Xilin Wu

Background: The causal relationship between daytime napping and the risk of Parkinson’s disease (PD) remains unclear, with prospective studies providing limited evidence. This study investigated the association between daytime napping frequency and duration and PD incidence and explored the causality relationship between this association by conducting Mendelian randomization (MR) analysis. Methods: This prospective cohort study included 393,302 participants, and accelerometer-measured daytime napping data were available only for 78,141 individuals. Cox proportional hazards regression was used to estimate the association between the daytime napping frequency and duration and the PD risk. The role of the systemic immune-inflammation index (SII) in the association between daytime napping frequency and PD risk was assessed through mediation analyses. Moreover, the causal association between the daytime napping frequency and the PD risk was preliminarily explored by conducting two-sample MR analyses. Results: The median follow-up duration was 12.18 years. The participants who reported napping sometimes or usually exhibited a significantly higher PD risk than those who never/rarely napped during the day [sometimes: hazard ratio (HR), 1.13; 95% confidence interval (CI), 1.03–1.23; usually: HR, 1.33; 95% CI, 1.14–1.55], and SII played a mediating role in this association. However, the MR analyses did not indicate that the daytime napping frequency and PD risk were significantly associated. The participants napping for over 1 h exhibited a significantly elevated PD risk (HR, 1.54; 95% CI, 1.11–2.16). Moreover, no significant interaction was identified between napping frequency or duration and genetic susceptibility to PD (P for interaction > 0.05). Conclusions: In this study, increased daytime napping frequency and duration were associated with an increased PD risk, but no causal relationship was observed between napping frequency and PD risk in the MR analysis. Larger GWAS-based cohort studies and MR studies are warranted to explore potential causal relationships.

Introduction: Stroke is a life-threatening condition that causes a major medical burden globally. The currently used methods for the prevention or prediction of stroke have certain limitations. Exposure to tobacco in early life, including smoking during adolescence and maternal smoking during pregnancy, can affect adolescent development and lead to several negative outcomes. However, the association between early-life tobacco exposure and stroke is not known. Methods: In this prospective cohort study, for the analyses involving exposure to maternal smoking during pregnancy and age of smoking initiation, we included 304,984 and 342,893 participants, respectively., respectively from the UK Biobank. Cox proportional hazard regression model and subgroup analyses were performed to investigate the association between early-life tobacco exposure and stroke. Mediation analyses were performed to identify the mediating role of biological aging in the association between early tobacco exposure and stroke. Results: Compared with participants whose mothers did not smoke during pregnancy, participants whose mothers smoked during pregnancy showed an 11% increased risk of stroke (HR: 1.11, 95% CI: 1.05–1.18, P < 0.001). Compared with participants who never smoked, participants who smoked during adulthood, adolescence and childhood showed a 22%, 24%, and 38% increased risk of stroke during their adulthood, respectively. Mediation analysis indicated that early-life tobacco exposure can cause stroke by increasing biological aging. Conclusion: This study reveals that exposure to tobacco during early life is associated with an increased risk of experiencing a stroke, and increased biological aging can be the underlying mechanism.

