Belinda Kaskow

Parkinson's disease (PD) is a progressive neurodegenerative disorder defined by motor impairments. However, people with PD (PwPD) experience a defined spectrum of non-motor symptoms, with gastrointestinal dysfunction the most common and earliest-presenting. Evidence suggests that PD pathology may originate in the gut, where microbial dysbiosis and immune dysregulation contribute to neuroinflammation, although mechanisms underlying this are unclear. PwPD (n = 31) and healthy controls (n = 28) were evaluated for clinical and gastrointestinal symptoms, faecal and plasma sample metabolomics, and comprehensive blood immunophenotyping. In PwPD, faecal samples exhibited reduced glutamate, succinate, and uracil concentrations, while plasma showed decreased 3-hydroxybutyrate and elevated creatine, succinate, and alanine levels. Immunophenotyping revealed a reduction in T cells, with evidence of altered effector capacity and functionality in CD4, CD8, MAIT and Vδ2 compartments. NK cells were expanded, while B cells were decreased in frequency with an enrichment of memory-like cells. Immune perturbations were correlated with levels of immunomodulatory metabolite succinate. Finally, clustering of blood parameters identified two PD endophenotypes distinguishable by gastrointestinal symptoms and T cell phenotypes associated with gut- and brain-tropism. These findings contribute to the growing understanding of metabolite-associated immune dysregulation in PD and highlight potential targets for early intervention in individuals presenting with gastrointestinal dysfunction.

Introduction: Targeting progressive multiple sclerosis (MS) addresses the current single biggest unmet need in the MS therapeutic landscape and anti-Epstein-Barr virus (EBV) therapy potentially strikes at the root cause. The SpironolacTone and famciclOvir in the treatment of Progressive MS to prevent disability progression (STOP-MS) trial has been developed to assess anti-EBV therapies in the treatment of progressive MS.

Methods and analysis: STOP-MS is a multi-arm, multi-stage, randomised, double-blind, placebo-controlled trial testing spironolactone and famciclovir to prevent disability progression in MS. Australians with progressive forms of MS, aged 25 to 70 years with established disability, are eligible. Recruitment commenced in March 2025 and the first participant was enrolled on 15 April 2025. The sample size for STOP-MS is 150 in stage 1 and 300 in stage 2. In stage 1, the composite primary outcome measures will be reduction of EBV DNA in saliva and serum EBV nuclear antigen-1 antibody titres. Minimum criteria for consideration of progression to stage 2 will be a 10% reduction in the composite outcome measure. In stage 2, the primary outcome measure will be 6-month confirmed disability progression analysed using Cox-proportional hazards.

Trial registration number: The STOP-MS trial has been acknowledged by the Therapeutics Goods Administration under the Clinical Trial Notification scheme (CT-2023-CTN-03 505-1) and is registered with the Australian and New Zealand Clinical Trial Registry (ACTRN12623000849695).

Background: Regulatory B cells (Bregs) play a pivotal role in suppressing immune responses, yet there is still a lack of cell surface markers that can rigorously identify them. In mouse models for multiple sclerosis (MS), TIM-1 or TIGIT expression on B cells is required for maintaining self-tolerance and regulating autoimmunity to the central nervous system. Here we investigated the activities of human memory B cells that differentially express TIM-1 and TIGIT to determine their potential regulatory function in healthy donors and patients with relapsing-remitting (RR) MS.

Methods: FACS-sorted TIM-1+/-TIGIT+/- memory B (memB) cells co-cultured with allogenic CD4+ T cells were analyzed for proliferation and induction of inflammatory markers using flow cytometry and cytokine quantification, to determine Th1/Th17 cell differentiation. Transcriptional differences were assessed by SMARTSeq2 RNA sequencing analysis.

Results: TIM-1-TIGIT- double negative (DN) memB cells strongly induce T cell proliferation and pro-inflammatory cytokine expression. The TIM-1+ memB cells enabled low levels of CD4+ T cell activation and gave rise to T cells that co-express IL-10 with IFNγ and IL-17A or FoxP3. T cells cultured with the TIM-1+TIGIT+ double positive (DP) memB cells exhibited reduced proliferation and IFNγ, IL-17A, TNFα, and GM-CSF expression, and exhibited strong regulation in Breg suppression assays. The functional activity suggests the DP memB cells are a bonafide Breg population. However, MS DP memB cells were less inhibitory than HC DP memB cells. A retrospective longitudinal study of anti-CD20 treated patients found that post-treatment DP memB cell frequency and absolute number were associated with response to therapy. Transcriptomic analyses indicated that the dysfunctional MS-derived DP memB/Breg population exhibited increased expression of genes associated with T cell activation and survival (CD80, ZNF10, PIK3CA), and had distinct gene expression compared to the TIGIT+ or TIM-1+ memB cells.

Conclusion: These findings demonstrate that TIM-1/TIGIT expressing memory B cell subsets have distinct functionalities. Co-expression of TIM-1 and TIGIT defines a regulatory memory B cell subset that is functionally impaired in MS.

Background: The neurofilament light chain (NfL) has emerged as a promising biomarker of multiple sclerosis (MS) disease activity, progression, and response to treatment. During axonal injury, neurofilament proteins are released into the extracellular space and their levels in CSF and blood are reflecting the degree of axonal damage in MS.

Objective: To measure the value of serum NfL as a biomarker of disease activity and progression, and its usefulness to monitor treatment response in patients with MS.

Methods: Serum NfL levels were measured in 542 patients with demyelinating disease, including clinically isolated syndrome (CIS; n=20), relapsing-remitting MS (RRMS; n=341), secondary progressive MS (SPMS; n=138), primary progressive MS (PPMS; n=43) and 10 healthy controls (HC) using single-molecule array technology (SIMOA). Treatment strategies were classified as “no treatment”, “injectable” and “high efficacy”. The Expanded Disability Status Scale (EDSS) score and patients’ demographics were also analysed.

Results: Serum NfL levels were significantly higher in patients with CIS vs HC (23.6 +/-3.4 vs 12.3 +/-1.6, p

Conclusion: Our findings support the potential value of serum NfL as a measure of disease activity and progression, and treatment response in multiple sclerosis