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 ß= -0.233, 95% CI: -0.351, -0.113; indirect ß= -0.483, 95% CI: -0.602, -0.364; direct ß = 0.250, 95% CI: 0.117, 0.384), but did not mediate the association between disease progression and caregiver strain (total ß = 0.323, 95% CI: 0.234, 0.412; indirect ß = 0.089, 95% CI: -0.027, 0.206; direct ß = 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.

Assessment Intervention Using the Rey-Osterrieth Complex Figure Test: A Clinical Illustration.

Therapeutic assessment (TA) aims to affect change in a client, in part, through an in vivo intervention using any number of assessment methods during a planned assessment intervention session (AIS). To date, neuropsychological tests have not been widely used in AIS. We suggest that the Rey-Osterrieth Complex Figure Test (RCFT) can be a helpful tool, especially when the assessment questions pertain to cognitive functioning, owing to its complexity and the fact that it taps several different cognitive functions. To illustrate this, we present the case of Mr. B, a 45-year-old man with a childhood history of neglect and abuse who was struggling with mood and cognitive complaints in the context of identifying a satisfying career. His performance on the RCFT had illuminated his cognitive style, and an AIS was built around observing and changing his approach to problem solving in the context of a supportive relationship. Based on the intervention, he was able to reassess his narrative of cognitive dysfunction, address his problems in organization, and practice using another person for support in problem solving.

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.

Absence of beta3 integrin accelerates early skeletal repair.

Integrins are heterodimeric transmembrane proteins that mediate cell-matrix interactions and modulate cell behavior. Beta3 subunit is a component of alphaIIbeta3 and alphaVbeta3 integrins. In this study, we first determined that beta3 transcripts are expressed by cells within fracture calluses at 7 and 10 days after injury in a mouse model. We then analyzed fracture healing in mice deficient of beta3 integrin with molecular, histomorphometric, and biomechanical techniques. We found that lack of beta3 integrin results in an extended bleeding time and leads to more bone formation and accelerated cartilage maturation at 7 days after injury. However, beta3 deficiency does not appear to affect later fracture healing. At days 14 and 21, histological appearance or biomechanical properties of fracture calluses are similar between wild type and mutant mice. We also found that altered fracture healing in beta3-null mice is not associated with accelerated angiogenesis, because no significant difference of length density and surface density of blood vessels in fracture limbs was detected at 3 days after injury between wild type and beta3-null mice. In conclusion, our findings demonstrate that beta3 integrin plays an important role during early fracture healing. Further research is required to determine the underlying mechanisms.

Action of IL-1beta during fracture healing.

After bone injury, developmental processes such as endochondral and intramembranous ossification are recapitulated as the skeleton regenerates. In contrast to development, skeletal healing involves inflammation. During the early stages of healing a variety of inflammatory cells infiltrate the injured site, debride the wound, and stimulate the repair process. Little is known about the inflammatory process during bone repair. In this work, we examined the effect of a pro-inflammatory cytokine, Interleukin-1 beta (IL-1beta), on osteoblast and stem cell differentiation and on intramembranous and endochondral ossification, because IL-1beta exerts effects on skeletal homeostasis and is upregulated in response to fracture. We determined that IL-1beta stimulated proliferation of osteoblasts and production of mineralized bone matrix, but suppressed proliferation and inhibited differentiation of bone marrow derived MSCs. We next performed loss- and gain-of-function experiments to determine if altering IL-1beta signaling affects fracture healing. We did not detect any differences in callus, cartilage, and bone matrix production during healing of nonstabilized or stabilized fractures in mice that lacked the IL-1beta receptor compared to wild-type animals. We observed subtle alterations in the healing process after administering IL-1beta during the early phases of repair. At day 10 after injury, the ratio of cartilage to callus was increased, and by day 14, the proportion of cartilage to total callus and to bone was reduced. These changes could reflect a slight acceleration of endochondral ossification, or direct effects on cartilage and bone formation.

Effect of age on vascularization during fracture repair.

Age affects fracture repair; however, the underlying mechanisms are not well understood. The goal of this study was to assess the effects that age has on vascularization during fracture healing. Tibial fractures were created in juvenile (4-week-old), middle-aged (6-month-old), and elderly (18-month-old) mice. The length density and surface density of blood vessels within fracture calluses were analyzed using stereology at 7 days after fracture. The expression of molecules that regulate vascular invasion of the fracture callus was also compared among the three age groups by immunohistochemistry and in situ hybridization. At 7 days after fracture, juvenile mice had a higher surface density of blood vessels compared to the middle-aged and elderly. Hypoxia-inducible factor-1 alpha protein and transcripts of vascular endothelial growth factor were detected at 3 days postinjury in juvenile but not middle-aged and elderly mice. Stronger Mmp-9 and -13 expression was detected in fracture calluses at day 7 in the juvenile compared to the middle-aged and elderly mice. At 21 days postfracture, expression of both Mmps was more robust in the elderly than juvenile and middle-aged animals. These data indicate that age affects vascularization during fracture repair, and the changes we observed are directly correlated with altered expression of biochemical factors that regulate the process of angiogenesis. However, whether the increased vascularization is the cause or result of accelerated bone repair in juvenile animals remains unknown. Nonetheless, our results indicate that enhancing vascularization during fracture repair in the elderly may provide unique therapeutic opportunities.