Where in the world? Latitude, longitude and season contribute to the complex co-ordinates determining cortisol levels.

OBJECTIVE: Cortisol is a critical stress hormone with circadian rhythms synchronized by light. There are seasonal differences in expression of pro-inflammatory genes and in some diseases moderated by glucocorticoids. As light changes with season and with latitude and longitude, we assessed changes in population cortisol associated with these parameters. DESIGN: Retrospective data audit. PATIENTS: Populations across 4 states of Australia over 3 years. MEASUREMENTS: Serum cortisol levels, age, gender, time of collection, sunrise time, season and location were determined. RESULTS: In 4 geographically separate populations (n = 84 937), sunrise time and time of sample collection were the most important factors influencing median cortisol. Over 2 hours in the morning cortisol could decrease by up to 76 nmol/L, and for each hour that sunrise time advanced there was up to 6.9% increase in cortisol. A cyclic seasonal pattern of cortisol was confirmed each year in all populations with autumn/winter cortisol highest compared to spring/summer with differences of up to 44 nmol/L. There was less change in cortisol in latitudes closer to the equator but cortisol progressively increased from 25 to 30°S of the equator. In more southerly latitudes, seasonal cortisol variation also increased, and over the entire latitude range, there was up to 50 nmol/L change in cortisol. Longitude variation within a time zone had a minimal effect on median cortisol. CONCLUSIONS: Location, time of year and time of day are important influences on population cortisol levels. Elevated autumn/winter morning cortisol levels are likely due to sampling closer to the circadian peak due to later sunrise time. Understanding how the environment can influence cortisol levels may further our knowledge of physiology and disease.

A time-adjusted cortisol cut-off can reduce referral rate for Synacthen stimulation test whilst maintaining diagnostic performance.

OBJECTIVE: Cortisol cut-offs can predict requirement for Synacthen stimulation tests (SST). We assessed the performance of a standard cortisol cut-off (375 nmol/L) across the morning and compared this with a time-adjusted cut-off. DESIGN: Retrospective audit PATIENTS: Community reference set (n=12 550) and SST patients (n=757). MEASUREMENTS: In the reference population, time-specific cortisol medians were calculated and used to convert cortisol to time-adjusted Multiples of the Median (MoM). In 757 SST patients, the predictive performance of a standard cortisol cut-off (375 nmol/L) and its time-adjusted MoM equivalent were compared. RESULTS: Median cortisol decreased by ~30 nmol/L per hour between 0700 and 1200h. In the reference population, proportions below the 375 nmol/L cut-off increased throughout the morning (range 35%-64%), whereas using the time-adjusted MoM cut-off proportions were consistent (range 46%-50%), with a 17% maximal difference in referral rates between the two cut-offs after 1100h. A similar pattern was noted in the SST cohort. When a cortisol MoM cut-off was used to predict SST success, the excess proportion of patients tested and misclassification rates were lower and more consistent than when the standard cut-off was used. A median cortisol of 375 nmol/L equated to 444 and 313 nmol/L before 0800 and after 1100 h, respectively. CONCLUSION: The use of a standard cortisol cut-off results in 17% more patients being referred for SST later in the morning. A time-adjusted cortisol cut-off provides consistent and lower referral rates, whilst maintaining similar or better performance than a standard single cut-off in predicting outcome of SST.

Evidence for central hypercortisolism and elevated blood pressure in adolescent offspring of mothers with pre-eclampsia.

