Peripheral GFAP and NfL as early biomarkers for dementia: longitudinal insights from the UK Biobank.

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.

Correlation between severe attacks and serum aquaporin-4 antibody titer in neuromyelitis optica spectrum disorder.

Aquaporin 4-immunoglobulin G (AQP4-IgG) specifically targets aquaporin 4 in approximately 80% of Neuromyelitis Optica Spectrum Disorder (NMOSD) cases. NMOSD is presently categorized as anti-AQP4-antibody (Ab) positive or negative based on AQP4-Ab presence. The association between antibody titers and patient prognosis remains unclear. Therefore, the present study explores the correlation between severe attacks and serum AQP4 Ab titers in patients with neuromyelitis optica spectrum disorder. Data were gathered retrospectively from 546 patients with NMOSD between September 1, 2009, and December 1, 2021. Patients were categorized based on their AQP4-Ab titers: AQP4 titer ≥ 1:320 were classified as the high-titer group, AQP4 (+ +), and AQP4 titer of ≤ 1:100 were classified as the low-titer group, AQP4 ( +). Clinical characteristics and prognoses between the two groups were compared. Patients with AQP4 ( +) exhibited few severe optic neuritis (SON) attacks (false discovery rate [FDR] corrected p < 0.001), a reduced percentage experiencing SON attacks, and a lower incidence of visual disability than patients with AQP4 (+ +). Patients with AQP4 (+ +) and AQP4 ( +) NMOSD exhibited significant difference in annual recurrence rate (ARR) (FDR-corrected p < 0.001). The lower AQP4 Ab titer group demonstrated reduced susceptibility to severe relapse with conventional immunosuppressive agents and rituximab (RTX) than the higher titer group. No significant differences in sex, age at onset, coexisting connective tissue diseases, motor disability, or mortality rates were observed between the two groups. Higher AQP4 Ab titers correlated with increased disease severity and visual disability in patients with NMOSD.

Causal relationship between multiple sclerosis and cortical structure: a Mendelian randomization study.

BACKGROUND: Observational studies have suggested an association between multiple sclerosis (MS) and cortical structure, but the results have been inconsistent. OBJECTIVE: We used two-sample Mendelian randomization (MR) to assess the causal relationship between MS and cortical structure. METHODS: MS data as the exposure trait, including 14,498 cases and 24,091 controls, were obtained from the International Multiple Sclerosis Genetics Consortium. Genome-wide association study (GWAS) data for cortical surface area (SAw/nw) and thickness (THw/nw) in 51,665 individuals of European ancestry were obtained from the ENIGMA Consortium. The inverse-variance weighted (IVW) method was used as the primary analysis for MR. Sensitivity analyses were conducted to evaluate heterogeneity and pleiotropy. Enrichment analysis was performed on MR analyses filtered by sensitivity analysis. RESULTS: After IVW and sensitivity analysis filtering, only six surviving MR results provided suggestive evidence supporting a causal relationship between MS and cortical structure, including lingual SAw (p = .0342, beta (se) = 5.7127 (2.6969)), parahippocampal SAw (p = .0224, beta (se) = 1.5577 (0.6822)), rostral middle frontal SAw (p = .0154, beta (se) = - 9.0301 (3.7281)), cuneus THw (p = .0418, beta (se) = - 0.0020 (0.0010)), lateral orbitofrontal THw (p = .0281, beta (se) = 0.0025 (0.0010)), and lateral orbitofrontal THnw (p = .0417, beta (se) = 0.0029 (0.0014)). Enrichment analysis suggested that leukocyte cell-related pathways, JAK-STAT signaling pathway, NF-kappa B signaling pathway, cytokine-cytokine receptor interaction, and prolactin signaling pathway may be involved in the effect of MS on cortical morphology. CONCLUSION: Our results provide evidence supporting a causal relationship between MS and cortical structure. Enrichment analysis suggests that the pathways mediating brain morphology abnormalities in MS patients are mainly related to immune and inflammation-driven pathways.

