Associations between adiposity and white matter hyperintensities: Cross-sectional and longitudinal analyses of 34,653 participants.

OBJECTIVES: White matter hyperintensities (WMH) increase the risk of stroke and cognitive impairment. This study aims to determine the cross-sectional and longitudinal associations between adiposity and WMH. METHODS: Participants were enrolled from the UK Biobank cohort. Associations of concurrent, past, and changes in overall and central adiposity with WMH were investigated by linear and nonlinear regression models. The association of longitudinal adiposity and WMH volume changes was determined by a linear mixed model. Mediation analysis investigated the potential mediating effect of blood pressure. RESULTS: In 34,653 participants with available adiposity measures and imaging data, the concurrent obese group had a 25.3% (ß [95% CI] = 0.253 [0.222-0.284]) higher WMH volume than the ideal weight group. Increment in all adiposity measures was associated with a higher WMH volume. Among them, waist circumference demonstrated the strongest effect (ß [95% CI] = 0.113 [0.101-0.125]). Past adiposity also demonstrated similar effects. Among the subset of 2664 participants with available WMH follow-up data, adiposity measures were predictive of WMH change. Regarding changes of adiposity, compared with ideal weight stable group, those who turned from ideal weight to overweight/obese had a 8.1% higher WMH volume (ß [95% CI] = 0.081 [0.039-0.123]), while participants who turned from overweight/obese to ideal weight demonstrated no significant WMH volume change. Blood pressure partly meditates the associations between adiposity and WMH. CONCLUSIONS: Both concurrent and past adiposity were associated with a higher WMH volume. The detrimental effects of adiposity on WMH occurred throughout midlife and in the elderly and may still exist after changes in obesity status.

Multipredictor risk models for predicting individual risk of Alzheimer's disease.

BACKGROUND: Early prevention of Alzheimer's disease (AD) is a feasible way to delay AD onset and progression. Information on AD prediction at the individual patient level will be useful in AD prevention. In this study, we aim to develop risk models for predicting AD onset at individual level using optimal set of predictors from multiple features. METHODS: A total of 487 cognitively normal (CN) individuals and 796 mild cognitive impairment (MCI) patients were included from Alzheimer's Disease Neuroimaging Initiative. All the participants were assessed for clinical, cognitive, magnetic resonance imaging and cerebrospinal fluid (CSF) markers and followed for mean periods of 5.6 years for CN individuals and 4.6 years for MCI patients to ascertain progression from CN to incident prodromal stage of AD or from MCI to AD dementia. Least Absolute Shrinkage and Selection Operator Cox regression was applied for predictors selection and model construction. RESULTS: During the follow-up periods, 139 CN participants had progressed to prodromal AD (CDR ≥ 0.5) and 321 MCI patients had progressed to AD dementia. In the prediction of individual risk of incident prodromal stage of AD in CN individuals, the AUC of the final CN model was 0.81 within 5 years. The final MCI model predicted individual risk of AD dementia in MCI patients with an AUC of 0.92 within 5 years. The models were also associated with longitudinal change of Mini-Mental State Examination (p < 0.001 for CN and MCI models). An Alzheimer's continuum model was developed which could predict the Alzheimer's continuum for individuals with normal AD biomarkers within 3 years with high accuracy (AUC = 0.91). CONCLUSIONS: The risk models were able to provide personalized risk for AD onset at each year after evaluation. The models may be useful for better prevention of AD.

Associations of circulating metabolites with cerebral white matter hyperintensities.

White matter hyperintensities (WMH) are the most compelling risk factors of stroke, dementia, and early mortality. We aimed to investigate the associations between WMH and circulating metabolites. We studied up to 8190 individuals from the UK Biobank, who have both measurements of 249 plasma metabolites and WMH volume. Linear regression models were applied in pooled samples, and age-stratified and sex-stratified subsamples to estimate the associations between WMH and metabolomic measures. We conducted three analytic models. In the basic model, we identified 45 metabolomic measures associated with WMH after multiple testing correction (p < 0.0022), 15 of which remained significant in additional adjustments, but no metabolites passed the full adjustment in pooled samples. The 15 WMH-related metabolites were subfractions of various sizes of high-density lipoprotein (HDL), fatty acids, and glycoprotein acetyls. Among them, one fatty acid metabolite and 12 HDL-related traits showed significant negative associations with WMH. Higher glycoprotein acetyls were associated with large WMH. Strong age and sex specificities were observed indicating distinct metabolomic features accompany WMH in different samples. More metabolites were identified in males and adults under 50 years old. Circulating metabolites showed remarkably widespread associations with WMH. Population specificities may shed light on the different pertinent implications of WMH.

