Here we elucidate the effect of Alzheimer disease (AD)-predisposing genetic backgrounds, APOE4, PSEN1ΔE9, and APPswe, on functionality of human microglia-like cells (iMGLs). We present a ...physiologically relevant high-yield protocol for producing iMGLs from induced pluripotent stem cells. Differentiation is directed with small molecules through primitive erythromyeloid progenitors to re-create microglial ontogeny from yolk sac. The iMGLs express microglial signature genes and respond to ADP with intracellular Ca2+ release distinguishing them from macrophages. Using 16 iPSC lines from healthy donors, AD patients and isogenic controls, we reveal that the APOE4 genotype has a profound impact on several aspects of microglial functionality, whereas PSEN1ΔE9 and APPswe mutations trigger minor alterations. The APOE4 genotype impairs phagocytosis, migration, and metabolic activity of iMGLs but exacerbates their cytokine secretion. This indicates that APOE4 iMGLs are fundamentally unable to mount normal microglial functionality in AD.
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•APOE4 genotype has a profound impact on several functions of microglia-like cells•Inflammatory responses are aggravated in cells with APOE4 genotype•Metabolism, phagocytosis, and migration are decreased in APOE4 microglia-like cells•Familial mutations APPswe and PSEN1ΔE9 have only minor effects on functionality
The study provides a useful, clinically relevant iPSC-derived model for investigating the role of genetic backgrounds of Alzheimer disease in human microglia-like cells. The effect of two Alzheimer mutations and the APOE4 genotype on the functionality of cells are characterized in detail. Results feature a profound impact of APOE4 genotype on several functions of cells.
The interplay between depression and socioeconomic position (SEP) in predicting cardiovascular outcomes has rarely been examined. We investigated whether SEP modified the effect of antidepressant use ...on coronary heart disease (CHD) mortality.
The data consisted of an 11% random sample of the Finnish population aged 40 to 79 years at the end of 1999 with an oversample of 80% of those who died in 2000 to 2007. Participants free of CHD at baseline (n = 362,271) were followed up for CHD mortality in 2000 to 2007. SEP was assessed via registry-based information on education, occupational position, and income. Antidepressant use served as a proxy for depression and was derived from registry data on prescription medication purchases in the 5-year period preceding baseline. Age- and sex-adjusted Cox regression models with sampling weights were used.
Individuals with antidepressant purchases in any year 1995 to 1999 had a higher risk of CHD deaths (hazard ratio HR = 1.68, 95% confidence interval CI = 1.62-1.75) than did those without purchases. Basic level of education (HR = 2.09, 95% CI = 2.01-2.17), blue-collar occupations (HR = 1.70, 95% CI = 1.65-1.75), and the lowest income tertile (HR = 2.79, 95% CI = 2.69-2.91) were related to increased relative risks for CHD mortality. No significant (p < .05) interactions emerged between the SEP indicators and antidepressant purchases indicating that the effect of antidepressant use on the relative risk for CHD was similar across varying levels of SEP.
Our study demonstrates that in a country with tax-funded universal health care services, low SEP does not exacerbate the adverse effects of depression-as measured by antidepressant treatment-on cardiovascular health.
BACKGROUND:Education is believed to have positive spillover effects across network connections. Partner’s education may be an important resource preventing the incidence of disease and helping ...patients cope with illness. We examined how partner’s education predicted myocardial infarction (MI) incidence and survival net of own education and other socioeconomic resources in Finland.
METHODS:A sample of adults aged 40–69 years at baseline in Finland in 1990 was followed up for MI incidence and mortality during the period 1991–2007 (n = 354,100).
RESULTS:Lower own and spousal education both contributed independently to a higher risk of MI incidence and fatality when mutually adjusted. Having a partner with basic education was particularly strongly associated with long-term fatality in women with a hazard ratio of 1.53 (95% confidence interval, 1.22–1.92) compared with women with tertiary level educated partners. There was some evidence that the incidence risk associated with basic spousal education was weaker in those with own basic education. The highest risks of MI incidence and fatality were consistently found in those without a partner, whereas the most favorable outcomes were in households where both partners had a tertiary level of education.
CONCLUSIONS:Accounting for spousal education demonstrates how health-enhancing resources accumulate to some households. Marriage between people of similar educational levels may therefore contribute to the widening of educational differences in MI incidence and survival.
To examine in a prospective setting whether different hostility measures, including Cynical Distrust, Trait Anger, Anger Out, Anger In, and Anger Control, are related to cardiovascular disease (CVD) ...and ischemic heart disease (IHD).
Participants comprised 25- to 74-year-old men (n = 3850) and women (n = 4083), followed up for 10 to 15 years. Trait Anger, Anger Out, Anger In, and Anger Control were assessed with the Spielberger State-Trait Anger Expression Inventory and Cynical Hostility with the Cynical Distrust Scale. Incident CVD and IHD were derived from hospital records/death certificates. Subjects with a history of CVD or IHD at baseline were excluded.
Subjects in the lowest Anger Control tertile had a higher risk of first nonfatal and fatal CVD incidence (relative risk RR, 1.35; 95% confidence interval CI, 1.06-1.73) than subjects in the highest tertile after adjustment for age, gender, education, marital status, smoking, body mass index, blood pressure, cholesterol, alcohol consumption, and depressive symptoms. Higher Cynical Distrust scores predicted nonfatal and fatal CVD (RR, 1.31; 95% CI, 1.09-1.56) and IHD (RR, 1.37; 95% CI, 1.08-1.74) events after adjustment for age, but these associations disappeared after further adjustment for gender, education, and marital status. Other hostility measures, i.e., Trait Anger, Anger Out, or Anger In, were not related to CVD or IHD outcomes.
