Association of Crohn's disease and ulcerative colitis with the risk of neurological diseases: a large-scale Mendelian randomization study.

Observational studies suggested increased risks of Alzheimer's disease (AD), Parkinson's disease (PD), and multiple sclerosis (MS) in patients with Crohn's disease (CD) and ulcerative colitis (UC). We aimed to assess the causality for the associations of CD and UC with the risks of AD, PD, and MS through a two-sample Mendelian randomization (MR) study. Independent single nucleotide polymorphisms associated with CD (17,897 cases and 33,977 controls) and UC (13,768 cases and 33,977 controls) were identified as genetic instruments based on a European-descent genome-wide association study (GWAS) released by the International Inflammatory Bowel Disease Genetics Consortium. Summary statistics for AD (combined: 25,881 cases and 256,837 controls), PD (combined: 35,836 cases and 665,686 controls), and MS (combined: 48,477 cases and 285,515 controls) were obtained from the largest GWASs and FinnGen study of European ancestry, respectively. MR estimates were generated using the inverse-variance weighted method in the main analysis with a series of sensitivity analyses. MR analyses were conducted per outcome database and were subsequently meta-analyzed to generate combined estimates. Genetically predicted UC was significantly associated with increased risks of AD (combined: OR, 1.03; 95% CI, 1.01-1.05; P = 1.80 × 10-3) and MS (combined: OR, 1.37; 95% CI, 1.23-1.53; P = 1.18 × 10-8), while there was no association between genetically predicted UC and the risk of PD. In contrast, no significant associations were observed for genetically predicted CD with AD, PD, and MS. MR-Egger regression showed no directional pleiotropy for the identified associations, and sensitivity analyses with different MR methods further confirmed these findings. This study suggested significant adverse effects of UC on AD and MS, highlighting that UC patients should receive early intervention with optimal adjunctive medical therapy to reduce the risks of AD and MS.

Plasma Polyamines and Short-Term Adverse Outcomes Among Patients With Ischemic Stroke: A Prospective Cohort Study.

BACKGROUND: Polyamines have been reported to be associated with neurological function, but the associations between polyamines and the prognosis of ischemic stroke remain unclear. We aimed to prospectively investigate whether elevated plasma polyamine levels are associated with adverse outcomes in patients with ischemic stroke. METHODS AND RESULTS: Plasma polyamine levels were measured at admission in 3570 patients with acute ischemic stroke, and clinical outcomes were assessed at 3 months after stroke onset. The primary outcome was a composite outcome of death and major disability (modified Rankin Scale score≥3), and secondary outcomes included the individual outcomes of death and major disability. During a 3-month follow-up period, 877 participants (25.1%) experienced the primary outcome. Increased putrescines were associated with a decreased risk of the primary outcome (the highest versus the lowest tertile: odds ratio, 0.72 [95% CI, 0.58-0.91]; P=0.005) and major disability (odds ratio, 0.59 [95% CI, 0.47-0.74]; P<0.001). Conversely, increased spermidines were associated with an increased risk of death (hazard ratio, 1.86 [95% CI, 1.10-3.14]; P=0.020), and increased spermines were associated with an increased risk of the primary outcome (odds ratio, 1.36 [95% CI, 1.08-1.71]; P=0.009) and major disability (odds ratio, 1.27 [95% CI, 1.01-1.59]; P=0.041). CONCLUSIONS: Among patients with ischemic stroke, high plasma putrescine levels were associated with a decreased risk of adverse outcomes, whereas high plasma spermidine and spermine levels were associated with an increased risk of adverse outcomes. Further studies are needed to investigate whether targeting these polyamines can improve the prognosis of patients with ischemic stroke. REGISTRATION: https://clinicaltrials.gov. Identifier: NCT01840072.

Associations of computer gaming with incident dementia, cognitive functions, and brain structure: a prospective cohort study and Mendelian randomization analysis.

