Utilization of geospatial distribution in the measurement of study cohort representativeness.

OBJECTIVE: The ability to apply results from a study to a broader population remains a primary objective in translational science. Distinct from intrinsic elements of scientific rigor, the extrinsic concept of generalization requires there be alignment between a study cohort and population in which results are expected to be applied. Widespread efforts have been made to quantify representativeness of a study cohorts. These techniques, however, often consider the study and target cohorts as monolithic collections that can be directly compared. Overlooking known impacts to health from socio-demographic and environmental factors tied to individual's geographical location, and potentially obfuscating misalignment in underrepresented population subgroups. This manuscript introduces several measures to account for geographic information in the measurement of cohort representation. METHODS: Metrics were defined across two themes. First, measures of recruitment, to assess a study cohort is drawn at an expected rate and in an expected geographical pattern with respect to individuals in a reference cohort. Quantifying the coverage and spread across the distinct geographic regions comprising the target population. Second, measures of individual characteristics, to assess if the study cohort accurately reflects the sociodemographic, clinical, and geographic diversity observed across a reference cohort. Employing intra-individual measures of distance and aggregate measures of alignment designed to account for geospatial proximity of individuals. RESULTS: As an empirical demonstration, methods are applied to an active clinical study examining asthma in Black and African American patients at a US Midwestern pediatric hospital. Results illustrate how areas of over- and under-recruitment can be identified and contextualized in light of study recruitment patterns. At an individual-level, highlighting the ability to identify a subset of features for which the study cohort closely resembled the broader population. In addition to an opportunity to dive deeper into misalignments, to identify study cohort members that are in some way distinct from the communities for which they are expected to represent. CONCLUSION: Together, these metrics provide a comprehensive spatial assessment of a study cohort with respect to a broader target population. Such an approach offers researchers a toolset by which to target expected generalization of results derived from a given study.

Consequences of cytochrome c oxidase assembly defects for the yeast stationary phase.

The assembly of cytochrome c oxidase (COX) is essential for a functional mitochondrial respiratory chain, although the consequences of a loss of assembled COX at yeast stationary phase, an excellent model for terminally differentiated cells in humans, remain largely unexamined. In this study, we show that a wild-type respiratory competent yeast strain at stationary phase is characterized by a decreased oxidative capacity, as seen by a reduction in the amount of assembled COX and by a decrease in protein levels of several COX assembly factors. In contrast, loss of assembled COX results in the decreased abundance of many mitochondrial proteins at stationary phase, which is likely due to decreased membrane potential and changes in mitophagy. In addition to an altered mitochondrial proteome, COX assembly mutants display unexpected changes in markers of cellular oxidative stress at stationary phase. Our results suggest that mitochondria may not be a major source of reactive oxygen species at stationary phase in cells lacking an intact respiratory chain.

Neighborhood Socioeconomic Status and Cognitive Trajectories in a Diverse Longitudinal Cohort.

OBJECTIVES: Although individual-level socioeconomic status is associated with poor outcomes, less is known regarding how the social context might affect cognitive outcomes. We examined the effect of neighborhood socioeconomic status (NSES) on baseline cognitive function and trajectories of decline. METHODS: The sample (N = 480) came from a longitudinal cohort recruited to study cognitive function. Mixed effects models examined the influence of NSES on baseline and rate of change in executive function, semantic memory, and episodic memory. RESULTS: NSES was positively associated with semantic memory scores at baseline, but not with executive function or episodic memory in adjusted models, nor was it associated with cognitive change in longitudinal analyses. In exploratory analyses, for individuals with dementia, those with higher NSES declined faster in executive function and semantic memory than did those with lower NSES. CONCLUSIONS: Results suggest that NSES has limited effects independent of personal characteristics; however, findings showed a complex relation of NSES and decline, with NSES effects observed only for individuals with dementia. Results are discussed in the context of cognitive reserve. CLINICAL IMPLICATIONS: Clinical assessments of individuals who present with cognitive impairment might benefit from an understanding of the neighborhood context from which patients come.

Neuropsychological Profiles Differentiate Alzheimer Disease from Subcortical Ischemic Vascular Dementia in an Autopsy-Defined Cohort.

