In this study, we investigated associations between neuropsychiatric symptoms (i.e., apathy, anxiety, and depression) and cerebral atrophy, white matter lesions (WML), beta-amyloid (Aβ) deposition, ...and cognitive decline in a nondemented sample. 104 cognitively unimpaired and 53 subjects with mild cognitive impairment were followed for up to 4 years within the Swedish BioFINDER study. Neuropsychiatric assessments included the Hospital Anxiety and Depression Scale and the Apathy Evaluation Scale. Magnetic resonance imaging and 18F-flutemetamol-positron emission tomography quantified brain atrophy, WML, and Aβ deposition. Mini-Mental State Examination assessed longitudinal global cognition. Regression analyses were used to test for associations. Apathy and anxiety were shown related to Aβ deposition and predicted cognitive decline. Anxiety also interacted with amyloid status to predict faster cognitive deterioration. Apathy was further related to frontotemporal and subcortical atrophy, as well as WML. To conclude, the associations between apathy and anxiety with Aβ deposition and cognitive decline point to these symptoms as early clinical manifestations of Alzheimer's disease.
•Apathy and anxiety are related to Aβ deposition and cognitive decline.•Anxiety interacts with Aβ to predict faster cognitive decline.•Apathy is associated with cerebral atrophy and white matter changes.
Background
Alzheimer’s disease is a progressive, irreversible, and fatal disease for which accumulation of amyloid beta is thought to play a key role in pathogenesis. Aducanumab is a human monoclonal ...antibody directed against aggregated soluble and insoluble forms of amyloid beta.
Objectives
We evaluated the efficacy and safety of aducanumab in early Alzheimer’s disease.
Design
EMERGE and ENGAGE were two randomized, double-blind, placebo-controlled, global, phase 3 studies of aducanumab in patients with early Alzheimer’s disease.
Setting
These studies involved 348 sites in 20 countries.
Participants
Participants included 1638 (EMERGE) and 1647 (ENGAGE) patients (aged 50–85 years, confirmed amyloid pathology) who met clinical criteria for mild cognitive impairment due to Alzheimer's disease or mild Alzheimer's disease dementia, of which 1812 (55.2%) completed the study.
Intervention
Participants were randomly assigned 1:1:1 to receive aducanumab low dose (3 or 6 mg/kg target dose), high dose (10 mg/kg target dose), or placebo via IV infusion once every 4 weeks over 76 weeks.
Measurements
The primary outcome measure was change from baseline to week 78 on the Clinical Dementia Rating Sum of Boxes (CDR-SB), an integrated scale that assesses both function and cognition. Other measures included safety assessments; secondary and tertiary clinical outcomes that assessed cognition, function, and behavior; and biomarker endpoints.
Results
EMERGE and ENGAGE were halted based on futility analysis of data pooled from the first approximately 50% of enrolled patients; subsequent efficacy analyses included data from a larger data set collected up to futility declaration and followed prespecified statistical analyses. The primary endpoint was met in EMERGE (difference of -0.39 for high-dose aducanumab vs placebo 95% CI, -0.69 to -0.09; P=.012; 22% decrease) but not in ENGAGE (difference of 0.03, 95% CI, -0.26 to 0.33; P=.833; 2% increase). Results of biomarker substudies confirmed target engagement and dose-dependent reduction in markers of Alzheimer's disease pathophysiology. The most common adverse event was amyloid-related imaging abnormalities-edema.
Conclusions
Data from EMERGE demonstrated a statistically significant change across all four primary and secondary clinical endpoints. ENGAGE did not meet its primary or secondary endpoints. A dose-and time-dependent reduction in pathophysiological markers of Alzheimer’s disease was observed in both trials.
Objective Reference values are usually defined based on blood samples from healthy men or nonpregnant women. This is not optimal as many biological markers changes during pregnancy and adequate ...reference values are of importance for correct clinical decisions. There are only few studies on the variations of laboratory tests during normal pregnancies, especially during the first two trimesters. It is thus a need to establish such reference values.