OBJECTIVE: Maternal total and free cortisol concentrations are reduced in pre-eclampsia (PE) and gestational hypertension (GH). However, the effect of this on the hypothalamic-pituitary-adrenal (HPA) axis function in the offspring is unknown. We examined the basal HPA axis activity in adolescent offspring of mothers with pre-pregnancy hypertension/GH/PE. DESIGN AND SUBJECTS: A total of 1182 participants (mean age 17·1 years) recruited from the Western Australian Pregnancy Cohort (Raine) Study provided fasting morning blood samples for basal HPA axis and concomitant clinical assessments, including blood pressure. MEASUREMENTS: Plasma ACTH, total cortisol, corticosteroid-binding globulin (CBG) and free cortisol calculated by Coolens' equation were measured from the blood samples collected at home before 10:00 am. RESULTS: Total plasma cortisol (689 ± 153 nmol/l vs 583 ± 172 nmol/l, P = 0·024), ACTH (15·5 ± 13 pmol/l vs 10·8 ± 5·1 pmol/l, P = 0·040) and calculated free cortisol (52 ± 21 nmol/l vs 42 ± 22 nmol/l, P = 0·052) were higher in the PE offspring than in controls. The pre-pregnancy hypertension group had evidence of a lower ACTH/plasma free cortisol ratio (0·22 vs 0·33 P = 0·020) and lower CBG (713 nmol/l vs 821 nmol/l, P = 0·004) compared with controls. Systolic blood pressure was elevated in the GH/PE group compared with controls (120 mmHg vs 116 mmHg, P = 0·006). CONCLUSIONS: Hypothalamic-pituitary-adrenal axis activity is increased in the adolescent offspring of mothers with pre-eclampsia. This may be an adaptation resulting from the reduced maternal cortisol during foetal life. The resulting mild hypercortisolism may have implications for long-term health outcomes and warrants further investigation.

Characterization and novel analyses of acute stress response patterns in a population-based cohort of young adults: influence of gender, smoking, and BMI.

Dysregulation of the biological stress response system has been implicated in the development of psychological, metabolic, and cardiovascular disease. Whilst changes in stress response are often quantified as an increase or decrease in cortisol levels, three different patterns of stress response have been reported in the literature for the Trier Social Stress Test (TSST) (reactive-responders (RR), anticipatory-responders (AR) and non-responders (NR)). However, these have never been systematically analyzed in a large population-based cohort. The aims of this study were to examine factors that contribute to TSST variation (gender, oral contraceptive use, menstrual cycle phase, smoking, and BMI) using traditional methods and novel analyses of stress response patterns. We analyzed the acute stress response of 798, 18-year-old participants from a community-based cohort using the TSST. Plasma adrenocorticotrophic hormone, plasma cortisol, and salivary cortisol levels were quantified. RR, AR, and NR patterns comprised 56.6%, 26.2%, and 17.2% of the cohort, respectively. Smokers were more likely to be NR than (RR or AR; adjusted, p < 0.05). Overweight and obese subjects were less likely to be NR than the other patterns (adjusted, p < 0.05). Males were more likely to be RR than NR (adjusted, p = 0.05). In addition, we present a novel AUC measure (AUCR), for use when the TSST baseline concentration is higher than later time points. These results show that in a young adult cohort, stress-response patterns, in addition to other parameters vary with gender, smoking, and BMI. The distribution of these patterns has the potential to vary with adult health and disease and may represent a biomarker for future investigation.

Florbetapir F18 PET Amyloid Neuroimaging and Characteristics in Patients With Mild and Moderate Alzheimer Dementia.

BACKGROUND: Clinical diagnosis of Alzheimer disease (AD) is challenging, with a 70.9%-87.3% sensitivity and 44.3%-70.8% specificity, compared with autopsy diagnosis. Florbetapir F18 positron emission tomography (FBP-PET) estimates beta-amyloid plaque density antemortem. METHODS: Of 2052 patients (≥55 years old) clinically diagnosed with mild or moderate AD dementia from 2 solanezumab clinical trials, 390 opted to participate in a FBP-PET study addendum. We analyzed baseline prerandomization characteristics. RESULTS: A total of 22.4% had negative FBP-PET scans, whereas 72.5% of mild and 86.9% of moderate AD patients had positive results. No baseline clinical variable reliably differentiated negative from positive FBP-PET scan groups. CONCLUSIONS: These data confirm the challenges of correctly diagnosing AD without using biomarkers. FBP-PET can aid AD dementia differential diagnosis by detecting amyloid pathology antemortem, even when the diagnosis of AD is made by expert clinicians.

Dynamic pituitary-adrenal interactions in response to cardiac surgery.

