[Show abstract][Hide abstract] ABSTRACT: Genome-wide association studies of 146 plasma protein levels in 818 individuals revealed 56 genome-wide significant associations (28 novel) with 47 analytes. Loci associated with plasma levels of 39 proteins tested have been previously associated with various complex traits such as heart disease, inflammatory bowel disease, Type 2 diabetes, and multiple sclerosis. These data suggest that these plasma protein levels may constitute informative endophenotypes for these complex traits. We found three potential pleiotropic genes: ABO for plasma SELE and ACE levels, FUT2 for CA19-9 and CEA plasma levels, and APOE for ApoE and CRP levels. We also found multiple independent signals in loci associated with plasma levels of ApoH, CA19-9, FetuinA, IL6r, and LPa. Our study highlights the power of biological traits for genetic studies to identify genetic variants influencing clinically relevant traits, potential pleiotropic effects, and complex disease associations in the same locus.
Full-text · Article · Jan 2016 · Scientific Reports
[Show abstract][Hide abstract] ABSTRACT: Although cigarette smoking remains the most common risk factor for heart disease among the young, few studies have explored the relationship of smoking with heart disease mortality risk among young people. This prospective study assesses the risk and burden of all heart disease (HD) and coronary heart disease (CHD) mortality associated with smoking among younger adults from a nationally representative sample of the United States.
National Health Interview Survey respondents' data from 1997-2004 were linked to their death records through 2006. The analyses were restricted to individuals 18 to 44 years of age during follow up (n = 121,284). Cox proportional hazard ratios (HR) were estimated with adjustment for sample weights and design effects. Attributable fractions (AF) of smoking were calculated.
After controlling for age, race, body mass index, history of hypertension and diabetes, and leisure time physical activity, current smoking related CHD mortality HR was 14.6 [95 % confidence interval or CI, 3.3-64.9] for females and 3.6 [95 % CI, 1.2-10.4] for males. The HR for all HD mortality was 3.1 [95 % CI, 1.3-7.6] for females and 2.4 [95 % CI, 1.2-4.7] for males. The AF of smoking for CHD deaths for female and male were 0.58 and 0.54 respectively. The AF of all HD mortality was 0.31 for male and 0.32 for female. The mean estimates of all HD deaths attributable to smoking during 1997-2006 among this age group were 52,214, of which 45,147 were CHD deaths.
Even after adjustment for multiple risk factors and without addressing passive smoking, our result showed a strong relationship between smoking and HD and CHD mortality among young adults that is likely causal.
Full-text · Article · Dec 2015 · Tobacco Induced Diseases
[Show abstract][Hide abstract] ABSTRACT: The aim of the study was to examine the association of different measures of obesity (body mass index or BMI, waist circumference or WC, waist to hip ratio or WHR and waist height ratio or WHtR) with coronary heart disease (CHD) in a Bangladeshi population. The study included 189 hospitalized CHD cases (133 men and 52 women) and 201 controls (137 men and 68 women). Logistic regression was done to assess the associations between obesity and CHD. The mean age was 53.1 ± 8.3 for men and 51.9 ± 8.4 for women. After adjustment for confounders the odds ratio (OR) of CHD for men was 1.69 (95% CI, 1.24-2.32), 1.94 (95% CI 1.40-2.70), and 1.32 (95% CI, 1.01-2.16) per 1 standard deviation (SD) increase in BMI, WC, and WHtR respectively. The OR for women was 2.64 (CI, 1.61-4.34), 1.82 (95% CI 1.12-2.95), 2.32 (95% CI, 1.36-3.96), and 1.94 (95% CI, 1.23-3.07) per 1 SD increase in BMI, WC, WHtR and WHR respectively. Since both total obesity and abdominal adiposity were associated with development of CHD and since measurement of WC and BMI are inexpensive, both should be included in the clinical setting for CHD risk assessment for this group of population.
