Yang An

National Institute on Aging, Baltimore, Maryland, United States

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Publications (80)475.96 Total impact

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    ABSTRACT: Despite considerable evidence for deleterious effects of aging on place learning and memory, less is known about the trajectory and the putative neural mechanisms of these decrements. The virtual Morris water task (vMWT) is a human analog of a nonhuman spatial navigation task. The present study investigated longitudinal changes in place learning in 51 healthy, nondemented adults (age 30–83 years) who completed the vMWT and a neuropsychological battery at 2 time-points (interval = ∼8 years). We also assessed cross-sectional associations between vMWT and brain structure, biochemical integrity, and standardized neuropsychological measures in a subset of 22 individuals who underwent magnetic resonance imaging at follow-up. Despite no longitudinal decrement in vMWT performance, there were cross-sectional age differences on the vMWT favoring younger adults. Negative associations were observed between vMWT latency and gray matter volumes in the right hippocampus, bilateral thalamus, and right medial orbitofrontal cortex and between vMWT latency and white matter fractional anisotropy in the bilateral uncinate fasciculus. Collectively, these results suggest a pattern of differences in the structural integrity of regions supporting successful navigation even in the absence of longitudinal performance decrements.
    No preview · Article · Mar 2016
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    ABSTRACT: We investigated whether: 1) serum levels of 25-hydroxyvitamin D [25(OH)D]; and 2) single nucleotide polymorphisms (SNPs) in the group-specific component (GC) gene regulating serum 25(OH)D levels are associated with cognition in older individuals; and 3) whether causal relationships exist between 25(OH)D and cognition during aging. Data from 1207 participants in the Baltimore Longitudinal Study of Aging were analyzed (mean follow-up 10.4 years) to test associations between serum 25(OH)D and cognition. Two GC SNPs were used to derive a composite genetic risk score associated with lower 25(OH)D concentrations. Lower serum 25(OH)D and higher GC composite scores were associated with lower executive function at baseline. Mendelian randomization analyses suggested a causal relationship between lower serum 25(OH)D and poorer executive function and psychomotor speed. The SNP score was also associated with lower performance on measures of visuospatial abilities at baseline but with attenuated declines over time in visuospatial abilities and executive function. Widespread associations between vitamin-D regulatory SNPs and cognition suggest a mechanistic basis for the relationship between serum 25(OH)D levels and cognition during aging.
    No preview · Article · Mar 2016
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    ABSTRACT: Age effects on cognitive functioning are well-documented, but effects of sex on trajectories of cognitive aging are less clear. We examined cognitive ability across a variety of measures for 1,065 to 2,127 participants (mean baseline age 64.1 to 69.7 years) from the Baltimore Longitudinal Study of Aging who were repeatedly tested over a mean follow-up interval of 3.0 to 9.0 years with a mean of 2.3 to 4.4 assessments. Memory and other cognitive tests were administered at each visit, assessing mental status, verbal learning and memory, figural memory, language, attention, perceptuomotor speed and integration, executive function, and visuospatial ability. Importantly, participants free from cognitive impairment at all time points were used in the analyses. Results showed that for all tests, higher age at baseline was significantly associated with lower scores, and performance declined over time. In addition, advancing age was associated with accelerated longitudinal declines in performance (trend for mental status). After adjusting for age, education, and race, sex differences were observed across most tests of specific cognitive abilities examined. At baseline, males outperformed females on the 2 tasks of visuospatial ability, and females outperformed males in most other tests of cognition. Sex differences in cognitive change over time indicated steeper rates of decline for men on measures of mental status, perceptuomotor speed and integration, and visuospatial ability, but no measures on which women showed significantly steeper declines. Our results highlight greater resilience to age-related cognitive decline in older women compared with men. (PsycINFO Database Record
    No preview · Article · Jan 2016 · Psychology and Aging
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    ABSTRACT: Recently, quantitative metabolomics identified a panel of 10 plasma lipids that were highly predictive of conversion to Alzheimer's disease (AD) in cognitively normal older individuals (n = 28, area under the curve [AUC] = 0.92, sensitivity/specificity of 90%/90%). We failed to replicate these findings in a substantially larger study from two independent cohorts—the Baltimore Longitudinal Study of Aging ([BLSA], n = 93, AUC = 0.642, sensitivity/specificity of 51.6%/65.7%) and the Age, Gene/Environment Susceptibility-Reykjavik Study ([AGES-RS], n = 100, AUC = 0.395, sensitivity/specificity of 47.0%/36.0%). In analyses applying machine learning methods to all 187 metabolite concentrations assayed, we find a modest signal in the BLSA with distinct metabolites associated with the preclinical and symptomatic stages of AD, whereas the same methods gave poor classification accuracies in the AGES-RS samples. We believe that ours is the largest blood biomarker study of preclinical AD to date. These findings underscore the importance of large-scale independent validation of index findings from biomarker studies with relatively small sample sizes.
