The effect of smoking during pregnancy on severity and directionality of externalizing and internalizing symptoms: A genetically informed approach

The objective was to examine the association between maternal smoking during pregnancy (SDP) and (I) severity and (II) directionality of externalizing and internalizing symptoms in a sample of sibling pairs while rigorously controlling for familial confounds. The Missouri Mothers and Their Children Study is a family study (N = 173 families) with sibling pairs (aged 7 to 16 years) who are discordant for exposure to SDP. This sibling comparison study is designed to disentangle the effects of SDP from familial confounds. An SDP severity score was created for each child using a combination of SDP indicators (timing, duration, and amount). Principal component analysis of externalizing and internalizing behavior, assessed with the Child Behavior Checklist and Teacher Report Form, was used to create symptom severity and directionality scores. The variance in severity and directionality scores was primarily a function of differences between siblings (71% and 85%, respectively) rather than differences across families (29% and 15%, respectively). The severity score that combines externalizing and internalizing symptom severity was not associated with SDP. However, a significant within-family effect of SDP on symptom directionality (b = 0.07

Prenatal Maternal Smoking and Tourette Syndrome: A Nationwide Register Study

Peer reviewe

Insuliiniresistenssi, aivot ja muistisairausriski

Tyypin 2 diabetes ja siihen liittyvä insuliiniresistenssi ovat muistisairauden riskitekijöitä. Insuliiniresistenssi ennustaa tiedonkäsittelytoimintojen heikentymistä jo henkilöillä, joille ei vielä ole kehittynyt diabetesta. Insuliinilla on useita tärkeitä säätelytehtäviä keskushermostossa. Se vaikuttaa esimerkiksi synapsien toimintaan ja niiden pitkäkestoiseen vahvistumiseen. Insuliiniresistenssiin liittyvään hyperinsulinemiaan on puolestaan yhdistetty paradoksaalisesti keskushermoston pienentynyt insuliinipitoisuus. Alzheimerin tautia sairastavilla insuliinin vaste keskushermostossa on heikentynyt. Insuliinilla ja Alzheimerin taudille tyypillisellä beeta-amyloidilla on aivoissa yhteinen hajottajaentsyymi. Muutokset tämän entsyymin toiminnassa ja määrässä voivat vaikuttaa beeta-amyloidin kertymään aivoissa. Insuliiniresistenssi voi altistaa kognition heikentymiselle myös aivojen pienten suonten muutosten kautta. Insuliiniresistenssi voi siis vaikuttaa tiedonkäsittelytoimintoihin ja Alzheimerin taudin neuropatologiaan useita eri reittejä.</p

Association of Early Beta-amyloid Accumulation and Neuroinflammation Measured with [11C]PBR28 in Elderly Individuals Without Dementia

OBJECTIVE: To examine whether early β-amyloid (Aβ) accumulation and metabolic risk factors are associated with neuroinflammation in elderly individuals without dementia. METHODS: We examined 54 volunteers (mean age 70.0, 56% women, 51% APOE ε4 carriers) with a TSPO-tracer [11C]PBR28 to assess neuroinflammation and with [11C]Pittsburgh compound B (PiB) to assess cerebral Aβ accumulation. [11C]PBR28 and [11C]PiB standardized uptake value ratios (SUVRs) were quantified in six regions of interests by using the cerebellar cortex as a pseudo-reference/reference region, respectively. Fasting venous glucose, insulin, and high sensitivity C-reactive protein (hs-CRP) values were determined. Homeostatic model assessment of insulin resistance (HOMA-IR) was calculated. A subset of individuals (n=11) underwent CSF sampling, and Aβ40, Aβ42, total-tau, phospho-tau, soluble TREM2 and YKL-40 levels were measured. RESULTS: Among the whole study group, no significant association was found between [11C]PiB and [11C]PBR28 SUVR composite scores (slope 0.02, p=0.30). However, higher [11C]PiB binding was associated with higher [11C]PBR28 binding among amyloid negative ([11C]PiB composite score ≤1.5) (TSPO-genotype, age and sex adjusted slope 0.26, p=0.008) but not among amyloid positive participants (slope: -0.004, p=0.88). Higher CSF sTREM2 (rs 0.72, p=0.01) and YKL-40 (rs=0.63, p=0.04) concentrations were associated with a higher [11C]PBR28 composite score. Higher body mass index, HOMA-IR, and hs-CRP were associated with higher [11C]PBR28 binding in brain regions where Aβ accumulation is first detected in Alzheimer's disease (AD). CONCLUSIONS: While there was no association between amyloid and neuroinflammation in the overall study group, neuroinflammation was associated with amyloid among the subgroup at early stages of amyloid pathology

