Sheng Chen

A quantitative biomarker for clinical staging is essential for amyotrophic lateral sclerosis (ALS) stratification. This study evaluated microstructural imp

Amyotrophic lateral sclerosis (ALS) urgently requires robust biomarkers for early diagnosis and prognostic stratification. This study aims to investigate the diagnostic and prognostic potential of membrane-bound and soluble immune checkpoint molecules in ALS pathogenesis. In the present study at Fujian Medical Union Hospital, 72 participants (46 ALS and 26 healthy controls [HC]) underwent flow cytometry analysis of PD-1 expression in CD4⁺ T cells and its subsets. A second cohort (n = 93, 44 ALS, 30 HC and 19 ALS mimics [Mimics]) was evaluated using Luminex technology for 14 serum immune checkpoint molecules. A single-molecule array was used to screen the neurofilament light chain (NFL) in serum. Flow cytometry revealed elevated PD1 expression in CD4⁺ T cells, particularly in Th9 and Th17 subsets (p < 0.05). ALS patients exhibiting a greater percentage of PD-1 in CD4⁺ T cells showed accelerated functional decline. Serum analyses identified four elevated soluble checkpoints in ALS versus both HCs and Mimics (sPD-1/sBTLA/sCTLA-4/sCD27, p < 0.05), with sCD28/TIM-3 showing higher in ALS than in Mimics, and sGITR/sCD137/sIDO/sCD80/sLAG3/sPD-L2 elevating in ALS compared to HCs. Soluble TIM-3 correlated inversely with ALSFRS-R, while sPD-L1 demonstrated dual associations: negative with ALSFRS-R and positive with NFL (all p < 0.05). Our research demonstrated a considerable increase in membrane-bound and soluble PD-1 in ALS patients, correlating with disease progression and worse prognosis. Furthermore, we explored 13 other immune checkpoint molecules. Collectively, these molecules may be implicated in peripheral immune mechanisms underlying ALS pathogenesis. While baseline PD-1 levels show some association with prognosis, their elevation potentially indicates an unfavorable course.

Background: Formation and aggregation of pathological proteins in the brain constitutes a critical hallmark of amyotrophic lateral sclerosis (ALS). However, the role of the glymphatic system in the clearance of pathological proteins in ALS remains unclear. The purpose of this cross-sectional study was to evaluate glymphatic system disturbance in ALS and its relation to neural function. Methods: This study included 38 healthy controls (HCs) and 30 patients with ALS who underwent diffusion tensor imaging (DTI) and resting-state functional magnetic resonance imaging (rs-fMRI). The disease severity, duration, and progression rate of ALS were recorded. Glymphatic system function was indirectly evaluated by DTI analysis along the perivascular space (ALPS) surrounding the deep medullary vein. Neural activity was examined in sensorimotor-related brain areas by measuring amplitude of low-frequency fluctuation (ALFF) based on rs-fMRI. A two-sample t-test or Mann-Whitney test was used to examine between-group differences in ALPS, diffusivities measured along the x-, y-, and z-axis in the association (Dxx_association, Dyy_association, Dzz_association) and projection (Dxx_projection, Dyy_projection, Dzz_projection) fiber areas, and ALFF indices. The associations between ALPS, diffusivities, ALFF, and clinical assessments were determined via Spearman correlation analysis, and diagnostic performance was evaluated with receiver operating characteristic curve analysis. Results: Patients with ALS exhibited significantly decreased ALPS and increased diffusivities (Dyy_association and Dyy_projection) as compared to HCs (all P values Conclusions: The glymphatic system function was impaired in ALS. This may contribute to spontaneous neural activity disturbance and could represent a mechanism for the development of sensorimotor deficits frequently observed in patients with ALS.

Aim: To clarify the role of Eomesodermin (EOMES) to serve as a disease‐relevant biomarker and the intracellular molecules underlying the immunophenotype shifting of CD4⁺T subsets in amyotrophic lateral sclerosis (ALS).Methods: The derivation and validation cohorts included a total of 148 ALS patients and 101 healthy controls (HCs). Clinical data and peripheral blood were collected. T‐cell subsets and the EOMES expression were quantified using multicolor flow cytometry. Serum neurofilament light chain (NFL) was measured. In 1‐year longitudinal follow‐ups, the ALSFRS‐R scores and primary endpoint events were further recorded in the ALS patients of the validation cohort.Results: In the derivation cohort, the CD4⁺EOMES⁺T‐cell subsets were significantly increased (p < 0.001). EOMES⁺ subset was positively correlated with increased serum NFL levels in patients with onset longer than 12 months. In the validation cohort, the elevated CD4⁺EOMES⁺T‐cell proportions and their association with NFL levels were also identified. The longitudinal study revealed that ALS patients with higher EOMES expression were associated with higher progression rates (p = .010) and worse prognosis (p = .003).Conclusions: We demonstrated that increased CD4⁺EOMES⁺T‐cell subsets in ALS were associated with disease progression and poor prognosis. Identifying these associations may contribute to a better understanding of the immunopathological mechanism of ALS.

X-linked immunodeficiency with Magnesium defect, Epstein-Barr virus infection, and Neoplasia (XMEN) is a primary immune deficiency caused by mutations in MAGT1 and is characterized by chronic infection with Epstein-Barr virus (EBV), CD4 lymphopenia, severe chronic viral infections, and defective T-lymphocyte activation. Herein, we described an XMEN patient carrying a MAGT1 p.Arg331* mutation that presented with prominent muscle involvement. The PET-CT and lower limbs MRI showed diffuse muscle inflammation. Histopathology staining revealed the infiltrated lymphocytes were stained with CD3, CD20, and EBER. We monitored the patient’s in-depth immunophenotype at the first visit and after two months of oral Mg 2+ supplementation. We noticed obviously decreased CD127 expression in CD4 + T cells, which could be reversed by Mg 2+ supplementation. Our findings suggested that the decreased CD127 expression may be an additional biomarker of XMEN.