    Full-text · Article · Jan 2016 · Alzheimer's and Dementia
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    Full-text · Conference Paper · Nov 2015
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    ABSTRACT: In MRI studies, linear multi-variate methods are often employed to identify regions or connections that are affected due to disease or normal aging. Such linear models inherently assume that there is a single, homogeneous abnormality pattern that is present in all affected individuals. While kernel-based methods can implicitly model a non-linear effect, and therefore the heterogeneity in the affected group, extracting and interpreting information about affected regions is difficult. In this paper, we present a method that explicitly models and captures heterogeneous patterns of change in the affected group relative to a reference group of controls. For this purpose, we use the Mixture-Of-Experts (MOE) framework, which combines unsupervised modeling of mixtures of distributions with supervised learning of classifiers. MOE approximates the non-linear boundary between the two groups with a piece-wise linear boundary, thus allowing discovery of multiple patterns of group differences. In the case of patient/control comparisons, each such pattern aims to capture a different dimension of a disease, and hence to identify patient subgroups. We validated our model using multiple simulation scenarios and performance measures. We applied this method to resting state functional MRI data from the Baltimore Longitudinal Study of Aging, to investigate heterogeneous effects of aging on brain function in cognitively normal older adults (>85 years) relative to a reference group of normal young to middle-aged adults (<60 years). We found strong evidence for the presence of two subgroups of older adults, with similar age distributions in each subgroup, but different connectivity patterns associated with aging. While both older subgroups showed reduced functional connectivity in the Default Mode Network (DMN), increases in functional connectivity within the pre-frontal cortex as well as the bilateral insula were observed only for one of the two subgroups. Interestingly, the subgroup showing this increased connectivity (unlike the other subgroup) was, cognitively similar at baseline to the young and middle-aged subjects in two of seven cognitive domains, and had a faster rate of cognitive decline in one of seven domains. These results suggest that older individuals whose baseline cognitive performance is comparable to that of younger individuals recruit their "cognitive reserve" later in life, to compensate for reduced connectivity in other brain regions.
    No preview · Article · Nov 2015 · NeuroImage
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    ABSTRACT: Introduction: Individualized estimates of age at detectable amyloid-beta (Aβ) accumulation, distinct from amyloid positivity, allow for analysis of onset age of Aβ accumulation as an outcome measure to understand risk factors. Methods: Using longitudinal Pittsburgh compound B (PiB) positron emission tomography data from Baltimore Longitudinal Study of Aging, we estimated the age at which each PiB+ individual began accumulating Aβ. We used survival analysis methods to quantify risk of accumulating Aβ and differences in onset age of Aβ accumulation in relation to APOE ε4 status and sex among 36 APOE ε4 carriers and 83 noncarriers. Results: Age at onset of Aβ accumulation for the APOE ε4- and ε4+ groups was 73.1 and 60.7, respectively. APOE ε4 positivity conferred a threefold risk of accumulating Aβ after adjusting for sex and education. Discussion: Estimation of onset age of amyloid accumulation may help gauge treatment efficacy in interventions to delay symptom onset in Alzheimer's disease.