BACKGROUND/AIMS: The aim of this study was to assess the ability of neuropsychological tests to differentiate autopsy-defined Alzheimer disease (AD) from subcortical ischemic vascular dementia (SIVD). METHODS: From a sample of 175 cases followed longitudinally that underwent autopsy, we selected 23 normal controls (NC), 20 SIVD, 69 AD, and 10 mixed cases of dementia. Baseline neuropsychological tests, including Memory Assessment Scale word list learning test, control oral word association test, and animal fluency, were compared between the three autopsy-defined groups. RESULTS: The NC, SIVD, and AD groups did not differ by age or education. The SIVD and AD groups did not differ by the Global Clinical Dementia Rating Scale. Subjects with AD performed worse on delayed recall (p < 0.01). A receiver operating characteristics analysis comparing the SIVD and AD groups including age, education, difference between categorical (animals) versus phonemic fluency (letter F), and the first recall from the word learning test distinguished the two groups with a sensitivity of 85%, specificity of 67%, and positive likelihood ratio of 2.57 (AUC = 0.789, 95% CI 0.69-0.88, p < 0.0001). CONCLUSION: In neuropathologically defined subgroups, neuropsychological profiles have modest ability to distinguish patients with AD from those with SIVD.

Existing Pittsburgh Compound-B positron emission tomography thresholds are too high: statistical and pathological evaluation.

Amyloid-ß, a hallmark of Alzheimer's disease, begins accumulating up to two decades before the onset of dementia, and can be detected in vivo applying amyloid-ß positron emission tomography tracers such as carbon-11-labelled Pittsburgh compound-B. A variety of thresholds have been applied in the literature to define Pittsburgh compound-B positron emission tomography positivity, but the ability of these thresholds to detect early amyloid-ß deposition is unknown, and validation studies comparing Pittsburgh compound-B thresholds to post-mortem amyloid burden are lacking. In this study we first derived thresholds for amyloid positron emission tomography positivity using Pittsburgh compound-B positron emission tomography in 154 cognitively normal older adults with four complementary approaches: (i) reference values from a young control group aged between 20 and 30 years; (ii) a Gaussian mixture model that assigned each subject a probability of being amyloid-ß-positive or amyloid-ß-negative based on Pittsburgh compound-B index uptake; (iii) a k-means cluster approach that clustered subjects into amyloid-ß-positive or amyloid-ß-negative based on Pittsburgh compound-B uptake in different brain regions (features); and (iv) an iterative voxel-based analysis that further explored the spatial pattern of early amyloid-ß positron emission tomography signal. Next, we tested the sensitivity and specificity of the derived thresholds in 50 individuals who underwent Pittsburgh compound-B positron emission tomography during life and brain autopsy (mean time positron emission tomography to autopsy 3.1 ± 1.8 years). Amyloid at autopsy was classified using Consortium to Establish a Registry for Alzheimer's Disease (CERAD) criteria, unadjusted for age. The analytic approaches yielded low thresholds (standard uptake value ratiolow = 1.21, distribution volume ratiolow = 1.08) that represent the earliest detectable Pittsburgh compound-B signal, as well as high thresholds (standard uptake value ratiohigh = 1.40, distribution volume ratiohigh = 1.20) that are more conservative in defining Pittsburgh compound-B positron emission tomography positivity. In voxel-wise contrasts, elevated Pittsburgh compound-B retention was first noted in the medial frontal cortex, then the precuneus, lateral frontal and parietal lobes, and finally the lateral temporal lobe. When compared to post-mortem amyloid burden, low proposed thresholds were more sensitive than high thresholds (sensitivities: distribution volume ratiolow 81.0%, standard uptake value ratiolow 83.3%; distribution volume ratiohigh 61.9%, standard uptake value ratiohigh 62.5%) for CERAD moderate-to-frequent neuritic plaques, with similar specificity (distribution volume ratiolow 95.8%; standard uptake value ratiolow, distribution volume ratiohigh and standard uptake value ratiohigh 100.0%). A receiver operator characteristic analysis identified optimal distribution volume ratio (1.06) and standard uptake value ratio (1.20) thresholds that were nearly identical to the a priori distribution volume ratiolow and standard uptake value ratiolow. In summary, we found that frequently applied thresholds for Pittsburgh compound-B positivity (typically at or above distribution volume ratiohigh and standard uptake value ratiohigh) are overly stringent in defining amyloid positivity. Lower thresholds in this study resulted in higher sensitivity while not compromising specificity.

White matter hyperintensities and their penumbra lie along a continuum of injury in the aging brain.