COVID-19 susceptibility, hospitalization, and severity and the risk of brain cortical structure: a mendelian randomization study.

BACKGROUND: Observational studies have reported structural changes in the brains of patients with COVID-19; it remains unclear whether these associations are causal. AIM: We evaluated the causal effects of COVID-19 susceptibility, hospitalization, and severity on cortical structures. DESIGN: Mendelian randomization (MR) study. METHODS: Data on the different COVID-19 phenotypes were obtained from the latest large-scale genome-wide association study (GWAS) (R7) of the COVID-19 Host Genetics Initiative. Brain structure data, including cortical thickness (TH) and surface area (SA), were obtained from the ENIGMA Consortium. Additionally, we employed the round 5 dataset released in January 2021 as the validation cohort. The inverse-variance weighted (IVW) method was used as the primary analysis in MR. Sensitivity analyses were conducted to evaluate heterogeneity and pleiotropy. We performed enrichment analysis on the MR analyses that passed the sensitivity analysis filtering. RESULTS: After IVW and sensitivity analyses, we observed causal associations between COVID-19 susceptibility and rostral middle frontal SAw (P = 0.0308, ß=-39.1236), cuneus THw (P = 0.0170, ß=-0.0121), medial orbitofrontal THw (P = 0.0002, ß = 0.0225), postcentral THw (P = 0.0217, ß= -0.0106), temporal pole THw (P = 0.0077, ß = 0.0359), medial orbitofrontal SAnw (P = 0.0106, ß= -24.0397), medial orbitofrontal THnw (P = 0.0007, ß = 0.0232), paracentral SAnw (P = 0.0483, ß= -20.1442), rostral middle frontal SAnw (P = 0.0368, ß= -81.9719), and temporal pole THnw (P = 0.0429, ß = 0.0353). COVID-19 hospitalization had causal effects on medial orbitofrontal THw (P = 0.0053, ß = 0.0063), postcentral THw (P = 0.0143, ß= -0.0042), entorhinal THnw (P = 0.0142, ß = 0.0142), medial orbitofrontal THnw (P = 0.0147, ß = 0.0065), and paracentral SAnw (P = 0.0119, ß= -7.9970). COVID-19 severity had causal effects on rostral middle frontal SAw (P = 0.0122, ß=-11.8296), medial orbitofrontal THw (P = 0.0155, ß = 0.0038), superior parietal THw (P = 0.0291, ß= -0.0021), lingual SAnw (P = 0.0202, ß=-11.5270), medial orbitofrontal THnw (P = 0.0290, ß = 0.0039), paracentral SAnw (P = 0.0180, ß= -5.7744), and pars triangularis SAnw (P = 0.0151, ß=-5.4520). CONCLUSION: Our MR results demonstrate a causal relationship between different COVID-19 phenotypes and cortical structures.

COVID-19 and the risk of neuromyelitis optica spectrum disorder: a Mendelian randomization study.

Background: An increasing number of studies have elucidated a close nexus between COVID-19 phenotypes and neuromyelitis optica spectrum disorder (NMOSD), yet the causality between them remains enigmatic. Methods: In this study, we conducted a Mendelian randomization (MR) analysis employing summary data sourced from genome-wide association studies (GWAS) pertaining to COVID-19 susceptibility, hospitalization, severity, and NMOSD. The primary MR analysis employed the Inverse variance weighted (IVW) approach, which was supplemented by MR-Egger, weighted median, simple mode, and weighted mode methods. We implemented various sensitivity analyses including Cochran's Q test, MR-PRESSO method, MR-Egger intercept, leave-one-out analysis, and funnel plot. Results: The MR results demonstrated a nominal association between COVID-19 susceptibility and the risk of AQP4+ NMOSD, as evidenced by the IVW method (OR = 4.958; 95% CI: 1.322-18.585; P = 0.018). Conversely, no causal association was observed between COVID-19 susceptibility, hospitalization, or severity and the increased risk of NMOSD, AQP4-NMOSD, or AQP4+ NMOSD. The comprehensive sensitivity analyses further bolstered the robustness and consistency of the MR estimates. Conclusion: Our findings provide compelling evidence for a causal effect of COVID-19 phenotype on AQP4+ NMOSD, shedding new light on the understanding of the comorbidity between COVID-19 and NMOSD.