[Show abstract][Hide abstract] ABSTRACT: Older adults with early forms of neurodegenerative disease are at risk for functional disability, which is often defined by the loss of independence in instrumental activities of daily living (IADLs). The current study investigated the influence of mild changes in everyday functional abilities (referred to as functional limitations) on risk for development of incident functional disability. A total of 407 participants, who were considered cognitively normal or diagnosed with mild cognitive impairment (MCI) at baseline, were followed longitudinally over an average 4.1 years (range=0.8–9.2 years). Informant-based ratings from the Everyday Cognition (ECog; Farias et al., 2008) and the Instrumental Activities of Daily Living (Lawton & Brody, 1969) scales assessed the degree of functional limitations and incident IADL disability, respectively. Cox proportional hazards models revealed that more severe functional limitations (as measured by the Total ECog score) at baseline were associated with approximately a four-fold increased risk of developing IADL disability a few years later. Among the ECog domains, functional limitations in Everyday Planning, Everyday Memory, and Everyday Visuospatial domains were associated with the greatest risk of incident functional disability. These results remained robust even after controlling for participants’ neuropsychological functioning on tests of executive functions and episodic memory. Current findings indicate that early functional limitations have prognostic value in identifying older adults at risk for developing functional disability. Findings highlight the importance of developing interventions to support everyday abilities related to memory, executive function, and visuospatial skills in an effort to delay loss of independence in IADLs. (
No preview · Article · Sep 2015 · Journal of the International Neuropsychological Society
[Show abstract][Hide abstract] ABSTRACT: Importance
Vitamin D (VitD) deficiency is associated with brain structural abnormalities, cognitive decline, and incident dementia.Objective
To assess associations between VitD status and trajectories of change in subdomains of cognitive function in a cohort of ethnically diverse older adults.Design, Setting, and Participants
Longitudinal multiethnic cohort study of 382 participants in an outpatient clinic enrolled between February 2002 and August 2010 with baseline assessment and yearly follow-up visits. Serum 25-hydroxyvitamin D (25-OHD) was measured, with VitD status defined as the following: deficient, less than 12 ng/mL (to convert to nanomoles per liter, multiply by 2.496); insufficient, 12 to less than 20 ng/mL; adequate, 20 to less than 50 ng/mL; or high, 50 ng/mL or higher. Subdomains of cognitive function were assessed using the Spanish and English Neuropsychological Assessment Scales. Associations were evaluated between 25-OHD levels (as continuous and categorical [deficient, insufficient, or adequate]) and trajectories of cognitive decline.Main Outcomes and Measures
Serum 25-OHD levels, cognitive function, and associations between 25-OHD levels and trajectories of cognitive decline.Results
Participants (N = 382 at baseline) had a mean (SD) age of 75.5 (7.0) years; 61.8% were women; and 41.4% were white, 29.6% African American, 25.1% Hispanic, and 3.9% other race/ethnicity. Diagnosis at enrollment included 17.5% with dementia, 32.7% with mild cognitive impairment, and 49.5% cognitively normal. The mean (SD) 25-OHD level was 19.2 (11.7) ng/mL, with 26.2% of participants being VitD deficient and 35.1% insufficient. The mean (SD) 25-OHD levels were significantly lower for African American and Hispanic participants compared with white participants (17.9 [15.8] and 17.2 [8.4] vs 21.7 [10.0] ng/mL, respectively; P < .001 for both). The mean (SD) 25-OHD levels were similarly lower in the dementia group compared with the mild cognitive impairment and cognitively normal groups (16.2 [9.4] vs 20.0 [10.3] and 19.7 [13.1] ng/mL, respectively; P = .006). The mean (SD) follow-up was 4.8 (2.5) years. Rates of decline in episodic memory and executive function among VitD-deficient (episodic memory: β = −0.04 [SE = 0.02], P = .049; executive function: β = −0.05 [SE = 0.02], P = .01) and VitD-insufficient (episodic memory: β = −0.06 [SE = 0.02], P < .001; executive function: β = −0.04 [SE = 0.02], P = .008) participants were greater than those with adequate status after controlling for age, sex, education, ethnicity, body mass index, season of blood draw, vascular risk, and apolipoprotein E4 genotype. Vitamin D status was not significantly associated with decline in semantic memory or visuospatial ability. Exclusion of participants with dementia did not substantially affect the associations between VitD status and rates of cognitive decline.Conclusions and Relevance
Low VitD status was associated with accelerated decline in cognitive function domains in ethnically diverse older adults, including African American and Hispanic individuals who exhibited a high prevalence of VitD insufficiency or deficiency. It remains to be determined whether VitD supplementation slows cognitive decline.
