Association between Psychological Distress and Incident Dementia in a Population-Based Cohort in Finland

Publisher Copyright: © 2022 Authors. All rights reserved.Importance: Symptoms of psychological distress have shown association with subsequent dementia, but the nature of association remains unclear. Objective: To examine the association of psychological distress with etiological risk of dementia and incidence of dementia in presence of competing risk of death. Design, Setting, and Participants: This cohort study consisted of population-based cross-sectional National FINRISK Study surveys collected in 1972, 1977, 1982, 1987, 1992, 1997, 2002, and 2007 in Finland with register-based follow-up; and the cohort was linked to Finnish Health Register data for dementia and mortality for each participant until December 31, 2017. Participants included individuals without dementia who had complete exposure data. Data were analyzed from May 2019 to April 2022. Exposures: Self-reported symptoms of psychological distress: stress (more than other people), depressive mood, exhaustion, and nervousness (often, sometimes, never). Main Outcomes and Measures: Incident all-cause dementia, ascertained through linkage to national health registers. Poisson cause-specific hazard model (emphasizing etiological risk) and Fine-Gray subdistribution hazard model (emphasizing effect on incidence) considering dementia and death without dementia as competing risks. Covariates of age, sex, baseline year, follow-up time, educational level, body mass index, smoking, diabetes, systolic blood pressure, cholesterol, and physical activity. Sensitivity analysis was performed to reduce reverse causation bias by excluding individuals with follow-up less than 10 years. Results: Among 67688 participants (34968 [51.7%] women; age range, 25 to 74 years; mean [SD] age, 45.4 years), 7935 received a diagnosis of dementia over a mean follow-up of 25.4 years (range, 10 to 45 years). Psychological distress was significantly associated with all-cause dementia in a multivariable Poisson model, with incidence rate ratios from 1.17 (95% CI, 1.08-1.26) for exhaustion to 1.24 (95% CI, 1.11-1.38) for stress, and remained significant in sensitivity analyses. A Fine-Gray model showed significant associations (with hazard ratios from 1.08 [95% CI, 1.01-1.17] for exhaustion to 1.12 [95% CI, 1.00-1.25] for stress) for symptoms other than depressive mood (hazard ratio, 1.08 [95% CI, 0.98-1.20]). All the symptoms showed significant associations with competing risk of death in both models. Conclusions and Relevance: In this cohort study, psychological distress symptoms were significantly associated with increased risk of all-cause dementia in the model emphasizing etiological risk. Associations with real incidence of dementia were diminished by the competing risk of death.Peer reviewe

Common Genetic Variation Near Melatonin Receptor 1A Gene Linked to Job-Related Exhaustion in Shift Workers

Study Objectives: Tolerance to shift work varies; only some shift workers suffer from disturbed sleep, fatigue, and job-related exhaustion. Our aim was to explore molecular genetic risk factors for intolerance to shift work. Methods: We assessed intolerance to shift work with job-related exhaustion symptoms in shift workers using the emotional exhaustion subscale of the Maslach Burnout Inventory-General Survey, and carried out a genome-wide association study (GWAS) using Illumina's Human610-Quad BeadChip (n = 176). The most significant findings were further studied in three groups of Finnish shift workers (n = 577). We assessed methylation in blood cells with the Illumina HumanMethylation450K BeadChip, and examined gene expression levels in the publicly available eGWAS Mayo data. Results: The second strongest signal identified in the GWAS (p = 2.3 x 10E-6) was replicated in two of the replication studies with p Conclusions: These findings suggest that a variant near MTNR1A may be associated with job-related exhaustion in shift workers. The risk variant may exert its effect via epigenetic mechanisms, potentially leading to reduced melatonin signaling in the brain. These results could indicate a link between melatonin signaling, a key circadian regulatory mechanism, and tolerance to shift work.Peer reviewe

A distinctive DNA methylation pattern in insufficient sleep

Short sleep duration or insomnia may lead to an increased risk of various psychiatric and cardio-metabolic conditions. Since DNA methylation plays a critical role in the regulation of gene expression, studies of differentially methylated positions (DMPs) might be valuable for understanding the mechanisms underlying insomnia. We performed a cross-sectional genome-wide analysis of DNA methylation in relation to self-reported insufficient sleep in individuals from a community-based sample (79 men, aged 39.3 +/- 7.3), and in relation to shift work disorder in an occupational cohort (26 men, aged 44.9 +/- 9.0). The analysis of DNA methylation data revealed that genes corresponding to selected DMPs form a distinctive pathway: "Nervous System Development" (FDR P value <0.05). We found that 78% of the DMPs were hypomethylated in cases in both cohorts, suggesting that insufficient sleep may be associated with loss of DNA methylation. A karyoplot revealed clusters of DMPs at various chromosomal regions, including 12 DMPs on chromosome 17, previously associated with Smith-Magenis syndrome, a rare condition comprising disturbed sleep and inverse circadian rhythm. Our findings give novel insights into the DNA methylation patterns associated with sleep loss, possibly modifying processes related to neuroplasticity and neurodegeneration. Future prospective studies are needed to confirm the observed associations.Peer reviewe