    No preview · Article · Nov 2015 · Alzheimer's & dementia: the journal of the Alzheimer's Association
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    ABSTRACT: Abstract: Background: Although observational studies have shown Vitamin-D deficiency is associated with increased risk of all-cause dementia, Alzheimer’s disease and age-associated cognitive decline, these results may be influenced by confounding and reverse causation. Examining the relationship between genetic variants regulating vitamin-D levels and brain function/structure may overcome some of these limitations. Methods: Data from non-demented participants in the Baltimore Longitudinal Study of Aging (BLSA), were used in the current analyses (n=848, mean follow-up interval 10.4 years). Serum concentrations of 25-hydroxyvitamin D [25(OH)D] and single nucleotide polymorphisms (SNPs) in the group-specific component (GC) (rs17467825, rs2282679, rs2298850, rs3755967) gene were examined for associations with cognitive performance using linear mixed models. A composite score of the 4 GC SNPs was created. In data from the BLSA neuroimaging substudy (BLSA-NI, n=120, mean follow-up interval 7.8 years), we tested whether GC SNPs influenced changes in brain volumes during aging. Results: As reported previously, GC SNPs were associated with serum concentration of [25(OH)D]. The minor allele of each GC SNP was associated with a 3.68 nmol/L (95% CI -4.72, -2.65) reduction in serum 25(OH)D. Lower serum [25(OH)D] concentration was associated with poorer performance on the clock drawing to command task at baseline (β=0.02, p=.007). At baseline, the composite GC SNP minor alleles were associated with poorer performance on the clock drawing (3:25 (β=-0.74, p=.01), Boston naming (BNT, β=-0.50, p=.01), Wide Range Achievement Test word reading subcomponent (WRAT; β=-0.44, p=.04) and Rey-Osterrieth Complex Figure-total copy (β=-0.85, p=.02) tests. In longitudinal analyses, minor alleles of GC SNPs were associated with attenuated declines on clock drawing, BNT, WRAT and Rey copy tests. Composite GC SNPs were associated with significantly faster rates of decline in volumes of total gray matter, middle occipital and middle frontal gyri, as well as the cuneus. GCs SNPs were marginally associated with faster declines in occipital gray matter. Conclusions: Vitamin-D exerts both state and trait-dependent effects on brain function and structure during aging. The widespread associations between vitamin-D regulatory SNPs and cognition as well as longitudinal rates of brain atrophy, suggests a mechanistic basis for the relationship between vitamin-D and mental health outcomes during aging.
    No preview · Conference Paper · Nov 2015
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    ABSTRACT: Understanding how midlife risk factors influence age at onset (AAO) of Alzheimer's disease (AD) may provide clues to delay disease expression. Although midlife adiposity predicts increased incidence of AD, it is unclear whether it affects AAO and severity of Alzheimer's neuropathology. Using a prospective population-based cohort, Baltimore Longitudinal Study of Aging (BLSA), this study aims to examine the relationships between midlife body mass index (BMI) and (1) AAO of AD (2) severity of Alzheimer's neuropathology and (3) fibrillar brain amyloid deposition during aging. We analyzed data on 1394 cognitively normal individuals at baseline (8643 visits; average follow-up interval 13.9 years), among whom 142 participants developed incident AD. In two subsamples of BLSA, 191 participants underwent autopsy and neuropathological assessment, and 75 non-demented individuals underwent brain amyloid imaging. Midlife adiposity was derived from BMI data at 50 years of age. We find that each unit increase in midlife BMI predicts earlier onset of AD by 6.7 months (P=0.013). Higher midlife BMI was associated with greater Braak neurofibrillary but not CERAD (Consortium to Establish a Registry for Alzheimer's Disease) neuritic plaque scores at autopsy overall. Associations between midlife BMI and brain amyloid burden approached statistical significance. Thus, higher midlife BMI was also associated with greater fibrillar amyloid measured by global mean cortical distribution volume ratio (P=0.075) and within the precuneus (left, P=0.061; right, P=0.079). In conclusion, midlife overweight predicts earlier onset of AD and greater burden of Alzheimer's neuropathology. A healthy BMI at midlife may delay the onset of AD.Molecular Psychiatry advance online publication, 1 September 2015; doi:10.1038/mp.2015.129.