[Show abstract][Hide abstract] ABSTRACT: The Alzheimer's Disease Neuroimaging Initiative (ADNI) is an ongoing, longitudinal, multicenter study designed to develop clinical, imaging, genetic, and biochemical biomarkers for the early detection and tracking of Alzheimer's disease (AD). The initial study, ADNI-1, enrolled 400 subjects with early mild cognitive impairment (MCI), 200 with early AD, and 200 cognitively normal elderly controls. ADNI-1 was extended by a 2-year Grand Opportunities grant in 2009 and by a competitive renewal, ADNI-2, which enrolled an additional 550 participants and will run until 2015. This article reviews all papers published since the inception of the initiative and summarizes the results to the end of 2013. The major accomplishments of ADNI have been as follows: (1) the development of standardized methods for clinical tests, magnetic resonance imaging (MRI), positron emission tomography (PET), and cerebrospinal fluid (CSF) biomarkers in a multicenter setting; (2) elucidation of the patterns and rates of change of imaging and CSF biomarker measurements in control subjects, MCI patients, and AD patients. CSF biomarkers are largely consistent with disease trajectories predicted by β-amyloid cascade (Hardy, J Alzheimer's Dis 2006;9(Suppl 3):151-3) and tau-mediated neurodegeneration hypotheses for AD, whereas brain atrophy and hypometabolism levels show predicted patterns but exhibit differing rates of change depending on region and disease severity; (3) the assessment of alternative methods of diagnostic categorization. Currently, the best classifiers select and combine optimum features from multiple modalities, including MRI, [18F]-fluorodeoxyglucose-PET, amyloid PET, CSF biomarkers, and clinical tests; (4) the development of blood biomarkers for AD as potentially noninvasive and low-cost alternatives to CSF biomarkers for AD diagnosis and the assessment of α-syn as an additional biomarker; (5) the development of methods for the early detection of AD. CSF biomarkers, β-amyloid 42 and tau, as well as amyloid PET may reflect the earliest steps in AD pathology in mildly symptomatic or even nonsymptomatic subjects and are leading candidates for the detection of AD in its preclinical stages; (6) the improvement of clinical trial efficiency through the identification of subjects most likely to undergo imminent future clinical decline and the use of more sensitive outcome measures to reduce sample sizes. Multimodal methods incorporating APOE status and longitudinal MRI proved most highly predictive of future decline. Refinements of clinical tests used as outcome measures such as clinical dementia rating-sum of boxes further reduced sample sizes; (7) the pioneering of genome-wide association studies that leverage quantitative imaging and biomarker phenotypes, including longitudinal data, to confirm recently identified loci, CR1, CLU, and PICALM and to identify novel AD risk loci; (8) worldwide impact through the establishment of ADNI-like programs in Japan, Australia, Argentina, Taiwan, China, Korea, Europe, and Italy; (9) understanding the biology and pathobiology of normal aging, MCI, and AD through integration of ADNI biomarker and clinical data to stimulate research that will resolve controversies about competing hypotheses on the etiopathogenesis of AD, thereby advancing efforts to find disease-modifying drugs for AD; and (10) the establishment of infrastructure to allow sharing of all raw and processed data without embargo to interested scientific investigators throughout the world.
No preview · Article · Jun 2015 · Alzheimer's & dementia: the journal of the Alzheimer's Association
[Show abstract][Hide abstract] ABSTRACT: High mammographic density (MD) is a strong risk factor for breast cancer. Chronic inflammation may be related to breast cancer risk through a mechanism involving the percent of breast area that is dense (percent MD). Longitudinal assessments, however, are lacking and thus were constructed to evaluate the relationship between chronic inflammation and percent MD.
We evaluated whether elevated (>3 mg/L) high-sensitivity C-reactive protein (hsCRP), a biomarker of inflammation, was associated with change in percent MD among 653 women aged 42-52 years at baseline in the Study of Women's Health Across the Nation, a longitudinal study of midlife women. We used a mixed model to analyze data from an average of 4.7 mammograms per woman collected during an average follow-up of 4.9 years (SD = 1.47).