Variation near MTNR1A associates with early development and interacts with seasons

First published: 07 October 201

Genome-wide association study of antisocial personality disorder

The pathophysiology of antisocial personality disorder (ASPD) remains unclear. Although the most consistent biological finding is reduced grey matter volume in the frontal cortex, about 50% of the total liability to developing ASPD has been attributed to genetic factors. The contributing genes remain largely unknown. Therefore, we sought to study the genetic background of ASPD. We conducted a genome-wide association study (GWAS) and a replication analysis of Finnish criminal offenders fulfilling DSM-IV criteria for ASPD (N = 370, N = 5850 for controls, GWAS; N = 173, N = 3766 for controls and replication sample). The GWAS resulted in suggestive associations of two clusters of single-nucleotide polymorphisms at 6p21.2 and at 6p21.32 at the human leukocyte antigen (HLA) region. Imputation of HLA alleles revealed an independent association with DRB1*01:01 (odds ratio (OR) = 2.19 (1.53-3.14), P = 1.9 x 10(-5)). Two polymorphisms at 6p21.2 LINC00951-LRFN2 gene region were replicated in a separate data set, and rs4714329 reached genome-wide significance (OR = 1.59 (1.37-1.85), P = 1.6 x 10(-9)) in the meta-analysis. The risk allele also associated with antisocial features in the general population conditioned for severe problems in childhood family (beta = 0.68, P = 0.012). Functional analysis in brain tissue in open access GTEx and Braineac databases revealed eQTL associations of rs4714329 with LINC00951 and LRFN2 in cerebellum. In humans, LINC00951 and LRFN2 are both expressed in the brain, especially in the frontal cortex, which is intriguing considering the role of the frontal cortex in behavior and the neuroanatomical findings of reduced gray matter volume in ASPD. To our knowledge, this is the first study showing genome-wide significant and replicable findings on genetic variants associated with any personality disorder.Peer reviewe

Variation near MTNR1A associates with early development and interacts with seasons

Melatonin is a circadian regulatory hormone with neuroprotective properties. We have previously demonstrated the association of the genetic variant rs12506228 near the melatonin receptor 1A gene (MTNR1A) with intolerance to shift‐work. Furthermore, this variant has been connected to Alzheimer's disease. Because of the previously suggested role of melatonin signalling in foetal neurocognitive and sleep development, we studied here the association of rs12506228 with early development. The study sample comprised 8‐month‐old infants from the Finnish CHILD‐SLEEP birth cohort (n = 1,301). Parental questionnaires assessed socioemotional, communication and motor development, as well as sleep length and night awakenings. The A allele of rs12506228 showed an association with slower socioemotional (p = .025) and communication (p = .0098) development, but no direct association with sleep. However, the association of the Finnish seasons with infant sleep length interacted with rs12506228. Taken together, rs12506228 near MTNR1A, which has been previously linked to adult and elderly traits, is shown here to associate with slower early cognitive development. In addition, these results suggest that the darker seasons associate with longer infant sleep time, but only in the absence of the rs12506228 AA genotype. Because the risk allele has been connected to fewer brain MT1 melatonin receptors, these associations may reflect the influence of decreased melatonin signalling in early development.Peer reviewe

Dementia care initiative in primary practice – study protocol of a cluster randomized trial on dementia management in a general practice setting

<p>Abstract</p> <p>Background</p> <p>Current guidelines for dementia care recommend the combination of drug therapy with non-pharmaceutical measures like counselling and social support. However, the scientific evidence concerning non-pharmaceutical interventions for dementia patients and their informal caregivers remains inconclusive. Targets of modern comprehensive dementia care are to enable patients to live at home as long and as independent as possible and to reduce the burden of caregivers. The objective of the study is to compare a complex intervention including caregiver support groups and counselling against usual care in terms of time to nursing home placement. In this paper the study protocol is described.</p> <p>Methods/Design</p> <p>The IDA (Initiative Demenzversorgung in der Allgemeinmedizin) project is designed as a three armed cluster-randomized trial where dementia patients and their informal caregivers are recruited by general practitioners. Patients in the study region of Middle Franconia, Germany, are included if they have mild or moderate dementia, are at least 65 years old, and are members of the German AOK (Allgemeine Ortskrankenkasse) sickness fund. In the control group patients receive regular treatment, whereas in the two intervention groups general practitioners participate in a training course in evidence based dementia treatment, recommend support groups and offer counseling to the family caregivers either beginning at baseline or after the 1-year follow-up. The study recruitment and follow-up took place from July 2005 to January 2009. 303 general practitioners were randomized of which 129 recruited a total of 390 patients. Time to nursing home admission within the two year intervention and follow-up period is the primary endpoint. Secondary endpoints are cognitive status, activities of daily living, burden of care giving as well as healthcare costs. For an economic analysis from the societal perspective, data are collected from caregivers as well as by the use of routine data from statutory health insurance and long-term care insurance.</p> <p>Discussion</p> <p>From a public health perspective, the IDA trial is expected to lead to evidence based results on the community effectiveness of non-pharmaceutical support measures for dementia patients and their caregivers in the primary care sector. For health policy makers it is necessary to make their decisions about financing new services based on strong knowledge about the acceptance of measures in the population and their cost-effectiveness.</p> <p>Trial registration</p> <p>ISRCTN68329593</p