Association between COVID-19 and myasthenia gravis (MG): A genetic correlation and Mendelian randomization study.

BACKGROUND: Observational studies have suggested an association between coronavirus disease 2019 (COVID-19) and myasthenia gravis (MG). Here, we aimed to estimate the genetic correlation and causal relationship between COVID-19 susceptibility, hospitalization, severity, and MG phenotypes using linkage disequilibrium score regression (LDSC) and Mendelian randomization (MR) approach. METHODS: Summary statistics of COVID-19 susceptibility, hospitalization, and severity were used as instrumental variables for exposure traits. Large-scale genome-wide association study (GWAS) data for MG were used as outcome traits. The inverse variance weighted approach was used for the main MR analysis, complemented by MR-Egger, weighted median, simple mode, and weighted mode methods. Sensitivity analysis was implemented using Cochran's Q test, MR-PRESSO method, and MR-Egger intercept test. RESULTS: LDSC analysis did not reveal any genetic correlation among COVID-19 susceptibility, hospitalization, severity, and MG phenotypes, including MG, early-onset MG, and late-onset MG (p > .05). Our MR analysis did not provide evidence supporting a causal effect of COVID-19 susceptibility, hospitalization, or severity on MG phenotypes (p > .05). Extensive sensitivity analysis strengthened the robustness and consistency of the MR estimates. CONCLUSION: Our study did not find evidence of a genetic correlation or causal relationship among COVID-19 susceptibility, hospitalization, severity, and MG. Future studies with more GWAS data are needed to evaluate the association between COVID-19 phenotypes and MG and its subgroups.

Associations of vitamin D-related single nucleotide polymorphisms with post-stroke depression among ischemic stroke population.

Objective: To investigate the relationship between single nucleotide polymorphisms (SNPs) related to vitamin D (VitD) metabolism and post-stroke depression (PSD) in patients with ischemic stroke. Methods: A total of 210 patients with ischemic stroke were enrolled at the Department of Neurology in Xiangya Hospital, Central South University, from July 2019 to August 2021. SNPs in the VitD metabolic pathway (VDR, CYP2R1, CYP24A1, and CYP27B1) were genotyped using the SNPscan™ multiplex SNP typing kit. Demographic and clinical data were collected using a standardized questionnaire. Multiple genetic models including dominant, recessive, and over-dominant models were utilized to analyze the associations between SNPs and PSD. Results: In the dominant, recessive, and over-dominant models, no significant association was observed between the selected SNPs in the CYP24A1 and CYP2R1 genes and PSD. However, univariate and multivariate logistic regression analysis revealed that the CYP27B1 rs10877012 G/G genotype was associated with a decreased risk of PSD (OR: 0.41, 95% CI: 0.18-0.92, p = 0.030 and OR: 0.42, 95% CI: 0.18-0.98, p = 0.040, respectively). Furthermore, haplotype association analysis indicated that rs11568820-rs1544410-rs2228570-rs7975232-rs731236 CCGAA haplotype in the VDR gene was associated with a reduced risk of PSD (OR: 0.14, 95% CI: 0.03-0.65, p = 0.010), whereas no significant association was observed between haplotypes in the CYP2R1 and CYP24A1 genes and PSD. Conclusion: Our findings suggest that the polymorphisms of VitD metabolic pathway genes VDR and CYP27B1 may be associated with PSD in patients with ischemic stroke.

The role of indoleamine 2,3-dioxygenase 1 in early-onset post-stroke depression.