OBJECTIVES: To characterize the dynamics of the pituitary-adrenal interaction during the course of coronary artery bypass grafting both on and off pump. Since our data pointed to a major change in adrenal responsiveness to adrenocorticotropic hormone, we used a reverse translation approach to investigate the molecular mechanisms underlying this change in a rat model of critical illness. CLINICAL STUDIES: Prospective observational study. ANIMAL STUDIES: Controlled experimental study. CLINICAL STUDIES: Cardiac surgery operating rooms and critical care units. ANIMAL STUDIES: University research laboratory. CLINICAL STUDIES: Twenty, male patients. ANIMAL STUDIES: Adult, male Sprague-Dawley rats. CLINICAL STUDIES: Coronary artery bypass graft-both on and off pump. ANIMAL STUDIES: Injection of either lipopolysaccharide or saline (controls) via a jugular vein cannula. CLINICAL STUDIES: Blood samples were taken for 24 hours from placement of the first venous access. Cortisol and adrenocorticotropic hormone were measured every 10 and 60 minutes, respectively, and corticosteroid-binding globulin was measured at the beginning and end of the 24-hour period and at the end of operation. There was an initial rise in both levels of adrenocorticotropic hormone and cortisol to supranormal values at around the end of surgery. Adrenocorticotropic hormone levels then returned toward preoperative values. Ultradian pulsatility of both adrenocorticotropic hormone and cortisol was maintained throughout the perioperative period in all individuals. The sensitivity of the adrenal gland to adrenocorticotropic hormone increased markedly at around 8 hours after surgery maintaining very high levels of cortisol in the face of "basal" levels of adrenocorticotropic hormone. This sensitivity began to return toward preoperative values at the end of the 24-hour sampling period. ANIMAL STUDIES: Adult, male Sprague-Dawley rats were given either lipopolysaccharide or sterile saline via a jugular vein cannula. Hourly blood samples were subsequently collected for adrenocorticotropic hormone and corticosterone measurement. Rats were killed 6 hours after the injection, and the adrenal glands were collected for measurement of steroidogenic acute regulatory protein, steroidogenic factor 1, and dosage-sensitive sex reversal, adrenal hypoplasia critical region, on chromosome X, gene 1 messenger RNAs and protein using real-time quantitative polymerase chain reaction and Western immunoblotting, respectively. Adrenal levels of the adrenocorticotropic hormone receptor (melanocortin type 2 receptor) messenger RNA and its accessory protein (melanocortin type 2 receptor accessory protein) were also measured by real-time quantitative polymerase chain reaction. In response to lipopolysaccharide, rats showed a pattern of adrenocorticotropic hormone and corticosterone that was similar to patients undergoing coronary artery bypass grafting. We were also able to demonstrate increased intra-adrenal corticosterone levels and an increase in steroidogenic acute regulatory protein, steroidogenic factor 1, and melanocortin type 2 receptor accessory protein messenger RNAs and steroidogenic acute regulatory protein, and a reduction in dosage-sensitive sex reversal, adrenal hypoplasia critical region, on chromosome X, gene 1 and melanocortin type 2 receptor messenger RNAs, 6 hours after lipopolysaccharide injection. CONCLUSIONS: Severe inflammatory stimuli activate the hypothalamic-pituitary-adrenal axis resulting in increased steroidogenic activity in the adrenal cortex and an elevation of cortisol levels in the blood. Following coronary artery bypass grafting, there is a massive increase in both adrenocorticotropic hormone and cortisol secretion. Despite a subsequent fall of adrenocorticotropic hormone to basal levels, cortisol remains elevated and coordinated adrenocorticotropic hormone-cortisol pulsatility is maintained. This suggested that there is an increase in adrenal sensitivity to adrenocorticotropic hormone, which we confirmed in our animal model of immune activation of the hypothalamic-pituitary-adrenal axis. Using this model, we were able to show that this increased adrenal sensitivity results from changes in the regulation of both stimulatory and inhibitory intra-adrenal signaling pathways. Increased understanding of the dynamics of normal hypothalamic-pituitary-adrenal responses to major surgery will provide us with a more rational approach to glucocorticoid therapy in critically ill patients.

Adverse events and dropouts in Alzheimer's disease studies: what can we learn?