    No preview · Article · Sep 2015 · Molecular Psychiatry
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    ABSTRACT: To determine whether weight loss in older adults may be a marker of impending burden of multimorbidity regardless of initial weight, testing the hypotheses that obesity but not overweight in elderly adults is associated with greater number of diseases than normal weight and that obese older adults who lose weight over time have the greatest burden of multimorbidity. Longitudinal cohort study (Invecchiare in Chianti Study). Community. Individuals aged 60 and older at baseline followed for an average of 4 years (N = 1,025). Multimorbidity was measured as number of diagnosed diseases. Baseline body mass index (BMI) was categorized as normal weight (<25.0 kg/m(2) ), overweight (25.0-29.9 kg/m(2) ), and obese (≥30.0 kg/m(2) ). Loss of weight was defined as decrease over time in BMI of at least 0.15 kg/m(2) per year. Age, sex, and education were covariates. Baseline obesity was cross-sectionally associated with high multimorbidity and greater longitudinal increase of multimorbidity than normal weight (P = .005) and overweight (P < .001). Moreover, obese participants who lost weight over follow-up had a significantly greater increase in multimorbidity than other participants, including obese participants who maintained or gained weight over time (P = .005). In nonobese participants, changes in weight had no effect on changes in multimorbidity over time. Sensitivity analyses confirmed that one specific disease did not drive the association and that competing mortality did not bias the association. Loss of weight in obese older persons is a strong biomarker of impending expansion of multimorbidity. Older obese individuals who lose weight should receive thoughtful medical attention. © 2015, Copyright the Authors Journal compilation © 2015, The American Geriatrics Society.
    No preview · Article · Aug 2015 · Journal of the American Geriatrics Society
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    ABSTRACT: It has been increasingly recognized at the basic science level that perturbations in ceramide metabolism are associated with the development and progression of many age-related diseases. However, the translation of this work to the clinic has lagged behind. Understanding the factors longitudinally associated with plasma ceramides and dihydroceramides (DHCer) at the population level and how these lipid levels change with age, and by sex, is important for the clinical development of future therapeutics and biomarkers focused on ceramide metabolism. We, therefore, examined factors cross-sectionally and longitudinally associated with plasma concentrations of ceramides and DHCer among Baltimore Longitudinal Study of Aging participants (n = 992; 3960 total samples), aged 55 years and older, with plasma at a mean of 4.1 visits (range 2-6). Quantitative analyses were performed on a high-performance liquid chromatography-coupled electrospray ionization tandem mass spectrometer. Linear mixed models were used to assess the relationships between plasma ceramide and DHCer species and demographics, diseases, medications, and lifestyle factors. Women had higher plasma concentrations of most ceramide and DHCer species and showed steeper trajectories of age-related increases compared to men. Ceramides and DHCer were more associated with waist-hip ratio than body mass index. Plasma cholesterol and triglycerides, prediabetes, and diabetes were associated with ceramides and DHCer, but the relationship showed specificity to the acyl chain length and saturation. These results demonstrate the importance of examining the individual species of ceramides and DHCer, and of establishing whether intra-individual age- and sex-specific changes occur in synchrony to disease onset and progression. © 2015 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.
    No preview · Article · Jul 2015 · Aging cell
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    ABSTRACT: Diffusion tensor imaging (DTI) measures are commonly used as imaging markers to investigate individual differences in relation to behavioral and health-related characteristics. However, the ability to detect reliable associations in cross-sectional or longitudinal studies is limited by the reliability of the diffusion measures. Several studies have examined reliability of diffusion measures within (i.e. intra-site) and across (i.e. inter-site) scanners with mixed results. Our study compares the test-retest reliability of diffusion measures within and across scanners and field strengths in cognitively normal older adults with a follow-up interval less than 2.25 years. Intra-class correlation (ICC) and coefficient of variation (CoV) of fractional anisotropy (FA) and mean diffusivity (MD) were evaluated in sixteen white matter and twenty-six gray matter bilateral regions. The ICC for intra-site reliability (0.32 to 0.96 for FA and 0.18 to 0.95 for MD in white matter regions; 0.27 to 0.89 for MD and 0.03 to 0.79 for FA in gray matter regions) and inter-site reliability (0.28 to 0.95 for FA in white matter regions, 0.02 to 0.86 for MD in gray matter regions) with longer follow-up intervals were similar to earlier studies using shorter follow-up intervals. The reliability of across field strengths comparisons was lower than intra- and inter-site reliability. Within and across scanner comparisons showed that diffusion measures were more stable in larger white matter regions (>1500 mm(3)). For gray matter regions, the MD measure showed stability in specific regions and was not dependent on region size. Linear correction factor estimated from cross-sectional or longitudinal data improved the reliability across field strengths. Our findings indicate that investigations relating diffusion measures to external variables must consider variable reliability across the distinct regions of interest and that correction factors can be used to improve consistency of measurement across field strengths. An important result of this work is that inter-scanner and field strength effects can be partially mitigated with linear correction factors specific to regions of interest. These data-driven linear correction techniques can be applied in cross-sectional or longitudinal studies. Copyright © 2015. Published by Elsevier Inc.