Background: The immune-inflammatory response has been widely considered to be involved in the pathogenesis of post-stroke depression (PSD), but there is ambiguity about the mechanism underlying such association. Methods: According to Diagnostic and Statistical Manual of Mental Disorders (5th edition), depressive symptoms were assessed at 2 weeks after stroke onset. 15 single nucleotide polymorphisms (SNPs) in genes of indoleamine 2,3-dioxygenase (IDO, including IDO1 and IDO2) and its inducers (including pro-inflammatory cytokines interferon [IFN]-γ, tumor necrosis factor [TNF]-α, interleukin [IL]-1ß, IL-2 and IL-6) were genotyped using SNPscan™ technology, and serum IDO1 levels were detected by double-antibody sandwich enzyme-linked immune-sorbent assay. Results: Fifty-nine patients (31.72%) were diagnosed with depression at 2 weeks after stroke onset (early-onset PSD). The IDO1 rs9657182 T/T genotype was independently associated with early-onset PSD (adjusted odds ratio [OR] = 3.008, 95% confidence interval [CI] 1.157-7.822, p = 0.024) and the frequency of rs9657182 T allele was significantly higher in patients with PSD than that in patients with non-PSD (χ2 = 4.355, p = 0.037), but these results did not reach the Bonferroni significance threshold (p > 0.003). Serum IDO1 levels were also independently linked to early-onset PSD (adjusted OR = 1.071, 95% CI 1.002-1.145, p = 0.044) and patients with PSD had higher serum IDO1 levels than patients with non-PSD in the presence of the rs9657182 T allele but not homozygous C allele (t = -2.046, p = 0.043). Stroke patients with the TNF-α rs361525 G/G genotype had higher serum IDO1 levels compared to those with the G/A genotype (Z = -2.451, p = 0.014). Conclusions: Our findings provided evidence that IDO1 gene polymorphisms and protein levels were involved in the development of early-onset PSD and TNF-α polymorphism was associated with IDO1 levels, supporting that IDO1 which underlie strongly regulation by cytokines may be a specific pathway for the involvement of immune-inflammatory mechanism in the pathophysiology of PSD.

Establishment and verification of a nomogram model for predicting the risk of post-stroke depression.

Objective: The purpose of this study was to establish a nomogram predictive model of clinical risk factors for post-stroke depression (PSD). Patients and Methods: We used the data of 202 stroke patients collected from Xuanwu Hospital from October 2018 to September 2020 as training data to develop a predictive model. Nineteen clinical factors were selected to evaluate their risk. Minimum absolute contraction and selection operator (LASSO, least absolute shrinkage and selection operator) regression were used to select the best patient attributes, and seven predictive factors with predictive ability were selected, and then multi-factor logistic regression analysis was carried out to determine six predictive factors and establish a nomogram prediction model. The C-index, calibration chart, and decision curve analyses were used to evaluate the predictive ability, accuracy, and clinical practicability of the prediction model. We then used the data of 156 stroke patients collected by Xiangya Hospital from June 2019 to September 2020 for external verification. Results: The selected predictors including work style, number of children, time from onset to hospitalization, history of hyperlipidemia, stroke area, and the National Institutes of Health Stroke Scale (NIHSS) score. The model showed good prediction ability and a C index of 0.773 (95% confidence interval: [0.696-0.850]). It reached a high C-index value of 0.71 in bootstrap verification, and its C index was observed to be as high as 0.702 (95% confidence interval: [0.616-0.788]) in external verification. Decision curve analyses further showed that the nomogram of post-stroke depression has high clinical usefulness when the threshold probability was 6%. Conclusion: This novel nomogram, which combines patients' work style, number of children, time from onset to hospitalization, history of hyperlipidemia, stroke area, and NIHSS score, can help clinicians to assess the risk of depression in patients with acute stroke much earlier in the timeline of the disease, and to implement early intervention treatment so as to reduce the incidence of PSD.

