2014 Progress Report: Identifying the Cognitive and Vascular Effects of Air Pollution Sources and Mixtures in the Framingharn Offspring and Third Generation Cohorts

EPA Grant Number: R834798C003
Subproject: this is subproject number 003 , established and managed by the Center Director under grant R834798
(EPA does not fund or establish subprojects; EPA awards and manages the overall grant for this center).

Center: Air Pollution Mixtures: Health Effects across Life Stages
Center Director: Koutrakis, Petros
Title: Identifying the Cognitive and Vascular Effects of Air Pollution Sources and Mixtures in the Framingharn Offspring and Third Generation Cohorts
Investigators: Mittleman, Murray , Schwartz, Joel
Current Investigators: Mittleman, Murray , Gold, Diane R. , Schwartz, Joel
Institution: Harvard University
EPA Project Officer: Ilacqua, Vito
Project Period: January 1, 2011 through December 31, 2015 (Extended to December 31, 2016)
Project Period Covered by this Report: January 1, 2014 through December 31,2014
RFA: Clean Air Research Centers (2009) RFA Text |  Recipients Lists
Research Category: Health Effects , Air

Objective:

Long- and short-term exposures to ambient air pollution are associated with adverse acute and chronic cardiovascular and perhaps cognitive function, but these effects are poorly understood. We are using data from the Framingham Offspring and Third Generation Cohorts, well-characterized populations that have not been previously investigated in association with ambient environmental exposures, to: 1) determine whether long-term exposures to ambient pollutants and mixtures are associated with cognitive impairment and cognitive interference; 2) test whether short- and long-term exposures to pollutants, mixtures and sources are associated with acute and chronic vascular and endothelial function; and 3) consider whether markers of biological susceptibility and vulnerability differentially influence these associations, allowing us to identify subpopulations at increased risk for harmful effects of air pollution.

 

Progress Summary:

Over the past year, we have continued to make progress on our specific aims. As projected on last year’s progress report, we have integrated additional exposure-measures including particle constituents and additional model-based data into the Framingham master dataset for Offspring Cycles 6, 7, 8 and Generation 3 Cycles 1 and 2. We continued to work on analyses of both short-term and long-term exposures to air pollutants, sources and mixtures on vascular, neurocognitive and pulmonary function.

In the past year, we published a manuscript describing associations between long-term exposures to ambient air pollution and impaired vascular response in the American Journal of Cardiology entitled “Relation of Long-term Exposure to Air Pollution to Brachial Artery Flow-Mediated Dilation and Reactive Hyperemia” (Wilker, et al., 2014). In this study, we evaluated the association between residential proximity to a major roadway (primary or secondary highway) and spatially resolved average fine particulate matter (PM2.5) and baseline brachial artery diameter and mean flow velocity, flow-mediated dilation %, and hyperemic flow velocity, in the Framingham Offspring and Third Generation Cohorts. We examined 5,112 participants (2,731 [53%] women, mean age 49 +/- 14 years) and found that spatially resolved average PM2.5 was associated with lower flow-mediated dilation% and hyperemic flow velocity. An interquartile range difference in PM2.5 (1.99 µg/m3) was associated with -0.16% (95% confidence interval [CI] - 0.27%, - 0.05%) lower flow-mediated dilation % and -0.72 (95%CI -1.38, -0.06) cm/s lower hyperemic flow velocity %. Residential proximity to a major roadway was negatively associated with flow-mediated dilation %. Compared with living at least 400 m away, living < 50 m from a major roadway was associated with 0.32% lower flow mediated dilation (95% CI -0.58%, -0.06%), but results for hyperemic flow velocity had wide confidence intervals -0.68 cm/s (95% CI -2.29, 0.93). These findings suggest that residential proximity to a major roadway and higher levels of spatially resolved estimates of PM2.5 at participant residences are associated with impaired conduit artery and microvascular function in this large community-based cohort of middle-aged and elderly adults.

