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.

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.

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.

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.

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.

Long-term safety and tolerability of atabecestat (JNJ-54861911), an oral BACE1 inhibitor, in early Alzheimer's disease spectrum patients: a randomized, double-blind, placebo-controlled study and a two-period extension study.

BACKGROUND: Atabecestat, a potent brain-penetrable inhibitor of BACE1 activity that reduces CSF amyloid beta (Aß), was developed for oral treatment for Alzheimer's disease (AD). The long-term safety and effect of atabecestat on cognitive performance in participants with predementia AD in two phase 2 studies were assessed. METHODS: In the placebo-controlled double-blind parent ALZ2002 study, participants aged 50 to 85 years were randomized (1:1:1) to placebo or atabecestat 10 or 50 mg once daily (later reduced to 5 and 25 mg) for 6 months. Participants entered ALZ2004, a 12-month treatment extension with placebo or atabecestat 10 or 25 mg, followed by an open-label phase. Safety, changes in CSF biomarker levels, brain volume, and effects on cognitive performance were assessed. RESULTS: Of 114 participants randomized in ALZ2002, 99 (87%) completed, 90 entered the ALZ2004 double-blind phase, and 77 progressed to the open-label phase. CSF Aß fragments and sAPPß were reduced dose-proportionately. Decreases in whole brain and hippocampal volumes were greater in participants with mild cognitive impairment (MCI) due to AD than in preclinical AD, but were not affected by treatment. In ALZ2004, change from baseline in RBANS trended toward worse scores for atabecestat versus placebo. Elevated liver enzyme adverse events reported in 12 participants on atabecestat resulted in dosage modification and increased frequency of safety monitoring. Treatment discontinuation normalized ALT or AST in all except one with pretreatment elevation, which remained mildly elevated. No case met ALT/AST > 3× ULN and total bilirubin > 2× ULN (Hy's law). CONCLUSION: Atabecestat was associated with trend toward declines in cognition, and elevation of liver enzymes. TRIAL REGISTRATION: ALZ2002: ClinicalTrials.gov, NCT02260674, registered October 9, 2014; ALZ2004: ClinicalTrials.gov, NCT02406027, registered April 1, 2015.

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.

Representativeness of European clinical trial populations in mild Alzheimer's disease dementia: a comparison of 18-month outcomes with real-world data from the GERAS observational study.

BACKGROUND: Comparison of disease progression between placebo-group patients from randomised controlled trials (RCTs) and real-world patients can aid in assessing the generalisability of RCT outcomes. This analysis compared outcomes between community-dwelling patients with mild Alzheimer's disease (AD) dementia from two RCTs (pooled European (EU) data from EXPEDITION and EXPEDITION 2) and similar patients from the EU GERAS observational study. METHODS: Data from placebo-group patients with mild AD dementia from the RCTs (EU countries only) were compared with data from GERAS patients with mild AD dementia. Between-group differences for changes over 18 months were analysed for cognition, functioning, neuropsychiatric symptoms, health-related quality of life (HRQoL) and caregiver time using propensity score-adjusted models. A sensitivity analysis compared EU/North American (EU/NA) EXPEDITION patients with GERAS patients. RESULTS: EU EXPEDITION patients (n = 168) were younger than GERAS patients (n = 566) (mean (standard deviation, SD) age 71.9 (7.4) versus 77.3 (6.9) years; p < 0.001) and were more likely to use AD treatment (95% versus 84%; p < 0.001). Cognitive performance was similar at baseline in both populations, although GERAS patients showed greater functional impairment (p = 0.005) and lower HRQoL (p < 0.05). At 18 months, no statistically significant differences between EXPEDITION (n = 133) and GERAS (n = 417) patients were observed for changes in cognitive, functional, neuropsychiatric and HRQoL outcomes. Least squares mean (95% confidence interval) change in caregiver time (hours/month) spent on instrumental activities of daily living (iADL; 29.22 (19.16, 39.27) versus 3.20 (-11.89, 18.28), p = 0.001) and supervision (66.59 (47.49, 85.69) versus 3.04 (-25.39, 31.48), p < 0.001) showed greater increases in GERAS than EXPEDITION. In the sensitivity analysis, changes in neuropsychiatric and HRQoL scores and caregiver time spent on basic ADL were also significantly greater in GERAS than in EU/NA EXPEDITION patients. CONCLUSIONS: Patients with mild AD dementia participating in the EU EXPEDITION RCTs and the GERAS observational study showed a similar decline in cognitive, functional and neuropsychiatric symptoms over 18 months, whereas changes in caregiver time measures were significantly greater in GERAS. Results indicate the importance of using similar regions when comparing real-world and RCT data. TRIAL REGISTRATION: ClinicalTrials.gov NCT00905372 EXPEDITION. Registered 18 May 2009. ClinicalTrials.gov NCT00904683 EXPEDITION 2. Registered 18 May 2009.