Elevated hsCRP at baseline was associated with lower baseline percent MD and a significantly slower annual decline over time of percent MD in an adjusted model that did not include body mass index (BMI) (β = 0.88, 95 % CI 0.44, 1.31). This association was attenuated and nonsignificant when BMI was included in the model (β = 0.37, 95 % CI -0.09, 0.84). Elevated hsCRP levels over time (time-varying elevated hsCRP levels) were also associated with a significantly slower decline in percent MD (β = 0.62, 95 % CI 0.30, 0.94). This association was attenuated, but still significant after adjusting for baseline BMI (β = 0.40, 95 % CI 0.07, 0.73).
These results suggest that inflammation may be related to slower reduction in percent MD.
No preview · Article · Jan 2015 · Cancer Causes and Control
[Show abstract][Hide abstract] ABSTRACT: Alzheimer disease (AD) and frontotemporal dementia (FTD) are 2 neurodegenerative diseases with differing cognitive and neuropathologic profiles. Although both diseases ultimately result in functional disability, differences in the profiles of everyday functioning between the 2 groups have not been well characterized. The present study examines potential differences in the types of everyday functional limitations present in these 2 dementias. The present study compared individuals with AD (N=240) or FTD (N=13). The Everyday Cognition (ECog) scale was used to measure distinct domains of everyday cognition: everyday memory, everyday language, everyday visuospatial ability, and a variety of everyday executive abilities. A total ECog score was used to represent global disability level. The groups showed equivalent levels of global disability. However, AD group exhibited worse Everyday Memory and Everyday Visuospatial abilities than the FTD group. Contrary to expectation, FTD was not more impaired in everyday executive abilities. Results remained similar when accounting for severity of cognitive impairment or disease duration. Findings suggest that a somewhat different pattern of everyday functional difficulties can be seen across dementia types.
No preview · Article · Jan 2015 · Alzheimer Disease and Associated Disorders
[Show abstract][Hide abstract] ABSTRACT: It is recognized that individuals with mild cognitive impairment (MCI) already demonstrate difficulty in aspects of daily functioning, which predicts disease progression. This study examined the relationship between self- versus informant-report of functional ability, and how those reports relate to objective disease measures across the disease spectrum (i.e. cognitively normal, MCI, Alzheimer's disease). A total of 1080 subjects with self- and/or informant-rated Everyday Cognition questionnaires were included. Objective measures included cognitive functioning, structural brain atrophy, cerebrospinal fluid abnormalities, and a marker of amyloid deposition using positron emission tomography with [18F]AV45 (florbetapir). Overall, informant-report was consistently more associated with objective markers of disease than self-report although self-reported functional status may still have some utility in early disease.
No preview · Article · Nov 2014 · Alzheimer's and Dementia
[Show abstract][Hide abstract] ABSTRACT: Background
It is unknown which commonly used Alzheimer disease (AD) biomarker values—baseline or progression—best predict longitudinal cognitive decline.
526 subjects from the Alzheimer's Disease Neuroimaging Initiative (ADNI). ADNI composite memory and executive scores were the primary outcomes. Individual-specific slope of the longitudinal trajectory of each biomarker was first estimated. These estimates and observed baseline biomarker values were used as predictors of cognitive declines. Variability in cognitive declines explained by baseline biomarker values was compared with variability explained by biomarker progression values.
About 40% of variability in memory and executive function declines was explained by ventricular volume progression among mild cognitive impairment patients. A total of 84% of memory and 65% of executive function declines were explained by fluorodeoxyglucose positron emission tomography (FDG-PET) score progression and ventricular volume progression, respectively, among AD patients.
For most biomarkers, biomarker progressions explained higher variability in cognitive decline than biomarker baseline values. This has important implications for clinical trials targeted to modify AD biomarkers.