Association of homocysteine and polymorphism of methylenetetrahydrofolate reductase with early-onset post stroke depression.

Background: Homocysteine (Hcy) has been indicated to be involved in pathophysiology of post stroke depression (PSD). There is a lack of research to study the relationship between Hcy metabolism genes and PSD. Our study aims to investigate the relationship among Hcy metabolism genes, Hcy, and early-onset PSD. Materials and methods: We recruited 212 patients with stroke and collected their peripheral blood sample, clinical data, and laboratory test on admission. 12 single nucleotide polymorphisms (SNPs) in methylenetetrahydrofolate reductase (MTHFR), methionine synthase reductase (MTRR), and methionine synthase (MTR) genes were genotyped by high-resolution melt analysis. PSD was diagnosed by DSM-V at 2 weeks after stroke. Binary logistic regression and haplotype analysis were used to examine the association between Hcy metabolism genes and PSD. Mediation analysis was performed to clarify whether the SNPs exerted their effect on PSD by affecting the Hcy level. Results: 81 patients were diagnosed with PSD, and the incidence rate was 38.2%. Hcy level in PSD group was significantly higher than it in non-PSD group (p = 0.019). MTHFR rs1801133 AA genotype an A allele were associated with an elevated risk of PSD after adjustment for some confounding factors (OR = 4.021, 95% CI: 1.459∼11.080, p = 0.007 for AA genotype; OR = 1.808, 95% CI: 1.172∼2.788, p = 0.007 for A allele). Furthermore, the effect of MTHFR rs1801133 AA genotype on PSD was mediated by Hcy (OR = 1.569, 95% CI: 0.013∼3.350, p < 0.05). Conclusion: MTHFR rs1801133 and Hcy were associated with PSD, and MTHFR rs1801133 may exert an effect on PSD via mediating Hcy level. This offers a new perspective for treating PSD and understanding the mechanism of PSD.

The potential risk factors of early-onset post-stroke depression from immuno-inflammatory perspective.

Background: Mounting evidence strongly uncovered that peripheral immuno-inflammatory response induced by acute stroke is associated with the appearance of post-stroke depression (PSD), but the mechanism remains unclear. Methods: 103 stroke patients were assessed at 2 weeks after onset using Diagnostic and Statistical Manual of Mental Disorders, 5th edition and then divided into PSD and non-PSD groups. Polymorphisms of inflammatory molecules (interleukin [IL]-1ß, IL-6, IL-10, IL-18, tumor necrosis factor-α [TNF-α], interferon-γ [IFN-γ] and C-reactive protein [CRP]), complete blood count parameters, splenic attenuation (SA) and splenic volume (SV) on unenhanced chest computed tomography, demographic and other clinical characteristics were obtained. Binary logistic regression model was used to analyze the associations between inflammation-related factors and the occurrence of PSD at 2 weeks after stroke. Results: 49 patients were diagnosed with PSD at 2 weeks after onset (early-onset PSD). The C/T genotypes of CRP rs2794520 and rs1205 were less in PSD group than non-PSD group (both adjusted odds ratio = 3.364; 95%CI: 1.039-10.898; p = 0.043). For CRP rs3091244, the frequency of G allele was higher (80.61% vs. 13.89%) while the frequency of A allele was lower (6.12% vs. 71.30%) in PSD patients than non-PSD patients (χ2 = 104.380; p<0.001). SA of PSD patients was lower than that of non-PSD patients in the presence of CRP rs2794520 C/T genotype and rs1205 C/T genotype (both t = 2.122; p = 0.039). Peripheral monocyte count was less in PSD group than non-PSD group (adjusted odds ratio = 0.057; 95%CI: 0.005-0.686; p = 0.024). Conclusions: CRP polymorphisms, SA based on CRP genotype, and peripheral monocytes are associated with the risk of early-onset PSD, suggesting peripheral immuno-inflammatory activities elicited by stroke in its aetiology.