BACKGROUND: Interpreting Alzheimer's disease (AD) clinical trial (CT) outcomes is complicated by treatment dropouts and adverse events (AEs). In elderly participants, AE rates, dropouts, and deaths are important considerations as they may undermine the validity of clinical trials. Published discontinuation and safety data are limited. METHODS: Safety data from 1054 placebo-treated participants in IDENTITY and IDENTITY-2, 76-week, Phase 3 AD studies conducted in 31 countries, were pooled, annualized, and summarized overall, by country and age group. RESULTS: Median age was 74.2 (interquartile range 67.9-79.5) years; 57.4% were female; and median observation time was 63.2 (interquartile range 41.6-77.4) weeks when study drug dosing was halted. Overall annualized rates for discontinuations, discontinuations due to AEs, serious adverse events (SAEs), and deaths were 21.6% (range 19.6%-24.0%), 8.2% (range 8.1%-8.3%), 12.0%, and 1.7%, respectively. AE and discontinuation rates varied by country and age groups. Fall, pneumonia, and atrial fibrillation AEs were more frequent in the oldest age group. CONCLUSIONS: These annualized placebo safety data provide insight into the course of enrolled patients with mild-to-moderate AD, and are useful in planning longer term trials and in monitoring safety.

Cardio-metabolic consequences of glucocorticoid replacement: relevance of ultradian signalling.

Chronic exposure to elevated glucocorticoid levels is associated with obesity, insulin resistance, impaired glucose tolerance, hypertension and dyslipidaemia, manifest classically in Cushing's syndrome and with high-dose glucocorticoid therapy. However, cardiovascular events are also reportedly higher in patients with primary and secondary hypoadrenalism receiving 'replacement' glucocorticoid doses. This has been attributed to an inability to mimic accurately the diurnal rhythm of cortisol with current oral replacement therapy and subsequent glucocorticoid excess. Although development of delayed release oral preparations has sought to overcome this problem, there has been little attention on the ultradian rhythm of glucocorticoids and its relevance for replacement therapy and associated cardio-metabolic comorbidity. Endogenous glucocorticoids are released in a pulsatile manner, and this ultradian rhythm is important in maintaining homeostatic control through glucocorticoid-receptor (GR)-dependent transcription regulation that rapidly responds to circulating hormone levels. Constant glucocorticoid exposure can result in continuous transcription, aberrant mRNA accumulation and abnormal protein levels. GR regulation of transcription programmes is highly cell and tissue specific, binding to distinct genomic loci in different cellular contexts. GR also interacts with a large cohort of DNA-binding factors with cell-specific interactions. The relevance of kinetic patterns of GR-dependent gene expression in vivo is not yet fully elucidated. However, given that GR gene variants are associated with cardiovascular disease, it is possible that ultradian delivery of glucocorticoid replacement may become important, at least in selected patients.

How good is a morning cortisol in predicting an adequate response to intramuscular synacthen stimulation?

CONTEXT: Previous studies have demonstrated that a morning serum cortisol of <100 nmol/l makes further dynamic testing such as the Synacthen stimulation test (SST) unnecessary to confirm adrenal insufficiency. The morning cortisol level that reliably predicts adrenal sufficiency (AS) is less well established, and values ranging from 300 to 500 nmol/l have been proposed. OBJECTIVE: The aim of this study was to determine the ambulatory morning cortisol level that predicts adrenal sufficiency, as defined by an adequate response to SST, using a receiver operating characteristics (ROC) curve. DESIGN: Observational retrospective cross-sectional study. METHOD & SUBJECTS: We conducted a retrospective audit of SST performed at PathWest Laboratory QEII from January 2006 to August 2008. A total of 761 results were obtained. Patients who were acutely ill or in intensive care, on glucocorticoid therapy, and those with inadequate data or multiple records were excluded from the analysis leaving 505 available for analysis. Baseline serum was obtained prior to intramuscular injection of 250 mcg Synacthen, and a second sample was obtained 30 min post-Synacthen. AS was defined as a 30-min post-Synacthen cortisol of >550 nmol/l; values ≤550 nmol/l were considered inadequate. RESULTS: Based on SST criteria, of the 505 patients included in the study, 350 patients (69%) were adrenal sufficient and 155 (31%) had adrenal insufficiency. Using the minimum ROC distance criterion, a basal cortisol value of >236 nmol/l was identified to predict AS with sensitivity 84% and specificity 71%. However, to increase the specificity to 95%, we recommend a basal cortisol cut-off of >375 nmol/l. For patients with known pituitary disease (n = 152), basal cortisol of >214 nmol/l (sensitivity 85% and specificity 71%) may obviate the need for SST in the appropriate clinical context, although 330 nmol/l gives a specificity of 95%. CONCLUSION: Basal morning cortisol is a viable first step in the evaluation of patients with suspected adrenal insufficiency.

