Categorizing people with late-onset Alzheimer's disease into biologically coherent subgroups is important for personalized medicine. We evaluated data from five studies (total n = 4050, of whom 2431 ...had genome-wide single-nucleotide polymorphism (SNP) data). We assigned people to cognitively defined subgroups on the basis of relative performance in memory, executive functioning, visuospatial functioning, and language at the time of Alzheimer's disease diagnosis. We compared genotype frequencies for each subgroup to those from cognitively normal elderly controls. We focused on APOE and on SNPs with p < 10
and odds ratios more extreme than those previously reported for Alzheimer's disease (<0.77 or >1.30). There was substantial variation across studies in the proportions of people in each subgroup. In each study, higher proportions of people with isolated substantial relative memory impairment had ≥1 APOE ε4 allele than any other subgroup (overall p = 1.5 × 10
). Across subgroups, there were 33 novel suggestive loci across the genome with p < 10
and an extreme OR compared to controls, of which none had statistical evidence of heterogeneity and 30 had ORs in the same direction across all datasets. These data support the biological coherence of cognitively defined subgroups and nominate novel genetic loci.
Abstract Objective This cross sectional study examined the relationship between parental health literacy (HL), diabetes related numeracy, and parental perceived diabetes self-efficacy on glycemic ...control in a sample of young children with Type 1 DM. Methods Seventy primary caregivers of children (age 3–9 years) with Type 1 DM were recruited and surveyed at diabetes outpatient clinic visits. Patients’ medical histories were obtained by medical chart review. Results Parental diabetes related numeracy ( r = −.52, p < 01), but not reading skills ( r = −.25, p = NS) were inversely correlated with the child's glycemic control (HbA1c). Parental perceived diabetes self-efficacy was also negatively correlated to their child's HbA1c ( r = −.47, p < 01). When numeracy and parental perceived diabetes self-efficacy were included as predictors of HbA1c, the model was significant ( F = 12.93, p < .01) with both numeracy ( β = −.46, p < .01) and parental perceived diabetes self-efficacy ( β = −.36, p = .01) as significant predictors of HbA1c. Conclusions Data from this study highlight the importance of considering the role of parental numeracy, in health outcomes for children with Type 1 DM. Practice implications Practitioners should assess parental health literacy and consider intervention when needed.
Current imaging diagnostic techniques are often insensitive to the underlying pathological changes following mild traumatic brain injury (TBI) or concussion so much so that the explicit definition of ...these uncomplicated mild brain injuries includes the absence of radiological findings. In the US military, this is complicated by the natural tendency of service members to down play symptoms for fear of removal from their unit particularly in combat making it challenging for clinicians to definitively diagnose and determine course of treatment. Questions remain regarding the long-term impact of these war-time brain injuries. The objective of the current study was to evaluate the long-term imaging sequelae of blast concussion in active-duty US military and leverage previous longitudinal data collected in these same patients to identify predictors of sustained DTI signal change indicative of chronic neurodegeneration. In total, 50 blast TBI and 44 combat-deployed controls were evaluated at this 5-year follow up by advanced neuroimaging techniques including diffusion tensor imaging and quantitative volumetry. While cross-sectional analysis of regions of white matter on DTI images did not reveal significant differences across groups after statistical correction, an approach flexible to the heterogeneity of brain injury at the single-subject level identified 74% of the concussive blast TBI cohort to have reductions in fractional anisotropy indicative of chronic brain injury. Logistic regression leveraging clinical and demographic data collected in the acute/sub-acute and 1-year follow up to determine predictors of these long-term imaging changes determined that brain injury diagnosis, older age, verbal memory and verbal fluency best predicted the presence of DTI abnormalities 5 years post injury with an AUC of 0.78 indicating good prediction strength. These results provide supporting evidence for the evolution not resolution of this brain injury pathology, adding to the growing body of literature describing imaging signatures of chronic neurodegeneration even after mild TBI and concussion.
Identifying novel, durable treatments for high-grade serous ovarian cancer (HGSOC) is paramount to extend both progression-free survival (PFS) and overall survival (OS) in patients afflicted with ...this disease. Dual-specificity phosphatase 1 (DUSP1) was identified as one of seven genes that may significantly affect prognosis in patients with HGSOC; however, the role of DUSP inhibition (DUSPi) in the treatment of HGSOC remains largely unknown. In this study, we show that DUSP1 is highly expressed in HGSOC and confers worse PFS and OS. Further, we corroborate data that show DUSP1 expression is directly associated with therapy resistance. Using a tissue microarray of 137 different serous ovarian carcinomas, we demonstrate the high expression of DUSP1 in primary and recurrent serous ovarian cancer. In both acquired and de novo therapy HGSOC-resistant models, DUSPi both inhibited cellular proliferation and promoted cell death. RPPA analysis of HGSOC cells revealed DUSPi led to the differential regulation of several pathways, including AMPK and mTORC. Further, in a patient-derived xenograft HGSOC model, DUSPi significantly inhibited tumor progression.
