Association of white matter hyperintensities and gray matter volume with cognition in older individuals without cognitive impairment

Both presence of white matter hyperintensities (WMH) and smaller total gray matter volume on brain magnetic resonance imaging (MRI) are common findings in old age, and contribute to impaired cognition. We tested whether total WMH volume and gray matter volume had independent associations with cognition in community-dwelling individuals without dementia or mild cognitive impairment (MCI). We used data from participants of the Rush Memory and Aging Project. Brain MRI was available in 209 subjects without dementia or MCI (mean age 80; education = 15 years; 74 % women). WMH and gray matter were automatically segmented, and the total WMH and gray matter volumes were measured. Both MRI-derived measures were normalized by the intracranial volume. Cognitive data included composite measures of five different cognitive domains, based on 19 individual tests. Linear regression analyses, adjusted for age, sex, and education, were used to examine the relationship of logarithmically-transformed total WMH volume and of total gray matter volume to cognition. Larger total WMH volumes were associated with lower levels of perceptual speed (p < 0.001), but not with episodic memory, semantic memory, working memory, or visuospatial abilities (all p > 0.10). Smaller total gray matter volumes were associated with lower levels of perceptual speed (p = 0.013) and episodic memory (p = 0.001), but not with the other three cognitive domains (all p > 0.14). Larger total WMH volume was correlated with smaller total gray matter volume (p < 0.001). In a model with both MRI-derived measures included, the relation of WMH to perceptual speed remained significant (p < 0.001), while gray matter volumes were no longer related (p = 0.14). This study of older community-dwelling individuals without overt cognitive impairment suggests that the association of larger total WMH volume with lower perceptual speed is independent of total gray matter volume. These results help elucidate the pathological processes leading to lower cognitive function in aging

Associations between Quantitative Mobility Measures Derived from Components of Conventional Mobility Testing and Parkinsonian Gait in Older Adults

Objective: To provide objective measures which characterize mobility in older adults assessed in the community setting and to examine the extent to which these measures are associated with parkinsonian gait. Methods: During conventional mobility testing in the community-setting, 351 ambulatory non-demented Memory and Aging Project participants wore a belt with a whole body sensor that recorded both acceleration and angular velocity in 3 directions. We used measures derived from these recordings to quantify 5 subtasks including a) walking, b) transition from sit to stand, c) transition from stand to sit, d) turning and e) standing posture. Parkinsonian gait and other mild parkinsonian signs were assessed with a modified version of the original Unified Parkinson’s Disease Rating Scale (mUPDRS). Results: In a series of separate regression models which adjusted for age and sex, all 5 mobility subtask measures were associated with parkinsonian gait and accounted for 2% to 32% of its variance. When all 5 subtask measures were considered in a single model, backward elimination showed that measures of walking sit to stand and turning showed independent associations with parkinsonian gait and together accounted for more than 35% of its variance. Cross-validation using data from a 2nd group of 258 older adults showed similar results. In similar analyses, only walking was associated with bradykinesia and sway with tremor. Interpretation Quantitative mobility subtask measures vary in their associations with parkinsonian gait scores and other parkinsonian signs in older adults. Quantifying the different facets of mobility has the potential to facilitate the clinical characterization and understanding the biologic basis for impaired mobility in older adults

Gas-Phase Oxygen Gradients in Strongly Interacting Galaxies: I. Early-Stage Interactions

A consensus is emerging that interacting galaxies show depressed nuclear gas metallicities compared to isolated star-forming galaxies. Simulations suggest that this nuclear underabundance is caused by interaction-induced inflow of metal-poor gas, and that this inflow concurrently flattens the radial metallicity gradients in strongly interacting galaxies. We present metallicities of over 300 HII regions in a sample of 16 spirals that are members of strongly interacting galaxy pairs with mass ratio near unity. The deprojected radial gradients in these galaxies are about half of those in a control sample of isolated, late-type spirals. Detailed comparison of the gradients with simulations show remarkable agreement in gradient distributions, the relationship between gradients and nuclear underabundances, and the shape of profile deviations from a straight line. Taken together, this evidence conclusively demonstrates that strongly interacting galaxies at the present day undergo nuclear metal dilution due to gas inflow, as well as significant flattening of their gas-phase metallicity gradients, and that current simulations can robustly reproduce this behavior at a statistical level.Comment: Accepted for publication in Ap