Association between clinical measures and florbetapir F18 PET neuroimaging in mild or moderate Alzheimer's disease dementia.

Clinical diagnosis of Alzheimer's disease (AD) is challenging, with 20% or more of patients misdiagnosed, even by expert clinicians. The authors conducted a retrospective, cross-sectional analysis comparing baseline neuropsychiatric and other clinical characteristics in 199 expert-diagnosed mild and moderate AD dementia patients participating in industry-sponsored clinical trials of an investigational therapy, where 18% lacked florbetapir positron emission tomography (PET) evidence of AD neuropathology. Significant differences were found only for cognition and ApoE ε4 status, but the large degree of score overlap would preclude using these measures to predict AD misdiagnosis. This study highlights the value of amyloid PET when evaluating patients with seemingly typical AD.

Immediate Reactions to Alzheimer Biomarker Disclosure in Cognitively Unimpaired Individuals in a Global Truncated Randomized Trial.

Background and Objectives: Preclinical Alzheimer disease (AD) trials simultaneously test candidate treatments and the implications of disclosing biomarker information to cognitively unimpaired individuals. Methods: The EARLY trial was a randomized, double-blind, placebo-controlled, phase 2b/3 study conducted in 143 centers across 14 countries from November 2015 to December 2018 after being stopped prematurely because of treatment-related hepatotoxicity. Participants age 60-85 years deemed cognitively unimpaired were disclosed an elevated or not elevated brain amyloid result by a certified clinician. Among 3,686 participants, 2,066 underwent amyloid imaging, 1,394 underwent CSF biomarker assessment, and 226 underwent both. Among biomarker-tested participants with at least one change score on an outcome of interest, 680 with elevated and 2,698 with not elevated amyloid were included in this analysis. We compared the Geriatric Depression Scale (GDS), the State-Trait Anxiety Scale (STAI), and the Columbia Suicide Severity Rating Scale (CSSRS) before disclosure between amyloid groups. After disclosure, we assessed for differences in the Impact of Events Scale (IES, collected 24-72 hours after disclosure), a measure of intrusive thoughts. Additional scales included the Concerns for AD scale. Results: Among 3378 included participants, the mean (SD) age was 69.0 (5.3); most were female (60%) and White race (84%). No differences were observed before disclosure between participants with elevated and not elevated amyloid for the GDS, STAI, or CSSRS. Participants with elevated amyloid demonstrated higher Concerns for AD scores compared with participants with not elevated amyloid before disclosure. Participants with elevated amyloid demonstrated higher IES scores (9.6 [10.8] vs 5.1 [8.0]) after disclosure and increased Concerns about AD. Patterns of reactions (elevated vs not elevated) were similar for biomarker modalities, although scores were lower among those undergoing CSF compared with PET testing. Although score differences were apparent comparing geographical regions, patterns of group differences were similar. Discussion: Although sample bias must be considered, these results suggest that amyloid disclosure resulted in increased perceived risk and mild distress in those learning an elevated result. Although this study did not assess psychological safety, observed associations intrusive thoughts and distress could be important considerations in the future clinical practice.

The age-specific comorbidity burden of mild cognitive impairment: a US claims database study.

BACKGROUND: Identifying individuals with mild cognitive impairment (MCI) who are likely to progress to Alzheimer's disease and related dementia disorders (ADRD) would facilitate the development of individualized prevention plans. We investigated the association between MCI and comorbidities of ADRD. We examined the predictive potential of these comorbidities for MCI risk determination using a machine learning algorithm. METHODS: Using a retrospective matched case-control design, 5185 MCI and 15,555 non-MCI individuals aged ≥50 years were identified from MarketScan databases. Predictive models included ADRD comorbidities, age, and sex. RESULTS: Associations between 25 ADRD comorbidities and MCI were significant but weakened with increasing age groups. The odds ratios (MCI vs non-MCI) in 50-64, 65-79, and ≥ 80 years, respectively, for depression (4.4, 3.1, 2.9) and stroke/transient ischemic attack (6.4, 3.0, 2.1). The predictive potential decreased with older age groups, with ROC-AUCs 0.75, 0.70, and 0.66 respectively. Certain comorbidities were age-specific predictors. CONCLUSIONS: The comorbidity burden of MCI relative to non-MCI is age-dependent. A model based on comorbidities alone predicted an MCI diagnosis with reasonable accuracy.

