Biomarker Changes during 20 Years Preceding Alzheimer's Disease.

BACKGROUND: Biomarker changes that occur in the period between normal cognition and the diagnosis of sporadic Alzheimer's disease have not been extensively investigated in longitudinal studies. METHODS: We conducted a multicenter, nested case-control study of Alzheimer's disease biomarkers in cognitively normal participants who were enrolled in the China Cognition and Aging Study from January 2000 through December 2020. A subgroup of these participants underwent testing of cerebrospinal fluid (CSF), cognitive assessments, and brain imaging at 2-year-to-3-year intervals. A total of 648 participants in whom Alzheimer's disease developed were matched with 648 participants who had normal cognition, and the temporal trajectories of CSF biochemical marker concentrations, cognitive testing, and imaging were analyzed in the two groups. RESULTS: The median follow-up was 19.9 years (interquartile range, 19.5 to 20.2). CSF and imaging biomarkers in the Alzheimer's disease group diverged from those in the cognitively normal group at the following estimated number of years before diagnosis: amyloid-beta (Aß)42, 18 years; the ratio of Aß42 to Aß40, 14 years; phosphorylated tau 181, 11 years; total tau, 10 years; neurofilament light chain, 9 years; hippocampal volume, 8 years; and cognitive decline, 6 years. As cognitive impairment progressed, the changes in CSF biomarker levels in the Alzheimer's disease group initially accelerated and then slowed. CONCLUSIONS: In this study involving Chinese participants during the 20 years preceding clinical diagnosis of sporadic Alzheimer's disease, we observed the time courses of CSF biomarkers, the times before diagnosis at which they diverged from the biomarkers from a matched group of participants who remained cognitively normal, and the temporal order in which the biomarkers became abnormal. (Funded by the Key Project of the National Natural Science Foundation of China and others; ClinicalTrials.gov number, NCT03653156.).

The relationship between atrial cardiopathy biomarkers and prognosis of patients with acute ischemic stroke after endovascular treatment.

Thromboembolism is a possible consequence of underlying atrial cardiopathy, which can occur even before the onset of atrial fibrillation. Our objective was to examine the association between biomarkers of atrial cardiopathy and outcomes of acute ischemic stroke (AIS) following endovascular treatment (EVT). We conducted a retrospective study that collected data from patients with AIS who underwent EVT and compared the outcomes between those with and without atrial cardiopathy. Neurological function was assessed using the modified Rankin Scale (mRS), with an mRS score >2 indicating poor function at day 90. Additionally, we evaluated secondary consequences, including symptomatic intracerebral hemorrhage (sICH), early neurological deterioration (END), and malignant cerebral edema (MCE). Our study included 87 patients (77.6 â€‹% male; mean age 60.93 â€‹± â€‹12.47 years). Among these patients, 29 (33.3 â€‹%) had atrial cardiopathy, while the remaining 58 (66.7 â€‹%) did not. In the atrial cardiopathy group, 12 patients (41.4 â€‹%) had poor functional outcomes (mRS>2), compared to 19 (32.8 â€‹%) in the non-atrial cardiopathy group. We observed sICH in 22 (25.3 â€‹%) patients, END in 14 (16.1 â€‹%) patients, MCE in 11 (12.6 â€‹%) patients, and two (2.3 â€‹%) patients who died in the hospital. We found that patients with PTFV1>5000 â€‹µV/ms (OR: 8.39, 95 â€‹% CI: 1.43-105.95, P â€‹= â€‹0.02) and NT-proBNP>250 â€‹pg/mL (OR: 5.09, 95 â€‹% CI: 1.20-27.63, P â€‹= â€‹0.03) had significantly higher risk of END. After adjusting for covariates in the Firth logistic regression, we further found that atrial cardiopathy was significantly associated with END, as revealed by both univariate (OR: 6.31, 95 â€‹% CI: 1.42-59.87, P â€‹= â€‹0.01) and multivariable firth regression models (Modle 1, OR: 7.10, 95 â€‹% CI: 1.57-67.38, P â€‹< â€‹0.01; Modle 2, OR: 7.82, 95 â€‹% CI: 1.69, 76.36, P â€‹< â€‹0.01; Modle 3, OR: 8.59, 95 â€‹% CI: 1.72-91.70, P â€‹< â€‹0.01). Moreover, we observed that atrial cardiopathy was associated with an increased risk of END in AIS patients with large artery atherosclerosis (LAA) receiving EVT. Therefore, clinicians should consider atrial cardiopathy as a possible underlying cause of AIS in their patients. Further investigation is warranted to elucidate the relationship between atrial cardiopathy and AIS's occurrence, progression, and prognosis.