An explanatory model of depression among female patients in Fars, Kurds, Turks ethnic groups of Iran

Background: Depressive disorder is globally estimated to be as many as one in five visits to primary health care. Approximately more than 50 of depressed women in primary care are not diagnosed. As a part of a major investigation into perceptions of women's depression, this study explored how female patients and their relatives conceptualize patients' conditions in three ethnic groups in Iran (Fars, Kurds and Turks). Methods: Qualitative methods were used for data collection. Depressed women and their relatives were purposively selected from the public psychiatric clinics affiliated to university of medical sciences in the three study cities. Twentyfive depressed women and 14 relatives were interviewed in three ethnic groups. Results: One theme "illness meaning", including three categories: perceived symptoms, label of the illness, and effects of the illness was found through the content analysis. The participants perceived symptoms of illness as somatic and psychological depending on the participant's assumed reason for the onset of the illness. There were most similarities in term used for of the illness in the three ethnic groups. Most of the study participants described the illness in terms of nerve problems/illness, and depression "afsordehgi". The most important effects that depressed women had experienced because of their illness were marital conflict or a guilt feeling originating from their inability to support family. Conclusion: These findings suggest the need to recognize and choose appropriate diagnostic approach for depressed women in the context of Iran

Albuminuria and Microalbuminuria as Predictors of Cognitive Performance in a General Population: An 11-Year Follow-Up Study

Microalbuminuria, defined as urine albumin-to-creatinine ratio (UACR)> 3.0 mg/mmol and 3.0 mg/mmol), and cognitive impairment. Previous studies on microalbuminuria, albuminuria, and cognition in the middle-aged have not provided repeated cognitive testing at different time-points. We hypothesized that albuminuria (micro-plus macroalbuminuria) and microalbuminuria would predict cognitive decline independently of previously reported risk factors for cognitive decline, including cardiovascular risk factors. In addition, we hypothesized that UACR levels even below the cut-off for microalbuminuria might be associated with cognitive functioning. These hypotheses were tested in the Finnish nationwide, population-based Health 2000 Survey (n = 5,921, mean age 52.6, 55.0% women), and its follow-up, Health 2011 (n = 3,687, mean age at baseline 49.3, 55.6% women). Linear regression analysis was used to determine the associations between measures of albuminuria and cognitive performance. Cognitive functions were assessed with verbal fluency, word-list learning, word-list delayed recall (at baseline and at follow-up), and with simple and visual choice reaction time tests (at baseline only). Here, we show that micro-plus macroalbuminuria associated with poorer wordlist learning and a slower reaction time at baseline, with poorer word-list learning at follow-up, and with a steeper decline in word-list learning during 11 years after multivariate adjustments. Also, higher continuous UACR consistently associated with poorer verbal fluency at levels below microalbuminuria. These results suggest that UACR might have value in evaluating the risk for cognitive decline

The remote monad design pattern

Remote Procedure Calls are expensive. This paper demonstrates how to reduce the cost of calling remote procedures from Haskell by using the remote monad design pattern, which amortizes the cost of remote calls. This gives the Haskell community access to remote capabilities that are not directly supported, at a surprisingly inexpensive cost. We explore the remote monad design pattern through six models of remote execution patterns, using a simulated Internet of Things toaster as a running example. We consider the expressiveness and optimizations enabled by each remote execution model, and assess the feasibility of our approach. We then present a full-scale case study: a Haskell library that provides a Foreign Function Interface to the JavaScript Canvas API. Finally, we discuss existing instances of the remote monad design pattern found in Haskell libraries

APOE ε4 gene dose effect on imaging and blood biomarkers of neuroinflammation and beta-amyloid in cognitively unimpaired elderly