Työuupumuksen geneettinen tausta : yhteys Alzheimerin tautiin

Occupational burnout syndrome and its core symptom, job-related exhaustion, are results of chronic exposure to work stress. However, there are interindividual differences in the manifestation and development of the symptoms. The differences are partly genetic: twin studies have shown about 30% heritability for job-related exhaustion. Among shift workers, job-related exhaustion can be a symptom of intolerance to shift work, a work form that causes sleep deprivation and misalignment of the sleep-wake cycle from circadian rhythms. There is a clear individual component also in intolerance to shift work. Alzheimer’s disease (AD), the most common cause of dementia, is a multifactorial disease with several genetic and environmental risk factors. Psychological stress, vulnerability to stress, sleep problems, and shift work have been suggested as risk factors for dementia and specifically AD. The first aim of the study was to search for molecular genetic risk variants for job-related exhaustion in all workers and specifically among shift workers. That was examined in the Health 2000 and the National FINRISK studies, which represented the Finnish general population, and in two occupational samples of airline workers and nurses. Secondly, our aim was to examine, if the identified risk variants were associated with dementia and AD in two cohorts of the very elderly, Vantaa 85+ and Kuopio 75+, in study samples with younger participants, Kuopio case-control sample and the National FINRISK study. Genome-wide study (GWAS) followed by three replication studies identified rs13219957 in the intron of UST (Uronyl-2-sulfotransferase) as a risk variant for job-related exhaustion in all workers. The genetic risk was likely mediated via epigenetic mechanisms, as in functional analyses the variant was associated with DNA methylation sites in the gene body of UST. When analysing job-related exhaustion specifically in shift workers, GWAS and two replication analyses revealed rs12506228 near MTNR1A (Melatonin receptor 1A) as a risk variant. The functional analyses suggested DNA methylation-mediated mechanism also for that risk variant, because rs12506228 correlated with differential methylation in the regulatory region of MTNR1A among shift workers, but not among general population, and the risk variant showed significant association with lower brain expression of MTNR1A. In addition, rs12506228 showed strong association with clinical and pathological AD in the very elderly cohorts but not in the younger study samples. The in vitro model demonstrated that overexpression of MTNR1A decreased beta-amyloid production and inhibition of MTNR1A increased it, providing mechanism for association of the MTNR1A expression-related variant and beta-amyloid pathology. The population cohort of FINRISK with time-specific register-based diagnoses for dementia and AD enabled the use of survival models, which account for the competing risk of death. The survival analyses in this younger population showed that the homozygous risk genotype of rs13219957, but not rs12506228, increased the risk of all-cause dementia. In addition, the genetic area of rs13219957 was associated with neurofibrillary pathology of AD in Vantaa 85+. Thus, our results suggest that rs12506228 is a risk factor for AD in very old age specifically, while rs13219957 is a more general but weak risk factor for dementia. In conclusion, this study identified, for the first time, molecular genetic risk variants for job-related exhaustion in all workers and specifically in shift workers, and suggested DNA methylation and RNA expression -mediated functional mechanisms. The association of the same variants also with dementia and AD propose partly shared genetic background between intolerance to stress or to shift work and AD.Työuupumusoireyhtymä ja sen ydinoire, työhön liittyvä uupumus, ovat reaktio pitkittyneeseen työstressiin. Kaikki eivät kuitenkaan saa työuupumusoireita pitkittyneen työstressin yhteydessä vaan alttiudessa