This is the first study to show that compared with four other hostility dimensions, low Anger Control predicts CVD events. Further studies should examine whether Anger Control is specific to anger or reflects more general psychosocial factors.
Lower socioeconomic position (SEP) is associated with an increased risk of myocardial infarction (MI) incidence and mortality, but the relative importance of different socioeconomic resources at ...different stages of the disease remains unclear.
A nationally representative register-based sample of 40- to 60-year-old Finnish men and women in 1995 (n= 302 885) were followed up for MI incidence and mortality in 1996-2007. We compared the effects of education, occupation, income and wealth on first MI incidence, first-day and long-term fatality. Cox's proportional hazards regression and logistic regression models were estimated adjusting for SEP covariates simultaneously to assess independent effects.
Fully adjusted models showed greatest relative inequalities of MI incidence by wealth in both sexes, with an increased risk also associated with manual occupations. Education was a significant predictor of incidence in men. Low income was associated with a greater risk of death on the day of MI incidence odds ratio (OR) = 1.40 in men and 1.95 in women when comparing lowest and highest income quintiles, and in men, with long-term fatality hazard ratio (HR) = 1.74. Wealth contributed to inequalities in first-day fatality in men and in long-term fatality in both sexes.
The results show that different socioeconomic resources have diverse effects on the disease process and add new evidence on the significant association of wealth with heart disease onset and fatality. Targeting those with the least resources could improve survival in MI patients and help reduce social inequalities in coronary heart disease mortality.
We examined whether obesity status and dieting history affected the associations of eating styles with measured obesity indicators and self-control among Finnish men (
n
=
2325) and women (
n
=
2699) ...aged 25–75 years. Uncontrolled and emotional eating were positively associated with obesity and reversely with self-control. Among obese subjects and current/past dieters, higher restrained eating was related to lower adiposity, uncontrolled and emotional eating, and higher self-control while these associations were opposite among normal weight subjects and never dieters. These results suggest that restrained eating may be related to better weight control among those who need and/or are motivated to lose weight while among others it may indicate problems with eating.
IntroductionDepression is a highly prevalent condition with typical onset in early adulthood. Internet-delivered cognitive behavioural therapy (iCBT) is a promising cost-effective and more widely ...available alternative to face-to-face CBT. However, it is not known whether it can reduce sickness absence in employees showing depressive symptoms. The randomised controlled trial component of the DAQI (Depression and sickness absence in young adults: a quasi-experimental trial and web-based treatment intervention) project aims to investigate if iCBT is effective in reducing sickness absence compared with care as usual (CAU) among young employees with depressive symptoms in primary care provided in an occupational health setting.Methods and analysisThis study will use a randomised controlled single-centre service-based trial of an existing iCBT programme (Mental Hub iCBT for Depression) to evaluate whether or not this treatment can reduce the number of sickness absence days in public sector employees aged 18–34 years who present at the occupational health service with mild depressive symptoms (score ≥9 on the Beck Depression Inventory-IA). Control participants will be offered CAU, with no constraints regarding the range of treatments. The active condition will consist of seven weekly modules of iCBT, with support from a web therapist. Primary outcome will be participants’ all-cause sickness absence as indicated in employer’s and national administrative records up to 6 months from study entry. Secondary outcomes relating to long-term sickness absence (over 11 calendar days) for mental and musculoskeletal disorders and psychotropic medication use will be obtained from the Finnish Social Insurance Institution’s administrative records; and short sickness absence spells (up to 11 calendar days) will be extracted from employer’s records. Analyses will be conducted on an intention-to-treat basis.Ethics and disseminationThe Coordinating Ethics Committee of the Hospital District of Helsinki and Uusimaa has approved the study (HUS/974/2019). The results will be published in peer-reviewed scientific journals and in publications for lay audience.Trial registration numberISRCTN10877837
Neural stem/progenitor cells (NPCs) generate new neurons in the brain throughout the lifetime in an intricate process called neurogenesis. Neurogenic alterations are a common feature of several ...adult-onset neurodegenerative diseases. The neuronal ceroid lipofuscinoses (NCLs) are the most common group of inherited neurodegenerative diseases that mainly affect children. Pathological features of the NCLs include accumulation of lysosomal storage material, neuroinflammation, and neuronal degeneration, yet the exact cause of this group of diseases remains poorly understood. The function of the CLN5 protein, causative of the CLN5 disease form of NCL, is unknown. In the present study, we sought to examine neurogenesis in the neurodegenerative disorder caused by loss of Cln5. Our findings demonstrate a novel, critical role for CLN5 in neurogenesis. We report for the first time that neurogenesis is increased in Cln5-deficient mice, which model the childhood neurodegenerative disorder caused by loss of Cln5. Our results demonstrate that in Cln5 deficiency, proliferation of NPCs is increased, NPC migration is reduced, and NPC differentiation towards the neuronal lineage is increased concomitantly with functional alterations in the NPCs. Moreover, the observed impairment in neurogenesis is correlated with increased expression of the pro-inflammatory cytokine IL-1β. A full understanding of the pathological mechanisms that lead to disease and the function of the NCL proteins are critical for designing effective therapeutic approaches for this devastating neurodegenerative disorder.
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