Effects of candesartan on cerebral microvascular function in mild cognitive impairment: Results of two clinical trials.

BACKGROUND: Cerebral microvascular dysfunction is commonly seen in Alzheimer's disease (AD) and vascular cognitive impairment (VCI). Cerebrovascular reactivity (CVR) to CO2 reflects cerebral microvascular health and may be modulated by the renin-angiotensin system (RAS). This study aimed to investigate the effects of RAS modulation on CVR in individuals with mild cognitive impairment (MCI) due to underlying vascular or AD etiologies. METHODS: This study presents findings of candesartan's effects on the secondary outcomes of two double-blind randomized clinical trials of 12-month therapy of candesartan versus lisinopril in VCI (CALIBREX (Candesartan vs Lisinopril Effects on the Brain and Endothelial Function in Executive MCI)) and candesartan versus placebo in prodromal AD (Candesartan's Effects on Alzheimer's Disease and Related Biomarkers (CEDAR)). Primary outcome results of these trials have been reported in previous publications. Participants underwent identical brain blood oxygenation level dependent (BOLD)-CVR in response to a 2-min CO2 challenge at baseline and 12 months. Regions of interest and voxel-wise CVR maps were derived from BOLD signal changes during CO2 challenge. CVR effects were compared between candesartan and lisinopril (CALIBREX) and candesartan and placebo (CEDAR) using mixed-model repeated measures. RESULTS: Data from 102 participants in the CALIBREX study (mean age = 65 years, 45% female, 63% African American) and 59 in the CEDAR study (mean age = 67 years, 32% female, 20% African American) were analyzed. Candesartan was associated with improved whole brain CVR compared to placebo in the CEDAR study (adjusted within-group mean difference for candesartan = 0.27 (95% confidence interval (CI) = 0.006, 0.53) vs placebo = -0.17 (95% CI = 0.42, 0.08), p-value = 0.018), and compared to lisinopril in the CALIBREX study (adjusted within-group mean difference for candesartan = 0.28 (95% CI = 0.10, 0.46) vs lisinopril = -0.08 (95% CI = -0.31, 0.14), p-value = 0.012), independent of blood pressure. In an exploratory meta-analysis of the two trials, improved CVR in the hippocampus was linked to improved attention and working memory (p = 0.044) and a trend for improved executive function (p = 0.087) with candesartan therapy. CONCLUSION: This study suggests that candesartan is associated with improved microvascular function in MCI, and these findings are independent of its blood pressure effect in these VCI and prodromal AD populations.

Cardiovascular Response to Mental Stress in Mild Cognitive Impairment and its Association with Cerebral Perfusion.

Mental stress has been linked to various chronic diseases including Alzheimer's disease, but the mechanisms underlying cognitive decline with mental stress are unknown. Reduced cardiovascular response to stress is associated with cardiovascular disease, and the latter is associated with cognitive impairment. We measured electrodermal activity, blood pressure, and cardiac hemodynamics in cognitively normal and mild cognitive impairment (MCI) adults (n = 76, mean age = 58 years, 46% MCI) during rest, a math test, and face-name recall tasks to derive the following cardiovascular indicators: mean arterial pressure, heart rate, stroke volume and cardiac output. These indicators were compared between the two groups. Cerebral blood perfusion via arterial spin-labeling MRI was measured in a subgroup who underwent an MRI scan (n = 30). Following exposure to mental stress, a decrease in stroke volume (p = 0.024) and cardiac output (p = 0.005) was found in the MCI group, but an increase in both parameters in the cognitively normal group. This difference was largest during face-name recall (standardized difference in stroke volume = -0.50, p = 0.029, and in cardiac output = -0.52, p = 0.023). Cardiac output during mental stress, but not at rest, decreased with cerebral perfusion (normal: p = 0.078, ß= 1.97, R2 = 0.090; MCI: p = 0.007, ß= 2.02, R2 = 0.008). No significant difference was found between the two groups at rest. This preliminary study suggests that individuals with MCI have an insufficient cardiac output, and in turn lower cerebral perfusion in response to mental stress.

Compartmental and Data-Based Modeling of Cerebral Hemodynamics: Nonlinear Analysis.

OBJECTIVE: As an extension to our study comparing a putative compartmental and data-based model of linear dynamic cerebral autoregulation (CA) and CO2-vasomotor reactivity (VR), we study the CA-VR process in a nonlinear context. METHODS: We use the concept of principal dynamic modes (PDM) in order to obtain a compact and more easily interpretable input-output model. This in silico study permits the use of input data with a dynamic range large enough to simulate the classic homeostatic CA and VR curves using a putative structural model of the regulatory control of the cerebral circulation. The PDM model obtained using theoretical and experimental data are compared. RESULTS: It was found that the PDM model was able to reflect accurately both the simulated static CA and VR curves in the associated nonlinear functions (ANFs). Similar to experimental observations, the PDM model essentially separates the pressure-flow relationship into a linear component with fast dynamics and nonlinear components with slow dynamics. In addition, we found good qualitative agreement between the PDMs representing the dynamic theoretical and experimental CO2-flow relationship. CONCLUSION: Under the modeling assumption and in light of other experimental findings, we hypothesize that PDMs obtained from experimental data correspond with passive fluid dynamical and active regulatory mechanisms. SIGNIFICANCE: Both hypothesis-based and data-based modeling approaches can be combined to offer some insight into the physiological basis of PDM model obtained from human experimental data. The PDM modeling approach potentially offers a practical way to quantify the status of specific regulatory mechanisms in the CA-VR process.

Cigarette smoke-induced differential expression of the genes involved in exocrine function of the rat pancreas.

OBJECTIVE: Little is known about the molecular and biological aspects of the epidemiological association between smoking and pancreatic pathology, such as chronic pancreatitis and pancreatic cancer. Recently, we reported that tobacco smoke exposure induced morphological alterations in the rat pancreas. Here, we have investigated the alterations in the expression of genes associated with exocrine pancreatic function and cellular differentiation upon exposure to cigarette smoke. METHODS: Female rats were exposed to environmental smoke inhalation for 2 d/wk (70 min/d) for 12 weeks. The expression profiles of trypsinogen, pancreas-specific trypsin inhibitor, cholecystokinin A receptor, cystic fibrosis transmembrane conductance regulator (CFTR), carbonic anhydrase, and Muc1 and Muc4 mucins transcripts were analyzed by RNA slot blot analysis. Muc4 expression was also examined by immunohistochemistry. RESULTS: Our data revealed that the ratio of trypsinogen to that of the protective pancreas-specific trypsin inhibitor was elevated upon cigarette smoke exposure. The expression of carbonic anhydrase and CFTR remained unaltered when inflammatory signs were not detected in histological examinations. On the other hand, when pancreatic inflammation was present, the levels of CFTR and carbonic anhydrase were increased, indicating ductal and/or centroacinar cell involvement. No changes in the expression of Muc1 and Muc4 mucins were observed. CONCLUSIONS: Our data show that cigarette smoke exposure leads to an increased vulnerability to pancreatic self-digestion. Moreover, the concomitant involvement of pancreatic ducts occurs only when focal pancreatic inflammation is present.