Association and prediction of Life's Essential 8 score, genetic susceptibility with MCI, dementia, and MRI indices: A prospective cohort study.

BACKGROUND: To examine the associations of Life's Essential 8 (LE8) and its predictive performance with mild cognitive impairment (MCI), dementia and brain MRI indices. METHODS: We used cohort data from UK Biobank. LE8 was categorized into low (<50 score), moderate (50-79 score), and high (≥80 score) levels. Cox regression models considering death as a competing risk were used to estimate the hazard ratios (HRs) and 95%CI on the association between LE8 and MCI and dementia. Multivariable linear regression models were used to analyze LE8 every 10-score increase and brain MRI indices. Area under the curve (AUC) was used to measure the predictive performances of LE8. RESULTS: We included 126,785 participants with a mean (SD) age of 56.0 (8.0) years and 53.5 % were female. The median follow-up was 13.0 years. Compared to individuals with a low LE8 score, those with a high LE8 score were associated with decreased risk of MCI (0.49, 95%CI: 0.40-0.62), all-cause dementia (0.60, 0.44-0.80), vascular dementia (VD, 0.44, 0.21-0.94), and non-Alzheimer non-vascular dementia (NAVD, 0.55, 0.35-0.84). High LE8 score was associated with increased total brain volume, hippocampus volume, grey matter volume, and grey matter in hippocampus volume (p all ≤0.001). LE8 combined age and sex had good performance for predicting all-cause dementia (AUC: 84.1 %), AD (85.4 %), VD (87.6 %), NAVD (81.4 %), and MCI (75.3 %). LIMITATIONS: Our findings only reflect the characteristics of UKB participants. CONCLUSIONS: High LE8 score was associated with reduced risk of MCI and dementia. It was also linked to brain MRI indices. LE8 score had good predicting performance for future risk of MCI and dementia.

Healthy lifestyle and all-cause and cause-specific dementia in individuals with type 2 diabetes and the roles of diabetes duration and insulin use in UK Biobank cohort.

AIMS: To examine the effect of a healthy lifestyle score derived from seven lifestyle factors recommended by the diabetes management guidelines on all-cause and cause-specific dementia in individuals with type 2 diabetes mellitus (T2DM), and how diabetes duration and insulin use status modify their association. MATERIALS AND METHODS: This study analysed data of 459 840 participants from the UK Biobank. We used Cox proportional hazards models to estimate hazard ratios (HRs) and 95% confidence intervals for the association of an overall healthy lifestyle score with all-cause and cause-specific dementia of Alzheimer's disease, vascular dementia and non-Alzheimer non-vascular dementia. RESULTS: Using diabetes-free participants who scored 5-7 as the reference group, in diabetes-free participants, we observed higher healthy lifestyle score was related to lower risk of all-cause and cause-specific dementia. However, in people with T2DM, those scored 2-3, 4 and 5-7 all had around the two-time risk of all-cause dementia (HR: 2.20-2.36), while those scored 0-1 had over a three-time risk (HR: 3.14, 95% confidence interval 2.34-4.21). A dose-response trend was observed with vascular dementia (each 2-point increase: 0.75, 0.61-0.93) and no significant association with Alzheimer's disease (0.95, 0.77-1.16). The reduced risk of all-cause and cause-specific dementia with higher lifestyle score was observed in patients with a diabetes duration less than 10 years, or in patients with no insulin use. CONCLUSION: In people with T2DM, higher healthy lifestyle score was associated with lower risk of all-cause dementia. Diabetes duration and insulin use moderated the association between healthy lifestyle score and risk of dementia.

Age at menopause and all-cause and cause-specific dementia: a prospective analysis of the UK Biobank cohort.

