Dehydroepiandrosterone, Cancer, and Aging.

The biological significance of dehydroepiandrosterone (DHEA) which, in the form of its sulfated ester is the most abundant steroid hormone in human plasma, is an enigma. Over the past years, numerous investigators have reported preclinical findings that DHEA has preventive and therapeutic efficacy in treating major age-associated diseases, including cancer, atherosclerosis, diabetes, obesity, as well as ameliorating the deleterious effects of excess cortisol exposure. Epidemiological studies have also found that low DHEA(S) levels predict an increased all-cause mortality. However, clinical trials, in which oral doses of DHEA at 50 mg-100 mg have been administered to elderly individuals for up to two years, have produced no clear evidence of benefit in parameters such as body composition, peak volume of oxygen consumption, muscle strength, or insulin sensitivity. I discuss why clinical trials, which use doses of DHEA in the 100 mg range, which are the human equivalent of about 1/20th the doses used in animal studies, are an inadequate test of DHEA's therapeutic potential. I also discuss three mechanisms of DHEA action that very likely contribute to its biological effects in animal studies. Lastly, I describe the development of a DHEA analog which lacks DHEA's androgenic and estrogenic action and that demonstrates enhanced potency and is currently in clinical trials. The use of such analogs may provide a better understanding of DHEA's potential therapeutic utility.

Lateralisation of subcortical functional connectivity during and after general anaesthesia.

BACKGROUND: Arousal and awareness are two important components of consciousness states. Functional neuroimaging has furthered our understanding of cortical and thalamocortical mechanisms of awareness. Investigating the relationship between subcortical functional connectivity and arousal has been challenging owing to the relatively small size of brainstem structures and thalamic nuclei, and their depth in the brain. METHODS: Resting state functional MRI scans of 72 healthy volunteers were acquired before, during, 1 h after, and 1 day after sevoflurane general anaesthesia. Functional connectivity of subcortical regions of interest vs whole brain and homotopic functional connectivity for assessment of left-right symmetry analyses of both cortical and subcortical regions of interest were performed. Both analyses used high resolution atlases generated from deep brain stimulation applications. RESULTS: Functional connectivity in subcortical loci within the thalamus and of the ascending reticular activating system was sharply restricted under anaesthesia, featuring a general lateralisation of connectivity. Similarly, left-right homology was sharply reduced under anaesthesia. Subcortical bilateral functional connectivity was not fully restored after emergence from anaesthesia, although greater restoration was seen between ascending reticular activating system loci and specific thalamic nuclei thought to be involved in promoting and maintaining arousal. Functional connectivity was fully restored to baseline by the following day. CONCLUSIONS: Functional connectivity in the subcortex is sharply restricted and lateralised under general anaesthesia. This restriction may play a part in loss and return of consciousness. CLINICAL TRIAL REGISTRATION: NCT02275026.

Cognitive Recovery by Decade in Healthy 40- to 80-Year-Old Volunteers After Anesthesia Without Surgery.

BACKGROUND: Postoperative delirium and postoperative cognitive dysfunction are the most common complications for older surgical patients. General anesthesia may contribute to the development of these conditions, but there are little data on the association of age with cognitive recovery from anesthesia in the absence of surgery or underlying medical condition. METHODS: We performed a single-center cohort study of healthy adult volunteers 40 to 80 years old (N = 71, mean age 58.5 years, and 44% women) with no underlying cognitive dysfunction. Volunteers underwent cognitive testing before and at multiple time points after 2 hours of general anesthesia consisting of propofol induction and sevoflurane maintenance, akin to a general anesthetic for a surgical procedure, although no procedure was performed. The primary outcome was time to recovery to cognitive baseline on the Postoperative Quality of Recovery Scale (PQRS) within 30 days of anesthesia. Secondary cognitive outcomes were time to recovery on in-depth neuropsychological batteries, including the National Institutes of Health Toolbox and well-validated paper-and-pencil tests. The primary hypothesis is that time to recovery of cognitive function after general anesthesia increases across decades from 40 to 80 years of age. We examined this with discrete-time logit regression (for the primary outcome) and linear mixed models for interactions of age decade with time postanesthesia (for secondary outcomes). RESULTS: There was no association between age group and recovery to baseline on the PQRS; 36 of 69 (52%) recovered within 60-minute postanesthesia and 63 of 69 (91%) by day 1. Hazard ratios (95% confidence interval) for each decade compared to 40- to 49-year olds were: 50 to 59 years, 1.41 (0.50-4.03); 60 to 69 years, 1.03 (0.35-3.00); and 70 to 80 years, 0.69 (0.25-1.88). There were no significant differences between older decades relative to the 40- to 49-year reference decade in recovery to baseline on secondary cognitive measures. CONCLUSIONS: Recovery of cognitive function to baseline was rapid and did not differ between age decades of participants, although the number in each decade was small. These results suggest that anesthesia alone may not be associated with cognitive recovery in healthy adults of any age decade.

