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Background: Epigenetics contributes to the pathogenesis of amyotrophic lateral sclerosis (ALS). We aimed to characterize the DNA methylation profiles associated with clinical heterogeneity in disease progression and survival among patients. Methods: We included a cohort of 41 patients with sporadic ALS, with a median follow-up of 86.9 months, and 27 rigorously matched healthy controls. Blood-based genome-wide DNA methylation analysis was conducted. Results: A total of 948 progression rate-associated differentially methylated positions, 298 progression rate-associated differentially methylated regions (R-DMRs), 590 survival time-associated DMPs, and 197 survival time-associated DMRs (S-DMRs) were identified, using complementary grouping strategies. Enrichment analysis of differentially methylated genes highlighted the involvement of synapses and axons in ALS progression and survival. Clinical analysis revealed a positive correlation between the average methylation levels of the R-DMR in PRDM8 and disease progression rate (r = 0.479, p = 0.002). Conversely, there was an inverse correlation between the average methylation levels of the R-DMR in ANKRD33 and disease progression rate (r = − 0.476, p = 0.002). In addition, patients with higher methylation levels within the S-DMR of ZNF696 experienced longer survival (p = 0.016), while those with elevated methylation levels in the S-DMR of RAI1 had shorter survival (p = 0.006). Conclusion: DNA methylation holds promise as a potential biomarker for tracking disease progression and predicting survival outcome and also offers targets for precision medicine. [ABSTRACT FROM AUTHOR]

Background: Multiple system atrophy (MSA) is a rare neurodegenerative disease characterized by Parkinsonism, ataxia, and autonomic nervous failure. Orthostatic hypotension (OH) is the main feature of central vascular autonomic failure in MSA. Objective: The study aimed elucidate the effects of OH on cognitive function, disease milestones, and survival. Methods: A total of 444 patients with clinically established MSA were enrolled. Mild and severe OH were defined as a decrease in systolic blood pressure (SBP)/diastolic blood pressure (DBP) >20/10 mmHg and SBP/DBP ≥30/15 mmHg, respectively. Results: In this study, 215 MSA patients presented without OH, 88 had mild OH, and 141 had severe OH. The proportion of MSA-C in the severe OH subgroup was significantly higher than that in the subgroup without OH (95/46 vs. 113/102, p = 0.021). The UMSARS I score and the frequency of supine hypertension (SH) in patients with OH were significantly higher than those in patients without OH (16.22 vs. 16.89 vs. 14.60, p < 0.001; 77/64 vs. 29/59 vs. 32/183, p < 0.001). Factors related to the severity of OH included sex (OR, 0.65; p = 0.031), onset age (OR, 0.98; p = 0.029), and SH (OR, 0.21; p < 0.001). The median survival time of patients with severe OH was significantly lower than that of patients without OH (6.79 vs. 8.13 years, p = 0.001). Consistently, Cox survival analysis found that compared with patients without OH, patients with severe OH had a significantly increased risk of death (OR, 2.22; p < 0.001). Conclusion: Our large cohort study of MSA provides additional evidence for the negative impact of severe OH on survival. [ABSTRACT FROM AUTHOR]

Background and purpose: Clarification of propagation patterns in amyotrophic lateral sclerosis (ALS) is challenging, but understanding these has implications for individual prognostication and clinical trial design. However, systematic knowledge in this area is lacking. The aim of this study was to characterize the spatial and temporal features of propagation patterns in ALS, and to evaluate the association between propagation patterns and survival. Methods: A cohort of 833 patients with ALS, diagnosed between January 2018 and December 2019 and followed to August 2021, was analysed. Spatial and temporal features of propagation patterns were determined based on the involved functional regions (bulbar, cervical, thoracic/respiratory and lumbar) in time order. The final propagation pattern was identified in patients with at least three functional regions involved. Kaplan–Meier analysis and Cox regression analysis were performed. Results: During a median follow‐up of 21.2 months, 19 final propagation patterns were identified in 657 patients (78.9%). In survival analysis, we found that the earlier the respiratory functional region becomes involved, the higher the risk of death (time order: 1st: hazard ratio [HR], 3.35, 95% confidence interval [CI] 1.23–9.15; 2nd: HR 2.45, 95% CI 1.55–3.87; 3rd: HR 1.94, 95% CI 1.52–2.49), adjusting for age, sex, diagnostic delay, revised ALS Functional Rating Scale score, cognitive impairment and riluzole. Shorter interval time between involved regions was an independent adverse prognostic factor. Conclusions: The propagation patterns of ALS are varied. The order in which the respiratory region becomes involved and the interval time between involvement of functional regions are predictors for prognosis. [ABSTRACT FROM AUTHOR]