Association of sleep behaviors with white matter hyperintensities and microstructural injury: a cross-sectional and longitudinal analysis of 26 354 participants.

STUDY OBJECTIVES: This study assessed the associations between sleep behaviors with white matter macro and microstructure. METHODS: A total of 26 354 participants in the UK Biobank (mean [standard deviation], age, 63.7 [7.5] years, 53.4% female) were included in this study. A healthy sleep score integrated sleep behaviors including chronotype, insomnia, sleep duration, daytime sleepiness, and snoring. Linear and nonlinear relationships were calculated between individual and aggregate sleep behaviors with white matter hyperintensities (WMH) and microstructural injury. RESULTS: A "U-shaped" relationship was revealed between sleep duration and WMH, and the lowest WMH was at 7.7 h per night. Four unhealthy sleep behaviors including late chronotype, sleep duration (>8 h or <7 h), excessive daytime sleepiness, and snoring significantly increased WMH impacts. Lower healthy sleep score was linked with increased WMH impacts (ß = 0.164, 95% CI = 0.110-0.218), and worse microstructure in association and thalamic white matter tracts. Increased body mass index, glycated hemoglobin A1c, and systolic blood pressure were potential mediators of the relationships between unhealthy sleep behaviors and increased WMH. However, higher BMI and low-density lipoprotein were revealed as protective mediators between snoring and improved white matter integrity including lower MD and higher ICVF. CONCLUSIONS: Unhealthy sleep behaviors were associated with increased WMH impacts and worse white matter microstructure in specific tracts across middle and older age. These findings provide the potential to improve white matter integrity by reversing unhealthy sleep behaviors.

Modified dementia risk score as a tool for the prediction of dementia: a prospective cohort study of 239745 participants.

Based on risk profiles, several approaches for predicting dementia risk have been developed. Predicting the risk of dementia with accuracy is a significant clinical challenge. The goal was to create a modified dementia risk score (MDRS) based on a big sample size. A total of 239,745 participants from UK Biobank were studied (mean follow-up of 8.7 years). The score value of each risk factor was estimated according to the ß coefficient in the logistic regression model. The total dementia risk score was the sum of each risk score. Kaplan Meier survival curves and Cox proportional hazards analyses were used to assess the associations between total score and dementia. Among all participants included, 3531 incident cases of all-cause dementia (ACD), 1729 cases of Alzheimer's disease (AD), and 925 cases of vascular dementia (VD) were identified. Several vascular risk factors (physical activity, current smoking status, and glycemic status) and depressive symptoms were found to be significantly related to dementia risk. The modified dementia risk scores predicted dementia well (model 1, area under curve 0.810; model 2, area under curve 0.832). In model 1, the cut-off value for high risk (HR) was 81 or higher, and in model 2 (including the APOE4), it was 98 or higher. According to Kaplan-Meier survival analyses, patients in the HR group had faster clinical progression (p < 0.0001) in either model 1 or 2. Cox regression analyses for HR versus low risk (LR) revealed that the Hazard radio for ACD was 7.541 (6.941 to 8.193) in model 1 and 8.348 (7.727 to 9.019) in model 2. MDRS is appropriate for dementia primary prevention, and may help quickly identify individuals with elevated risk of dementia.

Comparison of involved-field intensity-modulated radiotherapy combined with S-1 vs radiotherapy alone for elderly patients with esophageal cancer.