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.

Assessing quality of life in Alzheimer's disease: Implications for clinical trials.

INTRODUCTION: Characterization of the quality of life (QOL) in Alzheimer's disease (AD) scale within the context of a clinical trial may inform its applicability in future trials. METHODS: Using data from 1322 patients enrolled in two phase-III studies (EXPEDITION 1 [NCT00905372] and 2 [NCT00904683]) of intravenous solanezumab in outpatients with mild AD dementia, correlations between patient- and caregiver-assessed QOL and between QOL and clinical outcome measures were examined. Longitudinal effects of solanezumab over 80 weeks were explored, controlling for patient and caregiver baseline characteristics. RESULTS: Caregivers rated patients' QOL worse than did patients themselves. Patients' QOL was correlated, albeit modestly, with clinical/health measures. Patients' QOL changed minimally over 80 weeks, although a treatment effect of solanezumab on QOL was detected. DISCUSSION: Further investigations are needed to determine the optimal measures with which to quantify and qualify QOL of patients with mild AD.

Cortisol and CBG - Getting cortisol to the right place at the right time.

Cortisol is transported in the blood by corticosteroid-binding globulin (CBG), a non-inhibitory member of the serpin family of serine protease inhibitors. Recent structural advances reveal how CBG acts as a releasing-agent as well as a carrier of cortisol. Taken together, the structures of the various forms of CBG and of the closely related thyroxine binding-globulin, show how the inherent conformational mechanism of the serpins has been adapted to modulate hormone release to the tissues by changes in binding affinities. A deduction from this, of the temperature dependence of hormone binding, is remarkably borne out with CBG, with a doubling in plasma free cortisol as the body temperature rises to 39°C. Another insight, against a dogma in the corticosteroid field, is that the proteolytic cleavage of CBG in inflammation results in a partial and not a complete loss of cortisol binding. This becomes of medical importance in conjunction with recent evidence of a pool of the circulating cleaved-form of CBG. It is now evident that tissue levels of free cortisol are buffered by two responsive plasma pools, intact CBG with a high binding-affinity and, particularly in inflammation and sepsis, a further pool of cleaved-CBG with a ten-fold lower affinity. The new molecular understandings, as well as providing insights into the differential release of circulating hormones, also open prospects for therapeutic interventions and draw attention to the potential of CBG and TBG as vehicles for the targeted delivery of drugs.

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.

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.

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.

Associations between hypothalamic-pituitary-adrenal axis function and peak bone mass at 20years of age in a birth cohort.

In older adults, high-normal circulating cortisol levels are associated with lower bone mass, but relationships between hypothalamic-pituitary-adrenal axis function and peak bone mass in young adults have not been examined. We studied 411 male and 390 female participants in the Western Australia Pregnancy Cohort (Raine) Study. At 18years of age, participants underwent a Trier Social Stress Test (TSST) with measurement of plasma and salivary cortisol at baseline and at multiple time points after stress. Cortisol responses were classified as anticipatory responder (significant fall in cortisol during the test), reactive responder (significant increase) or non-responder. At 20years, total body bone mineral content (BMC) and density (BMD) were measured by DXA. In males, after adjustment for weight, height (for BMC and bone area only), alcohol and smoking, there was a significant inverse relationship between both plasma and salivary cortisol measured at baseline in the TSST and each of BMC and BMD, such that each additional 10% of salivary cortisol was associated with reductions of 6.9g (95% CI -11.7, -2.2) in BMC, and 1.8mg/cm(2) (95% CI -3.3, -0.4) in BMD. Males classified as anticipatory responders in the TSST had 3.2% lower BMC (adjusted mean±SE: 3131±28 vs. 3233±18g, P=0.006) and 2.5% lower BMD (1108±9 vs. 1136±6mg/cm(2), P=0.022) than reactive responders. In females, there were no significant relationships between baseline cortisol or TSST responses and BMC or BMD in covariate-adjusted analyses. We conclude that in young males (but not females), higher circulating cortisol at the baseline of the stress test and an anticipatory responder pattern on the TSST are associated with lower total body bone mass.

