Increasing evidence recognizes Alzheimer's disease (AD) as a multifactorial and heterogeneous disease with multiple contributors to its pathophysiology, including vascular dysfunction. The recently updated AD Research Framework put forth by the National Institute on Aging–Alzheimer's Association describes a biomarker‐based pathologic definition of AD focused on amyloid, tau, and neuronal injury. In response to this article, here we first discussed evidence that vascular dysfunction is an important early event in AD pathophysiology. Next, we examined various imaging sequences that could be easily implemented to evaluate different types of vascular dysfunction associated with, and/or contributing to, AD pathophysiology, including changes in blood‐brain barrier integrity and cerebral blood flow. Vascular imaging biomarkers of small vessel disease of the brain, which is responsible for >50% of dementia worldwide, including AD, are already established, well characterized, and easy to recognize. We suggest that these vascular biomarkers should be incorporated into the AD Research Framework to gain a better understanding of AD pathophysiology and aid in treatment efforts.

MR imaging was used to show global, diffusely distributed leakage of the blood-brain barrier in patients with early Alzheimer disease, which suggests that a compromised blood-brain barrier is part of the early pathology of Alzheimer disease and might be part of a cascade of pathologic events that eventually lead to cognitive decline. Purpose To investigate whether the blood-brain barrier (BBB) leaks blood-circulating substances in patients with early forms of Alzheimer disease (AD), and if so, to examine the extent and pattern of leakage. Materials and Methods This study was approved by the local medical ethical committees of the Maastricht University Medical Center and Leiden University Medical Center, and written informed consent was obtained from all subjects. For this pilot study, 16 patients with early AD and 17 healthy age-matched control subjects underwent dynamic contrast material–enhanced magnetic resonance (MR) imaging sequence with dual time resolution for 25 minutes. The Patlak graphical approach was used to quantify the BBB leakage rate and local blood plasma volume. Subsequent histogram analysis was used to determine the volume fraction of the leaking brain tissue. Differences were assessed with linear regression analysis, adjusted for confounding variables. Results The BBB leakage rate was significantly higher in patien...

Gut microbiota and its metabolites such as short chain fatty acids (SCFA), lipopolysaccharides (LPS), and trimethylamine-N-oxide (TMAO) impact cardiovascular health. In this review, we discuss how gut microbiota and gut metabolites can affect hypertension and atherosclerosis. Hypertensive patients were shown to have lower alpha diversity, lower abundance of SCFA-producing microbiota, and higher abundance of gram-negative bacteria, which are a source of LPS. Animal studies point towards a direct role for SCFAs in blood pressure regulation and show that LPS has pro-inflammatory effects. Translocation of LPS into the systemic circulation is a consequence of increased gut permeability. Atherosclerosis, a multifactorial disease, is influenced by the gut microbiota through multiple pathways. Many studies have focused on the pro-atherogenic role of TMAO, however, it is not clear if this is a causal factor. In addition, gut microbiota play a key role in bile acid metabolism and some interventions targeting bile acid receptors tend to decrease atherosclerosis. Concluding, gut microbiota affect hypertension and atherosclerosis through many pathways, providing a wide range of potential therapeutic targets. Challenges ahead include translation of findings and mechanisms to humans and development of therapeutic interventions that target cardiovascular risk by modulation of gut microbes and metabolites.