BACKGROUND AND PURPOSE: Aging is accompanied by clinically silent cerebral white matter injury identified through white matter hyperintensities (WMHs) on fluid-attenuated inversion recovery (FLAIR)- and diffusion tensor imaging-based measures of white matter integrity. The temporal course of FLAIR and diffusion tensor imaging changes within WMHs and their less-injured periphery (ie, their penumbra), however, has not been fully studied. We used longitudinal diffusion tensor imaging and FLAIR to explore these changes. METHODS: One hundred fifteen participants, aged 73.7±6.7 years, received clinical evaluations and MRIs on 2 dates. WMHs and fractional anisotropy (FA) maps were produced from FLAIR and diffusion tensor imaging and coregistered to a standardized space. Each distinct WMH was categorized as growing, stagnant, or noncontiguous incident. The penumbra of each WMH was similarly categorized as corresponding to a stagnant, growing, or noncontiguous incident WMH. Linear mixed-effect models were used to assess whether FA and FLAIR measurements changed between baseline and follow-up and differed between tissue categories. RESULTS: Baseline FA differed significantly by tissue category, with the following ordering of categories from highest to lowest FA: penumbra of noncontiguous incident, then stagnant, then growing WMHs; noncontiguous incident, then stagnant, then growing WMHs. Despite differences in baseline values, all tissue categories experienced declines in FA over time. Only noncontiguous incident WMHs showed significant FLAIR signal increases over time, and FLAIR signal significantly decreased in stagnant WMHs. CONCLUSIONS: WMHs and their penumbra vary in severity and together span a continuous spectrum of white matter injury that worsens with time. FLAIR fails to capture this continuous injury process fully but does identify a subclass of lesions that seem to improve over time.

The role of carotid intima-media thickness in predicting longitudinal cognitive function in an older adult cohort.

BACKGROUND AND PURPOSE: Carotid atherosclerosis is a risk factor for cerebrovascular disease in older adults. Although age-related cognitive decline has been associated with cerebrovascular disease, not much is known about the consequences of carotid atherosclerosis on longitudinal cognitive function. This study examines the longitudinal relationship between atherosclerosis and cognition in a sample of non-demented older subjects using baseline measurements of carotid intima media thickness (CIMT) and annual cognitive measures of executive function (EXEC) and verbal memory (MEM). METHODS: Baseline measurements included CIMT derived from B-mode carotid artery ultrasound, structural T1-weighted images of white matter hypointensities (WMH), white matter lesions (WML), and cerebral infarct. Hypertension, low-density lipoprotein (LDL), diabetes, and waist to hip ratios (WHR) were included as covariates in our models to control for cerebrovascular risks and central adiposity. Annual composite scores of EXEC and MEM functions were derived from item response theory. Linear mixed models were used to model longitudinal cognitive change. RESULTS: A significant inverse relationship was found between baseline CIMT and annual EXEC score, but not annual MEM score. Subjects included in the highest 4th quartile of CIMT showed a rate of annual decline in EXEC score that was significant relative to subjects in lower quartile groups (p<0.01). The relationship between the 4th quartile of CIMT and annual EXEC score remained significant after independently adjusting for imaging measures of white matter injury and cerebral infarct. CONCLUSIONS: Older adult subjects with the highest index of CIMT showed an annual decline in EXEC scores that was significant relative to subjects with lower quartile measurements of CIMT, independent of our measures of white matter injury and cerebral infarct. Our findings suggest that elevated measures of CIMT may mark an atherosclerotic state, resulting in a decline in executive function and not memory in non-demented older adults.

Drosophila Hindsight and mammalian RREB-1 are evolutionarily conserved DNA-binding transcriptional attenuators.

