction models and highlight its potential to inform earlier intervention strategies in MS and beyond.

The influence of macrophage growth factors on Theiler’s Murine Encephalomyelitis Virus (TMEV) infection and activation of macrophages

Viral infections have been associated with multiple sclerosis (MS), an immune-mediated disease in the central nervous system (CNS). Since Theiler's murine encephalomyelitis virus (TMEV) can induce MS-like demyelination, TMEV infection is the most widely used viral model for MS. Although the precise pathophysiology is unknown, altered fecal bacterial populations were associated with distinct immune gene expressions in the CNS. We aimed to determine the role of gut microbiota in TMEV infection by administering an antibiotic cocktail in drinking water before (prophylactic administration) or after (therapeutic administration) TMEV infection. The antibiotic administration reduced total eubacteria, including the phyla Bacillota and Bacteroidota, but increased the phylum Pseudomonadata in feces. Prophylactic administration did not alter TMEV-induced inflammatory demyelination clinically or histologically, without changes in anti-viral IgG1/IgG2c levels or lymphoproliferative responses; therapeutic administration temporarily suppressed the neurological signs. Although antibiotic treatment had minimal effects on TMEV infection, adding metronidazole and ampicillin in drinking water substantially reduced water intake in the antibiotic group of mice, resulting in significant body weight loss. Since dehydration and stress could affect immune responses and gut microbiota, caution should be exercised when planning or evaluating the oral antibiotic cocktail treatment in experimental animals.

To investigate disease progression and risk factors in a large geographically based population with multiple sclerosis (MS), using two different inception points--clinical onset and date of birth. The authors reviewed a database of subjects with definite MS and symptom onset prior to July 1988. The main outcome was sustained progression to Expanded Disability Status Scale (EDSS) 6 (requires a cane), using the date of birth and date of MS onset as inception points in separate analyses. Risk factors examined were sex, relapsing vs primary progressive course, onset age, and onset symptoms. The study included 2,837 patients, followed prospectively for 22,723 patient years. The median time to EDSS 6 was 27.9 years, 15 years after onset; only 21% reached EDSS 6, and by age 50, 28% required a cane. Men progressed 38% more quickly than women from onset (p < 0.0005), yet both required canes at similar ages: 58.8 years for men and 60.1 for women (p = 0.082). A younger onset age predicted a slower progression, but those older at onset were consistently older when reaching EDSS 6. A primary progressive course predicted a more rapid progression from both onset (p < 0.0005) and birth (hazard ratio = 2.7 [95% CI: 2.2 to 3.3]). No onset symptom consistently predicted progression. Disability progression in multiple sclerosis (MS) accrued more slowly than found in earlier longitudinal studies. The authors also challenged two fundamental concepts in MS, demonstrating that neither male sex nor older onset age was associated with worse disease outcome.

Background: Thalamic atrophy is proposed to be a major predictor of disability progression in multiple sclerosis (MS), while thalamic function remains understudied. Objectives: To study how thalamic functional connectivity (FC) is related to disability and thalamic or cortical network atrophy in two large MS cohorts. Methods: Structural and resting-state functional magnetic resonance imaging (fMRI) was obtained in 673 subjects from Amsterdam (MS: N = 332, healthy controls (HC): N = 96) and Graz (MS: N = 180, HC: N = 65) with comparable protocols, including disability measurements in MS (Expanded Disability Status Scale, EDSS). Atrophy was measured for the thalamus and seven well-recognized resting-state networks. Static and dynamic thalamic FC with these networks was correlated with disability. Significant correlates were included in a backward multivariate regression model. Results: Disability was most strongly related (adjusted R2 = 0.57, p < 0.001) to higher age, a progressive phenotype, thalamic atrophy and increased static thalamic FC with the sensorimotor network (SMN). Static thalamus–SMN FC was significantly higher in patients with high disability (EDSS ⩾ 4) and related to network atrophy but not thalamic atrophy or lesion volumes. Conclusion: The severity of disability in MS was related to increased static thalamic FC with the SMN. Thalamic FC changes were only related to cortical network atrophy, but not to thalamic atrophy.

