A Multiancestral Genome-Wide Exome Array Study of Alzheimer Disease, Frontotemporal Dementia, and Progressive Supranuclear Palsy

Importance Previous studies have indicated a heritable component of the etiology of neurodegenerative diseases such as Alzheimer disease (AD), frontotemporal dementia (FTD), and progressive supranuclear palsy (PSP). However, few have examined the contribution of low-frequency coding variants on a genome-wide level. Objective To identify low-frequency coding variants that affect susceptibility to AD, FTD, and PSP. Design, Setting, and Participants We used the Illumina HumanExome BeadChip array to genotype a large number of variants (most of which are low-frequency coding variants) in a cohort of patients with neurodegenerative disease (224 with AD, 168 with FTD, and 48 with PSP) and in 224 control individuals without dementia enrolled between 2005-2012 from multiple centers participating in the Genetic Investigation in Frontotemporal Dementia and Alzheimer’s Disease (GIFT) Study. An additional multiancestral replication cohort of 240 patients with AD and 240 controls without dementia was used to validate suggestive findings. Variant-level association testing and gene-based testing were performed. Main Outcomes and Measures Statistical association of genetic variants with clinical diagnosis of AD, FTD, and PSP. Results Genetic variants typed by the exome array explained 44%, 53%, and 57% of the total phenotypic variance of AD, FTD, and PSP, respectively. An association with the known AD gene ABCA7 was replicated in several ancestries (discovery P = .0049, European P = .041, African American P = .043, and Asian P = .027), suggesting that exonic variants within this gene modify AD susceptibility. In addition, 2 suggestive candidate genes, DYSF (P = 5.53 × 10−5) and PAXIP1 (P = 2.26 × 10−4), were highlighted in patients with AD and differentially expressed in AD brain. Corroborating evidence from other exome array studies and gene expression data points toward potential involvement of these genes in the pathogenesis of AD. Conclusions and Relevance Low-frequency coding variants with intermediate effect size may account for a significant fraction of the genetic susceptibility to AD and FTD. Furthermore, we found evidence that coding variants in the known susceptibility gene ABCA7, as well as candidate genes DYSF and PAXIP1, confer risk for AD

Emotional Behavior in Couples with bvFTD: Implications for Caregiver Relationship Satisfaction and Psychological Well-being

AbstractEmotional Behavior in Couples with bvFTD: Implications for Caregiver Relationship Satisfaction and Psychological Well-beingbyAnna SapozhnikovaDoctor of Philosophy in PsychologyUniversity of California, BerkeleyProfessor Robert W. Levenson, ChairEmotions are an important part of marital life. Prior research indicates that patients with behavioral variant frontotemporal dementia (bvFTD) experience significant impairments in socioemotional functioning, including emotional blunting, inappropriate behavior and decreased empathy (Neary et al., 1998). These changes in patients often strain marriages and can lead to a decline in marital satisfaction and increase the risk of depression in the healthy spouse (Ascher et al., 2010, Braun et al., 2010). However, few studies have explored the emotional dynamics of couples living with bvFTD in a systematic way (Braun et al., 2009). The aim of this study was to extend our understanding of the emotional dynamics of couples where one spouse has bvFTD as well as to understand the association between emotional behavior during the marital interaction and the caregiving spouse’s relationship satisfaction and psychological well-being, looking specifically at depression. This study examined emotional behavior and emotional reciprocity of couples where one spouse is diagnosed with either bvFTD (N=30) or Alzheimer’s disease (N=30) in the context of a 10-minute naturalistic marital interaction in comparison to healthy controls (N=29). Emotional behavior was coded using the Specific Affect Coding System (SPAFF), which consists of five positive emotional behavior codes, ten negative emotional behavior codes, and a neutral code. Emotional reciprocity between spouses was established using the Allison and Liker (1982) statistic. The study also examined the relationship between positive and negative emotional behavior as well as escalating and de-escalating patterns of emotional reciprocity and the caregiving spouse’s self-reported marital satisfaction and levels of depression. The current findings reveal a loss of humor and reciprocity of positive emotion and an exacerbation in negative emotion (e.g., criticism, sadness) and conflict escalation in couples with bvFTD during a marital interaction. Furthermore, low positive emotion, high negative emotion and conflict escalation are associated with low marital satisfaction and high negative emotion is related to increased levels of depression in the spousal caregiver

Instructional design in foreign language teaching

This paper offers a presentation of two original multimedia educational resources with interactive online tasks in the German language developed within the course “Teacher”s and translator”s electronic resource” in cooperation with the students of the Faculty of Foreign Languages and International Communication of Tver State University. The purpose of our projects assumes, in the first place, deliberate formation of a learning environment meeting the needs of a target audience. In the process of working over the projects, the authors took into consideration the principles of instructional design that served as a theoretical basis for the development of educational materials. Instructional design is viewed by the authors of the article as a separate branch of practical pedagogy which primarily focuses on the application of pedagogical knowledge in practice, namely, development of high-quality efficient educational resources with the use of modern information technologies. The distinctive feature of the theory of instructional design is consideration of not so much the cognitive parameters and mental processes characterising the learning process as the efficient methods and learning formats stimulating these cognitive processes. The most important result of our work is the conclusion that the projects developed with regard for the principles of instructional design under the ADDIE model contribute to enhancement of students’ cognitive abilities and increase the amount and quality of information assimilated by them; at the same time, the learning becomes more systemic and practice-oriented from the first stages of project analysis and planning. The novelty of our approach specifically lies in practical treatment of instructional design as a tool for development of learning materials, invigoration of learning activities and tutor support of students

Caregiver "objective attitude" toward patients with neurodegenerative disease: Consequences for caregiver strain and relationship closeness.