Transient changes in white matter microstructure during general anesthesia.

Cognitive dysfunction after surgery under general anesthesia is a well-recognized clinical phenomenon in the elderly. Physiological effects of various anesthetic agents have been studied at length. Very little is known about potential effects of anesthesia on brain structure. In this study we used Diffusion Tensor Imaging to compare the white matter microstructure of healthy control subjects under sevoflurane anesthesia with their awake state. Fractional Anisotropy, a white mater integrity index, transiently decreases throughout the brain during sevoflurane anesthesia and then returns back to baseline. Other DTI metrics such as mean diffusivity, axial diffusivity and radial diffusivity were increased under sevoflurane anesthesia. Although DTI metrics are age dependent, the transient changes due to sevoflurane were independent of age and sex. Volumetric analysis shows various white matter volumes decreased whereas some gray matter volumes increased during sevoflurane anesthesia. These results suggest that sevoflurane anesthesia has a significant, but transient, effect on white matter microstructure. In spite of the transient effects of sevoflurane anesthesia there were no measurable effects on brain white matter as determined by the DTI metrics at 2 days and 7 days following anesthesia. The role of white matter in the loss of consciousness under anesthesia will need to be studied and MRI studies with subjects under anesthesia will need to take these results into account.

Resting-state functional connectivity in early postanaesthesia recovery is characterised by globally reduced anticorrelations.

BACKGROUND: A growing body of literature addresses the possible long-term cognitive effects of anaesthetics, but no study has delineated the normal trajectory of neural recovery attributable to anaesthesia alone in adults. We obtained resting-state functional MRI scans on 72 healthy human volunteers between ages 40 and 80 (median: 59) yr before, during, and after general anaesthesia with sevoflurane, in the absence of surgery, as part of a larger study on cognitive function postanaesthesia. METHODS: Region-of-interest analysis, independent component analysis, and seed-to-voxel analysis were used to characterise resting-state functional connectivity and to differentiate between correlated and anticorrelated connectivity before, during, and after general anaesthesia. RESULTS: Whilst positively correlated functional connectivity remained essentially unchanged across these perianaesthetic states, anticorrelated functional connectivity decreased globally by 35% 1 h after emergence from general anaesthesia compared with baseline, as seen by the region-of-interest analysis. This decrease corresponded to a consistent reduction in expression of canonical resting-state networks, as seen by independent component analysis. All measures returned to baseline 1 day later. CONCLUSIONS: The normal perianaesthesia trajectory of resting-state connectivity in healthy adults is characterised by a transient global reduction in anticorrelated activity shortly after emergence from anaesthesia that returns to baseline by the following day. CLINICAL TRIAL REGISTRATION: NCT02275026.

Glucose-6-Phosphate Dehydrogenase (G6PD) Deficiency and Late-stage Age-Related Macular Degeneration.

Purpose: Age-related macular degeneration (AMD) is the leading cause of blindness in the elderly in Western Countries. Evidence indicates that Glucose-6-Phosphate Dehydrogenase (G6PD) deficiency, a common genetic abnormality, may protect against ischemic heart and cerebrovascular disease, ocular vascular disorders, and colorectal cancer. This study was undertaken to ascertain whether G6PD deficiency may protect against AMD. Materials and Methods: 79 men with late-stage AMD and 79 male, age-matched cataract controls without AMD were recruited in March-December 2016. Smoking status, clinical history, and drug use were recorded. A blood sample was taken from each participant. Complete blood count, hemoglobin, glucose, creatinine, cholesterol, triglycerides, transaminases, bilirubin, and erythrocyte G6PD activity were measured. Stepwise logistic regression was used to investigate the association between G6PD deficiency and AMD. Results: G6PD deficiency was found in 7 (8.9%) AMD patients and 8 (10.1%) controls, a not statistically significant difference. Stepwise logistic regression disclosed that AMD was significantly associated with increased diastolic blood pressure (OR=1.09, 95% CI=1.03-1.15, P=0.02) and LDL-cholesterol (OR=1.02, 95% CI=1.0001-1.03, P=0.049) and lower values of white blood cell (WBC) count (OR=0.71, 95% CI=0.56-0.88, P=0.02) and aspartate aminotransferase (AST) (OR=0.92, 95% CI=0.85-0.99, P=0.044). Conclusion: Results suggest that G6PD deficiency has no protective effect on nor is a risk factor for AMD. Larger studies are necessary to confirm whether increased diastolic blood pressure and LDL-cholesterol and lower values of WBC count and AST are risk factors for AMD.