BACKGROUND: It is estimated that about 30% of esophageal cancer (EC) patients are over 70 years old. Therefore, there is less evidence on the diagnosis and management of elderly EC patients. It is important to explore how elderly EC patients benefit from radical radiochemotherapy regimens, including the target area of radiotherapy (RT), radiation dose and fraction, and choice of chemotherapy drugs. AIM: To compare the efficacy of involved-field intensity-modulated RT (IF-IMRT) combined with S-1 vs RT alone in the treatment of elderly EC patients in terms of safety, short-term response, and survival. METHODS: Thirty-four EC patients aged > 70 years were prospectively enrolled between December 2017 and December 2019. Based on the random number table, they were divided into an IF-IMRT + S-1 group and an IF-IMRT alone group, with 17 patients in each group. All patients were treated with IF-IMRT at a dose of 50.4-56 Gy in 28-30 fractions (1.8-2 Gy/fraction, 5 fractions/wk). Oral S-1 was administered concomitantly in the IF-IMRT + S-1 group for 14 consecutive days, and a second cycle was started 7 d after drug withdrawal. After RT, 4 cycles of S-1 treatment were offered as the consolidation chemotherapy. The safety, short-term response, and survival were observed after the treatment. RESULTS: As of April 2022, these 34 patients had been followed up for 15.2-32.5 mo, with a median follow-up period of 24.5 mo. Complete efficacy indicators were obtained from all the patients. The objective response rate was 88.2% vs 76.5%, respectively, in the IF-IMRT + S-1 group and the RT alone group, where as the disease control rate was 100% vs 82.4%, respectively. The incidence of adverse events including grade 1-2 fatigue, granulocytopenia, thrombocytopenia, anemia, radiation esophagitis, radiation-induced skin injury, and radiation-induced lung injury was not significantly different between these two groups, so was the incidence of the grade 3 radiation esophagitis (0% vs 5.7%). The rate of progressive disease (PD) was 52.9% (n = 9) in the IF-IMRT + S-1 group and 64.7% (n = 11) in the RT alone group. The median progression-free survival (PFS) was 23.4 mo vs 16.3 mo, and the 2-year PFS rate was 42% vs 41.2%. The median overall survival (OS) was 27.0 mo vs 23.0 mo, and the 2-year OS rate was 58.8% vs 47.1%. Multivariate analysis showed that age was a significant prognostic factor (P = 0.0019); patients aged < 75 years had a significant survival advantage over patients aged ≥ 75 years. The locations of EC also affected the prognosis. In the IF-IMRT + S-1 group, the number of chemotherapy cycles was a significant prognostic factor (P = 0.0125), and the risk of PD was significantly lower in EC patients who had received 6 cycles of chemotherapy than those who had received 2-5 cycles of chemotherapy. CONCLUSION: Compared with IF-IMRT alone, IF-IMRT + S-1 shows the benefits of preventing PD and prolonging survival without increasing adverse reactions. Therefore, this concurrent radiochemotherapy deserves clinical application.

Genetic determinants of circulating metabolites and the risk of stroke and its subtypes.

BACKGROUND AND PURPOSE: Circulating metabolites have been implicated in stroke pathogenesis, but their genetic determinants are understudied. Using a Mendelian randomization approach, our aim was to provide evidence for the relationship of circulating metabolites and the risk of stroke and its subtypes. METHODS: Genetic instruments of 102 circulating metabolites were obtained from a genome-wide association study, including 24,925 European individuals. Stroke was extracted from the MEGASTROKE dataset (67,162 cases; 454,450 controls) and a lacunar stroke dataset (7338 cases; 254,798 controls). The magnetic resonance imaging markers of cerebral small vessel disease and microstructural injury were evaluated by a genome-wide association study of white matter hyperintensities (N = 18,381), fractional anisotropy (N = 17,663), mean diffusivity (N = 17,467) and brain microbleeds (N = 25,862). The inverse-variance weighted method Mendelian randomization was used as the primary analytical method, and directional pleiotropy and heterogeneity were examined in sensitivity analyses. RESULTS: A genetic predisposition to a higher level of cholesterol in small and low-density lipoprotein (LDL) was associated with risk of stroke (odds ratio [OR] 1.14, 95% confidence interval [CI] 1.08-1.21, p = 5.98 × 10-7 ), especially for large-artery atherosclerotic stroke (OR 1.34, 95% CI 1.19-1.52, p = 1.90 × 10-6 ). Total lipids in LDL particles were also associated with risk of stroke. A genetically determined higher cholesterol level in high-density lipoprotein (HDL-C) was associated with risk of intracerebral haemorrhage (OR 1.74, 95% CI 1.23-2.45, p = 1.66 × 10-3 ). No statistically significant association was found between genetic predisposition to circulating metabolites and magnetic resonance imaging markers of cerebral small vessel disease and microstructural injury. CONCLUSIONS: Genetically determined levels of lipids in small LDL were associated with the risk of stroke, suggesting that a therapeutic strategy targeting small LDL levels may be crucial for stroke prevention. HDL-C was positively associated with the risk of intracerebral haemorrhage.

Causal Relations between Exposome and Stroke: A Mendelian Randomization Study.