BACKGROUND: Computer gaming has recently been suggested to be associated with benefits for cognition, but its impact on incident dementia remains uncertain. We aimed to investigate the observational associations of playing computer games with incident dementia, cognitive functions, and brain structural measures, and further explore the genetic associations between computer gaming and dementia. METHODS: We included 471,346 White British participants without dementia at baseline based on the UK Biobank, and followed them until November 2022. We estimated the risk of dementia using Cox proportional hazard models, and assessed the changes of cognitive functions and brain structural measures using logistic regression models and linear regression models. Mendelian randomization (MR) analyses were performed to examine the association between genetically determined computer gaming and dementia. RESULTS: High frequency of playing computer games was associated with decreased risk of incident dementia (HR, 0.81 [95% CI: 0.69, 0.94]). Individuals with high frequency of playing computer games had better performance in prospective memory (OR, 1.46 [1.26, 1.70]), reaction time (beta, -0.195 [-0.243, -0.147]), fluid intelligence (0.334 [0.286, 0.382]), numeric memory (0.107 [0.047, 0.166]), incorrect pairs matching (-0.253 [-0.302, -0.203]), and high volume of gray matter in hippocampus (0.078 [0.023, 0.134]). Genetically determined high frequency of playing computer games was associated with a low risk of dementia (OR, 0.37 [0.15, 0.91]). CONCLUSIONS: Computer gaming was associated with a decreased risk of dementia, favorable cognitive function, and better brain structure, suggesting that computer gaming could modulate cognitive function and may be a promising target for dementia prevention.

Alcohol drinking modified the effect of plasma YKL-40 levels on stroke-specific mortality of acute ischemic stroke.

OBJECTIVES: Our study aimed to evaluate the association between plasma human cartilage glycoprotein-39 (YKL-40) and stroke-specific mortality at two years in acute ischemic stroke patients according to the drinking status and amount of alcohol consumption. We further investigated the effect of the interaction between these conditions and YKL-40 levels on the outcome. METHODS: We measured plasma YKL-40 levels in 3267 participants from the China Antihypertensive Trial in Acute Ischemic Stroke. Outcome data on stroke-specific mortality were collected at two years after stroke onset. RESULTS: During the two years of follow-up, 208 (6.4 %) patients, including 44 drinkers and 164 nondrinkers, died of stroke-specific causes. The patients in the highest quartile of YKL-40 had a 3.52-fold (95 % CI: 1.15-10.76, P for trend = 0.006) risk of stroke-specific mortality compared with those in the lowest quartile among drinkers. However, no significant association between YKL-40 and the outcome was observed among nondrinkers (HR: 1.18, 95 % CI: 0.75-1.86, P for trend = 0.08). Alcohol drinking modified the effect of YKL-40 on the outcome (P for interaction = 0.04). Subgroup analyses revealed that each 1-unit increase in log-transformed YKL-40 was associated with a 72 % greater risk of stroke-specific mortality for light drinkers. This association was amplified with a 226 % increased risk of the outcome among heavy drinkers. CONCLUSIONS: Elevated YKL-40 levels were associated with an increased risk of stroke-specific mortality at two years among drinkers with ischemic stroke. Drinking status substantially modified the effect of plasma YKL-40 levels on the outcome. This effect was amplified with the increased amount of alcohol consumption. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT01840072.

Physical Activity, Sleep, and Risk of Late-Onset Severe Mental Illness: A Prospective Cohort Study From UK Biobank.

BACKGROUND AND HYPOTHESIS: Previous studies have found that both physical inactivity and poor sleep are deleteriously associated with severe mental illness (SMI). The aim of current study was to investigate the joint association of physical activity (PA) and sleep with late-onset SMI (schizophrenia and bipolar disorder) risk. STUDY DESIGN: A total of 340 187 (for schizophrenia)/340 239 (for bipolar disorder) participants without schizophrenia or bipolar disorder from the UK Biobank were included. Baseline PA levels were categorized as high, intermediate, and low according to the total volume of PA. Sleep was categorized into healthy, intermediate, and poor according to an established composited sleep score of chronotype, sleep duration, insomnia, snoring, and daytime sleepiness. We derived 9 PA-sleep combinations, accordingly. STUDY RESULTS: After an average follow-up of 13.2 years, 814 participants experienced schizophrenia and 846 participants experienced bipolar disorder. Both low PA level, intermediate, and poor sleep were independently associated with increased risk of SMI. PA level and sleep had additive and multiplicative interactions on SMI risk. Compared to those with high PA level and healthy sleep, individuals with low PA and poor sleep had the highest risk of SMI (hazard ratio: 1.95; 95% CI: 1.02-3.70, P < .001) for schizophrenia; (hazard ratio: 3.81; 95% CI: 2.35-6.15) for bipolar disorder. A higher PA level may attenuate the detrimental effects of poor sleep. CONCLUSION: Both low PA and poor sleep was associated with increasing risk of late-onset SMI. Those with low PA and poor sleep had the highest risk of late-onset SMI, suggesting likely synergistic effects. Our findings supported the need to target both PA and sleep behaviors in research and clinical practice.