Background: The association between coffee and mortality risk has been found in most previous studies, and recent studies have found an association between coffee consumption and cognition. However, there is still a lack of research exploring whether the association between coffee and mortality is influenced by cognitive function.Objective: The purpose of this study was to explore the association of coffee, caffeine intake in coffee and decaffeinated coffee with all-cause mortality and cardiovascular disease (CVD) mortality in older adults with different cognitive performances.Methods: The study was based on data from the National Health and Nutrition Examination Survey (NHANES) 2011–2014. Coffee and caffeine consumption data were obtained from two 24-h dietary recalls. Individual cognitive functions were assessed by CERAD-word learning test (CERAD-WLT), animal fluency test (AFT), and digit symbol substitution test (DSST). In addition, principal component analysis (PCA) was performed with the above test scores to create global cognitive score. The lowest quartile of scores was used to classify cognitive performance. Cox regression and restricted cubic spline (RCS) were applied to assess the relationship between coffee and caffeine consumption and mortality.Results: In the joint effects analysis, we found that those with cognitive impairment and who reported without drinking coffee had the highest risk of all-cause and cardiovascular mortality compared with others. In the analysis of population with cognitive impairment, for all-cause mortality, those who showed cognitive impairment in the AFT displayed a significant negative association between their total coffee consumption and mortality {T3 (HR [95% CI]), 0.495 [0.291–0.840], p = 0.021 (trend analysis)}. For DSST and global cognition, similar results were observed. Whereas for CERAD-WLT, restricted cubic spline (RCS) showed a “U-shaped” association between coffee consumption and mortality. For CVD mortality, a significant negative trend in coffee consumption and death was observed only in people with cognitive impairment in AFT or DSST. In addition, we observed that decaffeinated coffee was associated with reduced mortality in people with cognitive impairment.Conclusion: Our study suggested that the association between coffee consumption and mortality is influenced by cognition and varies with cognitive impairment in different cognitive domains.

Mutations of the leucine-rich repeat kinase 2 (LRRK2) gene are associated with pronounced sleep disorders or cognitive dysfunction in neurodegenerative diseases. However, the effects of LRRK2 deficiency on sleep rhythms and sleep deprivation-related cognitive changes, and the relevant underlying mechanism, remain unrevealed. In this study, Lrrk2^-/- and Lrrk2^+/+ mice were subjected to normal sleep (S) or sleep deprivation (SD). Sleep recording, behavioral testing, Golgi-cox staining, immunofluorescence, and real-time PCR were employed to evaluate the impacts of LRRK2 deficiency on sleep behaviors and to investigate the underlying mechanisms. The results showed that after SD, LRRK2-deficient mice displayed lengthened NREM and shortened REM, and reported decreased dendritic spines, increased microglial activation, and synaptic endocytosis in the prefrontal cortex. Meanwhile, after SD, LRRK2 deficiency aggravated cognitive impairments, especially in the recall memory cued by fear conditioning test. Our findings evidence that LRRK2 modulates REM/NREM sleep and its deficiency may exacerbate sleep deprivation-related cognitive disorders by perturbing synaptic plasticity and microglial synaptic pruning in mice.

Aging and apolipoprotein E4 (ApoE4) can increase the risk of cognitive impairment and neurodegenerative disorders, including Alzheimer's disease (AD), and patients with type 2 diabetes mellitus are highly susceptible to cognitive dysfunction. Recent research has indicated that metformin, a prescribed drug for type 2 diabetes, may affect cognitive function; however, findings regarding its efficacy are largely controversial. The current study reported that a 5‐mo metformin administration (300 mg/kg/d) starting at 13 mo old improved the spatial memory of ApoE3‐target replacement (TR) mice, not ApoE4‐TR mice. It found that in aged ApoE3‐TR mice, metformin treatment, at a molecular level, inhibited AMPK activity, increased insulin signaling, and activated mammalian target of rapamycin signaling, resulting in an enhanced expression of postsynaptic proteins; but the response of the neuronal AMPK activity and insulin signaling to metformin was blunt in aged ApoE4‐TR mice. Meanwhile, metformin treatment also increased the phosphorylation of tau in both ApoE3‐TR and ApoE4‐TR mice, implying that metformin may have side effects in human. These findings suggest that metformin can improve the cognitive performance of aged mice in an APOE genotype–dependent manner, which provides empirical insights into the clinical value of metformin for ApoE4‐ and age‐related AD prevention and treatment.—Zhang, J., Lin, Y., Dai, X., Fang, W., Wu, X., Chen, X. Metformin treatment improves the spatial memory of aged mice in an APOE genotype–dependent manner. FASEB J. 33, 7748–7757 (2019). www.fasebj.org

Objective:To review recent research advances on tau, a major player in Alzheimer's disease (AD) pathogenesis, a biomarker for AD onset, and potential target for AD therapy.Data Sources:This review was based on a comprehensive search using online literature databases, including PubMed, Web of Science