Association between "weekend warrior" physical activity and the incidence of neurodegenerative diseases.

While guidelines recommend 150 â€‹min of moderate to vigorous physical activity (MVPA) weekly to enhance health, it remains unclear whether concentrating these activities into 1-2 days of the week, "weekend warrior" (WW) pattern, has the same benefit for neurodegenerative diseases (NDDs). This study aimed to evaluate the associations of WW pattern and the risk of NDDs. This prospective study was conducted using accelerometer-based physical activity data for a full week from June 2013 to December 2015 in the UK Biobank. These individuals were categorized into distinct physical activity patterns, including the WW pattern (i.e., over 50% or 75% of recommended MVPA achieved over 1-2 days), regular pattern, and inactive pattern. Cox proportional hazards model was used to evaluate the association between physical activity patterns and outcomes. Compared to inactive group, WW pattern and regular pattern was similarly linked to a reduced risk of all-cause dementia (WW: Hazard Ratio [HR]: 0.68, 95% Confidence Interval [CI]: 0.56-0.84; regular: HR: 0.86, 95% CI: 0.67-1.1) and all-cause Parkinsonism (WW: HR: 0.47, 95% CI: 0.35-0.63; regular: HR: 0.69, 95% CI: 0.5-0.95). When the exercise threshold was increased to 75% of MVPA, both patterns still were associated with decreased risk of incident all-cause dementia (WW: HR: 0.61, 95% CI: 0.41-0.91; regular: HR: 0.76, 95% CI: 0.63-0.92) and all-cause Parkinsonism (WW: HR: 0.22, 95% CI: 0.10-0.47; regular: HR: 0.59, 95% CI: 0.46-0.75). Concentrating recommended physical activities into 1-2 days per week is associated with a lower incidence of NDDs.

Sex differences in cardiovascular outcomes in patients with acute pancreatitis.

INTRODUCTION: The risk of cardiovascular disease increases in patients with acute pancreatitis. However, it remains unknown whether this increase varies between males and females. OBJECTIVES: To assess sex differences in cardiovascular outcomes among acute pancreatitis patients during long-term follow-up. PATIENTS AND METHODS: Participants were recruited from the UK-biobank, which is a population-based cohort study consisting of 502 368 individuals aged 40-69 years old. Cardiovascular outcomes were defined as major cardiovascular and cerebrovascular adverse events (MACCE), encompassing all-cause death, myocardial infarction, and stroke. We compared sex difference in MACCE incidence using incidence rate per 1,000 person-years. The association between sex and MACCE risk was assessed using Cox proportional hazards models and win-ratio method, adjusted for demographic, lifestyle, metabolic factors and medication use. RESULTS: A total of 1371 participants with acute pancreatitis were included, 42.5% were male. Over a median follow-up of 13.9 years, 226 MACCE cases occurred. The incidence rate of MACCE for male was 16.44, compared to 9.80 in female. Multivariate Cox regression analysis indicated a higher risk of MACCE in male compared to female (HR 1.80 [95% CI 1.36-2.38]). Adjusted HR for all-cause mortality, myocardial infarction, and stroke were 1.49, 2.75, and 1.67, respectively. The adjusted win ratio by inverse probability of treatment weighting was 0.55 (P <0.001), suggesting a worse outcome in male acute pancreatitis patients. CONCLUSIONS: Male experienced more adverse cardiovascular outcomes than female in the long follow-up after acute pancreatitis, suggesting a need for sex-specific management strategies in acute pancreatitis patients.

Association between three-territory sign and prognosis of acute ischemic stroke patients with malignancy.

