The association between methylmalonic acid, a biomarker of mitochondrial dysfunction, and cause-specific mortality in Alzheimer's disease and Parkinson's disease.

Background: Alzheimer's disease (AD) and Parkinson's disease (PD) are the leading causes of death among the elderly. Recent research has demonstrated that mitochondrial dysfunction, which is hallmark of neurodegenerative diseases, is a contributor to the development of these diseases. Methods and materials: Methylmalonic acid (MMA), AD, PD, inflammatory markers and covariates were extracted from the National Health and Nutrition Examination Survey (NHANES). The classification of the inflammatory markers was done through quartile conversion. A restricted cubic spike function was performed to study their dose-response relationship. MMA subgroups from published studies were used to explore the correlation between different subgroups and cause-specific mortality. Multivariable weighted Cox regression was carried out to investigate MMA and cause-specific mortality in patients with AD and PD. Weighted survival analysis was used to study the survival differences among MMA subgroups. Results: A non-linear correlation was observed between MMA and AD-specific death and PD-specific mortality. The presence of MMA Q4 was linked to increased death rates among AD patients (HR = 6.39, 95%CI: 1.19-35.24, P = 0.03) after controlling for potential confounders in a multivariable weighted Cox regression model. In PD patients, the MMA Q4 (Q4: HR: 5.51, 95 % CI: 1.26-24, P = 0.02) was also related to increased mortality. The results of survival analysis indicated that the poorer prognoses were observed in AD and PD patients with MMA Q4. Conclusion: The higher level of mitochondria-derived circulating MMA was associated with a higher mortality rate in AD and PD patients. MMA has the potential to be a valuable indicator for evaluating AD and PD patients' prognosis in the clinic.

Higher oxidative balance score decreases risk of stroke in US adults: evidence from a cross-sectional study.

Background: The oxidative balance score (OBS) can be used to represent the overall burden of oxidative stress in an individual. This study aimed to explore the association between the risk of stroke and OBS. Methods and materials: The National Health and Nutrition Examination Survey (NHANES) from 1999 to 2018 was used to extract a series of variables for participants who took the stroke questionnaire. The construction of OBS relied on diet and lifestyle components, which included 16 nutrients and 4 lifestyle factors. Weighted multivariable-adjusted logistic regression was performed to investigate the association between stroke risk and OBS. A stratified analysis was also conducted. The dose-response relationship between stroke risk and OBS was elucidated by performing a restricted cubic spline function. Results: A total of 20,680 participants were included for analysis, 768 of whom suffered from stroke. Based on weighted multivariable logistic regression analysis, we discovered that the stroke prevalence decreased by 2% for each OBS unit added [OR: 0.98 (0.97-1.00), P < 0.01]. For the OBS subgroup, we also discovered that higher OBS was related to a reduction in the risk of stroke [Q4 vs. Q1: OR:0.65 (0.46-0.90), P < 0.01]. The prevalence of stroke declined by 3% with every OBS unit added to the diet component [OR: 0.97 (0.96-0.99), P < 0.01]. For the dietary OBS subgroup, higher OBS in diet components was associated with a decrease in the prevalence of stroke [Q4 vs. Q1: OR: 0.65, (0.47-0.91), P < 0.05]. Further stratified analysis showed that every OBS unit raised was associated with a decline in stroke prevalence, which was statistically significant in participants in subgroups of ≥60 years, female, no-diabetes mellitus and no-hypertension. OBS and stroke prevalence were correlated in a linear manner. Conclusion: The study found that a higher OBS was associated with a decrease in stroke prevalence, which could be a significant indicator for evaluating stroke risk.

Identification of genetic molecular markers and immune infiltration characteristics of Alzheimer's disease through weighted gene co-expression network analysis.

Background: Alzheimer's disease (AD) is a progressive neurodegenerative disease that leads to cognitive impairment and memory loss. Currently, the pathogenesis and underlying causative genes of AD remain unclear, and there exists no effective treatment for this disease. This study explored AD-related diagnostic and therapeutic biomarkers from the perspective of immune infiltration by analyzing public data from the NCBI Gene Expression Omnibus database. Method: In this study, weighted gene co-expression network analysis (WGCNA) was conducted to identify modules and hub genes contributing to AD development. A protein-protein interaction network was constructed when the genes in the modules were enriched and examined by Gene Ontology (GO)/Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis. Furthermore, a gene network was established using topological WGCNA, from which five hub genes were selected. Logistic regression analysis and receiver operating characteristic curve analysis were performed to explore the clinical value of genes in AD diagnosis. The genes in the core module intersected with the hub genes, and four intersection genes (ATP2A2, ATP6V1D, CAP2, and SYNJ1) were selected. These four genes were enriched by gene set enrichment analysis (GSEA). Finally, an immune infiltration analysis was performed. Results: The GO/KEGG analysis suggested that genes in the core module played a role in the differentiation and growth of neural cells and in the transmission of neurotransmitters. The GSEA of core genes showed that these four genes were mainly enriched in immune/infection pathways (e.g., cholera infection and Helicobacter pylori infection pathways) and other metabolic pathways. An investigation of immune infiltration characteristics revealed that activated mast cells, regulatory T cells, plasma cells, neutrophils, T follicular helper cells, CD8 T cells, resting memory CD4 T cells, and M1 macrophages were the core immune cells contributing to AD progression. qRT-PCR analysis showed that the ATP6V1D is upregulated in AD. Conclusion: The results of enrichment and immuno-osmotic analyses indicated that immune pathways and immune cells played an important role in the occurrence and development of AD. The selected key genes were used as biomarkers related to the pathogenesis of AD to further explore the pathways and cells, which provided new perspectives on therapeutic targets in AD.