There is evidence that the clinical course of multiple sclerosis is age related. The present study evaluated the relationship between age and rate of disability progression in a large hospital-based cohort of definite cases of multiple sclerosis (n= 1,463). Patients were followed every 6 to 12 months for a total period of observation of 11,387.8 person-years. Expanded Disability Status Scale scores increased significantly with increasing current age and longer duration of disease (p=0.007). Median times to reach Expanded Disability Status Scale scores of 4.0 and 6.0, assessed using an extended Kaplan-Meier method with age as a categorical time-varying covariate, were significantly longer among patients aged 20 to 35 years compared with patients aged 36 to 50 and 51 to 65 years (p < 0.0001). Significant associations were observed between mean Expanded Disability Status Scale scores and age at disease onset, current age, and the interaction of age at disease onset and current age (p < 0.001). Current age had a greater effect (59% of variability in the model) on disease severity than did age at disease onset. Furthermore, a multiplicative effect on Expanded Disability Status Scale score was observed for age at disease onset and current age combined, indicating a faster rate of disease progression in older patients. In conclusion, the results of the current study demonstrate the impact of age on rate of disability progression in multiple sclerosis and suggest that an age-adjusted progression index may be a more relevant criterion for defining differences between multiple sclerosis groups.

To assess whether biological aging as measured by leukocyte telomere length (LTL) is associated with clinical disability and brain volume loss in multiple sclerosis (MS). Adults with MS/clinically isolated syndrome in the University of California, San Francisco EPIC cohort study were included. LTL was measured on DNA samples by quantitative polymerase chain reaction and expressed as telomere to somatic DNA (T/S) ratio. Expanded Disability Status Scale (EDSS) and 3-dimensional T1-weighted brain magnetic resonance imaging were performed at baseline and follow-up. Associations of baseline LTL with cross-sectional and longitudinal outcomes were assessed using simple and mixed effects linear regression models. A subset (n = 46) had LTL measured over time, and we assessed the association of LTL change with EDSS change with mixed effects models. Included were 356 women and 160 men (mean age = 43 years, median disease duration = 6 years, median EDSS = 1.5 [range = 0-7], mean T/S ratio = 0.97 [standard deviation = 0.18]). In baseline analyses adjusted for age, disease duration, and sex, for every 0.2 lower LTL, EDSS was 0.27 higher (95% confidence interval [CI] = 0.13-0.42, p < 0.001) and brain volume was 7.4mm3 lower (95% CI = 0.10-14.7, p = 0.047). In longitudinal adjusted analyses, those with lower baseline LTL had higher EDSS and lower brain volumes over time. In adjusted analysis of the subset, LTL change was associated with EDSS change over 10 years; for every 0.2 LTL decrease, EDSS was 0.34 higher (95% CI = 0.08-0.61, p = 0.012). Shorter telomere length was associated with disability independent of chronological age, suggesting that biological aging may contribute to neurological injury in MS. Targeting aging-related mechanisms is a potential therapeutic strategy against MS progression. ANN NEUROL 2019;86:671-682.

The scope and activation mechanisms of chemokine gene expression in primary astrocytes following infection with Theiler's virus

Innate immune CD11b+Gr-1+ cells are a heterogeneous population of cells which include neutrophils and myeloid- derived suppressor cells (MDSC). CD11b+Gr-1+ cells that express Ly6C are MDSC which can directly suppress T cell responses. Theiler's murine encephalomyelitis virus (TMEV) is a mouse model of multiple sclerosis in which mice develop a chronic progressive demyelinating disease associated with a myelin- specific CD4+ T cell response. We have previously shown that the innate immune response directly affects the initiation and progression of demyelinating disease. Thus, we wanted to determine the role of CD11b+Gr-1+ cells in the innate immune response during TMEV- induced demyelinating disease. TMEV- infected mice had a large number of infiltrating CD11b+Gr-1+ cells composed of Ly6Chigh cells in the central nervous system (CNS) during the innate immune response. Depletion of Gr-1+ cells in TMEV-infected mice resulted in increased expression of IFNγ, IL-12, and IL-17 in the CNS during the innate immune response and altered development of demyelinating disease. Most importantly, CD11b+Gr-1+ cells suppressed the activation of CD4+ and CD8+ T cells in TMEV- infected mice. These results suggest that innate immune CD11b+Gr-1+ cells, specifically the MDSC, influence the adaptive immune response and modulate the development and progression of demyelinating disease. This work was supported by the National Multiple Sclerosis Society Grant RG3625.