STUDY QUESTION: Are there associations between natural or surgical menopause and incident dementia by age at menopause? SUMMARY ANSWER: Compared to age at menopause of 46-50 years, earlier natural menopause (≤40 and 41-45 years) was related to higher risk of all-cause dementia, while a U-shape relationship was observed between age at surgical menopause and risk of dementia. WHAT IS KNOWN ALREADY: Menopause marks the end of female reproductive period. Age at menopause reflects the length of exposure to endogenous estrogen. Evidence on the association between age at natural, surgical menopause, and risk of dementia has been inconsistent. STUDY DESIGN, SIZE, DURATION: A population-based cohort study involving 160 080 women who participated in the UK Biobank study. PARTICIPANTS/MATERIALS, SETTING, METHODS: Women with no dementia at baseline, and had no missing data on key exposure variables and covariates were included. Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% CIs on the association of categorical menopause age with incident all-cause dementia, Alzheimer's disease (AD) and vascular dementia (VD). Restricted cubic splines were used to model the non-linear relationship between continuous age at natural, surgical menopause, and risk of dementia. In addition, we analyzed the interaction effect of ever-used menopausal hormone therapy (MHT) at baseline, income level, leisure activities, and age at menopause on risk of dementia. MAIN RESULTS AND THE ROLE OF CHANCE: Compared to women with age at menopause of 46-50 years, women with earlier natural menopause younger than 40 years (1.36, 1.01-1.83) and 41-45 years (1.19, 1.03-1.39) had a higher risk of all-cause dementia, while late natural menopause >55 years was linked to lower risk of dementia (0.83, 0.71-0.98). Compared to natural menopause, surgical menopause was associated with 10% higher risk of dementia (1.10, 0.98-1.24). A U-shape relationship was observed between surgical menopause and risk of dementia. Women with surgical menopause before age 40 years (1.94, 1.38-2.73) and after age 55 years (1.65, 1.21-2.24) were both linked to increased risk of all-cause dementia. Women with early natural menopause without ever taking MHT at baseline had an increased risk of AD. Also, in each categorized age at the menopause level, higher income level or higher number of leisure activities was linked to a lowers risk of dementia. LIMITATIONS, REASONS FOR CAUTION: Menopausal age was based on women's self-report, which might cause recall bias. WIDER IMPLICATION OF THE FINDINGS: Women who experienced natural menopause or had surgical menopause at an earlier age need close monitoring and engagement for preventive health measures to delay the development of dementia. STUDY FUNDING/COMPETING INTERESTS: This work was supported by the Start-up Foundation for Scientific Research in Shandong University (202099000066), Science Fund Program for Excellent Young Scholars of Shandong Provence (Overseas) (2022HWYQ-030), and the National Natural Science Foundation of China (82273702). There are no competing interests. TRIAL REGISTRATION NUMBER: N/A.

Midlife Life's Simple 7, Psychosocial Health, and Physical Frailty, Hospital Frailty, and Comprehensive Frailty 10 Years Later.

This study aims to examine the associations between midlife Life's Simple 7 (LS7) status, psychosocial health (social isolation and loneliness), and late-life multidimensional frailty indicators, and to investigate their synergistic effect on frailty. We used cohort data from the UK Biobank. Frailty was assessed using physical frailty phenotype, hospital frailty risk score, and frailty index. Cox proportional-hazards models were used to estimate the hazard ratios (HRs) and 95% confidence intervals (CIs) on the association between the LS7 score, psychosocial health, and frailty. For the association of LS7 with physical and comprehensive frailty, 39,047 individuals were included. After a median follow-up of 9.0 years, 1329 (3.4%) people were identified with physical frailty, and 5699 (14.6%) with comprehensive frailty. For the association of LS7 with hospital frailty, 366,570 people were included. After a median follow-up of 12.0 years, 18,737 (5.1%) people were identified with hospital frailty. Compared to people with a poor LS7 score, those with an intermediate (physical frailty: 0.64, 0.54-0.77; hospital frailty: 0.60, 0.58-0.62; and comprehensive frailty: 0.77, 0.69-0.86) and optimal LS7 score (physical frailty: 0.31, 0.25-0.39; hospital frailty: 0.39, 0.37-0.41; and comprehensive frailty: 0.62, 0.55-0.69) were associated with a lower risk of frailty. Poor psychosocial health was associated with an increased risk of frailty. People who had a poor psychosocial status and poor LS7 score had the highest risk of frailty. A better LS7 score in midlife was associated with a reduced risk of physical, hospital, and comprehensive frailty. There was a synergistic effect of psychosocial status and LS7 on frailty.

Sex-specific associations between diabetes and dementia: the role of age at onset of disease, insulin use and complications.