Background: Multiple cerebral infarcts are usually secondary to cardiogenic embolism, particularly through atrial fibrillation (AF). The three-territory sign (TTS) is an imaging marker that reflects multiple cerebral lesions involving three vascular territories measured by diffusion-weighted imaging (DWI), and the most common etiology is an underlying malignancy. Recent studies have shown that TTS is six times more frequently observed in acute ischemic stroke (AIS) patients with malignancy than in those with AF-related AIS. However, the relevance of TTS to the prognosis of IS patients with malignancy remains unclear. Methods: Over a 5-year period (May 2016 to 31 June 2021), AIS admissions with DWI were identified from the First Affiliated Hospital of Xi'an Jiaotong University. Patients were divided into two groups according to whether they had malignancy or AF, resulting in a total of 80 patients with known malignancy (malignancy group) and 92 patients with AF (AF group). All DWI images were reviewed to determine the territory lesion count. Demographic, clinical, and laboratory data, together with radiographic examination data and modified Rankin Scale (mRS) score within a year, were collected. The main outcome was the association between TTS and the prognosis of AIS patients with malignancy, analyzed by a multivariate logistic regression model. Results: A total of 172 patients met the selection criteria, including 17 (21.3%) patients in the malignancy group and 8 (8.7%) patients in the AF group with TTS. Age and sex distributions were similar for AIS patients of malignancy and AF. The TTS was 2.4 times more likely to be observed in AIS patients with malignancy compared to AF-related IS patients. The univariate analysis showed that hypertension (OR = 1.137, 95%CI: 1.002-1.291), D-dimer (OR = 1.328, 95%CI: 1.022-1.726), fibrin degradation product (OR = 1.117, 95%CI: 1.010-1.236), and lactate dehydrogenase (LDH; OR = 1.007, 95%CI: 1.000-1.015) were the risk factors for the high mortality rate. Multivariate analysis showed that TTS was the independent risk factor for mortality in AIS patients with malignancy (adjusted OR: 6.866, 95% CI: 1.371-34.395). Conclusion: TTS was more frequently observed in AIS patients with malignancy than AF-related AIS and substantially related to high poor outcome (mRS > 2) in AIS patients with malignancy, indicating diagnostic and prognostic value in malignancy-associated hypercoagulation stroke.

The Relationship Between Atrial Cardiopathy Biomarkers and Prognosis of Patients With Embolic Stroke of Undetermined Source.

Objective: To compare the proportion of atrial cardiopathy in patients with embolic stroke of undetermined source (ESUS) and other non-cardiac strokes, and to evaluate the prognostic value of atrial cardiopathy biomarkers in patients with ESUS. Methods: This retrospective study enrolled patients with ischemic stroke from January 2018 to April 2020 in a single stroke center, and compared the proportion of atrial cardiopathy in (1) ESUS group, (2) large artery atherosclerosis (LAA) group, and (3) small-vessel occlusion (SVO) group. Then, it compared the baseline characteristics between ESUS patients with atrial cardiopathy and cardioembolism (CE) group. In addition, the relationship was compared between the biomarkers of atrial cardiopathy and prognosis in patients with ESUS. Results: In total, 316 patients with ischemic stroke were included that included 105 (33.23%) ESUS, 84 (26.58%) LAA, 73 (23.10%) SVO, and 54 (17.09%) CE. Among these patients, patients with ESUS were younger, and had lower triglyceride, lower low-density lipoprotein than non-ESUS group. The proportion of atrial cardiopathy in ESUS group was higher than LAA group or SVO group (42.86 vs. 17.86 vs. 8.22%, p < 0.001). Compared with non-atrial cardiopathy group, patients with atrial cardiopathy were older, had lower EF value, larger left ventricular diameter, and longer PR interval. Among 105 patients with ESUS, 11 (10.78%) cases died, 32 (31.37%) cases had poor functional outcome (mRS >2). In the multivariable model, the risk factor associated with the death risk of patients with ESUS was N-terminal pro-B-type natriuretic peptide (NT-proBNP) >250 pg/ml [p = 0.025, hazard ratio (HR) = 4.626, 95% CI: 1.212-17.652] after a 1-year follow-up. Conclusions: Atrial cardiopathy is more common in patients with ESUS, and the characteristics of ESUS patients with atrial cardiopathy are similar to those in patients with CE. NT-proBNP >250 pg/ml is related to the risk of death in patients with ESUS.

Cerebral Small Vessel Diseases and Outcomes for Acute Ischemic Stroke Patients after Endovascular Therapy.