Design Longitudinal study of laboratory markers in normal pregnancies.
Setting Uppsala University Hospital, Sweden.
Population Healthy pregnant females.
Methods We have studied 25 frequently used laboratory tests during 52 normal pregnancies. Each woman was sampled up to nine times and the samples were divided according to collection time into the following groups: gestational week 7–17; week 17–24; week 24– 28; week 28–31; week 31–34; week 34–38; predelivery (0–2 weeks before delivery) and postpartum (>6 weeks after delivery). The 2.5 and 97.5 percentiles for these markers were calculated according to the recommendations of the International Federation of Clinical Chemistry on the statistical treatment of reference values.
Results Reference intervals are reported for plasma alanine aminotransferase, albumin, alkaline phosphatase, pancreas amylase, apolipoprotein A1, apolipoprotein B, aspartate aminotransferase, bilirubin, calcium, chloride, creatinine, cystatin C, ferritin, γ‐glutamyltransferase, iron, lactate dehydrogenase, magnesium, phosphate, potassium, sodium, transferrin, triglycerides, thyroid‐stimulating hormone, urate and urea during these pregnancy periods.
Conclusions Most of the analytes change during normal pregnancy. It is thus of importance to use special reference values during pregnancy.
Objectives
We compare various aspects in the early chain of care among patients with haemorrhagic stroke and ischaemic stroke.
Materials & methods
The Emergency Medical Services (EMS) and nine ...emergency hospitals, each with a stroke unit, were included. All patients hospitalised with a first and a final diagnosis of stroke between 15 December 2010 and 15 April 2011 were included. The primary endpoint was the system delay (from call to the EMS until diagnosis). Secondary endpoints were: (i) use of the EMS, (ii) delay from symptom onset until call to the EMS; (iii) priority at the dispatch centre; (iv) priority by the EMS; and (v) suspicion of stroke by the EMS nurse and physician on admission to hospital.
Results
Of 1336 patients, 172 (13%) had a haemorrhagic stroke. The delay from call to the EMS until diagnosis was significantly shorter in haemorrhagic stroke. The patient's decision time was significantly shorter in haemorrhagic stroke. The priority level at the dispatch centre did not differ between the two groups, whereas the EMS nurse gave a significantly higher priority to patients with haemorrhage. There was no significant difference between groups with regard to the suspicion of stroke either by the EMS nurse or by the physician on admission to hospital.
Conclusions
Patients with a haemorrhagic stroke differed from other stroke patients with a more frequent and rapid activation of EMS.
Summary Workers often attribute poor sleep to factors at work. Despite the large number of workers with sleep disturbances, there is a lack of consensus on the relationship between the work ...environment and sleep. The purpose of this systematic review therefore was to conduct a comprehensive evaluation. To this end, we employed standardized methods to systematically locate, review, and tabulate the results of prospective or randomized studies of the impact of work factors on sleep disturbances. From the 7981 articles located in five databases, 24 fulfilled our inclusion criteria and formed the base of the review including meta-analyses of the effect sizes. Results showed that the psychosocial work variables of social support at work, control, and organizational justice were related to fewer sleep disturbances, while high work demands, job strain, bullying, and effort-reward imbalance were related to more future sleep disturbances. Moreover, working a steady shift was associated with disturbances while exiting shift work was associated with less disturbed sleep. We conclude that psychosocial work factors and the scheduling of work have an impact on sleep disturbances and this might be utilized in the clinic as well as for planning work environments. Future research needs to employ better methodology and focus on underlying mechanisms.
Purpose
In the last decade, the research community has focused on defining reliable biomarkers for the early detection of Alzheimer’s disease (AD) pathology. In 2017, the Geneva AD Biomarker Roadmap ...Initiative adapted a framework for the systematic validation of oncological biomarkers to cerebrospinal fluid (CSF) AD biomarkers—encompassing the 42 amino-acid isoform of amyloid-β (Aβ42), phosphorylated-tau (P-tau), and Total-tau (T-tau)—with the aim to accelerate their development and clinical implementation. The aim of this work is to update the current validation status of CSF AD biomarkers based on the Biomarker Roadmap methodology.
