Background: Peripheral glial fibrillary acidic protein (GFAP) and neurofilament light chain (NfL) are sensitive markers of neuroinflammation and neuronal damage. Previous studies with highly selected participants have shown that peripheral GFAP and NfL levels are elevated in the pre-clinical phase of Alzheimer’s disease (AD) and dementia. However, the predictive value of GFAP and NfL for dementia requires more evidence from population-based cohorts. Methods: This was a prospective cohort study to evaluate UK Biobank participants enrolled from 2006 to 2010 using plasma GFAP and NfL measurements measured by Olink Target Platform and prospectively followed up for dementia diagnosis. Primary outcome was the risk of clinical diagnosed dementia. Secondary outcomes were cognition. Linear regression was used to assess the associations between peripheral GFAP and NfL with cognition. Cox proportional hazard models with cross-validations were used to estimate associations between elevated GFAP and NfL with risk of dementia. All models were adjusted for covariates. Results: A subsample of 48,542 participants in the UK Biobank with peripheral GFAP and NfL measurements were evaluated. With an average follow-up of 13.18 ± 2.42 years, 1312 new all-cause dementia cases were identified. Peripheral GFAP and NfL increased up to 15 years before dementia diagnosis was made. After strictly adjusting for confounders, increment in NfL was found to be associated with decreased numeric memory and prolonged reaction time. A greater annualized rate of change in GFAP was significantly associated with faster global cognitive decline. Elevation of GFAP (hazard ratio (HR) ranges from 2.25 to 3.15) and NfL (HR ranges from 1.98 to 4.23) increased the risk for several types of dementia. GFAP and NfL significantly improved the predictive values for dementia using previous models (area under the curve (AUC) ranges from 0.80 to 0.89, C-index ranges from 0.86 to 0.91). The AD genetic risk score and number of APOE*E4 alleles strongly correlated with GFAP and NfL levels. Conclusions: These results suggest that peripheral GFAP and NfL are potential biomarkers for the early diagnosis of dementia. In addition, anti-inflammatory therapies in the initial stages of dementia may have potential benefits.

Objectives: The coexistence of neuromyelitis optica spectrum disorder (NMOSD) with other autoimmune diseases has been well recognized. However, the causal association between these two conditions has not been fully studied. The etiology and therapies of NMOSD coexisting with autoimmune diseases also need to be elucidated.Methods: We performed two-sample Mendelian randomization (MR) analysis to examine the causality. Genome-wide association (GWAS) summary data from NMOSD, autoimmune thyroid disease (AITD), systemic lupus erythematosus (SLE), and Sjogren’s syndrome (SS) were used to identify genetic instruments. Causal single-nucleotide polymorphisms (SNPs) were annotated and searched for cis-expression quantitative trait loci (cis-eQTL) data. Pathway enrichment analysis was performed to identify the mechanism of NMOSD coexisting with AITD, SLE, and SS. Potential therapeutic chemicals were searched using the Comparative Toxicogenomics Database.Results: The MR analysis found that AITD, SLE, and SS were causally associated with NMOSD susceptibility, but not vice versa. Gene Ontology (GO) enrichment analysis revealed that MHC class I-related biological processes and the interferon-gamma-mediated signaling pathway may be involved in the pathogenesis of NMOSD coexisting with AITD, SLE, and SS. A total of 30 chemicals were found which could inhibit the biological function of cis-eQTL genes.Conclusions: Our findings could help better understand the etiology of NMOSD and provide potential therapeutic targets for patients with coexisting conditions.

Purpose: To compare the optical coherence tomography (OCT)/OCT angiography (OCTA) measures in patients with neuromyelitis optica spectrum disorder (NMOSD) and myelin oligodendrocyte glycoprotein antibody disease (MOGAD).Methods: Twenty-one MOG, 21 NMOSD, and 22 controls were enrolled in our study. The retinal structure [retinal nerve fiber layer (RNFL) and ganglion cell–inner plexiform layer (GCIPL)] was imaged and assessed with the OCT; OCTA was used to image the macula microvasculature [superficial vascular plexus (SVP), intermediate capillary plexus (ICP), and deep capillary plexus (DCP)]. Clinical information such as disease duration, visual acuity, and frequency of optic neuritis and disability was recorded for all patients.Results: Compared with NMOSD patients, MOGAD patients showed significantly reduced SVP density (P = 0.023). No significant difference (P > 0.05) was seen in the microvasculature and structure when NMOSD-ON was compared with MOG-ON. In NMOSD patients, EDSS, disease duration, reduced visual acuity, and frequency of ON significantly correlated (P < 0.05) with SVP and ICP densities; in MOGAD patients, SVP correlated with EDSS, duration, reduced visual acuity, and frequency of ON (P < 0.05), while DCP density correlated with disease duration, visual acuity, and frequency of ON.Conclusions: Distinct structural and microvascular changes were identified in MOGAD patients compared with NMOSD patients suggesting that the pathological mechanisms are different in NMOSD and MOGAD. Retinal imaging via the SS-OCT/OCTA might have the potential to be used as a clinical tool to evaluate the clinical features associated with NMOSD and MOGAD.

Background: Multiple sclerosis (MS) leads to demyelination and neurodegeneration with autoimmune responses in central nervous system. Patients begin with a relapsing–remitting (RR) course, and more than 80% of them may advance to secondary progressive MS (SPMS), which is characteristic for the gradual decline of neurological functions without demonstrated treating method to prevent. This study aims to investigate the contribution of peripheral CD8 + T cells during the conversion from RRMS to SPMS, as well as reveal potential diagnostic signature in distinguishing SPMS. Methods: Single-cell RNA sequencing was employed to reveal the heterogeneity of CD8 + T cells between SPMS and RRMS. In addition, flow cytometry was used to further characterized CD8 + T cell dynamic changes in patients. T cell receptor sequencing was performed to detect the clonal expansion of MS. Using Tbx21 siRNA, T-bet was confirmed to manipulate GzmB expression. The correlation between GzmB + CD8 + T cell subsets and clinical characteristics of MS and their potential diagnostic value for SPMS were evaluated by generalized linear regression models and receiver operating characteristic (ROC) curve respectively. Results: Other than diminished naïve CD8 + T cell, elevating of activated CD8 + T cell subsets were observed in SPMS patients. Meanwhile, this aberrant amplified peripheral CD8 + T cells not only exhibited terminal differentiated effector (EMRA) phenotype with GzmB expression, but also possessed distinct trajectory from clonal expansion. In addition, T-bet acted as a key transcriptional factor that elicited GzmB expression in CD8 + T_EMRA cells of patients with SPMS. Finally, the expression of GzmB in CD8 + T cells was positively correlated with disability and progression of MS, and could effectively distinguish SPMS from RRMS with a high accuracy. Conclusions: Our study mapped peripheral immune cells of RRMS and SPMS patients and provided an evidence for the involvement of GzmB + CD8 + T_EMRA cells in the progression of MS, which could be used as a diagnostic biomarker for distinguishing SPMS from RRMS.