The correlation between cerebral small vessel disease (CSVD) and the outcomes of acute ischemic stroke (AIS) patients after endovascular therapy (EVT) remains elusive. We aimed to investigate the effect of combined white matter hyperintensities (WMH) and enlarged perivascular spaces (EPVS) as detected in magnetic resonance imaging (MRI) at baseline on clinical outcomes in patients with AIS who underwent EVT. AIS patients that experienced EVT were retrospectively analyzed in this single-center study. Using MRIs taken prior to EVT, we rated WMH and EPVS as the burden of CSVD and dichotomized the population into two groups: absent-to-moderate and severe. Neurological outcome was assessed at day 90 with a modified Rankin Scale (mRS). Symptomatic intracerebral hemorrhage (sICH), early neurological deterioration (END), malignant cerebral edema (MCE), and hospital death were secondary outcomes. Of the 100 patients (64.0% male; mean age 63.71 ± 11.79 years), periventricular WMHs (28%), deep WMHs (41%), EPVS in basal ganglia (53%), and EPVS in centrum semiovale (73%) were observed. In addition, 69% had an absent-to-moderate total CSVD burden and 31.0% had a severe burden. The severe CSVD was not substantially linked to either the primary or secondary outcomes. Patients with AIS who underwent EVT had an elevated risk (OR: 7.89, 95% CI: 1.0, 62.53) of END if they also had EPVS. When considering WMH and EPVS together as a CSVD burden, there seemed to be no correlation between severe CSVD burden and sICH, END, or MCE following EVT for AIS patients. Further studies are warranted to clarify the relationship between CSVD burden and the occurrence, progression, and prognosis of AIS.

Atrial Cardiomyopathy Predicts Worse Outcome in Patients With Lung Cancer.

Background: Reports of the clinical outcomes associated with the co-occurrence of atrial cardiomyopathy (ACM) and lung cancer (LC) are limited. Objectives: This study aims to investigate the influence of ACM on the prognosis of LC patients and related clinical determinants. Methods: Newly diagnosed LC patients from January 1st, 2015, to December 31st, 2020, were retrospectively enrolled at the First Affiliated Hospital of Xi'an Jiaotong University. The demographics and overall survival (OS) of the patients with or without ACM were compared. The survival rate was analyzed using the Kaplan-Meier method and multivariate Cox regression analysis. Binary logistic regression analysis was used to determine the risk factors for ACM. Results: A total of 306 patients (65.04 ± 10.30 years of age, 72.88% male) were analyzed. The prevalence of ACM in the non-small cell lung cancer (241, 78.76%) and small cell lung cancer (65, 21.24%) population was not statistically different. Overall, 53 (17.32%) LC patients had coexisting ACM. ACM patients were older (69 vs. 64, p = 0.0013) and had higher D-dimer levels (1.0 vs. 0.6, p = 0.001), lower serum calcium levels (2.23 vs. 2.31, p = 0.001), lower left ventricular ejection fraction (LVEF) values (67% vs. 69%, p = 0.036) and had more frequent coronary comorbidity disease (16.98% vs. 8.82%, p = 0.031). The median OS for patients with or without ACM was 15 months and 25 months, respectively (p = 0.018). Coexisting ACM compared to non-ACM was associated with worse OS in patients with LC (HR = 1.543, 95% CI: 1.042-2.283, p = 0.030). Conclusion: Coexisting ACM is associated with undesirable survival outcomes in patients with LC. These findings could help us to better understand the cardiac burden in these patients and provide additional risk stratification for them.

Atrial cardiomyopathy: from cell to bedside.

Atrial cardiomyopathy refers to structural and electrical remodelling of the atria, which can lead to impaired mechanical function. While historical studies have implicated atrial fibrillation as the leading cause of cardioembolic stroke, atrial cardiomyopathy may be an important, underestimated contributor. To date, the relationship between atrial cardiomyopathy, atrial fibrillation, and cardioembolic stroke remains obscure. This review summarizes the pathogenesis of atrial cardiomyopathy, with a special focus on neurohormonal and inflammatory mechanisms, as well as the role of adipose tissue, especially epicardial fat in atrial remodelling. It reviews the current evidence implicating atrial cardiomyopathy as a cause of embolic stroke, with atrial fibrillation as a lagging marker of an increased thrombogenic atrial substrate. Finally, it discusses the potential of antithrombotic therapy in embolic stroke with undetermined source and appraises the available diagnostic techniques for atrial cardiomyopathy, including imaging techniques such as echocardiography, computed tomography, and magnetic resonance imaging as well as electroanatomic mapping, electrocardiogram, biomarkers, and genetic testing. More prospective studies are needed to define the relationship between atrial cardiomyopathy, atrial fibrillation, and embolic stroke and to establish a prompt diagnosis and specific treatment strategies in these patients with atrial cardiomyopathy for the secondary and even primary prevention of embolic stroke.