BACKGROUND AND PURPOSE: To explore the causal relationships of elements of the exposome with ischemic stroke and its subtypes at the omics level and to provide evidence for stroke prevention. METHODS: We conducted a Mendelian randomization study between exposure and any ischemic stroke (AIS) and its subtypes (large-artery atherosclerotic disease [LAD], cardioembolic stroke [CE], and small vessel disease [SVD]). The exposure dataset was the UK Biobank involving 361,194 subjects, and the outcome dataset was the MEGASTROKE consortium including 52,000 participants. RESULTS: We found that higher blood pressure (BP) (systolic BP: odds ratio [OR], 1.02; 95% confidence interval [CI], 1.01 to 1.04; diastolic BP: OR, 1.03; 95% CI, 1.01 to 1.05; pulse pressure: OR, 1.03; 95% CI, 1.00 to 1.06), atrial fibrillation (OR, 1.18; 95% CI, 1.13 to 1.25), and diabetes (OR, 1.13; 95% CI, 1.07 to 1.18) were significantly associated with ischemic stroke. Importantly, higher education (OR, 0.69; 95% CI, 0.60 to 0.79) decreased the risk of ischemic stroke. Higher systolic BP (OR, 1.06; 95% CI, 1.02 to 1.10), pulse pressure (OR, 1.08; 95% CI, 1.02 to 1.14), diabetes (OR, 1.28; 95% CI, 1.13 to 1.45), and coronary artery disease (OR, 1.58; 95% CI, 1.25 to 2.00) could cause LAD. Atrial fibrillation could cause CE (OR, 1.90; 95% CI, 1.71 to 2.11). For SVD, higher systolic BP (OR, 1.04; 95% CI, 1.00 to 1.07), diastolic BP (OR, 1.06; 95% CI, 1.01 to 1.12), and diabetes (OR, 1.22; 95% CI, 1.10 to 1.36) were causal factors. CONCLUSIONS: The study revealed elements of the exposome causally linked to ischemic stroke and its subtypes, including conventional causal risk factors and novel protective factors such as higher education.

Investigating Causal Relations Between Circulating Metabolites and Alzheimer's Disease: A Mendelian Randomization Study.

BACKGROUND: Metabolomics is a promising approach that can be used to understand pathophysiological pathways of Alzheimer's disease (AD). However, the causal relationships between metabolism and AD are poorly understood. OBJECTIVE: We aimed to investigate the causal association between circulating metabolites and risk of AD through two-sample Mendelian randomization (MR) approach. METHODS: Genetic associations with 123 circulating metabolic traits were utilized as exposures. Summary statistics data from International Genomics of Alzheimer's Project was used in primary analysis, including 21,982 AD cases and 41,944 controls. Validation was performed using family history of AD data from UK Biobank (27,696 cases of maternal AD, 14,338 cases of paternal AD, and 272,244 controls). We utilized inverse-variance weighted method as primary method. RESULTS: We found significantly increased risks of developing AD per standard deviation increase in the levels of circulating ApoB (odd ratio[OR] = 3.18; 95% confidence interval[CI]: 1.52-6.66, p = 0.0022), glycoprotein acetyls (OR = 1.21; 95% CI: 1.05-1.39, p = 0.0093), total cholesterol (OR = 2.73; 95% CI: 1.41-5.30, p = 0.0030), and low-density lipoprotein (LDL) cholesterol (OR = 2.34; 95% CI: 1.53-3.57, p = 0.0001). Whereas glutamine (OR = 0.81; 95% CI: 0.71-0.92, p = 0.0011) were significantly associated with lower risk of AD. We also detected causal effects of several different composition of LDL fractions on increased AD risk, which has been verified in validation. However, we found no association between circulating high-density lipoprotein cholesterol and AD. CONCLUSION: Our findings suggest causal effects of circulating glycoprotein acetyls, ApoB, LDL cholesterol, and serum total cholesterol on higher risk of AD, whereas glutamine showed the protective effect.

Staging tau pathology with tau PET in Alzheimer's disease: a longitudinal study.