Genetically Determined Plasma Hepatocyte Growth Factor Levels Are Associated With the Risk and Prognosis of Ischemic Stroke.

BACKGROUND: Observational studies suggest that hepatocyte growth factor (HGF) is associated with the risk and prognosis of ischemic stroke, but the causality of these associations remains unclear. Therefore, we conducted Mendelian randomization (MR) analyses to explore the associations of genetically determined plasma HGF levels with the risk and prognosis of ischemic stroke. METHODS: A total of 13 single-nucleotide polymorphisms associated with plasma HGF were selected as genetic instruments based on the data from a genome-wide association study with 21 758 European participants. Summary data about the risk of ischemic stroke were obtained from the MEGASTROKE (Multiancestry Genome-Wide Association Study of Stroke) Consortium with 34 217 ischemic stroke cases and 406 111 controls of European ancestry, and summary data about the prognosis of ischemic stroke were obtained from the GISCOME study (Genetics of Ischaemic Stroke Functional Outcome) with 6165 European patients with ischemic stroke. We conducted an inverse-variance weighted Mendelian randomization analysis followed by a series of sensitivity analyses to evaluate the associations of genetically determined plasma HGF with the risk and prognosis of ischemic stroke. RESULTS: The primary analyses showed that genetically determined high HGF was associated with an increased risk of ischemic stroke (odds ratio per SD increase, 1.11 [95% CI, 1.04-1.19]; P=1.10×10-3) and poor prognosis of ischemic stroke (odds ratio per SD increase, 2.43 [95% CI, 1.76-3.52]; P=6.35×10-8). In the secondary analysis, genetically determined plasma HGF was associated with a high risk of large atherosclerotic stroke (odds ratio per SD increase, 1.39 [95% CI, 1.18-1.63]; P=5.08×10-5) but not small vessel stroke and cardioembolic stroke. Mendelian randomization-Egger regression showed no directional pleiotropy for all associations, and the sensitivity analyses with different Mendelian randomization methods further confirmed these findings. CONCLUSIONS: We found positive associations of genetically determined plasma HGF with the risk and prognosis of ischemic stroke, suggesting that HGF might be implicated in the occurrence and development of ischemic stroke.

Association of Cardiac Biomarkers in Combination With Cognitive Impairment After Acute Ischemic Stroke.

BACKGROUND: Poststroke cognitive impairment is a severe and common clinical complication that constitutes a substantial global health burden. We aimed to evaluate the association of 3 cardiac biomarkers in combination with poststroke cognitive impairment and their prognostic significance. METHODS AND RESULTS: This prospective study included 566 patients with ischemic stroke. Cardiac biomarkers, including sST2 (soluble suppression of tumorigenicity-2 receptor), GDF-15 (growth differentiation factor-15), and NT-proBNP (N-terminal pro-B-type natriuretic peptide), were measured. Cognitive impairment was defined as a Mini-Mental State Examination score of <27 or a Montreal Cognitive Assessment score of <25 at 3 months after ischemic stroke. Odds of cognitive impairment 3 months after ischemic stroke increased with the number of elevated cardiac biomarkers (sST2, GDF-15, and NT-proBNP; Ptrend<0.001). The multivariable adjusted odds ratios (95% CIs) of cognitive impairment defined by the Mini-Mental State Examination and Montreal Cognitive Assessment were 2.45 (1.48-4.07) and 1.86 (1.10-3.14) for the participants with ≥2 elevated cardiac biomarkers, respectively, compared with those without any elevated cardiac biomarker. Additionally, higher cardiac biomarker scores were associated with an increased risk of cognitive impairment (Ptrend<0.05). Simultaneously adding all 3 cardiac biomarkers to the basic model with traditional risk factors significantly improved the risk prediction of Mini-Mental State Examination-defined cognitive impairment (net reclassification improvement=34.99%, P<0.001; integrated discrimination index=2.67%, P<0.001). Similar findings were observed using the Montreal Cognitive Assessment scores. CONCLUSIONS: An increased number of elevated novel cardiac biomarkers were associated with an increased odds of poststroke cognitive impairment, suggesting that a combination of these cardiac biomarkers may improve the risk prediction of cognitive impairment. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01840072.