BACKGROUND: Neuroinflammation, characterized by increased reactivity of microglia and astrocytes in the brain, is known to be present at various stages of the Alzheimer's disease (AD) continuum. However, its presence and relationship with amyloid pathology in cognitively normal at-risk individuals is less clear. Here, we used positron emission tomography (PET) and blood biomarker measurements to examine differences in neuroinflammation and beta-amyloid (Aβ) and their association in cognitively unimpaired homozygotes, heterozygotes, or non-carriers of the APOE ε4 allele, the strongest genetic risk for sporadic AD. METHODS: Sixty 60-75-year-old APOE ε4 homozygotes (n = 19), heterozygotes (n = 21), and non-carriers (n = 20) were recruited in collaboration with the local Auria biobank. The participants underwent 11C-PK11195 PET (targeting 18-kDa translocator protein, TSPO), 11C-PiB PET (targeting Aβ), brain MRI, and neuropsychological testing including a preclinical cognitive composite (APCC). 11C-PK11195 distribution volume ratios and 11C-PiB standardized uptake value ratios (SUVRs) were calculated for regions typical for early Aβ accumulation in AD. Blood samples were drawn for measuring plasma glial fibrillary acidic protein (GFAP) and plasma Aβ1-42/1.40. RESULTS: In our cognitively unimpaired sample, cortical 11C-PiB-binding increased according to APOE ε4 gene dose (median composite SUVR 1.47 (range 1.38-1.66) in non-carriers, 1.55 (1.43-2.02) in heterozygotes, and 2.13 (1.61-2.83) in homozygotes, P = 0.002). In contrast, cortical composite 11C-PK11195-binding did not differ between the APOE ε4 gene doses (P = 0.27) or between Aβ-positive and Aβ-negative individuals (P = 0.81) and associated with higher Aβ burden only in APOE ε4 homozygotes (Rho = 0.47, P = 0.043). Plasma GFAP concentration correlated with cortical 11C-PiB (Rho = 0.35, P = 0.040), but not 11C-PK11195-binding (Rho = 0.13, P = 0.47) in Aβ-positive individuals. In the total cognitively unimpaired population, both higher composite 11C-PK11195-binding and plasma GFAP were associated with lower hippocampal volume, whereas elevated 11C-PiB-binding was associated with lower APCC scores. CONCLUSIONS: Only Aβ burden measured by PET, but not markers of neuroinflammation, differed among cognitively unimpaired elderly with different APOE ε4 gene dose. However, APOE ε4 gene dose seemed to modulate the association between neuroinflammation and Aβ

Midlife insulin resistance, APOE genotype, and late-life brain amyloid accumulation

ObjectiveTo examine whether midlife insulin resistance is an independent risk factor for brain amyloid accumulation in vivo after 15 years, and whether this risk is modulated by APOE epsilon 4 genotype.MethodsThis observational study examined 60 elderly volunteers without dementia (mean age at baseline 55.4 and at follow-up 70.9 years, 55.5% women) from the Finnish population-based, nationwide Health2000 study with [C-11]Pittsburgh compound B-PET imaging in 2014-2016. The participants were recruited according to their homeostatic model assessment of insulin resistance (HOMA-IR) values in the year 2000, and their APOE epsilon 4 genotype. The exposure group (IR+, n = 30) consisted of individuals with HOMA-IR > 2.17 at baseline (highest tertile of the Health2000 study population), and the control group (IR-, n = 30) consisted of individuals with HOMA-IR < 1.25 at baseline (lowest tertile). The groups were enriched for APOE epsilon 4 carriers, resulting in 50% (n = 15) APOE epsilon 4 carriers in both groups. Analyses were performed with multivariate logistic and linear regression.ResultsAn amyloid-positive PET scan was found in 33.3% of the IR-group and 60.0% of the IR+ group (odds ratio 3.0, 95% confidence interval 1.1-8.9, p = 0.04). The increased risk was seen in carriers and noncarriers of APOE epsilon 4 genotype. Higher midlife, but not late-life continuous HOMA-IR was associated with a greater brain amyloid burden at follow-up after multivariate adjustments for other cognitive and metabolic risk factors (ss = 0.11, 95% confidence interval 0.002-0.22, p = 0.04).ConclusionsThese results indicate that midlife insulin resistance is an independent risk factor for brain amyloid accumulation in elderly individuals without dementia