    Full-text · Article · Jul 2015 · NeuroImage

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    ABSTRACT: Quantification of β-amyloid (Aβ) in vivo is often accomplished using the distribution volume ratio (DVR), based on a simplified ratio tissue model. We investigated the local relationships between DVR and cerebral blood flow (CBF), as well as relative blood flow (R1), in nondemented older adults. Fifty-five nondemented participants (mean age 78.5 years) in the Baltimore Longitudinal Study of Aging underwent (15)O-H2O PET CBF and dynamic (11)C-PiB-PET. (15)O-H2O PET images were normalized and smoothed using SPM5. A simplified reference tissue model with linear regression and spatial constraints was used to generate parametric DVR images. The DVR images were regressed on CBF images on a voxel-by-voxel basis using robust Biological Parametric Mapping, adjusting for age and sex (FDR P = 0.05, k=50). DVR images were also regressed on R1 images, a measure of the transport rate constant from vascular space to tissue. All analyses were performed in the entire sample, and in high and low tertiles of mean cortical DVR. Voxel-based analyses showed that increased DVR is associated with increased CBF in frontal, parietal, temporal, and occipital cortices. However, this association appears to spare regions that typically show early β-amyloid (Aβ) deposition. A more robust relationship between DVR and CBF was observed in the lowest tertile of DVR, i.e., negligible cortical Aβ load, compared to the highest tertile of cortical DVR and Aβ load. Spatial distributions of the DVR-CBF and DVR-R1 correlations showed similar patterns. No reliable negative voxel-wise relationships between DVR and CBF or R1 were observed. Robust associations between DVR and CBF at negligible Aβ levels, together with similar spatial distributions of DVR-CBF and DVR-R1 correlations, suggest that regional distribution of DVR reflects blood flow and tracer influx rather than pattern of Aβ deposition in those with minimal Aβ load. DVR-CBF associations in individuals with higher DVR are more likely to reflect true associations between patterns of Aβ deposition and CBF or neural activity. These findings have important implications for analysis and interpretation of voxel-wise correlations with external variables in individuals with varying amounts of Aβ load. Copyright © 2015 by the Society of Nuclear Medicine and Molecular Imaging, Inc.
    No preview · Article · May 2015 · Journal of Nuclear Medicine
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    ABSTRACT: Apolipoprotein E (APOE) genotype influences onset age of Alzheimer's disease but effects on disease progression are less clear. We investigated amyloid-β (Aβ) levels and change in relationship to APOE genotype, using 2 different measures of Aβ in 2 different longitudinal cohorts. Aβ accumulation was measured using positron emission tomography (PET) imaging and (11)C-Pittsburgh compound-B (PiB) in 113 Baltimore Longitudinal Study of Aging participants (mean age 77.3 years; 107 normal, 6 cognitively impaired) and cerebral spinal fluid (CSF) Aβ1-42 assays in 207 BIOCARD study participants (mean age 62 years; 195 normal, 12 cognitively impaired). Participants in both cohorts had up to 7 serial assessments (mean 2.3-2.4). PET-PiB retention increased and CSF Aβ1-42 declined longitudinally. APOE ε4 was significantly associated with higher PET-PiB retention and lower CSF Aβ1-42, independent of age and sex, but APOE genotype did not significantly affect Aβ change over time. APOE ε4 carriers may be further along in the disease process, consistent with earlier brain Aβ deposition and providing a biological basis for APOE genotype effects on onset age of Alzheimer's disease. Copyright © 2015 Elsevier Inc. All rights reserved.