A biological research framework to define Alzheimer' disease with dichotomized biomarker measurement was proposed by National Institute on Aging-Alzheimer's Association (NIA-AA). However, it cannot characterize the hierarchy spreading pattern of tau pathology. To reflect in vivo tau progression using biomarker, we constructed a refined topographic 18F-AV-1451 tau PET staging scheme with longitudinal clinical validation. Seven hundred and thirty-four participants with baseline 18F-AV-1451 tau PET (baseline age 73.9 ± 7.7 years, 375 female) were stratified into five stages by a topographic PET staging scheme. Cognitive trajectories and clinical progression were compared across stages with or without further dichotomy of amyloid status, using linear mixed-effect models and Cox proportional hazard models. Significant cognitive decline was first observed in stage 1 when tau levels only increased in transentorhinal regions. Rates of cognitive decline and clinical progression accelerated from stage 2 to stage 3 and stage 4. Higher stages were also associated with greater CSF phosphorylated tau and total tau concentrations from stage 1. Abnormal tau accumulation did not appear with normal ß-amyloid in neocortical regions but prompt cognitive decline by interacting with ß-amyloid in temporal regions. Highly accumulated tau in temporal regions independently led to cognitive deterioration. Topographic PET staging scheme have potentials in early diagnosis, predicting disease progression, and studying disease mechanism. Characteristic tau spreading pattern in Alzheimer's disease could be illustrated with biomarker measurement under NIA-AA framework. Clinical-neuroimaging-neuropathological studies in other cohorts are needed to validate these findings.

Herpesvirus infections and Alzheimer's disease: a Mendelian randomization study.

BACKGROUND: Observational studies have suggested that herpesvirus infection increased the risk of Alzheimer's disease (AD), but it is unclear whether the association is causal. The aim of the present study is to evaluate the causal relationship between four herpesvirus infections and AD. METHODS: We performed a two-sample Mendelian randomization analysis to investigate association of four active herpesvirus infections with AD using summary statistics from genome-wide association studies. The four herpesvirus infections (i.e., chickenpox, shingles, cold sores, mononucleosis) are caused by varicella-zoster virus, herpes simplex virus type 1, and Epstein-Barr virus (EBV), respectively. A large summary statistics data from International Genomics of Alzheimer's Project was used in primary analysis, including 21,982 AD cases and 41,944 controls. Validation was further performed using family history of AD data from UK Biobank (27,696 cases of maternal AD, 14,338 cases of paternal AD and 272,244 controls). RESULTS: We found evidence of a significant association between mononucleosis (caused by EBV) and risk of AD after false discovery rates (FDR) correction (odds ratio [OR] = 1.634, 95% confidence interval [CI] = 1.092-2.446, P = 0.017, FDR-corrected P = 0.034). It has been verified in validation analysis that mononucleosis is also associated with family history of AD (OR [95% CI] = 1.392 [1.061, 1.826], P = 0.017). Genetically predicted shingles were associated with AD risk (OR [95% CI] = 0.867 [0.784, 0.958], P = 0.005, FDR-corrected P = 0.020), while genetically predicted chickenpox was suggestively associated with increased family history of AD (OR [95% CI] = 1.147 [1.007, 1.307], P = 0.039). CONCLUSIONS: Our findings provided evidence supporting a positive relationship between mononucleosis and AD, indicating a causal link between EBV infection and AD. Further elucidations of this association and underlying mechanisms are likely to identify feasible interventions to promote AD prevention.

Genetically determined low income modifies Alzheimer's disease risk.

BACKGROUND: Socioeconomic status (SES) is considered to be associated with the prevalence of Alzheimer's disease (AD). However, the causal association remain unclear. Here, we determining whether income has a causal protective effect on the risk of developing AD using Mendelian randomization (MR). METHODS: Single-nucleotide polymorphisms (SNPs) that are strongly associated with household income levels (P<5×10-8) from the UK Biobank (UKB) (n=286,301) were selected as instrumental variables for this study. Confounding instruments were removed through data set browsing. Selected SNPs were then harmonized with results from an AD genome-wide meta-analysis (71,880 cases, 383,378 controls) including both case-control and proxy cases. The analysis was conducted using MR methods, and multiple sensitivity analyses were applied for testing of potential bias. RESULTS: After confounding instrument removal and clumping, 9 SNPs associated with household income level identified by the UKB were left for the MR analysis. Our results demonstrated that higher household income level was causally related with a lower risk of AD (odds ratio 0.78, 95% confidence interval: 0.69-0.89; P<0.001). Multiple sensitivity analyses suggested no obvious evidence for heterogeneity or pleiotropy of the results. CONCLUSIONS: Under MR assumptions, our results suggest robust evidence of a causal association between household income and AD risk, which may provide potential prevention strategies for this devastating disease.

Cortical structure and the risk for Alzheimer's disease: a bidirectional Mendelian randomization study.