Abstract
Objectives
To characterize the extent to which brief cognitive assessments administered in the population-representative U.S. Health and Retirement Study (HRS) and its International Partner ...Studies can be considered to be measuring a single, unidimensional latent cognitive function construct.
Methods
Cognitive function assessments were administered in face-to-face interviews in 12 studies in 26 countries (N = 155,690), including the U.S. HRS and selected International Partner Studies. We used the time point of the first cognitive assessment for each study to minimize differential practice effects across studies and documented cognitive test item coverage across studies. Using confirmatory factor analysis models, we estimated single-factor general cognitive function models and bifactor models representing memory-specific and nonmemory-specific cognitive domains for each study. We evaluated model fits and factor loadings across studies.
Results
Despite relatively sparse and inconsistent cognitive item coverage across studies, all studies had some cognitive test items in common with other studies. In all studies, the bifactor models with a memory-specific domain fit better than single-factor general cognitive function models. The data fit the models at reasonable thresholds for single-factor models in 6 of the 12 studies and for the bifactor models in all 12 of the 12 studies.
Discussion
The cognitive assessments in the U.S. HRS and its International Partner Studies reflect comparable underlying cognitive constructs. We discuss the assumptions underlying our methods, present alternatives, and future directions for cross-national harmonization of cognitive aging data.
Objective: Studies use different instruments to measure cognitirating cognitive tests permit direct comparisons of individuals across studies and pooling data for joint analyses. Method: We began our ...legacy item bank with data from the Adult Changes in Thought study (n = 5,546), the Alzheimer's Disease Neuroimaging Initiative (n = 3,016), the Rush Memory and Aging Project (n = 2,163), and the Religious on such as the Mini-Mental State Examination, the Alzheimer's Disease Assessment Scale-Cognitive Subscale, the Wechsler Memory Scale, and the Boston Naming Test. CocalibOrders Study (n = 1,456). Our workflow begins with categorizing items administered in each study as indicators of memory, executive functioning, language, visuospatial functioning, or none of these domains. We use confirmatory factor analysis models with data from the most recent visit on the pooled sample across these four studies for cocalibration and derive item parameters for all items. Using these item parameters, we then estimate factor scores along with corresponding standard errors for each domain for each study. We added additional studies to our pipeline as available and focused on thorough consideration of candidate anchor items with identical content and administration methods across studies. Results: Prestatistical harmonization steps such qualitative and quantitative assessment of granular cognitive items and evaluating factor structure are important steps when trying to cocalibrate cognitive scores across studies. We have cocalibrated cognitive data and derived scores for four domains for 76,723 individuals across 10 studies. Conclusions: We have implemented a large-scale effort to harmonize and cocalibrate cognitive domain scores across multiple studies of cognitive aging. Scores on the same metric facilitate meta-analyses of cognitive outcomes across studies or the joint analysis of individual data across studies. Our systematic approach allows for cocalibration of additional studies as they become available and our growing item bank enables robust investigation of cognition in the context of aging and dementia.
Key Points
Question: What considerations were addressed in setting up and implementing a robust workflow that harmonizes and cocalibrates cognitive data across studies of older adults? Findings: Data from thousands of individuals at tens of thousands of study visits have been cocalibrated to the same metrics for four different cognitive domains. Importance: These data will facilitate analyses of cognition across studies, despite varying levels of overlap in cognitive tests used across studies. Next Steps: Cocalibrated scores and standard errors for the studies incorporated in our item banking efforts to date are available to investigators. Additional studies will be incorporated in the coming years using the same methods.
The small heat shock proteins (sHSPs) are a diverse family of molecular chaperones. It is well established that these proteins are crucial components of the plant heat shock response. They also have ...important roles in other stress responses and in normal development. We have conducted a comparative sequence analysis of the sHSPs in three complete angiosperms genomes: Arabidopsis thaliana, Populus trichocarpa, and Oryza sativa. Our phylogenetic analysis has identified four additional plant sHSP subfamilies and thus has increased the number of plant sHSP subfamilies from 7 to 11. We have also identified a number of novel sHSP genes in each genome that lack close homologs in other genomes. Using publicly available gene expression data and predicted secondary structures, we have determined that the sHSPs in plants are far more diverse in sequence, expression profile, and in structure than had been previously known. Some of the newly identified subfamilies are not stress regulated, may not posses the highly conserved large oligomer structure, and may not even function as molecular chaperones. We found no consistent evolutionary patterns across the three species studied. For example, gene conversion was found among the sHSPs in O. sativa but not in A. thaliana or P. trichocarpa. Among the three species, P. trichocarpa had the most sHSPs. This was due to an expansion of the cytosolic I sHSPs that was not seen in the other two species. Our analysis indicates that the sHSPs are a dynamic protein family in angiosperms with unexpected levels of diversity.