    Full-text · Article · Apr 2015 · Neurobiology of aging
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    ABSTRACT: Memory performance in older persons can reflect genetic influences on cognitive function and dementing processes. We aimed to identify genetic contributions to verbal declarative memory in a community setting. We conducted genome-wide association studies for paragraph or word list delayed recall in 19 cohorts from the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium, comprising 29,076 dementia- and stroke-free individuals of European descent, aged ≥45 years. Replication of suggestive associations (p < 5 × 10(-6)) was sought in 10,617 participants of European descent, 3811 African-Americans, and 1561 young adults. rs4420638, near APOE, was associated with poorer delayed recall performance in discovery (p = 5.57 × 10(-10)) and replication cohorts (p = 5.65 × 10(-8)). This association was stronger for paragraph than word list delayed recall and in the oldest persons. Two associations with specific tests, in subsets of the total sample, reached genome-wide significance in combined analyses of discovery and replication (rs11074779 [HS3ST4], p = 3.11 × 10(-8), and rs6813517 [SPOCK3], p = 2.58 × 10(-8)) near genes involved in immune response. A genetic score combining 58 independent suggestive memory risk variants was associated with increasing Alzheimer disease pathology in 725 autopsy samples. Association of memory risk loci with gene expression in 138 human hippocampus samples showed cis-associations with WDR48 and CLDN5, both related to ubiquitin metabolism. This largest study to date exploring the genetics of memory function in ~40,000 older individuals revealed genome-wide associations and suggested an involvement of immune and ubiquitin pathways. Copyright © 2014 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.
    Full-text · Article · Nov 2014 · Biological psychiatry
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    ABSTRACT: Excessively elevated resting metabolic rate (RMR) for persons of a certain age, sex, and body composition is a mortality risk factor. Whether elevated RMR constitutes an early marker of health deterioration in older adult has not been fully investigated. Using data from the Baltimore Longitudinal Study of Aging, we hypothesized that higher RMR (i) was cross-sectionally associated with higher multimorbidity and (ii) predicted higher multimorbidity in subsequent follow-ups. The analysis included 695 Baltimore Longitudinal Study of Aging participants, aged 60 or older at baseline, of whom 248 had follow-up data available 2 years later and 109 four years later. Multimorbidity was assessed as number of chronic diseases. RMR was measured by indirect calorimetry and was tested in regression analyses adjusted for covariates age, sex, and dual-energy x-ray absorptiometry-measured total body fat mass and lean mass. Baseline RMR and multimorbidity were positively associated, independent of covariates (p = .002). Moreover, in a three-wave bivariate autoregressive cross-lagged model adjusted for covariates, higher prior RMR predicted greater future multimorbidity above and beyond the cross-sectional and autoregressive associations (p = .034). RMR higher than expected, given age, sex, and body composition, predicts future higher multimorbidity in older adults and may be used as early biomarker of impending health deterioration. Replication and the development of normative data are required for clinical translation. Published by Oxford University Press on behalf of the Gerontological Society of America 2014.
    Full-text · Article · Nov 2014 · The Journals of Gerontology Series A Biological Sciences and Medical Sciences

Publication Stats

1k Citations
475.96 Total Impact Points

Institutions

  • 2006-2015
    • National Institute on Aging
      • • Laboratory of Behavioral Neuroscience
      • • Laboratory of Personality and Cognition (LPC)
      Baltimore, Maryland, United States
  • 2012-2014
    • University of Maryland, Baltimore
      Baltimore, Maryland, United States
  • 2009-2012
    • MedStar Health Research Institute
      هایتسویل، مریلند, Maryland, United States
  • 2011
    • Boston University
      • Department of Biostatistics
      Boston, Massachusetts, United States