Progressive loss of neurons in a specific brain area is one of the manifestations of Alzheimer's disease (AD). Much effort has been devoted to investigating brain atrophy and AD. However, the causal relationship between cortical structure and AD is not clear. We conducted a bidirectional two-sample Mendelian randomization analysis to investigate the causal relationship between cortical structure (surface area and thickness of the whole cortex and 34 cortical regions) and AD risk. Genetic variants used as instruments came from a large genome-wide association meta-analysis of cortical structure (33,992 participants of European ancestry) and AD (AD and AD-by-proxy, 71,880 cases, 383,378 controls). We found suggestive associations of the decreased surface area of the temporal pole (OR (95% CI): 0.95 (0.9, 0.997), p = 0.04), and decreased thickness of cuneus (OR (95% CI): 0.93 (0.89, 0.98), p = 0.006) with higher AD risk. We also found a suggestive association of vulnerability to AD with the decreased surface area of precentral (ß (SE): -43.4 (21.3), p = 0.042) and isthmus cingulate (ß (SE): -18.5 (7.3), p = 0.011). However, none of the Bonferroni-corrected p values of the causal relationship between cortical structure and AD met the threshold. We show suggestive evidence of an association of the atrophy of the temporal pole and cuneus with higher AD risk. In the other direction, there was a suggestive causal relationship between vulnerability to AD and the decreased surface area of the precentral and isthmus cingulate. Our findings shed light on the associations of cortical structure with the occurrence of AD.

Investigating causal relationships between exposome and human longevity: a Mendelian randomization analysis.

BACKGROUND: Environmental factors are associated with human longevity, but their specificity and causality remain mostly unclear. By integrating the innovative "exposome" concept developed in the field of environmental epidemiology, this study aims to determine the components of exposome causally linked to longevity using Mendelian randomization (MR) approach. METHODS: A total of 4587 environmental exposures extracting from 361,194 individuals from the UK biobank, in exogenous and endogenous domains of exposome were assessed. We examined the relationship between each environmental factor and two longevity outcomes (i.e., surviving to the 90th or 99th percentile age) from various cohorts of European ancestry. Significant results after false discovery rates correction underwent validation using an independent exposure dataset. RESULTS: Out of all the environmental exposures, eight age-related diseases and pathological conditions were causally associated with lower odds of longevity, including coronary atherosclerosis (odds ratio = 0.77, 95% confidence interval [0.70, 0.84], P = 4.2 × 10-8), ischemic heart disease (0.66, [0.51, 0.87], P = 0.0029), angina (0.73, [0.65, 0.83], P = 5.4 × 10-7), Alzheimer's disease (0.80, [0.72, 0.89], P = 3.0 × 10-5), hypertension (0.70, [0.64, 0.77], P = 4.5 × 10-14), type 2 diabetes (0.88 [0.80, 0.96], P = 0.004), high cholesterol (0.81, [0.72, 0.91], P = 0.0003), and venous thromboembolism (0.92, [0.87, 0.97], P = 0.0028). After adjusting for genetic correlation between different types of blood lipids, higher levels of low-density lipoprotein cholesterol (0.72 [0.64, 0.80], P = 2.3 × 10-9) was associated with lower odds of longevity, while high-density lipoprotein cholesterol (1.36 [1.13, 1.62], P = 0.001) showed the opposite. Genetically predicted sitting/standing height was unrelated to longevity, while higher comparative height size at 10 was negatively associated with longevity. Greater body fat, especially the trunk fat mass, and never eat sugar or foods/drinks containing sugar were adversely associated with longevity, while education attainment showed the opposite. CONCLUSIONS: The present study supports that some age-related diseases as well as education are causally related to longevity and highlights several new targets for achieving longevity, including management of venous thromboembolism, appropriate intake of sugar, and control of body fat. Our results warrant further studies to elucidate the underlying mechanisms of these reported causal associations.

Subtle cognitive impairment as a marker of Alzheimer's pathologies and clinical progression in cognitively normal individuals.

INTRODUCTION: Subtle cognitive impairment (SCI) may appear before pathological changes surpass thresholds for abnormality. We aimed to investigate whether SCI could predict Alzheimer's pathologies and advancement. METHODS: A total of 816 cognitively normal individuals were enrolled to assess the longitudinal neuropathological and clinical correlates of baseline SCI, via linear mixed-effects and Cox proportional-hazard models. Cross-lagged panel models were used in specific time waves. RESULTS: SCI individuals had a faster increase in brain amyloid burden and a higher risk of conversion. They also showed greater rates of cerebrospinal fluid (CSF) phosphorylated tau (p-tau)181 increase and glucose metabolism decrease. In addition, baseline SCI predicted worse clinical progression, whereas multi-domain SCI advanced faster compared to the single domain group. DISCUSSION: Baseline SCI could be an imperative prediction indicator of clinical and pathological progression. It enables cognitive measures to be informative at a very early stage and provided objective criteria for high-risk population screening.