During the 2013-14 year, we have also completed single-pollutant analyses of short-term air pollution exposure and digital microvascular function (measured through peripheral arterial tonometry) in the Framingham Offspring and Third Generation cohorts. In this community-based cohort of middle aged and older participants, we found that resting baseline pulse amplitude was higher within 1-3 days of higher levels of ambient air pollutants. In particular, a higher 3-day average of PM2.5, black carbon and higher particle number were associated with higher baseline pulse amplitude by 6.4% per 5 µg/m3 PM2.5 (95% CI: 2.0%, 10.9%), 7.5% per 0.4 µg/m3 black carbon (95% CI: 1.9%, 13.6%) and 13.2% per 15,000 #/cm3 particle number (95% CI: 4.7%, 22.5%) after adjusting for age, age2, sex, cohort, presence of diabetes, body mass index, triglyceride level, ratio of total cholesterol to high density lipoprotein, mean systolic blood pressure, median household income of census tract 2000, years of education, smoking status, day of week, season (sine and cosine of day of year), time trend, temperature, relative humidity, temperature*relative humidity and use of statin or anti-hypertensive medication. However, we did not observe consistent associations between any of the pollutants and hyperemic response. The results of this study are currently in press in the American Journal of Epidemiology (Ljungman, et al., 2014).

As an extension of our work on digital microvascular function, we used methods developed by the Biostatistics Core (Austin, et al., 2012 and 2013) to study the impact of multi-pollutant mixtures of elemental PM constituents, gases, and meteorology on the association between PM2.5 and digital vascular function by using k-means clustering of days during the study period. We found that PM2.5 on days with mixtures containing a relatively high number of particles compared to mass concentration and with local sources of combustion such as traffic, commercial heating oil and wood burning was more strongly associated with higher baseline pulse amplitude than PM2.5 other days. The results of this work were presented at the American Heart Association’s Cardiovascular Disease, Epidemiology and Prevention Scientific Sessions in San Diego in March 2014 and currently are under review at a peer-reviewed journal (Ljungman, et al.).

In another study based on the Framingham cohorts, we examined the associations between short-term air pollution and arterial stiffness using central arterial tonometry-based measures including carotid femoral pulse wave velocity, forward pulse pressure amplitude and augmentation index. In 3,188 participants we explored associations between 1, 3, 7 and 14 day moving averages of PM2.5, black carbon, particle number, sulfate and nitrogen oxides and the above mentioned measures and adjusted for age, sex, body mass index, heart rate, smoking status, diabetes, lipids, cohort, education level, income level, long-term time trends, day of week, season and ambient temperature and humidity. Higher air pollution levels were not associated with higher pulse wave velocity or forward pressure amplitude. Higher PM2.5 and sulfate was associated with higher augmentation index. These results will be presented at the International Society of Environmental Epidemiology meeting in Seattle in August 2014 (Ljungman, et al.) and a manuscript describing these results is in preparation.

Our study of the association between ambient air pollution exposures and measures of brain structure and function in Framingham Offspring participants will be presented in August 2014 at the International Society of Environmental Epidemiology in Seattle, Washington (Wilker, et al.). While long-term exposure to ambient air pollution is associated with impaired cognitive function in elderly people, whether it is related to structural changes in the brain has not been reported. Framingham Offspring Study participants who attended the seventh exam (1998-2001), were age ≥60 years and free of dementia and stroke (1999-2005) were eligible for inclusion (n=961). We constructed linear regression models of the cross-sectional associations between residential proximity to a major roadway (primary or secondary highway) and spatially resolved average fine particulate matter (PM2.5) and measures of total cerebral brain volume, hippocampal volume, log-transformed white matter hyperintensity volume (WMH), and extreme white matter, determined as a binary outcome by whether the log of the ratio of WMHV to total cranial volume was >1 SD above the age-adjusted mean. We hypothesized that higher exposures would be associated with smaller total cerebral brain and hippocampal volumes and larger WMH. We found that a 2µg/m3 increase in PM2.5 was associated with -0.27% (95%CI: -0.54, -0.01) lower total cerebral brain volume. Living close to a major roadway was associated with less white matter hyperintensity in categorical models (p-trend=0.02), but no clear pattern of association was observed for extreme white matter. These findings suggest that air pollution may be associated with insidious effects on structural brain aging even in dementia and stroke free persons. A manuscript describing these results is in preparation.

In terms of respiratory outcomes, we investigated associations between short-term exposure to PM2.5, NO2 and O3 measured at the Harvard Supersite Monitor and pulmonary function testing. We found negative associations with FEV1 and FVC for exposure to each of the 3 criteria pollutants within current EPA standards. These findings were published in the American Journal of Respiratory and Critical Care Medicine (Rice, et al., 2013). We also have investigated associations between longer-term exposure to traffic-related pollution at home address, as defined by distance from residence to nearest major roadway and modeled exposure to PM2.5 and have found negative associations with pulmonary function. These results will be presented at the International Society of Environmental Epidemiology meeting in Seattle in August 2014 (Rice, et al.).

