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

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 patients compared with that in control subjects in the total gray matter (P < .05) and cortex (P = .03). Patients had a significantly higher volume fraction of the leaking brain tissue in the gray matter (P = .004), normal-appearing white matter (P < .04), deep gray matter (P = .01), and cortex (P = .004). When all subjects were considered, scores on the Mini-Mental State Examination decreased significantly with increasing leakage in the deep gray matter (P = .007) and cortex (P < .05). Conclusion The results of this study showed global BBB leakage in patients with early AD that is associated with cognitive decline. A compromised BBB may be part of a cascade of pathologic events that eventually lead to cognitive decline and dementia. RSNA, 2016 Online supplemental material is available for this article.

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.

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.

Generation of bile flow is a regulated, ATP-dependent process and depends on the coordinated action of a number of transporter proteins in the sinusoidal and canalicular domains of the hepatocyte. Dysfunction of any of these proteins leads to retention of substrates, with conjugated hyperbilirubinemia or cholestasis as a result. In recent years many of the transport proteins involved in bile formation have been identified, cloned, and functionally characterized. The hepatocyte sinusoidal membrane contains transport proteins for the hepatic uptake of organic anions and cations and for the uptake of bile acids. The multispecific organic anion transporting polypeptide (OATP) mediates the hepatic uptake of organic anions and a variety of organic amphiphilic compounds, including organic cations. The organic cation transporter OCT1 more specifically transports small organic cations. NTCP is the Na(+)-bile acid cotransporting protein that mediates the hepatic uptake of bile acids. The canalicular transport proteins are able to transport endogenous and exogenous metabolites into the bile against steep concentration gradients. Most of these transporters are members of the large ATP-binding cassette (ABC) superfamily, and their transport function directly depends on the hydrolysis of Mg2+/ATP. At least five ABC transporter proteins have been characterized so far: 1) the human multidrug resistance protein MDR1 mediates the excretion of hydrophobic, mostly cationic, metabolites; 2) MDR3 is involved in phosphatidylcholine secretion; 3) the canalicular bile acid transporter cBAT mediates secretion of monovalent bile salts and provides the molecular basis of bile acid-dependent bile flow; 4) SPGP, product of the P-glycoprotein sister gene, is exclusively expressed in the liver but its function is currently unknown; and 5) the human multidrug resistance protein MRP2 mediates the excretion of multivalent anionic conjugates.