Safety profile of Alzheimer's disease populations in Alzheimer's Disease Neuroimaging Initiative and other 18-month studies.

BACKGROUND: Demonstration of a disease-modifying effect of a therapeutic agent on Alzheimer's disease (AD) requires a trial lasting for at least 18 months. An understanding of expected rates of adverse events (AEs), overall discontinuations, and discontinuations due to AEs, serious AEs, and deaths would be useful in planning such trials. METHODS: We examined safety information for patients taking placebo from five published 18-month AD trials and for patients from the Alzheimer's Disease Neuroimaging Initiative study. RESULTS: AEs reported consistently across multiple studies were dyspnea (occurring in 5.3%-5.8% of patients), headache (4.0%-5.5%), constipation (4.3%-4.7%), nausea (2.0%-5.8%), joint swelling (3.6%-3.7%), vomiting (3.6%-3.7%), and anxiety (3.2%-3.6%). Larger multinational studies, as compared with smaller studies with fewer sites and geographies, demonstrated greater overall discontinuations (24.6%-33.0% vs 8.2%-21.0%) and greater discontinuations due to AEs (9.5%-11.6% vs 2.7%-3.2%). Rates of death (1.8%-2.4%) and SAEs (19.9%-21.2%) were consistent across 18 month published studies and in ADNI; fall was the most common SAE (2.6%-4.0%) where SAEs were reported. CONCLUSIONS: In general, comparable types of AEs, frequency of deaths, and serious AEs were seen for patients taking placebo in five randomized, controlled 18-month AD trials and in Alzheimer's Disease Neuroimaging Initiative, whereas rates of discontinuations were more variable. Evaluation across studies was complicated by inconsistent methods of reporting safety information. Evaluation of large databases of placebo patients from therapeutic AD trials is needed to further enhance the understanding of expected safety outcomes in clinical trials of AD patients.

The anticipatory response to stress and symptoms of depression and anxiety in early adulthood.

BACKGROUND: Whilst cortisol reactivity has been associated with depression and anxiety disorders, research examining cortisol reactivity with early symptoms of these conditions in males and females is limited. METHODS: At age 18, 748 males and females from Gen2 of the Raine Study were assessed for their salivary cortisol response to a psychosocial stressor using the Trier Social Stress Test (TSST). Participants later completed the Depression Anxiety Stress Scale (DASS-21) at age 20 which was used as the outcome measure in regression models. RESULTS: We found differences in DASS-21 across TSST responder categories in females but not males. Female reactive-responders (RR) and non-responders (NR) had increased symptoms of depression and anxiety compared to anticipatory-responders (AR). AR were associated with the lowest symptomology in females. We found limited evidence for an association between salivary cortisol summary measures (CBL, CMAX, CMIN, CRANGE, AUCG and AUCR) and depression/anxiety symptoms at age 20. CONCLUSIONS: This study sheds new light on adaptive and maladaptive physiological responses to psychosocial stress in terms of depression and anxiety symptoms. These preliminary findings indicate the pattern of response to a psychosocial stressor may contribute to individual vulnerability for stress-related diseases in a sex-specific manner.

Rapid glucocorticoid receptor-mediated inhibition of hypothalamic-pituitary-adrenal ultradian activity in healthy males.