The Drosophila Hindsight (hnt) gene encodes a C2H2-type Zinc-finger protein, HNT, that plays multiple developmental roles including control of embryonic germ band retraction and regulation of retinal cell fate and morphogenesis. While the developmental functions of the human HNT homolog, RREB-1, are unknown, it has been shown to function as a transcriptional modulator of several tumor suppressor genes. Here we investigate HNT's functional motifs, target genes and its regulatory abilities. We show that the C-terminal region of HNT, containing the last five of its 14 Zinc fingers, binds in vitro to DNA elements very similar to those identified for RREB-1. We map HNT's in vivo binding sites on salivary gland polytene chromosomes and define, at high resolution, where HNT is bound to two target genes, hnt itself and nervy (nvy). Data from both loss-of-function and over-expression experiments show that HNT attenuates the transcription of these two targets in a tissue-specific manner. RREB-1, when expressed in Drosophila, binds to the same polytene chromosome sites as HNT, attenuates expression of the hnt and nvy genes, and rescues the germ band retraction phenotype. HNT's ninth Zinc finger has degenerated or been lost in the vertebrate lineage. We show that a HNT protein mutant for this finger can also attenuate target gene expression and rescue germ band retraction. Thus HNT and RREB-1 are functional homologs at the level of DNA binding, transcriptional regulation and developmental control.

Everyday cognition in older adults: associations with neuropsychological performance and structural brain imaging.

The recently developed Everyday Cognition scales (ECog) measure multiple cognitively relevant functional domains (e.g., Everyday Memory, Everyday Language, Everyday Visuospatial abilities, and three everyday executive domains). The present study further evaluated the validity of the ECog by examining its relationship with objective measures of neuropsychological function, and neurobiological markers of disease as reflected by structural neuroimaging. Participants included 474 older adults (244 normals, 142 with MCI, 88 with dementia). The neuropsychological domains measured were episodic memory, semantic memory, spatial ability, and executive functioning. Brain MRI volumes included total brain (BV), hippocampus (HC) and dorsolateral prefrontal cortex (DLPFC). Neuropsychological measures of episodic memory and executive function were most consistently related to the ECog domains; spatial abilities had a specific relationship to the Everyday Visuospatial ECog domain. HC and BV volumes were related to most ECog domains, while DLPFC volume was independently related to two everyday executive domains (Everyday Planning and Everyday Organization). The pattern of associations varied somewhat as a function of diagnosis. Episodic memory and HC had more consistent associations with the ECog domains in older adults with MCI/dementia than in cognitively normal elderly.

Computerized measures of finger tapping: effects of hand dominance, age, and sex.

Computerized measures of digit tapping rate were obtained over 3 successive, 10-sec. periods in the right and left index fingers, from a community sample of 1,519 participants (ages 18 to 65 years; 607 men, 912 women). Differences between the dominant and non-dominant hands were found for tapping rate, movement initiation, and button down times, and the decline in tapping rate over the successive, 10-sec. periods. Declines were found in tapping rate in older participants in association with increased intertap variability. Men had higher tapping rates than women in all age ranges. The computerized finger tapping test is an efficient and precise measure of tapping speed and kinetics of potential utility in research and clinical studies of motor performance.

Regulation at Drosophila's Malic Enzyme highlights the complexity of transvection and its sensitivity to genetic background.

Transvection, a type of trans-regulation of gene expression in which regulatory elements on one chromosome influence elements on a paired homologous chromosome, is itself a complex biological phenotype subject to modification by genetic background effects. However, relatively few studies have explored how transvection is affected by distal genetic variation, perhaps because it is strongly influenced by local regulatory elements and chromosomal architecture. With the emergence of the "hub" model of transvection and a series of studies showing variation in transvection effects, it is becoming clear that genetic background plays an important role in how transvection influences gene transcription. We explored the effects of genetic background on transvection by performing two independent genome wide association studies (GWASs) using the Drosophila genetic reference panel (DGRP) and a suite of Malic enzyme (Men) excision alleles. We found substantial variation in the amount of transvection in the 149 DGRP lines used, with broad-sense heritability of 0.89 and 0.84, depending on the excision allele used. The specific genetic variation identified was dependent on the excision allele used, highlighting the complex genetic interactions influencing transvection. We focussed primarily on genes identified as significant using a relaxed P-value cutoff in both GWASs. The most strongly associated genetic variant mapped to an intergenic single nucleotide polymorphism (SNP), located upstream of Tiggrin (Tig), a gene that codes for an extracellular matrix protein. Variants in other genes, such transcription factors (CG7368 and Sima), RNA binding proteins (CG10418, Rbp6, and Rig), enzymes (AdamTS-A, CG9743, and Pgant8), proteins influencing cell cycle progression (Dally and Eip63E) and signaling proteins (Atg-1, Axo, Egfr, and Path) also associated with transvection in Men. Although not intuitively obvious how many of these genes may influence transvection, some have been previously identified as promoting or antagonizing somatic homolog pairing. These results identify several candidate genes to further explore in the understanding of transvection in Men and in other genes regulated by transvection. Overall, these findings highlight the complexity of the interactions involved in gene regulation, even in phenotypes, such as transvection, that were traditionally considered to be primarily influenced by local genetic variation.