Atrial Cardiomyopathy: An Emerging Cause of the Embolic Stroke of Undetermined Source.

Nearly 30% of ischemic strokes have an unknown cause, which are referred to as cryptogenic strokes (CS). Imaging studies suggest that a large proportion of these patients show features that are consistent with embolism, and thus the term embolic stroke of undetermined source (ESUS) was proposed to describe these CS patients. Atrial cardiomyopathy predisposes to thrombus formation and thus embolic stroke even in the absence of atrial fibrillation (AF). This may provide a mechanistic link with ESUS, suggesting that anticoagulant therapy may be more beneficial than antiplatelet therapy in ESUS patients with atrial cardiomyopathy. The present review discusses the concept of atrial cardiomyopathy and ESUS and the relationship between them based on the mechanisms and clinical evidence, suggests that atrial cardiomyopathy may be a potential mechanism of ESUS, and highlights a theoretical basis that supports that anticoagulant therapy may be more applicable to ESUS patients with atrial cardiomyopathy and aims to help us better understand and identify the risk of ESUS, thereby improving the management of these patients in clinical practice.

Atrial Cardiomyopathy and Atrial Fibrillation in Cancer.

The number of patients with oncologic and cardiologic comorbidities is increasing. A growing number of evidence shows an inextricable link between cancer, atrial fibrillation, and atrial cardiomyopathy. Cancer itself and resultant inflammation, anticancer treatment, and other comorbidities lead to atrial remodeling and fibrosis, which increases the tendency to develop atrial cardiomyopathy and atrial fibrillation. The scarcity of current literature and ambiguous results make its relationship difficult to fully understand. In this review, we will summarize existing evidence of the relationships and interactions among cancer, atrial cardiomyopathy, and atrial fibrillation and discuss the underlying mechanisms, and provide better information for the management of these patients.

Dysfunctional Coagulation in COVID-19: From Cell to Bedside.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes coronavirus disease 2019 (COVID-19), which can induce multisystem disease. Human angiotensin-converting enzyme 2 (ACE2) widely expressing in arterial and venous endothelial cells and arterial smooth muscle cells has been identified as a functional receptor for SARS-CoV-2. Dysfunction of ACE2 leads to abnormal activation of the renin-angiotensin system and a systemic endotheliitis that may relate to abnormal coagulation and sepsis. Meanwhile, innate immune response and inflammation activation participate in dysfunctional coagulation. Previous research indicated that dysfunctional coagulation was one of the important risk factors accountable for a high risk of severe disease and death in patients with COVID-19. Understanding the possible mechanisms of dysfunctional coagulation and appropriate anticoagulation therapeutic strategies are important to prevent disease deterioration and reduce fatality rates during the ongoing COVID-19 pandemic.

Cardiovascular disease during the COVID-19 pandemic: Think ahead, protect hearts, reduce mortality.

Coronavirus disease 2019 (COVID-19) is rapidly spreading globally. As of October 3, 2020, the number of confirmed cases has been nearly 34 million with more than 1 million fatalities. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is accountable for COVID-19. Newly diagnosed and worsening cardiovascular disease are common complications in COVID-19 patients, including acute cardiac injury, hypertension, arrhythmia, myocardial infarction, heart failure and sudden cardiac arrest. The mechanisms contributing to cardiac disease burden include hypoxemia, inflammatory factor storm, dysfunctional angiotensin converting enzyme 2 (ACE2), and drug-induced cardiac toxicity. Notably, the macrophages expressing ACE2 as direct host cells of SARS-CoV-2 secrete chemokine and inflammatory cytokines, as well as a decrease in cellular immune responses to SARS-CoV-2 infection due to elevated exhaustion levels and dysfunctional diversity of T cells, that may be accountable for the "hyperinflammation and cytokine storm syndrome" and subsequently acute cardiac injury and deteriorating cardiovascular disease in COVID-19 patients. However, no targeted medication or vaccines for COVID-19 are yet available. The management of cardiovascular disease in patients with COVID-19 include general supportive treatment, circulatory support, other symptomatic treatment, psychological assistance as well as online consultation. Further work should be concentrated on better understanding the pathogenesis of COVID-19 and accelerating the development of drugs and vaccines to reduce the cardiac disease burden and promote the management of COVID-19 patients, especially those with a severe disease course and cardiovascular complications.