A complex dynamic ultradian rhythm underlies the hypothalamic-pituitary-adrenal (HPA) circadian rhythm. We have investigated in normal human male subjects the importance, site of action, and receptor-mediated processes involved in rapid basal corticosteroid feedback and its interaction with corticotrophin releasing hormone (CRH) drive. Pro-opiomelanocortin (POMC), ACTH, and cortisol were measured every 10 min from healthy males during the awakening period or late afternoon using an automated blood sampling system. Mathematical modeling into discrete pulses of activity revealed that intravenous infusion of the synthetic mixed glucocorticoid/mineralocorticoid agonist prednisolone produced rapid inhibition of ACTH and cortisol pulsatility within 30 min in the morning and afternoon. Any pulse that had commenced at the time of injection was unaffected, and subsequent pulsatility was inhibited. Prednisolone also inhibited ACTH and cortisol secretion in response to exogenous CRH stimulation, inferring rapid feedback inhibition at the anterior pituitary. Circulating POMC peptide concentrations were unaffected, suggesting that the rapid corticosteroid inhibitory effect specifically targeted ACTH secretion from pituitary corticotrophs. Prednisolone fast feedback was only reduced by glucocorticoid receptor antagonist pretreatment and not by mineralocorticoid receptor antagonism, suggesting a glucocorticoid receptor-mediated pathway. The intravenous prednisolone suppression test provides a powerful new tool to investigate HPA abnormalities underlying metabolic and psychiatric disease states.

Prenatal and childhood stress exposure and the sex specific response to psychosocial stress in adulthood.

BACKGROUND: Early life stress exposures may cause dysregulation of the Hypothalamic Pituitary Adrenal (HPA)-axis and cortisol production, with timing and sex-specific effects. Studies examining the impact of early life stress on cortisol responses to stress have focused on severe trauma and have produced inconsistent results. The aim of this study was to investigate whether common early life stressors, experienced prenatally or throughout childhood and adolescence, play a role in the dysregulation of the HPA-axis in early adulthood. METHODS: Exposures to common life stress events were examined prenatally and as longitudinal trajectories of stress exposure from birth to age 17 in males and females from Gen2 of the Raine Study. At age 18 years, 986 participants were assessed for their salivary cortisol response to a psychosocial stressor - the Trier Social Stress Test (TSST). RESULTS: In males there was an association between high prenatal stress exposure at 18 weeks gestation and a heightened TSST response. We found evidence for sex-specific associations with increasing stress exposure during adolescence (the ascending trajectory) whereby males were more likely to be non-responders to the TSST and females were more likely to be responders. CONCLUSION: Our results point to sex differences in how stress exposure in-utero and exposure increasing during adolescence may affect regulation of the HPA-axis later in life. However, overall common life stress events experienced in-utero, during childhood and adolescence show limited impact on the HPA-axis stress response in early adulthood.

Management of adrenocortical carcinoma in Western Australia: a perspective over 14 years.

BACKGROUND: Adrenocortical carcinoma is a rare but aggressive form of endocrine neoplasm that confers a poor prognosis. To date, the only Australian data published is from New South Wales. This paper describes our experience in Western Australia with a focus on surgical approach and outcomes. METHODS: A retrospective study of patients treated for adrenocortical carcinoma in Western Australia over 14 years was performed. RESULTS: Over the 14-year period, a total of 33 patients underwent surgery for adrenocortical carcinoma. Resection outcomes were superior in an open en bloc approach with an 85% R0 margin (P = 0.007). Local recurrence rates were lowest in an open en bloc approach (11%) compared to laparoscopic (75%). Multivariate analysis showed that an en bloc resection is highly correlated with an R0 resection (P < 0.05) and significantly associated with lower (odds ratio = 0.06) local recurrence (P = 0.009). Higher volume surgeons (>5 cases) had lower operative times and blood loss. Compliance with mitotane was significantly improved with close monitoring of levels. The European Network for the Study of Adrenal Tumours (ENSAT) stage at presentation was most predictive of long-term survival with 100% of stage I patients alive compared to 53% of stage II, 25% of stage III and 17% of stage IV patients at the end of the follow-up period. CONCLUSION: An open en bloc approach with a low threshold for multi-visceral resection performed by high volume surgeons have improved outcomes in local recurrence, operative times and blood loss.

Findings of Efficacy, Safety, and Biomarker Outcomes of Atabecestat in Preclinical Alzheimer Disease: A Truncated Randomized Phase 2b/3 Clinical Trial.