The bidirectional association between frailty index and cardiovascular disease: A Mendelian randomization study.

BACKGROUND AND AIM: Observational studies have suggested a relationship between frailty and cardiovascular disease (CVD), but the causality is still uncertain. We used bidirectional Mendelian randomization (MR) design to investigate the potential causal associations between frailty and four main CVDs, including hypertension, myocardial infarction (MI), heart failure (HF), and atrial fibrillation (AF). METHODS AND RESULTS: Independent single-nucleotide polymorphisms for frailty index (FI) and CVDs (hypertension, MI, HF, and AF) were selected as genetic instruments based on European-descent genome-wide association studies (GWASs). Summary-level data for outcomes on FI (n = 175,226), hypertension (n = 463,010), MI (n = 171,875), HF (n = 977323), and AF (n = 1,030,836) was derived from five large-scale GWASs of European ancestry. We used the inverse-variance weighted (IVW) method to examine the bidirectional associations between FI and CVDs in the main analyses. In the IVW MR analyses, genetically determined high FI was significantly associated with increased risks of hypertension (odds ratio [OR] per 1-SD increase: 1.07 [95 % confidence interval, 1.05-1.08]), MI (OR per 1-SD increase: 1.74 [1.21-2.51]), HF (OR per 1-SD increase: 1.28 [1.10-1.48]), and AF (OR per 1-SD increase: 1.20 [1.08-1.33]). In addition, genetically determined hypertension (beta: 1.406 [1.225-1.587]), MI (beta: 0.045 [0.023-0.067]), HF (beta: 0.105 [0.066-0.143]) and AF (beta: 0.021 [0.012-0.031]) were significantly associated with high FI. These findings were robustly supported by a series of sensitivity analyses with different MR models. CONCLUSIONS: We found potential bidirectional causal associations between elevated FI and increased risks of CVD, suggesting mutual risk factors between frailty and CVD.

High-Serum Brain-Derived Neurotrophic Factor Levels Are Associated With Decreased Risk of Poststroke Cognitive Impairment.

BACKGROUND: BDNF (brain-derived neurotrophic factor) is widely implicated in the pathophysiological process of stroke, but the effect of BDNF on poststroke cognitive impairment (PSCI) remains unclear. We aimed to investigate the association between baseline serum BDNF and the risk of PSCI at 3 months in a multicenter study based on a preplanned ancillary study of the CATIS trial (China Antihypertensive Trial in Acute Ischemic Stroke). METHODS: We examined serum BDNF levels at baseline and used the Mini-Mental State Examination and Montreal Cognitive Assessment to evaluate cognitive function at 3-month follow-up after ischemic stroke. PSCI was defined as Mini-Mental State Examination score <27 or Montreal Cognitive Assessment score <25. Logistic regression analyses were performed to evaluate the association between serum BDNF and the risk of 3-month PSCI. RESULTS: In this ancillary study, a total of 660 patients with ischemic stroke with hypertension were included, and 593 patients (mean age, 59.90±10.44 years; 410 males and 183 females) were finally included in this analysis. According to mini-mental state examination score, after adjustment for age, sex, education, baseline National Institutes of Health Stroke Scale score, APOE ɛ4 carriers, and other potential confounders, the odds ratio of PSCI for the highest tertile of BDNF was 0.60 ([95% CI, 0.39-0.94]; P=0.024) compared with the lowest tertile. Multiple-adjusted spline regression model showed a linear association of serum BDNF levels with PSCI at 3 months (P value for linearity=0.010). Adding serum BDNF to conventional prognostic factors slightly improved the risk reclassification of PSCI (net reclassification improvement: 27.46%, P=0.001; integrated discrimination index: 1.02%, P=0.015). Similar significant findings were observed when PSCI was defined by the Montreal Cognitive Assessment score. CONCLUSIONS: Elevated serum BDNF levels were associated with a decreased risk of PSCI at 3 months, suggesting that serum BDNF might be a potential predictive biomarker for PSCI among patients with ischemic stroke with hypertension.