The role of corneal hysteresis during the evaluation of patients with possible normal-tension glaucoma.

PURPOSE: There are multiple reports of the role of corneal hysteresis (CH) as an independent risk factor for the diagnosis and risk of progression of normal-tension glaucoma (NTG). Our study measured CH with the Ocular Response Analyzer (ORA) in patients with intraocular pressure (IOP) <21 mmHg to investigate if a low CH would identify NTG in this Asian-based practice. METHODS: This was a prospective cross-sectional study of patients who underwent routine eye examination during 2016 in a private practice in Honolulu, Hawaii, where most patients are Asian. Inclusion criteria are: 1) ≥65 years 2) IOP <21 (compensated IOP by ORA), and 3) CH values <10 using ORA as measured by a single experienced technician. Exclusion criteria are: 1) sight-limiting ocular or corneal disease that would preclude accurate measurements for the purposes of the study. 2) Any patient who had difficulty in being tested with the ORA. 3) Patients who had any history of any type of glaucoma. All patients that met the inclusion criteria underwent fundus photography to measure cup-to-disc ratio and cup-to-disc asymmetry and also had central corneal thickness measured. Thickness of the retina nerve fiber layer was measured by ocular coherence tomography. The eyes with an average retina nerve fiber layer thickness less than 80 µm were classified as possible NTG and were scheduled for a visual field test. The field examination was considered valid only if the fixation, false positives, and false negatives were within the acceptable range. Patient demographics and data on preexisting diseases were collected including age, sex, coexisting medical conditions, and previous intraocular surgery. Those with thinning of retina nerve fiber layer on optical coherence tomography had a Humphrey visual field test to confirm the diagnosis of glaucoma. RESULTS: Seventy-six eyes of 46 patients that met the eligibility criteria were included in the study. Twenty-one previously undiagnosed eyes were confirmed as having NTG, which corresponds to an incidence of 27.6%. CONCLUSION: CH measurement is a valuable test to assist in early diagnosis of NTG, especially in the elderly Asian population. With an established diagnosis, aggressive early treatments medically or surgically to further lower IOP can prevent irreversible blindness, which can severely impact the patient's family and socioeconomic status.

Delineating the Trajectory of Cognitive Recovery From General Anesthesia in Older Adults: Design and Rationale of the TORIE (Trajectory of Recovery in the Elderly) Project.

BACKGROUND: Mechanistic aspects of cognitive recovery after anesthesia and surgery are not yet well characterized, but may be vital to distinguishing the contributions of anesthesia and surgery in cognitive complications common in the elderly such as delirium and postoperative cognitive dysfunction. This article describes the aims and methodological approach to the ongoing study, Trajectory of Recovery in the Elderly (TORIE), which focuses on the trajectory of cognitive recovery from general anesthesia. METHODS: The study design employs cognitive testing coupled with neuroimaging techniques such as functional magnetic resonance imaging, diffusion tensor imaging, and arterial spin labeling to characterize cognitive recovery from anesthesia and its biological correlates. Applying these techniques to a cohort of age-specified healthy volunteers 40-80 years of age, who are exposed to general anesthesia alone, in the absence of surgery, will assess cognitive and functional neural network recovery after anesthesia. Imaging data are acquired before, during, and immediately after anesthesia, as well as 1 and 7 days after. Detailed cognitive data are captured at the same time points as well as 30 days after anesthesia, and brief cognitive assessments are repeated at 6 and 12 months after anesthesia. RESULTS: The study is underway. Our primary hypothesis is that older adults may require significantly longer to achieve cognitive recovery, measured by Postoperative Quality of Recovery Scale cognitive domain, than younger adults in the immediate postanesthesia period, but all will fully recover to baseline levels within 30 days of anesthesia exposure. Imaging data will address systems neuroscience correlates of cognitive recovery from general anesthesia. CONCLUSIONS: The data acquired in this project will have both clinical and theoretical relevance regardless of the outcome by delineating the mechanism behind short-term recovery across the adult age lifespan, which will have major implications for our understanding of the effects of anesthetic drugs.

Inspiring and Equipping Students to Be Ethical Leaders.

This chapter describes the behaviors of the ethical leader and explores the reasons why leaders do not always act ethically. The chapter also offers five recommendations to help educators integrate the practices of ethical leadership into their work with student leaders.