Associations of the neutrophil to lymphocyte ratio with intracranial artery stenosis and ischemic stroke.

BACKGROUND: The neutrophil-to-lymphocyte ratio (NLR) has emerged as an inflammatory marker. However, the associations of NLR with intracranial artery stenosis (ICAS) and ischemic stroke remain unclear. This study aimed to examine the associations of NLR with ICAS and ischemic stroke among a large and high-risk population. METHODS: Participants with records of clinical characteristics were prospectively recruited from the Neurology Department and Health & Physical Examination Center of Qingdao Municipal Hospital. Logistic regression analysis was used to examine the associations of NLR with ICAS and ischemic stroke. Moreover, we also conducted parametric mediation analysis to estimate the effect of NLR on the risk of ischemic stroke mediated through ICAS. RESULTS: A total of 2989 participants were enrolled in this study. After adjusting for covariates, NLR (OR = 1.125, 95%CI 1.070-1.183) and ICAS (OR = 1.638, 95%CI 1.364-1.967) were significantly associated with ischemic stroke. Compared with the first quartile NLR, the second, third and fourth quartiles NLR were independent risk predictors for ischemic stroke (P for trend < 0.001); the third and fourth quartiles were independent predictors for ICAS (P for trend < 0.001). The mediation analysis showed that ICAS partially mediated the association between NLR and ischemic stroke, accounting for 14.4% of the total effect (P < 0.001). CONCLUSIONS: NLR was significantly associated with ICAS and ischemic stroke. Besides, ICAS partially mediated the association between NLR and ischemic stroke.

Association of Plasma Neurofilament Light With Small Vessel Disease Burden in Nondemented Elderly: A Longitudinal Study.

BACKGROUND AND PURPOSE: Neurofilament light chain (NfL) is a promising predictive biomarker of active axonal injury and neuronal degeneration diseases. We aimed to evaluate if an increase in plasma NfL levels could play a monitoring role in the progression of cerebral small vessel disease (CSVD) among the nondemented elders, which are highly prevalent in elderly individuals and associated with an increased risk of stroke and dementia. METHODS: The study included 496 nondemented participants from the Alzheimer disease neuroimaging initiative database. All participants underwent plasma NfL measurements and 3.0-Tesla magnetic resonance imaging of the brain; 387 (78.0%) underwent longitudinal measurements. The number of cerebral microbleeds, lacunar infarcts, and volumetric white matter hyperintensities, as well as Fazekas scores, were measured. Cross-sectional and longitudinal associations between CSVD burden and NfL levels were evaluated using multivariable-adjusted models. RESULTS: Plasma NfL was higher in the moderate-severe CSVD burden group (45.2±16.0 pg/mL) than in the nonburden group (34.3±15.1 pg/mL; odds ratio [OR]=1.71 [95% CI, 1.24-2.35]) at baseline. NfL was positively associated with the presence of cerebral microbleeds (OR=1.29 [95% CI, 1.01-1.64]), lacunar infarcts (OR=1.43 [95% CI, 1.06-1.93]), and moderate-severe white matter hyperintensities (OR=1.67 [95% CI, 1.24-2.25]). Longitudinally, a higher change rate of NfL could predict more progression of CSVD burden (OR=1.38 [95% CI, 1.08-1.76]), white matter hyperintensities (OR=1.41 [95% CI, 1.10-1.79]), and lacunar infarcts (OR=1.99 [95% CI, 1.42-2.77]). CONCLUSIONS: Plasma NfL level is a valuable noninvasive biomarker that supplements magnetic resonance imaging scans and possibly reflects the severity of CSVD burden. Furthermore, high plasma NfL levels tend to represent an increased CSVD risk, and dynamic increases in NfL levels might predict a greater progression of CSVD.

Social Isolation, Social Interaction, and Alzheimer's Disease: A Mendelian Randomization Study.