Associations among vascular risk factors, carotid atherosclerosis, and cortical volume and thickness in older adults.

BACKGROUND AND PURPOSE: The purpose of this study was to investigate whether the Framingham Cardiovascular Risk Profile and carotid artery intima-media thickness are associated with cortical volume and thickness. METHODS: Consecutive subjects participating in a prospective cohort study of aging and mild cognitive impairment enriched for vascular risk factors for atherosclerosis underwent structural MRI scans at 3-T and 4-T MRI at 3 sites. Freesurfer (Version 5.1) was used to obtain regional measures of neocortical volumes (mm3) and thickness (mm). Multiple linear regression was used to determine the association of Framingham Cardiovascular Risk Profile and carotid artery intima-media thickness with cortical volume and thickness. RESULTS: One hundred fifty-two subjects (82 men) were aged 78 (±7) years, 94 had a clinical dementia rating of 0, 58 had a clinical dementia rating of 0.5, and the mean Mini-Mental State Examination was 28±2. Framingham Cardiovascular Risk Profile score was inversely associated with total gray matter volume and parietal and temporal gray matter volume (adjusted P<0.04). Framingham Cardiovascular Risk Profile was inversely associated with parietal and total cerebral gray matter thickness (adjusted P<0.03). Carotid artery intima-media thickness was inversely associated with thickness of parietal gray matter only (adjusted P=0.04). Including history of myocardial infarction or stroke and radiological evidence of brain infarction, or apolipoprotein E genotype did not alter relationships with Framingham Cardiovascular Risk Profile or carotid artery intima-media thickness. CONCLUSIONS: Increased cardiovascular risk was associated with reduced gray matter volume and thickness in regions also affected by Alzheimer disease independent of infarcts and apolipoprotein E genotype. These results suggest a "double hit" toward developing dementia when someone with incipient Alzheimer disease also has high cardiovascular risk.

White matter hyperintensity penumbra.

BACKGROUND AND PURPOSE: White matter hyperintensities (WMHs) are associated with progressive age-related cognitive decline and cardiovascular risk factors, but their biological relevance as indicators of generalized white matter injury is unclear. Diffusion tensor imaging provides more sensitive indications of subtle white matter disruption and can therefore clarify whether WMHs represent foci of generalized white matter damage that extends over a broader neighborhood. METHODS: Two hundred eight participants from the University of California, Davis Alzheimer's Disease Center received a comprehensive clinical evaluation and brain MRI including fluid-attenuated inversion recovery and diffusion tensor imaging sequences. Voxelwise maps of WMHs were produced from fluid-attenuated inversion recovery using a standardized WMH detection protocol. Fractional anisotropy maps were calculated from diffusion tensor imaging. All WMH and fractional anisotropy maps were coregistered to a standardized space. For each normal-appearing white matter voxel in each subject fluid-attenuated inversion recovery scan, a neighborhood white matter injury score was calculated that increased with increasing number and proximity of WMH in the vicinity of the normal-appearing white matter voxel. Fractional anisotropy was related to neighborhood white matter injury using a nonlinear mixed effect model controlling for relevant confounding factors. RESULTS: Fractional anisotropy was found to decrease as neighborhood white matter injury increased (ß = -0.0017/%, P < 0.0001) with an accelerated rate (P < 0.0001) for neighborhood white matter injury >0.4. An increase of 1% in neighborhood white matter injury score was associated with a decrease in mean fractional anisotropy of 0.012 (P < 0.001). CONCLUSIONS: WMH may represent foci of more widespread and subtle white matter changes rather than distinct, sharply delineated anatomic abnormalities. We use the term white matter hyperintensities penumbra to explain this phenomenon.

Cognitive activities during adulthood are more important than education in building reserve.