Many caregivers of patients with neurodegenerative disease experience physical and psychological strain, which is associated with negative health outcomes. Caregiver strain may be partly attributable to negative emotional responses (e.g.of resentment) to the behavioral, cognitive, and physical changes associated with patients' disease. The philosopher Peter Strawson observed that in dealing with people who have neurological impairments, we often choose to suspend such emotional responses, adopting what he labeled the "objective attitude," though this may come at the expense of our relationships with them. In this study, we assessed the mediating effect of caregivers' adoption of the objective attitude on caregiver strain and relationship closeness in the setting of disease progression. Caregivers of patients with neurodegenerative disorders (n = 215) completed the Clinical Dementia Rating, Relationship-Closeness scale, Caregiver Strain Index, and a novel questionnaire assessing the adoption of the objective attitude. A structural equation model assessing associations among these variables demonstrated good fit (χ2 (88)=164.621, p < 0.001; CFI = 0.929, RMSEA = 0.064.) and showed that adoption of the objective attitude mediated the association between disease progression and relationship closeness (total β= -0.233, 95% CI: -0.351, -0.113; indirect β= -0.483, 95% CI: -0.602, -0.364; direct β = 0.250, 95% CI: 0.117, 0.384), but did not mediate the association between disease progression and caregiver strain (total β = 0.323, 95% CI: 0.234, 0.412; indirect β = 0.089, 95% CI: -0.027, 0.206; direct β = 0.153, 95% CI: -0.043, 0.349). For future work, we propose longitudinal measurements of these constructs to test the directionality of associations and consideration of how models for caregiver support can draw upon interdisciplinary insights

Caregiver "objective attitude" toward patients with neurodegenerative disease: Consequences for caregiver strain and relationship closeness.

Many caregivers of patients with neurodegenerative disease experience physical and psychological strain, which is associated with negative health outcomes. Caregiver strain may be partly attributable to negative emotional responses (e.g.of resentment) to the behavioral, cognitive, and physical changes associated with patients' disease. The philosopher Peter Strawson observed that in dealing with people who have neurological impairments, we often choose to suspend such emotional responses, adopting what he labeled the "objective attitude," though this may come at the expense of our relationships with them. In this study, we assessed the mediating effect of caregivers' adoption of the objective attitude on caregiver strain and relationship closeness in the setting of disease progression. Caregivers of patients with neurodegenerative disorders (n = 215) completed the Clinical Dementia Rating, Relationship-Closeness scale, Caregiver Strain Index, and a novel questionnaire assessing the adoption of the objective attitude. A structural equation model assessing associations among these variables demonstrated good fit (χ2 (88)=164.621, p < 0.001; CFI = 0.929, RMSEA = 0.064.) and showed that adoption of the objective attitude mediated the association between disease progression and relationship closeness (total β= -0.233, 95% CI: -0.351, -0.113; indirect β= -0.483, 95% CI: -0.602, -0.364; direct β = 0.250, 95% CI: 0.117, 0.384), but did not mediate the association between disease progression and caregiver strain (total β = 0.323, 95% CI: 0.234, 0.412; indirect β = 0.089, 95% CI: -0.027, 0.206; direct β = 0.153, 95% CI: -0.043, 0.349). For future work, we propose longitudinal measurements of these constructs to test the directionality of associations and consideration of how models for caregiver support can draw upon interdisciplinary insights

Biosynthesis and Properties of a P(3HB-<i>co</i>-3HV-<i>co</i>-4HV) Produced by <i>Cupriavidus necator</i> B-10646

Synthesis of P(3HB-co-3HV-co-4HV) copolymers by the wild-type strain Cupriavidus necator B-10646 on fructose or sodium butyrate as the main C-substrate with the addition of γ-valerolactone as a precursor of 3HV and 4HV monomers was studied. Bacterial cells were cultivated in the modes that enabled production of a series of copolymers with molar fractions of 3HV (from 7.3 to 23.4 mol.%) and 4HV (from 1.9 to 4.7 mol.%) with bacterial biomass concentration (8.2 ± 0.2 g/L) and PHA content (80 ± 2%). Using HPLC, DTA, DSC, X-Ray, SEM, and AFM, the physicochemical properties of copolymers and films prepared from them have been investigated as dependent on proportions of monomers. Copolymers are characterized by a reduced degree of crystallinity (Cx 38–49%) molecular weight characteristics Mn (45–87 kDa), and Mw (201–248 kDa) compared with P(3HB). The properties of the films surface of various composition including the porosity and surface roughness were studied. Most of the samples showed a decrease in the average pore area and an increase in their number with a total increase in 3HV and 4HV monomers. The results allow scaling up the productive synthesis of P(3HB-co-3HV-co-4HV) copolymers using Cupriavidus necator B-10646

Probing tricarbocyanine dyes for targeted delivery of anthracyclines

Heptamethine carbocyanine dyes possess bright fluorescence in the near IR range and affinity to cancer cells. Thus, these dyes could be utilized as fluorescent labels and vectors for drug delivery in their covalent conjugates with cytotoxic compounds. In this work we synthesized four drug-dye conjugates of tricarbocyanine dyes with anthracycline drug daunorubicin using a CuAAC reaction. Conjugates with hydrophobic dyes possess submicromolar cytotoxicity. Fluorescent imaging revealed significant accumulation of the conjugates in mitochondria, suggesting an enhancement of an additional mechanism of anthracycline cytotoxicity – generation of ROS. The hypothesis was supported by significant reduction of activity of the conjugates in presence of an antioxidant compound