BACKGROUND: Social isolation and social interaction have been suggested to be associated with Alzheimer's disease. However, the causality cannot be unambiguously assessed as traditional epidemiological methods are easily subject to unmeasured confounders and potential bias. OBJECTIVE: To examine bidirectional relationships between social isolation, social interaction, and Alzheimer's disease using Mendelian randomization method for assessing potential causal inference. METHODS: This bidirectional two-sample Mendelian randomization study used independent genetic variants associated with social isolation and social interaction (n = 302,567-487,647), and Alzheimer's disease (n = 455,258). MR analyses were performed using the inverse-variance-weighted (IVW) as the main MR analytical method to estimate the causal effect. For sensitivity analyses, we applied weighted median, MR Egger to further assess the credibility of the causal effect. RESULTS: Of the five types of social engagement examined in our study, only one showed evidence of an association with the risk of Alzheimer's disease. Attendance at a gym or sports club (IVW OR per SD change: 0.670; 95% CI: 0.463-0.970; p = 0.034) was inversely associated with the risk of Alzheimer's disease. We also found that AD may reduce the attendance at religious group (IVW OR per SD change: 1.017; 95% CI: 1.005-1.030; p = 0.004). CONCLUSION: This study suggests that regular attendance at a gym or sports club is causally associated with reduced risk of Alzheimer's disease. Further studies are warranted to elucidate potential mechanisms.

Dose-response relationship between blood pressure and intracranial atherosclerotic stenosis.

BACKGROUND AND AIMS: We aimed to explore the association between blood pressure, intracranial atherosclerotic stenosis (ICAS) risks and ICAS burden in the Chinese population. METHODS: A retrospective hospital-based multi-center case-control study with large sample size was conducted. 1055 ICAS patients and 1296 non-ICAS subjects with complete clinical information and intracranial artery evaluation were identified between 2014 and 2019. Cerebral arteries were evaluated by magnetic resonance angiography, and/or computed tomography, and/or digital subtraction angiography. Two or more neurologists were involved in reading and assessment of images. The association between ICAS and burden of ICAS with blood pressure was evaluated with univariate logistic models and multivariate logistic models. RESULTS: With every increase of 10 mmHg in systolic blood pressure, diastolic blood pressure and pulse pressure, the odds of ICAS increased by 32%, 28% and 35% in multivariate analysis, respectively (odds ratio = 1.32, 1.28, and 1.35 respectively, all p < 0.001). Similarly, every increment of 10 mmHg in systolic blood pressure and pulse pressure was associated with an increased risk of ICAS burden (each odds ratio = 1.08, p < 0.05). CONCLUSIONS: Systolic blood pressure, diastolic blood pressure, and pulse pressure were associated with the risk of ICAS in a dose-response manner. Moreover, higher systolic blood pressure and pulse pressure could lead to higher ICAS burdens.

Investigating Causal Relations Between Risk Tolerance, Risky Behaviors, and Alzheimer's Disease: A Bidirectional Two-Sample Mendelian Randomization Study.

BACKGROUND: Several studies have shown risky behaviors and risk tolerance are associated with Alzheimer's disease. However, the underlying causality remains unclear. Risky behavior and risk tolerance may induce the onset of Alzheimer's disease, and/or vulnerability to Alzheimer's disease may result in more risky behaviors. OBJECTIVE: To examine bidirectional relationships between risky behavior, risk tolerance, and Alzheimer's disease using Mendelian randomization method for assessing potential causal inference. METHODS: This bidirectional two-sample Mendelian randomization study used independent genetic variants associated with risky behaviors and risk tolerance (n = 370, 771- 939, 908), and Alzheimer's disease (n = 71, 880 - 37, 613) as genetic instruments from large meta-analyses of genome-wide association studies. RESULTS: Our results support a strong protective casual effect of risk-taking tendency on AD (odds ratio [OR] = 0.79; 95% CI, 0.67- 0.94, p = 0.007). There was weak statistically significant relationship between number of sexual partners and AD (OR = 0.50, 95% CI, 0.27- 0.93, p = 0.04), and between family history of AD and automobile speeding propensity (OR = 1.018, 95% CI, 1.005 to 1.031; p = 0.007). Contrary to expectations, there was no statistically significant causal effect of AD on risk-taking tendency (ß=  0.015, 95% CI, - 0.005 to 0.04; p = 0.14). CONCLUSION: Under Mendelian randomization assumptions, our results suggest a protective relationship between risk-taking tendency and the risk of AD. This finding may provide valuable insights into Alzheimer's disease pathogenesis and the development of preventive strategies.