Background: Sex hormone levels in men change during aging. These changes may be associated with insulin sensitivity and the metabolic syndrome. Methods: We studied the association between endogenous sex hormones and characteristics of the metabolic syndrome in 400 independently living men between 40 and 80 yr of age in a cross-sectional study. Serum concentrations of lipids, glucose, insulin, total testosterone (TT), SHBG, estradiol (E₂), and dehydroepiandrosterone sulfate (DHEA-S) were measured. Bioavailable testosterone (BT) was calculated using TT and SHBG. Body height, weight, waist-hip circumference, blood pressure, and physical activity were assessed. Smoking and alcohol consumption was estimated from self-report. The metabolic syndrome was defined according to the National Cholesterol Education Program definition, and insulin sensitivity was calculated by use of the quantitative insulin sensitivity check index. Results: Multiple logistic regression analyses showed an inverse relationship according to 1 sd increase for circulating TT [odds ratio (OR) = 0.43; 95% confidence interval (CI), 0.32–0.59], BT (OR = 0.62; 95% CI, 0.46–0.83), SHBG (OR = 0.46; 95% CI, 0.33–0.64), and DHEA-S (OR = 0.76; 95% CI, 0.56–1.02) with the metabolic syndrome. Each sd increase in E₂ levels was not significantly associated with the metabolic syndrome (OR = 1.16; 95% CI, 0.92–1.45). Linear regression analyses showed that higher TT, BT, and SHBG levels were related to higher insulin sensitivity; β-coefficients (95% CI) were 0.011 (0.008–0.015), 0.005 (0.001–0.009), and 0.013 (0.010–0.017), respectively, whereas no effects were found for DHEA-S and E₂. Estimates were adjusted for age, smoking, alcohol consumption, and physical activity score. Further adjustment for insulin levels and body composition measurements attenuated the estimates, and the associations were similar in the group free of cardiovascular disease and diabetes. Conclusions: Higher testosterone and SHBG levels in aging males are independently associated with a higher insulin sensitivity and a reduced risk of the metabolic syndrome, independent of insulin levels and body composition measurements, suggesting that these hormones may protect against the development of metabolic syndrome.

OBJECTIVE: To determine the relationship between aging, life-style factors and health-related factors and endogenous sex hormone levels. DESIGN: Cross-sectional study of 400 independently living men between 40 and 80 Years of age. METHODS: After exclusion of subjects who were not physically or mentally able to visit the study center, 400 men were randomly selected from a population-based sample. Total testosterone (TT), bioavailable testosterone (BT) (i.e. not bound to sex hormone-binding globulin (SHBG)), SHBG, estradiol (E(2)) and dehydroepiandrosterone-sulfate (DHEA-S) were investigated for their relationship with age, body mass index (BMI), waist circumference, smoking, physical activity and general health status. Multivariate models using ANCOVA analyses were used to examine the contribution of life-style factors to sex hormone variability. RESULTS: TT, BT and DHEA-S decreased with age; 0.2, 0.7 and 1.2%/Year respectively. SHBG showed an increase with age of 1.1%/Year. No changes with age were found for E(2). General health status modified the association of TT and SHBG with age (P interaction 0.10 and 0.002 respectively). Increased BMI and waist circumference were associated with decreased TT, BT, SHBG and DHEA-S and increased E(2) (all P<0.01). Current smoking, lower alcohol intake and a higher physical activity score were associated with higher TT and SHBG levels. CONCLUSION: This study showed the important determinants of sex hormones were age, BMI, waist circumference, smoking, general health status and physical activity. Furthermore, it can be concluded that general health status modified the effect between sex hormones and age. For future observational studies it should be taken into account that the above-mentioned determinants may alter the association between sex hormones and diseases and related conditions.

Background— The burden of atherosclerosis especially afflicts the increasing older segment of the population. Recent evidence has emphasized a protective role of endogenous sex hormones in the development of atherosclerosis in aging men. Methods and Results— We studied the association between endogenous sex hormones and progression of atherosclerosis in 195 independently living elderly men. Participants underwent measurements of carotid intima-media thickness (IMT) at baseline in 1996 and again in 2000. At baseline, serum concentrations of testosterone (total and free) and estradiol (total and free E ₂ ) were measured. Serum free testosterone concentrations were inversely related to the mean progression of IMT of the common carotid artery after adjustment for age (β=−3.57; 95% CI, −6.34 to −0.80). Higher serum total and free E ₂ levels were related to progression of IMT of the common carotid artery after adjustment for age (β=0.38; 95% CI, −0.11 to 0.86; and β=0.018; 95% CI, −0.002 to 0.038, respectively). These associations were independent of body mass index, waist-to-hip ratio, presence of hypertension and diabetes, smoking, and serum cholesterol levels Conclusions— Low free testosterone levels were related to IMT of the common carotid artery in elderly men independently of cardiovascular risk factors.