BACKGROUND: Whether the association of type 2 diabetes (T2DM) with dementia was differed by sex remains unclear, and the roles of age at onset of disease, insulin use and diabetes' complications in their association are unknown. METHODS: This study analyzed data of 447 931 participants from the UK Biobank. We used Cox proportional hazards models to estimate sex-specific hazard ratios (HRs) and 95% confidence intervals (CI), and women-to-men ratio of HRs (RHR) for the association between T2DM and incident dementia [all-cause dementia, Alzheimer's disease (AD), and vascular dementia (VD)]. The roles of age at onset of disease, insulin use and diabetes' complications in their association were also analyzed. RESULTS: Compared to people with no diabetes at all, people with T2DM had increased risk of all-cause dementia (HR 2.85, 95% CI 2.56-3.17). The HRs between T2DM and AD were higher in women than men, with an RHR (95%CI) of 1.56 (1.20, 2.02). There was a trend that people who experienced T2DM before age 55 had higher risk of VD than those who had T2DM after age 55. In addition, there was a trend that T2DM had higher effect on VD that occurred before age 75 years than events that occurred after age 75. Patients with T2DM using insulin had higher risk of all-cause dementia than those without insulin, with an RHR (95%CI) of 1.54 (1.00-2.37). People with complications had doubled risk of all-cause dementia, AD and VD. CONCLUSIONS: Adopting a sex-sensitive strategy to address the risk of dementia in patients with T2DM is instrumental for a precision medicine approach. Meanwhile, it is warranted to consider patients' age at onset of T2DM, insulin use status and complications conditions.

Quantitative Fluorescence Imaging of the Intracellular Redox State by Real-Time Spatial and Temporal Simultaneous Analysis of O2•- Levels and Keap1 Translocation.

Dysregulated redox homeostasis under pathological conditions can eventually culminate in oxidative stress and associated disease damage. Spatial and temporal regulation of intracellular redox states involves two crucial parameters for elucidating oxidative stress-related molecular mechanisms. However, the lack of methods for real-time analysis of redox states is a considerable hurdle for the in-depth interpretation of pathogenic mechanisms. Herein, given the over-produced reactive oxygen species (ROS) and the translocation of redox-sensitive proteins as the potential biomarkers of oxidative stress, we developed a novel ROS-macromolecular protein synergistic imaging strategy that relied on a small-molecule fluorescent CPR-SK probe. The CPR-SK specifically activated the caffeic acid moieties or targeting peptides (EWWW) toward the biomarkers, including superoxide (O2•-) fluctuations and Keap1 translocation, achieving simultaneous real-time imaging of dual molecular events during oxidative stress. Importantly, in situ, CPR-SK exhibited both gentle elevation of O2•- and subsequent migration of Keap1 from the cytoplasm to the nucleus, which were key indicators for determining slight injuries induced by hepatic ischemia-reperfusion. The results clearly demonstrated that this spatiotemporal imaging method was a reliable tool for analyzing dynamic intracellular changes of the redox state and elucidating the molecular mechanisms of oxidative stress-related diseases.

Precision Navigation of Hepatic Ischemia-Reperfusion Injury Guided by Lysosomal Viscosity-Activatable NIR-II Fluorescence.

Hepatic ischemia-reperfusion injury (HIRI) is responsible for postoperative liver dysfunction and liver failure. Precise and rapid navigation of HIRI lesions is critical for early warning and timely development of pretreatment plans. Available methods for assaying liver injury fail to provide the exact location of lesions in real time intraoperatively. HIRI is intimately associated with oxidative stress which impairs lysosomal degradative function, leading to significant changes in lysosomal viscosity. Therefore, lysosomal viscosity is a potential biomarker for the precise targeting of HIRI. Hence, we developed a viscosity-activatable second near-infrared window fluorescent probe (NP-V) for the detection of lysosomal viscosity in hepatocytes and mice during HIRI. A reactive oxygen species-malondialdehyde-cathepsin B signaling pathway during HIRI was established. We further conducted high signal-to-background ratio NIR-II fluorescence imaging of HIRI mice. The contour and boundary of liver lesions were delineated, and as such the precise intraoperative resection of the lesion area was implemented. This research demonstrates the potential of NP-V as a dual-functional probe for the elucidation of HIRI pathogenesis and the direct navigation of HIRI lesions in clinical applications.

Sex differences in the association between cardiovascular diseases and dementia subtypes: a prospective analysis of 464,616 UK Biobank participants.