In addition to our work on the Framingham study, we have completed related work on the methods of exchangeability in the case-crossover design. This work is currently in press at the International Journal of Epidemiology (Mittleman and Mostofsky, 2014). Sources of nonexchangeability including confounding and bias arise in cohort and case-control studies when there are differences in the distribution of determinants of the outcome between exposure groups. In case-only studies, this issue is addressed by comparing each individual to his/herself. Although case-only designs use self-matching and only include individuals who develop the outcome of interest, issue of non-exchangeability are identical to those that arise in traditional case-control and cohort studies. In this paper, we described one type of case-only design, the case-crossover design, and we discussed how the concept of exchangeability can be used to understand issues of confounding, carryover effects, period effects and selection bias in case-crossover studies. We described approaches in the design and/or analysis stage that can be used to eliminate or minimize sources of bias.

Finally, in a paper that is currently in press at Cerebrovascular Diseases Extra (Mostofsky, et al., 2014), we conducted a time-stratified case-crossover study of 1,705 patients residing in the Boston metropolitan region that were hospitalized with neurologist-confirmed ischemic stroke to evaluate whether changes in temperature trigger an ischemic stroke in the following hours and days and whether humid days are particularly harmful. We found that the incidence rate ratio of ischemic stroke was 1.09 (95% confidence interval 1.01-1.18) times higher following a 5ºC decrement in average apparent temperature over the 2 days preceding symptom onset. The higher risk associated with cooler temperatures peaked in the first 14-34 hours. There was no statistically significant difference in the association between temperature and ischemic stroke across seasons. The risk of ischemic stroke was not meaningfully different across subgroups of patients defined by health characteristics. The association between ischemic stroke and ambient temperature was stronger on days with higher levels of relative humidity.

Future Activities:

In the coming year, we will complete our analyses of long-term air pollution exposure and arterial stiffness in the Framingham Offspring and Third Generation cohorts using central tonometry measures. We will estimate long-term exposure using satellite model-based PM2.5 and distance to major roadway.  Work in the coming year also will focus on examining associations between exposures to ambient air pollution and cognitive function. Analyses will include tests of global cognitive function such as the Mini-Mental State Exam, and a battery of tests evaluating specific domains of cognitive function administered to Framingham Offspring participants. In the younger participants of the Third Generation, we will use the CERAD Word List and Victoria Stroop Tests. Additionally, we will be investigating associations between air pollution exposure and quantitative CT measures of airway disease and emphysema in the Framingham Heart Study. Finally, Kirsten Dorans and Wenyuan Li, two doctoral students, will begin work on long-term exposure to traffic-related pollution and CT-based measures of coronary and aortic calcifications as measures of atherosclerosis as well as short- and long-term exposure to traffic-related pollution and measures of carbohydrate metabolism and related outcomes.