Methods
A panel of experts in AD biomarkers convened in November 2019 at a 2-day workshop in Geneva. The level of maturity (fully achieved, partly achieved, preliminary evidence, not achieved, unsuccessful) of CSF AD biomarkers was assessed based on the Biomarker Roadmap methodology before the meeting and presented and discussed during the workshop.
Results
By comparison to the previous 2017 Geneva Roadmap meeting, the primary advances in CSF AD biomarkers have been in the area of a unified protocol for CSF sampling, handling and storage, the introduction of certified reference methods and materials for Aβ42, and the introduction of fully automated assays. Additional advances have occurred in the form of defining thresholds for biomarker positivity and assessing the impact of covariates on their discriminatory ability.
Conclusions
Though much has been achieved for phases one through three, much work remains in phases four (real world performance) and five (assessment of impact/cost). To a large degree, this will depend on the availability of disease-modifying treatments for AD, given these will make accurate and generally available diagnostic tools key to initiate therapy.
We propose an integrative risk factor framework to enhance understanding of individual differences in adjustment to bereavement and to encourage more systematic analysis of factors contributing to ...bereavement outcome (e.g., examination of interactions between variables and establishing pathways in the adaptation process). The examination of individual differences in adaptation to bereavement is essential for practical (e.g. targeting high risk individuals for intervention) and theoretical (e.g. testing the validity of theoretical claims about sources of differences) purposes. And yet, existing theoretical approaches have not led to systematic empirical examination and empirical studies in the current literature are fraught with shortcomings. Derived from Cognitive Stress Theory Lazarus, R. S. & Folkman, S. (1984).
Stress, appraisal, and coping. New York: Springer and the stressor-specific Dual Process Model of Coping with Bereavement Stroebe, M. S., & Schut, H. A. W. (1999). The dual process model of coping with bereavement: Rationale and description.
Death Studies,
23, 197–224, the framework incorporates an analysis of stressors, intra/interpersonal risk/protective factors, and appraisal and coping processes that are postulated to impact on outcome. Advantages of using the approach are outlined. Challenges in undertaking such research are addressed.
Purpose
The development of blood biomarkers that reflect Alzheimer’s disease (AD) pathophysiology (phosphorylated tau and amyloid-β) has offered potential as scalable tests for dementia differential ...diagnosis and early detection. In 2019, the Geneva AD Biomarker Roadmap Initiative included blood biomarkers in the systematic validation of AD biomarkers.
Methods
A panel of experts convened in November 2019 at a two-day workshop in Geneva. The level of maturity (fully achieved, partly achieved, preliminary evidence, not achieved, unsuccessful) of blood biomarkers was assessed based on the Biomarker Roadmap methodology and discussed fully during the workshop which also evaluated cerebrospinal fluid (CSF) and positron emission tomography (PET) biomarkers.
Results
Plasma p-tau has shown analytical validity (phase 2 primary aim 1) and first evidence of clinical validity (phase 3 primary aim 1), whereas the maturity level for Aβ remains to be partially achieved. Full and partial achievement has been assigned to p-tau and Aβ, respectively, in their associations to ante-mortem measures (phase 2 secondary aim 2). However, only preliminary evidence exists for the influence of covariates, assay comparison and cut-off criteria.
Conclusions
Despite the relative infancy of blood biomarkers, in comparison to CSF biomarkers, much has already been achieved for phases 1 through 3 – with p-tau having greater success in detecting AD and predicting disease progression. However, sufficient data about the effect of covariates on the biomarker measurement is lacking. No phase 4 (real-world performance) or phase 5 (assessment of impact/cost) aim has been tested, thus not achieved.
Aims
To assess if low occupational class was an independent predictor of Type 2 diabetes in men in Sweden over a 35‐year follow‐up, after adjustment for both conventional risk factors and ...psychological stress.