BACKGROUND: Whether the association of cardiovascular diseases (CVDs) with dementia differs by sex remains unclear, and the role of socioeconomic, lifestyle, genetic, and medical factors in their association is unknown. METHODS: We used data from the UK Biobank, a population-based cohort study of 502,649 individuals. We used Cox proportional hazards models to estimate sex-specific hazard ratios (HRs) and 95% confidence intervals (CI), and women-to-men ratio of HRs (RHR) for the association between CVD (coronary heart diseases (CHD), stroke, and heart failure) and incident dementia (all-cause dementia, Alzheimer's Disease (AD), and vascular dementia (VD)). The moderator roles of socioeconomic (education, income), lifestyle (smoking, BMI, leisure activities, and physical activity), genetic factors (APOE allele status), and medical history were also analyzed. RESULTS: Compared to people who did not experience a CVD event, the HRs (95%CI) between CVD and all-cause dementia were higher in women compared to men, with an RHR (Female/Male) of 1.20 (1.13, 1.28). Specifically, the HRs for AD were higher in women with CHD and heart failure compared to men, with an RHR (95%CI) of 1.63 (1.39, 1.91) and 1.32 (1.07, 1.62) respectively. The HRs for VD were higher in men with heart failure than women, with RHR (95%CI) of 0.73 (0.57, 0.93). An interaction effect was observed between socioeconomic, lifestyle, genetic factors, and medical history in the sex-specific association between CVD and dementia. CONCLUSION: Women with CVD were 1.5 times more likely to experience AD than men, while had 15% lower risk of having VD than men.

Integrative metabolome and transcriptome analyses reveal the molecular mechanism underlying variation in floral scent during flower development of Chrysanthemum indicum var. aromaticum.

Chrysanthemum indicum var. aromaticum (CIA) is an endemic plant that occurs only in the high mountain areas of the Shennongjia Forest District in China. The whole plant, in particular the flowers of CIA, have intense fragrance, making it a novel resource plant for agricultural, medicinal, and industrial applications. However, the volatile metabolite emissions in relation to CIA flower development and the molecular mechanisms underlying the generation of floral scent remain poorly understood. Here, integrative metabolome and transcriptome analyses were performed to investigate floral scent-related volatile compounds and genes in CIA flowers at three different developmental stages. A total of 370 volatile metabolites, mainly terpenoids and esters, were identified, of which 89 key differential metabolites exhibited variable emitting profiles during flower development. Transcriptome analysis further identified 8,945 differentially expressed genes (DEGs) between these samples derived from different flower developmental stages and KEGG enrichment analyses showed that 45, 93, and 101 candidate DEGs associated with the biosynthesis of phenylpropanoids, esters, and terpenes, respectively. Interestingly, significant DEGs involved into the volatile terpenes are only present in the MEP and its downstream pathways, including those genes encoding ISPE, ISPG, FPPS, GPPS, GERD, ND and TPS14 enzymes. Further analysis showed that 20 transcription factors from MYB, bHLH, AP2/EFR, and WRKY families were potentially key regulators affecting the expressions of floral scent-related genes during the CIA flower development. These findings provide insights into the molecular basis of plant floral scent metabolite biosynthesis and serve as an important data resources for molecular breeding and utilization of CIA plants in the future.

In Situ Observation of mtDNA Damage during Hepatic Ischemia-Reperfusion.

Hepatic ischemia-reperfusion (IR) injury is a severe pathophysiological event during liver surgery or transplantation and could lead to liver failure or even death. The energy supply of mitochondria plays an essential role in preventing IR injury. Mitochondrial DNA (mtDNA) is involved in maintaining the balance of energy by participating in an oxidative phosphorylation process. However, the exact relationship between IR and mtDNA remains unclear by reason of the lack of an accurate real-time analysis method. Herein, we fabricated a mitochondria-targeting fluorescent probe (mtDNA-BP) to explore mtDNA stability and supervise the changes in mtDNA in IR liver. By virtue of pyridinium electropositivity and suitable size, mtDNA-BP could accumulate in mitochondria and insert into the mtDNA groove, which made mtDNA-BP fluoresce strongly. This is attributed to the reduction of the intramolecular rotation energy loss that is restricted by DNA. By in situ fluorescence imaging, we observed in real time that mtDNA damage was aggravated by deteriorating IR injury, so the ROS-mtDNA-mediated IR damage signal pathway was speculated. Furthermore, on the basis of mtDNA-BP real-time response capability for mtDNA, we established a drug-screening method for inhibiting IR injury and found superior therapeutic performance of two potential drugs: pioglitazone and salidroside. This work contributes to our understanding of mtDNA-related disease and provides a new drug analysis method.