Use of low-dose oral theophylline as an adjunct to inhaled corticosteroids in preventing exacerbations of chronic obstructive pulmonary disease: study protocol for a randomised controlled trial.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is associated with high morbidity, mortality, and health-care costs. An incomplete response to the anti-inflammatory effects of inhaled corticosteroids is present in COPD. Preclinical work indicates that 'low dose' theophylline improves steroid responsiveness. The Theophylline With Inhaled Corticosteroids (TWICS) trial investigates whether the addition of 'low dose' theophylline to inhaled corticosteroids has clinical and cost-effective benefits in COPD. METHOD/DESIGN: TWICS is a randomised double-blind placebo-controlled trial conducted in primary and secondary care sites in the UK. The inclusion criteria are the following: an established predominant respiratory diagnosis of COPD (post-bronchodilator forced expiratory volume in first second/forced vital capacity [FEV1/FVC] of less than 0.7), age of at least 40 years, smoking history of at least 10 pack-years, current inhaled corticosteroid use, and history of at least two exacerbations requiring treatment with antibiotics or oral corticosteroids in the previous year. A computerised randomisation system will stratify 1424 participants by region and recruitment setting (primary and secondary) and then randomly assign with equal probability to intervention or control arms. Participants will receive either 'low dose' theophylline (Uniphyllin MR 200 mg tablets) or placebo for 52 weeks. Dosing is based on pharmacokinetic modelling to achieve a steady-state serum theophylline of 1-5 mg/l. A dose of theophylline MR 200 mg once daily (or placebo once daily) will be taken by participants who do not smoke or participants who smoke but have an ideal body weight (IBW) of not more than 60 kg. A dose of theophylline MR 200 mg twice daily (or placebo twice daily) will be taken by participants who smoke and have an IBW of more than 60 kg. Participants will be reviewed at recruitment and after 6 and 12 months. The primary outcome is the total number of participant-reported COPD exacerbations requiring oral corticosteroids or antibiotics during the 52-week treatment period. DISCUSSION: The demonstration that 'low dose' theophylline increases the efficacy of inhaled corticosteroids in COPD by reducing the incidence of exacerbations is relevant not only to patients and clinicians but also to health-care providers, both in the UK and globally. TRIAL REGISTRATION: Current Controlled Trials ISRCTN27066620 was registered on Sept. 19, 2013, and the first subject was randomly assigned on Feb. 6, 2014

Large-scale associations between the leukocyte transcriptome and BOLD responses to speech differ in autism early language outcome subtypes.

Heterogeneity in early language development in autism spectrum disorder (ASD) is clinically important and may reflect neurobiologically distinct subtypes. Here, we identified a large-scale association between multiple coordinated blood leukocyte gene coexpression modules and the multivariate functional neuroimaging (fMRI) response to speech. Gene coexpression modules associated with the multivariate fMRI response to speech were different for all pairwise comparisons between typically developing toddlers and toddlers with ASD and poor versus good early language outcome. Associated coexpression modules were enriched in genes that are broadly expressed in the brain and many other tissues. These coexpression modules were also enriched in ASD-associated, prenatal, human-specific, and language-relevant genes. This work highlights distinctive neurobiology in ASD subtypes with different early language outcomes that is present well before such outcomes are known. Associations between neuroimaging measures and gene expression levels in blood leukocytes may offer a unique in vivo window into identifying brain-relevant molecular mechanisms in ASD

Two novel loci, COBL and SLC10A2, for Alzheimer's disease in African Americans

INTRODUCTION: African Americans' (AAs) late-onset Alzheimer's disease (LOAD) genetic risk profile is incompletely understood. Including clinical covariates in genetic analyses using informed conditioning might improve study power. METHODS: We conducted a genome-wide association study (GWAS) in AAs employing informed conditioning in 1825 LOAD cases and 3784 cognitively normal controls. We derived a posterior liability conditioned on age, sex, diabetes status, current smoking status, educational attainment, and affection status, with parameters informed by external prevalence information. We assessed association between the posterior liability and a genome-wide set of single-nucleotide polymorphisms (SNPs), controlling for APOE and ABCA7, identified previously in a LOAD GWAS of AAs. RESULTS: Two SNPs at novel loci, rs112404845 (P = 3.8 × 10-8), upstream of COBL, and rs16961023 (P = 4.6 × 10-8), downstream of SLC10A2, obtained genome-wide significant evidence of association with the posterior liability. DISCUSSION: An informed conditioning approach can detect LOAD genetic associations in AAs not identified by traditional GWAS

The ATLAS3D project - XXIX : The new look of early-type galaxies and surrounding fields disclosed by extremely deep optical images

Date of Acceptance: 25/09/2014Galactic archaeology based on star counts is instrumental to reconstruct the past mass assembly of Local Group galaxies. The development of new observing techniques and data reduction, coupled with the use of sensitive large field of view cameras, now allows us to pursue this technique in more distant galaxies exploiting their diffuse low surface brightness (LSB) light. As part of the ATLAS3D project, we have obtained with the MegaCam camera at the Canada-France-Hawaii Telescope extremely deep, multiband images of nearby early-type galaxies (ETGs). We present here a catalogue of 92 galaxies from the ATLAS3D sample, which are located in low- to medium-density environments. The observing strategy and data reduction pipeline, which achieve a gain of several magnitudes in the limiting surface brightness with respect to classical imaging surveys, are presented. The size and depth of the survey are compared to other recent deep imaging projects. The paper highlights the capability of LSB-optimized surveys at detecting new prominent structures that change the apparent morphology of galaxies. The intrinsic limitations of deep imaging observations are also discussed, among those, the contamination of the stellar haloes of galaxies by extended ghost reflections, and the cirrus emission from Galactic dust. The detection and systematic census of fine structures that trace the present and past mass assembly of ETGs are one of the prime goals of the project. We provide specific examples of each type of observed structures - tidal tails, stellar streams and shells - and explain how they were identified and classified. We give an overview of the initial results. The detailed statistical analysis will be presented in future papers.Peer reviewedFinal Accepted Versio