Importance: Atabecestat, a nonselective oral ß-secretase inhibitor, was evaluated in the EARLY trial for slowing cognitive decline in participants with preclinical Alzheimer disease. Preliminary analyses suggested dose-related cognitive worsening and neuropsychiatric adverse events (AEs). Objective: To report efficacy, safety, and biomarker findings in the EARLY trial, both on and off atabecestat treatment, with focus on potential recovery of effects on cognition and behavior. Design, Setting, and Participants: Randomized, double-blind, placebo-controlled, phase 2b/3 study conducted from November 2015 to December 2018 after being stopped prematurely. The study was conducted at 143 centers across 14 countries. Participants were permitted to be followed off-treatment by the original protocol, collecting safety and efficacy data. From 4464 screened participants, 557 amyloid-positive, cognitively normal (Clinical Dementia Rating of 0; aged 60-85 years) participants (approximately 34% of originally planned 1650) were randomized before the trial sponsor stopped enrollment. Interventions: Participants were randomized (1:1:1) to atabecestat, 5 mg (n = 189), 25 mg (n = 183), or placebo (n = 185). Main Outcomes and Measures: Primary outcome: change from baseline in Preclinical Alzheimer Cognitive Composite score. Secondary outcomes: change from baseline in the Cognitive Function Index and the Repeatable Battery for the Assessment of Neuropsychological Status total scale score. Safety was monitored throughout the study. Results: Of 557 participants, 341 were women (61.2%); mean (SD) age was 70.4 (5.56) years. In May 2018, study medication was stopped early owing to hepatic-related AEs; participants were followed up off-treatment for 6 months. Atabecestat, 25 mg, showed significant cognitive worsening vs placebo for Preclinical Alzheimer Cognitive Composite at month 6 (least-square mean difference, -1.09; 95% CI, -1.66 to -0.53; P < .001) and month 12 (least-square mean, -1.62; 95% CI, -2.49 to -0.76; P < .001), and at month 3 for Repeatable Battery for the Assessment of Neuropsychological Status (least-square mean, -3.70; 95% CI, -5.76 to -1.63; P < .001). Cognitive Function Index participant report showed nonsignificant worsening at month 12. Systemic and neuropsychiatric-related treatment-emergent AEs were greater in atabecestat groups vs placebo. After stopping treatment, follow-up cognitive testing and AE assessment provided evidence of reversibility of drug-induced cognitive worsening and AEs in atabecestat groups. Conclusions and Relevance: Atabecestat treatment was associated with dose-related cognitive worsening as early as 3 months and presence of neuropsychiatric treatment-emergent AEs, with evidence of reversibility after 6 months off treatment. Trial Registration: ClinicalTrials.gov Identifier: NCT02569398.

Endonasal endoscopic resection of suprasellar craniopharyngioma: A retrospective single-center case series.

INTRODUCTION: Endoscopic endonasal approach (EEA) has recently been proposed as an option for resection of primary and recurrent suprasellar craniopharyngioma. However, surgical outcome has not yet been fully evaluated, especially in regards to recurrent cases. METHODS: We analysed our institution (Sir Charles Gairdner University Hospital, Perth, Australia) case-series retrospectively. There were 16 patients operated through an endonasal endoscopic approach from February 2014 to February 2019 for suprasellar craniopharyngiomas. There were 14 primary, and two recurrent lesions. Extent of resection, complications, visual and endocrinological outcomes are presented. RESULTS: Mean age of the patients was 42.9 ± 19.3 years old, with 56% female. The most common clinical symptoms were headaches (9 patients, 56%) and bi-temporal hemianopsia (9 patients, 56%), followed by unilateral optic neuropathy (5 cases, 31%), memory loss (1 case, 6%), hydrocephalus (1 case, 6%), delayed growth and puberty (1 case, 6%), and secondary amenorrhoea (1 case, 6%). Only two cases (12%) initially presented with normal visual function. Gross total resection (GTR) was achieved in 10/16 patients (62.5%), with subtotal resection (STR) in the remainder. Visual symptoms improved in 13/16 patients (81%) and remained unchanged in 3/16 patients (19%). Most common complications included new endocrinological deficit in nine patients (56%), mostly diabetes insipidus, and cerebrospinal fluid leak requiring a new intervention in three patients (19%). There was one mortality case (complicated meningitis, stroke and vasospasm). Mean follow-up time was 22.05 ± 14 months and three patients (19%) had a recurrence of the disease during this period and were referred for radiation therapy. CONCLUSION: Endonasal endoscopic approach is a safe and effective surgical option for both primary and recurrent suprasellar craniopharyngiomas.