Novel preventive therapies are needed for postoperative delirium, which especially affects older patients. A mouse model is presented that captures inflammation-associated cortical slow wave activity ...(SWA) observed in patients, allowing exploration of the mechanistic role of prostaglandin-adenosine signalling.
EEG and cortical cytokine measurements (interleukin 6, monocyte chemoattractant protein-1) were obtained from adult and aged mice. Behaviour, SWA, and functional connectivity were assayed before and after systemic administration of lipopolysaccharide (LPS)+piroxicam (cyclooxygenase inhibitor) or LPS+caffeine (adenosine receptor antagonist). To avoid the confounder of inflammation-driven changes in movement which alter SWA and connectivity, electrophysiological recordings were classified as occurring during quiescence or movement, and propensity score matching was used to match distributions of movement magnitude between baseline and post-LPS administration.
LPS produces increases in cortical cytokines and behavioural quiescence. In movement-matched data, LPS produces increases in SWA (likelihood-ratio test: χ2(4)=21.51, P<0.001), but not connectivity (χ2(4)=6.39, P=0.17). Increases in SWA associate with interleukin 6 (P<0.001) and monocyte chemoattractant protein-1 (P=0.001) and are suppressed by piroxicam (P<0.001) and caffeine (P=0.046). Aged animals compared with adult animals show similar LPS-induced SWA during movement, but exaggerated cytokine response and increased SWA during quiescence.
Cytokine-SWA correlations during wakefulness are consistent with observations in patients with delirium. Absence of connectivity effects after accounting for movement changes suggests decreased connectivity in patients is a biomarker of hypoactivity. Exaggerated effects in quiescent aged animals are consistent with increased hypoactive delirium in older patients. Prostaglandin-adenosine signalling may link inflammation to neural changes and hence delirium.
INTRODUCTION
We sought to determine structural magnetic resonance imaging (MRI) characteristics across subgroups defined based on relative cognitive domain impairments using data from the Alzheimer's ...Disease Neuroimaging Initiative (ADNI) and to compare cognitively defined to imaging‐defined subgroups.
METHODS
We used data from 584 people with Alzheimer's disease (AD) (461 amyloid positive, 123 unknown amyloid status) and 118 amyloid‐negative controls. We used voxel‐based morphometry to compare gray matter volume (GMV) for each group compared to controls and to AD‐Memory.
RESULTS
There was pronounced bilateral lower medial temporal lobe atrophy with relative cortical sparing for AD‐Memory, lower left hemisphere GMV for AD‐Language, anterior lower GMV for AD‐Executive, and posterior lower GMV for AD‐Visuospatial. Formal asymmetry comparisons showed substantially more asymmetry in the AD‐Language group than any other group (p = 1.15 × 10−10). For overlap between imaging‐defined and cognitively defined subgroups, AD‐Memory matched up with an imaging‐defined limbic predominant group.
DISCUSSION
MRI findings differ across cognitively defined AD subgroups.
Objective: To calibrate cognitive assessment data across multiple waves of the Framingham Heart Study (FHS), addressing study design considerations, ceiling effects, and measurement precision. ...Method: FHS participants completed several cognitive assessments including screening instruments and more comprehensive batteries at different study visits. We used expert opinion to assign each cognitive test item to a single domain-memory, executive function, language, visuospatial abilities, or none of the above. As part of a larger cross-study harmonization effort, we calibrated each domain separately using bifactor confirmatory factor analysis (CFA) models, incorporating item parameters for anchor items previously calibrated from other studies and freely estimating item parameters for FHS-specific items. We obtained scores and standard errors (SEs) for each participant at each study visit. We addressed psychometric considerations of ceiling effects and measurement precision. Results: Overall, memory domain scores were the most precisely estimated. Scores for all domains from visits where the Mini-Mental State Examination (MMSE) was the only test administered were imprecisely estimated and suffered from ceiling effects. Scores from visits with a more extensive battery were estimated more precisely and better differentiated between ability levels. Conclusions: The harmonized and calibrated cognitive data from the FHS should prove useful for future analyses examining cognition and cognitive decline. They will be of particular interest when combining FHS with other studies that have been similarly calibrated. Researchers should be aware of varying levels of measurement precision and the possibility of ceiling effects in their planned analyses of data from the FHS and similar studies.
Key Points
Question: What methods and special considerations are needed to derive calibrated cognitive factor scores and use them in future analyses in the FHS, and other similar studies that have evolving cognitive batteries over time or different batteries administered at different study visits? Findings: The FHS used different cognitive instruments at different study visits. These instruments had different measurement properties, including ceiling effects and substantial differences in measurement precision. Importance: Cognitive domain scores from the FHS data can be used in subsequent research. Investigators should consider measurement precision and ceiling effects in their analyses. Next Steps: The calibrated cognitive data generated in this project have been integrated with other study data from the FHS. Interested investigators should integrate lessons from this article in their plans for analyses of the rich cognitive data available from the FHS.
PDF