Hypothalamic-pituitary-adrenal axis activity under resting conditions and cardiovascular risk factors in adolescents.

BACKGROUND: Activation of the hypothalamic-pituitary-adrenal (HPA) axis has been associated with higher levels of cardiovascular (CVD) risk factors in adults. This study aimed to assess the relation between measures of HPA axis activity under resting conditions and CVD risk factors in a general population of adolescents at 17 years. METHODS: A total of 1134 adolescents from the Western Australian Pregnancy Cohort (Raine) Study had phenotypic and socio-demographic data. The associations between HPA axis measures (plasma ACTH, total cortisol, calculated free cortisol, corticosteroid binding globulin (CBG), and salivary cortisol) and a range of cardiovascular risk factors were examined using multivariable linear regression models, with adjustment for gender, adiposity, birth weight, gestational age, and socio-behavioural factors. RESULTS: Plasma total cortisol was positively associated with systolic blood pressure (SBP) (p=0.011), total cholesterol, HDL-cholesterol, and triglycerides (all p<0.001), and hs-CRP (p=0.047). Salivary cortisol was associated positively with HDL-C (p=0.033) and negatively with LDL-cholesterol (p=0.016); plasma calculated free cortisol was positively associated with triglycerides (p=0.006); plasma CBG was positively associated with total cholesterol and HDL-cholesterol (both p<0.001), LDL-cholesterol (p=0.022), and hs-CRP (p=0.001). After correction for multiple comparisons, significant associations remained for total cortisol with total cholesterol, HDL-C, and triglycerides; for calculated free cortisol with triglycerides; and for CBG with HDL-C, total cholesterol, and hs-CRP. Plasma ACTH was not associated with any cardiovascular risk factor. There was no association between BMI and any measure of HPA axis activity. CONCLUSION: In an adolescent population, HPA axis measures under resting conditions are associated with a range of CVD risk factors. Clarification of the mechanisms underlying these associations in adolescence would be an important step in understanding the evolution of adult CVD.

Empirically Defining Trajectories of Late-Life Cognitive and Functional Decline.

BACKGROUND: Alzheimer's disease (AD) is associated with variable cognitive and functional decline, and it is difficult to predict who will develop the disease and how they will progress. OBJECTIVE: This exploratory study aimed to define latent classes from participants in the Alzheimer's Disease Neuroimaging Initiative (ADNI) database who had similar growth patterns of both cognitive and functional change using Growth Mixture Modeling (GMM), identify characteristics associated with those trajectories, and develop a decision tree using clinical predictors to determine which trajectory, as determined by GMM, individuals will most likely follow. METHODS: We used ADNI early mild cognitive impairment (EMCI), late MCI (LMCI), AD dementia, and healthy control (HC) participants with known amyloid-ß status and follow-up assessments on the Alzheimer's Disease Assessment Scale - Cognitive Subscale or the Functional Activities Questionnaire (FAQ) up to 24 months postbaseline. GMM defined trajectories. Classification and Regression Tree (CART) used certain baseline variables to predict likely trajectory path. RESULTS: GMM identified three trajectory classes (C): C1 (n = 162, 13.6%) highest baseline impairment and steepest pattern of cognitive/functional decline; C3 (n = 819, 68.7%) lowest baseline impairment and minimal change on both; C2 (n = 211, 17.7%) intermediate pattern, worsening on both, but less steep than C1. C3 had fewer amyloid- or apolipoprotein-E ɛ4 (APOE4) positive and more healthy controls (HC) or EMCI cases. CART analysis identified two decision nodes using the FAQ to predict likely class with 82.3% estimated accuracy. CONCLUSIONS: Cognitive/functional change followed three trajectories with greater baseline impairment and amyloid and APOE4 positivity associated with greater progression. FAQ may predict trajectory class.