Methods
A random population‐based sample of 6874 men aged 47–56 years without a history of diabetes was divided into five occupational classes and the men were followed from 1970 to 2008. Diabetes cases were identified through the Swedish inpatient and death registers. Subdistribution hazard ratios (SHRs) and 95% CIs from competing risk regressions, cumulative incidence and conditional probabilities were calculated, after accounting for the risk of death attributed to other causes.
Results
A total of 907 (13%) men with diabetes were identified over 35 years with a median follow‐up of 27.9 years. The cumulative incidence of diabetes, when taking into account death as a competing event, was 11% in high officials, 12% in intermediate non‐manual employees, 14% in assistant non‐manual employees, 14% in skilled workers, and 16% in unskilled and semi‐skilled workers. Men with unskilled and semi‐skilled manual occupations had a significantly higher risk of diabetes than high officials (reference) after adjustment for age, BMI, hypertension, smoking and physical activity (SHR 1.39, 95% CI 1.08–1.78). Additional adjustment for self‐reported psychological stress did not attenuate the results.
Conclusions
A low occupational class suggests a greater risk of Type 2 diabetes, independently of conventional risk factors and psychological stress.
What's new?
Studies with a follow‐up of 15 years have shown that Type 2 diabetes disproportionately affects people with a lower socio‐economic status.
With the world's aging population, it is important to determine if risk factors persist into older age groups.
In contrast to many other studies, we adjusted the analysis, not only for conventional risk factors, but also for psychological stress and competing risk of death.
The present study shows that low occupational class at mid‐life remains an independent predictor for Type 2 diabetes after a 35‐year follow‐up.
Background
Cerebral endothelial dysfunction occurs in a spectrum of neurodegenerative diseases. Whether biomarkers of microvascular endothelial dysfunction can predict dementia is largely unknown. We ...explored the longitudinal association of midregional pro‐atrial natriuretic peptide (MR‐proANP), C‐terminal endothelin‐1 (CT‐proET‐1) and midregional proadrenomedullin (MR‐proADM) with dementia and subtypes amongst community‐dwelling older adults.
Methods
A population‐based cohort of 5347 individuals (men, 70%; age, 69 ± 6 years) without prevalent dementia provided plasma for determination of MR‐proANP, CT‐proET‐1 and MR‐proADM. Three‐hundred‐and‐seventy‐three patients (7%) were diagnosed with dementia (120 Alzheimer's disease, 83 vascular, 102 mixed, and 68 other aetiology) over a period of 4.6 ± 1.3 years. Relations between baseline biomarker plasma concentrations and incident dementia were assessed using multivariable Cox regression analysis.
Results
Higher levels of MR‐proANP were significantly associated with increased risk of all‐cause and vascular dementia (hazard ratio HR per 1 SD: 1.20, 95% confidence interval CI, 1.07–1.36; P = 0.002, and 1.52; 1.21–1.89; P < 0.001, respectively). Risk of all‐cause dementia increased across the quartiles of MR‐proANP (p for linear trend = 0.004; Q4, 145–1681 pmol L−1 vs. Q1, 22–77 pmol L−1: HR: 1.83; 95%CI: 1.23–2.71) and was most pronounced for vascular type (p for linear trend = 0.005: HR: 2.71; 95%CI: 1.14–6.46). Moreover, the two highest quartiles of CT‐proET‐1 predicted vascular dementia with a cut‐off value at 68 pmol L−1 (Q3–Q4, 68–432 pmol L−1 vs. Q1–Q2,4–68 pmol L−1; HR: 1.94; 95%CI: 1.12–3.36). Elevated levels of MR‐proADM indicated no increased risk of developing dementia after adjustment for traditional risk factors.
Conclusions
Elevated plasma concentration of MR‐proANP is an independent predictor of all‐cause and vascular dementia. Pronounced increase in CT‐proET‐1 indicates higher risk of vascular dementia.
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