Full-text · Article · Nov 2014 · Alzheimer's and Dementia
[Show abstract][Hide abstract] ABSTRACT: Both traumatic brain injury (TBI) and posttraumatic stress disorder (PTSD) are common problems resulting from military service, and both have been associated with increased risk of cognitive decline and dementia resulting from Alzheimer's disease (AD) or other causes. This study aims to use imaging techniques and biomarker analysis to determine whether traumatic brain injury (TBI) and/or PTSD resulting from combat or other traumas increase the risk for AD and decrease cognitive reserve in Veteran subjects, after accounting for age. Using military and Department of Veterans Affairs records, 65 Vietnam War veterans with a history of moderate or severe TBI with or without PTSD, 65 with ongoing PTSD without TBI, and 65 control subjects are being enrolled in this study at 19 sites. The study aims to select subject groups that are comparable in age, gender, ethnicity, and education. Subjects with mild cognitive impairment (MCI) or dementia are being excluded. However, a new study just beginning, and similar in size, will study subjects with TBI, subjects with PTSD, and control subjects with MCI. Baseline measurements of cognition, function, blood, and cerebrospinal fluid biomarkers; magnetic resonance images (structural, diffusion tensor, and resting state blood-level oxygen dependent (BOLD) functional magnetic resonance imaging); and amyloid positron emission tomographic (PET) images with florbetapir are being obtained. One-year follow-up measurements will be collected for most of the baseline procedures, with the exception of the lumbar puncture, the PET imaging, and apolipoprotein E genotyping. To date, 19 subjects with TBI only, 46 with PTSD only, and 15 with TBI and PTSD have been recruited and referred to 13 clinics to undergo the study protocol. It is expected that cohorts will be fully recruited by October 2014. This study is a first step toward the design and statistical powering of an AD prevention trial using at-risk veterans as subjects, and provides the basis for a larger, more comprehensive study of dementia risk factors in veterans.
Full-text · Article · Jun 2014 · Alzheimer's and Dementia
[Show abstract][Hide abstract] ABSTRACT: Chromosome 22q11.2 deletion syndrome (22q11.2DS), fragile X syndrome (FXS), and Turner syndrome (TS) are complex and variable developmental syndromes caused by different genetic abnormalities; yet, they share similar cognitive impairments in the domains of numbers, space, and time. The atypical development of foundational neural networks that underpin the attentional system is thought to result in further impairments in higher-order cognitive functions. The current study investigates whether children with similar higher-order cognitive impairments but different genetic disorders also show similar impairments in alerting, orienting and executive control of attention.
Girls with 22q11.2DS, FXS, or TS and typically developing (TD) girls, aged 7 to 15 years, completed an attention network test, a flanker task with alerting and orienting cues. Exploration of reaction times and accuracy allowed us to test for potential commonalities in attentional functioning in alerting, orienting and executive control. Linear regression models were used to test whether the predictors of group and chronological age were able to predict differences in attention indices.
Girls with 22q11.2DS, FXS, or TS demonstrated unimpaired function of the alerting system and impaired function of the executive control system. Diagnosis-specific impairments were found such that girls with FXS made more errors and had a reduced orienting index, while girls with 22q11.2DS showed specific age-related deficits in the executive control system.
These results suggest that the control but not the implementation of attention is selectively impaired in girls with 22q11.2DS, TS or FXS. Additionally, the age effect on executive control in girls with 22q11.2DS implies a possible altered developmental trajectory.
Full-text · Article · Mar 2014 · Journal of Neurodevelopmental Disorders
[Show abstract][Hide abstract] ABSTRACT: Abstract Individuals with chromosome 22q11.2 deletion syndrome (22q11.2DS) have been shown to have impairments in processing spatiotemporal information. The authors examined whether children with 22q11.2DS exhibit impairments in spatial working memory performance due to these weaknesses, even when controlling for maintenance of attention. Children with 22q11.2DS (n = 47) and typically developing controls (n = 49) ages 6-15 years saw images within a grid and after a delay, then indicated the positions of the images in the correct temporal order. Children with 22q11.2DS made more spatial and temporal errors than controls. Females with 22q11.2DS made more spatial and temporal errors than males. These results extend findings of impaired spatiotemporal processing into the memory domain in 22q11.2DS by documenting their influence on working memory performance.