työuupumukselle on yksilöllisiä eroja. Yksilölliset erot johtuvat osittain geneettisistä tekijöistä: työuupumuksen perinnöllinen osuus on ollut noin 30 % kaksostutkimuksissa. Vuorotyöläisillä työuupumus voi heijastaa huonoa vuorotyön sietoa. Vuorotyö on työmuoto, joka aiheuttaa univajetta ja sisäisen ja ulkoisen rytmin epätahtisuutta. Myös vuorotyön sietoon vaikuttavat selkeästi yksilölliset ominaisuudet. Alzheimerin tauti on yleisin dementia syy. Se on monitekijäinen sairaus, johon vaikuttaa useita geneettisiä ja ympäristöriskitekijöitä. Psykologisen stressin, stressiherkkyyden, univaikeuksien ja vuorotyön on esitetty olevan riskitekijöitä dementialle ja erityisesti Alzheimerin taudille. Tutkimuksen ensimmäinen tavoite oli tunnistaa molekyyligeneettisiä riskitekijöitä työuupumusoireelle kaikkien työntekijöiden keskuudessa ja erikseen vuorotyöläisten keskuudessa. Tutkimus toteutettiin yleistä suomalaista väestöä edustavissa Terveys 2000 ja Kansallisen FINRISKI-tutkimuksen aineistoissa sekä lentokentän työntekijöitä ja sairaanhoitajia edustavissa työelämäaineistoissa. Tutkimuksen toinen tavoite oli selvittää, liittyvätkö työuupumuksen ja vuorotyöuupumuksen molekyyligeneettiset riskitekijät dementiaan ja Alzheimerin tautiin. Tämä osa tutkimusta tapahtui kahdessa hyvin vanhoja suomalaisia edustavassa kohortissa sekä nuoremmista suomalaisista koostuvissa aineistoissa. Genominlaajuinen assosiaatioanalyysi ja kolme toistotutkimusta osoittivat, että yhden emäksen polymorfismi rs13219957 UST-geenin (Uronyyli-2-sulfotransferaasi) intronissa yhdistyy työuupumusoireeseen, kun tutkitaan kaikkia työntekijöitä. On todennäköistä, että epigeneettiset mekanismit ovat välittämässä tätä yhteyttä, koska toiminnallisissa analyyseissa variantti liittyi DNA:n metylaation määrään UST:n alueella. Kun tutkittiin työuupumusoiretta vuorotyöläisillä, genominlaajuinen assosiaatioanalyysi ja kaksi toistotutkimusta osoittivat riskivariantiksi yhden emäksen polymorfismin rs12506228, joka sijaitsee lähellä geeniä MTNR1A (melatoniinireseptori 1A). Myös tässä tapauksessa funktionaaliset tutkimukset tukivat ajatusta epigeneettisestä mekanismista yhteyden välittäjänä. Rs12506228 liittyi DNA:n metylaatiotasoihin MTNR1A:n säätelyalueella vuorotyöläisillä, mutta ei kaikkia työntekijöitä tutkittaessa. Lisäksi rs12506228:n riskimuoto yhdistyi matalampaan MTNR1A:n ilmentymiseen aivoissa. Vuorotyöuupumuksen lisäksi rs12506228 yhdistyi voimakkaasti kliiniseen ja patologiseen Alzheimerin tautiin hyvin iäkkäitä suomalaisia edustavissa kohorteissa mutta ei nuoremmissa aineistoissa. Solumallissa MTNR1A:n yli-ilmentyminen vähensi amyloidi betan tuotantoa ja MTNR1A:n hiljennys lisäsi sitä. Amyloid betan tuotannon säätely on mahdollinen mekanismi, joka voisi yhdistää MTNR1A:n ilmentymiseen liittyvän rs12506228 variantin ja aivojen amyloidi beeta patologian. FINRISKI-tutkimuksen väestöaineistoon liitettiin rekisteripohjaiset dementian ja Alzheimerin taudin diagnoosit, tieto kuolleisuudesta ja tapahtuma-aika, mikä mahdollisti sellaisten välttöaika-analyysien (survival models) käytön, jossa huomioidaan myös kuolema kilpailevana tapahtumana. Tässä nuoremmassa populaatioaineistossa välttöaika-analyysit näyttivät, että homotsygoottinen rs13219957 genotyyppi, mutta ei rs12506228, liittyi korkeampaan dementian riskiin. Rs13219957 assosioitui myös Alzheimerin taudille tyypilliseen aivojen neurofibrillipatologiaan. Esitämme siis, että rs12506228 olisi riskitekijä Alzheimerin taudille hyvin vanhalla iällä ja rs13219957 yleisempi mutta heikko riskitekijä dementialle. Tässä tutkimuksessa tunnistimme ensimmäistä kertaa molekyyligeneettisiä riskitekijöitä työuupumusoireelle kaikkien työntekijöiden keskuudessa sekä erikseen vuorotyöläisillä. Havaitut yhteydet saattavat välittyä DNA:n metylaation ja RNA:n ilmentymisen muutosten kautta. Samojen varianttien yhdistyminen dementiaan ja Alzheimerin tautiin viittaa siihen, että stressinsiedon ja vuorotyöhön taustalla olisi osittain samoja mekanismeja kuin Alzheimerin taudin taustalla

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