Cognitive reserve is thought to reflect life experiences. Which experiences contribute to reserve and their relative importance is not understood. Subjects were 652 autopsied cases from the Rush Memory and Aging Project and the Religious Orders Study. Reserve was defined as the residual variance of the regressions of cognitive factors on brain pathology and was captured in a latent variable that was regressed on potential determinants of reserve. Neuropathology variables included Alzheimer's disease markers, Lewy bodies, infarcts, microinfarcts, and brain weight. Cognition was measured with six cognitive domain scores. Determinants of reserve were socioeconomic status (SES), education, leisure cognitive activities at age 40 (CA40) and at study enrollment (CAbaseline) in late life. The four exogenous predictors of reserve were weakly to moderately inter-correlated. In a multivariate model, all except SES had statistically significant effects on Reserve, the strongest of which were CA40 (ß = .31) and CAbaseline (ß = .28). The Education effect was negative in the full model (ß = -.25). Results suggest that leisure cognitive activities throughout adulthood are more important than education in determining reserve. Discrepancies between cognitive activity and education may be informative in estimating late life reserve.

Neuropathological associates of multiple cognitive functions in two community-based cohorts of older adults.

Studies of neuropathology-cognition associations are not common and have been limited by small sample sizes, long intervals between autopsy and cognitive testing, and lack of breadth of neuropathology and cognition variables. This study examined domain-specific effects of common neuropathologies on cognition using data (N = 652) from two large cohort studies of older adults. We first identified dimensions of a battery of 17 neuropsychological tests, and regional measures of Alzheimer's disease (AD) neuropathology. We then evaluated how cognitive factors were related to dimensions of AD and additional measures of cerebrovascular and Lewy Body disease, and also examined independent effects of brain weight. All cognitive domains had multiple neuropathology determinants that differed by domain. Neocortical neurofibrillary tangles were the strongest predictors of most domains, while medial temporal tangles showed a weaker relationship with episodic memory. Neuritic plaques had relatively strong effects on multiple domains. Lewy bodies and macroscopic infarcts were associated with all domains, while microscopic infarcts had more limited associations. Brain weight was related to all domains independent of specific neuropathologies. Results show that cognition is complexly determined by multiple disease substrates. Neuropathological variables and brain weight contributed approximately a third to half of the explained variance in different cognitive domains.

Measuring cognitive reserve based on the decomposition of episodic memory variance.

In later adulthood brain pathology becomes common and trajectories of cognitive change are heterogeneous. Among the multiple determinants of late-life cognitive course, cognitive reserve has been proposed as an important factor that modifies or buffers the impact of brain pathology on cognitive function. This article presents and investigates a novel method for measuring and investigating such factors. The core concept is that in a population where pathology is common and variably present, 'reserve' may be defined as the difference between the cognitive performance predicted by an individual's level of pathology and that individual's actual performance. By this definition, people whose measured cognitive performance is better than predicted by pathology have high reserve, whereas those who perform worse than predicted have low reserve. To test this hypothesis, we applied a latent variable model to data from a diverse ageing cohort and decomposed the variance in a measure of episodic memory into three components, one predicted by demographics, one predicted by pathology as measured by structural MRI and a 'residual' or 'reserve' term that included all remaining variance. To investigate the plausibility of this approach, we then tested the residual component as an operational measure of reserve. Specific predictions about the effects of this putative reserve measure were generated from a general conceptual model of reserve. Each was borne from the results. The results show that the current level of reserve, as measured by this decomposition approach, modifies rates of conversion from mild cognitive impairment to dementia, modifies rates of longitudinal decline in executive function and, most importantly, attenuates the effect of brain atrophy on cognitive decline such that atrophy is more strongly associated with cognitive decline in subjects with low reserve than in those with high reserve. Decomposing the variance in cognitive function scores offers a promising new approach to the measure and study of cognitive reserve.

Cognitive decline in the elderly: an analysis of population heterogeneity.

BACKGROUND: studies of cognitive ageing at the group level suggest that age is associated with cognitive decline; however, there may be individual differences such that not all older adults will experience cognitive decline. OBJECTIVE: to evaluate patterns of cognitive decline in a cohort of older adults initially free of dementia. DESIGN, SETTING AND SUBJECTS: elderly Catholic clergy members participating in the Religious Orders Study were followed for up to 15 years. Cognitive performance was assessed annually. METHODS: performance on a composite global measure of cognition was analysed using random effects models for baseline performance and change over time. A profile mixture component was used to identify subgroups with different cognitive trajectories over the study period. RESULTS: from a sample of 1,049 participants (mean age 75 years), three subgroups were identified based on the distribution of baseline performance and change over time. The majority (65%) of participants belonged to a slow decline class that did not experience substantial cognitive decline over the observation period [-0.04 baseline total sample standard deviation (SD) units/year]. About 27% experienced moderate decline (-0.19 SD/year), and 8% belonged to a class experiencing rapid decline (-0.57 SD/year). A subsample analysis revealed that when substantial cognitive decline does occur, the magnitude and rate of decline is correlated with neuropathological processes. CONCLUSIONS: in this sample, the most common pattern of cognitive decline is extremely slow, perceptible on a time scale measured by decades, not years. While in need of cross validation, these findings suggest that cognitive changes associated with ageing may be minimal and emphasise the importance of understanding the full range of age-related pathologies that may diminish brain function.