Full-text · Article · Mar 2014 · American Journal on Intellectual and Developmental Disabilities
[Show abstract][Hide abstract] ABSTRACT: The everyday functional capacities of older adults are determined by multiple factors. The primary goal of the present study was to evaluate whether apathy and depression have unique influences on degree of functional impairment, independent of the effects of specific cognitive impairments. Participants included 344 older adults (199 normal, 87 with MCI, 58 with dementia). The Everyday Cognition (ECog) scales were used to measure both global and domain-specific functional abilities. Neuropsychiatric symptoms of depression and apathy were measured by the Neuropsychiatric Inventory (NPI), and specific neuropsychological domains measured included episodic memory and executive functioning. Results indicated that worse memory and executive function, as well as greater depression and apathy, were all independent and additive determinants of poorer functional abilities. Apathy had a slightly more restricted effect than the other variables across the specific functional domains assessed. Secondary analysis suggested that neuropsychiatric symptoms may be more strongly associated with everyday function within cognitively normal and MCI groups, while cognitive impairment is more strongly associated with everyday function in dementia. Thus, a somewhat different set of factors may be associated with functional status across various clinical groups.
No preview · Article · Feb 2014 · The Clinical Neuropsychologist
[Show abstract][Hide abstract] ABSTRACT: Generalized linear mixed models were used to examine longitudinal trajectories of everyday functional limitations by diagnostic stability/progression. Older adults (N = 384) were followed an average 3.6 years; participants were grouped by diagnosis at study baseline and last follow-up (normal cognition, Mild Cognitive Impairment, or dementia at each time point). At study baseline there were clear group differences; most notably among participants initially characterized as cognitively normal, those who developed Mild Cognitive Impairment or dementia over follow-up already demonstrated greater functional impairment compared with those who remained cognitively normal. Change in functional impairment progressed slowly in the early disease groups, but showed an accelerated worsening in those converting to dementia. (PsycINFO Database Record (c) 2013 APA, all rights reserved).
No preview · Article · Dec 2013 · Psychology and Aging
[Show abstract][Hide abstract] ABSTRACT: Patients with multiple sclerosis (MS) demonstrate thinning of peripapillary retinal nerve fiber layer (RNFL) and decreased macular volume as measured by optical coherence tomography (OCT). To our knowledge, there are no previous reports from a large MS OCT database with strict quality control measures that quantitate RNFL and macula in patients with relapsing-remitting multiple sclerosis.
The University of California Davis OCT Reading Center gathered OCT data at baseline as part of the North American phase 3 trial of fingolimod (Gilenya). Average RNFL thickness (RNFLT) and macular volume (TMV) were measured using time domain OCT (TD-OCT). RNFL quadrants, clock hours, and macular subfields were included. With strict quality control and accounting for signal strength differences, scans were categorized as "reduced" or "not reduced" for each field, based on being less than 5th percentile for age-matched controls derived from the normative database in the scanner software. Patients were deemed "abnormal" if at least 1 eye had reduced values for a given parameter. Patients with abnormalities in corresponding RNFL and macular subfields were compared by cross-tabulation.
The TD-OCT data were prospectively collected from 939 of the 1,083 trial patients, 712 of whom met all final quality and data inclusion criteria. Of the final cohort, 242 (34.0%) demonstrated reduced (less than 5th percentile) average RNFLT in at least 1 eye. One hundred seventy-eight (25.0%) patients had reduced TMV. One hundred twenty-eight (18.0%) demonstrated both reduced TMV and RNFLT in the same eye, whereas 42 (5.8%) had reduced TMV and RNFLT in both eyes. Of the 242 patients with reduced average RNFL thickness, 128 (52.9%) also had reduced TMV. Fifty patients had reduced TMV in the absence of reduced RNFLT in at least 1 eye, a cohort prevalence of 7.0%. Quadrant and subfield analysis showed a predominance of temporal and inferior RNFL thinning, with inferior macular thinning corresponding best to RNFL thinning.
RNFL and macular thinning/volume loss is common at baseline in relapsing-remitting multiple sclerosis, as measured by TD-OCT. When the RNFL is thin, the macular volume is reduced in more than half of the patients. There is a population of reduced TMV without any reduction in RNFLT. Documenting the prevalence and distribution of these structural abnormalities supports recent reports and suggests new retinal areas to probe for functional vision changes in MS.
No preview · Article · Sep 2013 · Journal of neuro-ophthalmology: the official journal of the North American Neuro-Ophthalmology Society