The measurement of everyday cognition: development and validation of a short form of the Everyday Cognition scales.

BACKGROUND: This study describes the development and validation of a shortened version of the Everyday Cognition (ECog) scales [Tomaszewski Farias et al. Neuropsychology 2008;22:531-44], an informant-rated questionnaire designed to detect cognitive and functional decline. METHODS: External, convergent, and divergent validities and internal consistency were examined. Data were derived from informant ratings of 907 participants who were either cognitively normal, had mild cognitive impairment (MCI), or had dementia. RESULTS: Twelve items were included in the shortened version (ECog-12). The ECog-12 strongly correlated with established functional measures and neuropsychological scores, only weakly with age and education, and demonstrated high internal consistency. The ECog-12 showed excellent discrimination between the dementia and normal groups (area under the receiver operator characteristic curve = 0.95, CI = 0.94-0.97), and showed promise in discriminating normal older adults from those with any cognitive impairment (i.e., MCI or dementia). Discrimination between the MCI and normal groups was poor. CONCLUSIONS: The ECog-12 shows promise as a clinical tool for assisting clinicians in identifying individuals with dementia.

An experimental test of the effects of redacting grant applicant identifiers on peer review outcomes.

Background: Blinding reviewers to applicant identity has been proposed to reduce bias in peer review. Methods: This experimental test used 1200 NIH grant applications, 400 from Black investigators, 400 matched applications from White investigators, and 400 randomly selected applications from White investigators. Applications were reviewed by mail in standard and redacted formats. Results: Redaction reduced, but did not eliminate, reviewers' ability to correctly guess features of identity. The primary, preregistered analysis hypothesized a differential effect of redaction according to investigator race in the matched applications. A set of secondary analyses (not preregistered) used the randomly selected applications from White scientists and tested the same interaction. Both analyses revealed similar effects: Standard format applications from White investigators scored better than those from Black investigators. Redaction cut the size of the difference by about half (e.g. from a Cohen's d of 0.20-0.10 in matched applications); redaction caused applications from White scientists to score worse but had no effect on scores for Black applications. Conclusions: Grant-writing considerations and halo effects are discussed as competing explanations for this pattern. The findings support further evaluation of peer review models that diminish the influence of applicant identity. Funding: Funding was provided by the NIH.

20-hydroxyecdysone (20E) signaling regulates amnioserosa morphogenesis during Drosophila dorsal closure: EcR modulates gene expression in a complex with the AP-1 subunit, Jun.

Steroid hormones influence diverse biological processes throughout the animal life cycle, including metabolism, stress resistance, reproduction, and lifespan. In insects, the steroid hormone, 20-hydroxyecdysone (20E), is the central hormone regulator of molting and metamorphosis, and plays roles in tissue morphogenesis. For example, amnioserosa contraction, which is a major driving force in Drosophila dorsal closure (DC), is defective in embryos mutant for 20E biosynthesis. Here, we show that 20E signaling modulates the transcription of several DC participants in the amnioserosa and other dorsal tissues during late embryonic development, including zipper, which encodes for non-muscle myosin. Canonical ecdysone signaling typically involves the binding of Ecdysone receptor (EcR) and Ultraspiracle heterodimers to ecdysone-response elements (EcREs) within the promoters of responsive genes to drive expression. During DC, however, we provide evidence that 20E signaling instead acts in parallel to the JNK cascade via a direct interaction between EcR and the AP-1 transcription factor subunit, Jun, which together binds to genomic regions containing AP-1 binding sites but no EcREs to control gene expression. Our work demonstrates a novel mode of action for 20E signaling in Drosophila that likely functions beyond DC, and may provide further insights into mammalian steroid hormone receptor interactions with AP-1.