Journal Articles on this Report : 16 Displayed | Download in RIS Format

Other subproject views: All 53 publications 36 publications in selected types All 36 journal articles
Other center views: All 410 publications 347 publications in selected types All 347 journal articles
Type Citation Sub Project Document Sources
Journal Article Gold DR, Mittleman MA. New insights into pollution and the cardiovascular system: 2010 to 2012. Circulation 2013;127(18):1903-1913. R834798 (2013)
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  • Journal Article Ljungman PL, Wilker EH, Rice MB, Schwartz J, Gold DR, Koutrakis P, Vita JA, Mitchell GF, Vasan RS, Benjamin EJ, Mittleman MA, Hamburg NM. Short-term exposure to air pollution and digital vascular function. American Journal of Epidemiology 2014;180(5):482-489. R834798 (Final)
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  • Journal Article Lue S-H, Wellenius GA, Wilker EH, Mostofsky E, Mittleman MA. Residential proximity to major roadways and renal function. Journal of Epidemiology & Community Health 2013;67(8):629-634. R834798 (2013)
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  • Journal Article Mittleman MA, Mostofsky E. Exchangeability in the case-crossover design. International Journal of Epidemiology 2014;43(5):1645-1655. R834798 (2014)
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  • Journal Article Mostofsky E, Wilker EH, Schwartz J, Zanobetti A, Gold DR, Wellenius GA, Mittleman MA. Short-term changes in ambient temperature and risk of ischemic stroke. Cerebrovascular Diseases Extra 2014;4(1):9-18. R834798 (2014)
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  • Journal Article Rice MB, Ljungman PL, Wilker EH, Gold DR, Schwartz JD, Koutrakis P, Washko GR, O'Connor GT, Mittleman MA. Short-term exposure to air pollution and lung function in the Framingham Heart Study. American Journal of Respiratory and Critical Care Medicine 2013;188(11):1351-1357. R834798 (Final)
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  • Journal Article Rice MB, Thurston GD, Balmes JR, Pinkerton KE. Climate change. A global threat to cardiopulmonary health. American Journal of Respiratory and Critical Care Medicine 2014;189(5):512-519. R834798 (Final)
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  • Journal Article Rosenbloom JI, Wilker EH, Mukamal KJ, Schwartz J, Mittleman MA. Residential proximity to major roadway and 10-year all-cause mortality after myocardial infarction. Circulation 2012;125(18):2197-2203. R834798 (2012)
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  • Journal Article Wang Y, Eliot MN, Koutrakis P, Gryparis A, Schwartz JD, Coull BA, Mittleman MA, Milberg WP, Lipsitz LA, Wellenius GA. Ambient air pollution and depressive symptoms in older adults: results from the MOBILIZE Boston Study. Environmental Health Perspectives 2014;122(6):553-558. R834798 (Final)
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  • Journal Article Wellenius GA, Burger MR, Coull BA, Schwartz J, Suh HH, Koutrakis P, Schlaug G, Gold DR, Mittleman MA. Ambient air pollution and the risk of acute ischemic stroke. Archives of Internal Medicine 2012;172(3):229-234. R834798 (2012)
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  • Journal Article Wellenius GA, Boyle LD, Coull BA, Milberg WP, Gryparis A, Schwartz J, Mittleman MA, Lipsitz LA. Residential proximity to nearest major roadway and cognitive function in community-dwelling seniors: results from the MOBILIZE Boston Study. Journal of the American Geriatric Society 2012;60(11):2075-2080. R834798 (2012)
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  • Journal Article Wellenius GA, Boyle LD, Wilker EH, Sorond FA, Coull BA, Koutrakis P, Mittleman MA, Lipsitz LA. Ambient fine particulate matter alters cerebral hemodynamics in the elderly. Stroke 2013;44(6):1532-1536. R834798 (2013)
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  • Journal Article Wilker EH, Yeh G, Wellenius GA, Davis RB, Phillips RS, Mittleman MA. Ambient temperature and biomarkers of heart failure: a repeated measures analysis. Environmental Health Perspectives 2012;120(8):1083-1087. R834798 (2012)
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  • Journal Article Wilker EH, Mostofsky E, Lue S-H, Gold D, Schwartz J, Wellenius GA, Mittleman MA. Residential proximity to high-traffic roadways and poststroke mortality. Journal of Stroke & Cerebrovascular Diseases 2013;22(8):e366-e372. R834798 (2013)
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  • Journal Article Wilker EH, Wu C-D, McNeely E, Mostofsky E, Spengler J, Wellenius GA, Mittleman MA. Green space and mortality following ischemic stroke. Environmental Research 2014;133:42-48. R834798 (2014)
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  • Journal Article Wilker EH, Ljungman PL, Rice MB, Kloog I, Schwartz J, Gold DR, Koutrakis P, Vita JA, Mitchell GF, Vasan RS, Benjamin EJ, Hamburg NM, Mittleman MA. Relation of long-term exposure to air pollution to brachial artery flow-mediated dilation and reactive hyperemia. American Journal of Cardiology 2014;113(12):2057-2063. R834798 (2014)
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  • Supplemental Keywords:

    Scientific Discipline, Air, air toxics, Health Risk Assessment, Air Pollution Effects, Biochemistry, Environmental Monitoring, Biology, ambient air quality, children's health, complex mixtures, health effects, particulates, sensitive populations, air pollutants, biological sensitivities, exposure and effects, lung epithelial cells, susceptible populations, chemical composition, neurotoxicity, human exposure, toxicity, coronary artery disease, cardiopulmonary, cardiotoxicity, environmental effects, human health, mortality

    Progress and Final Reports:

    Original Abstract
  • 2010 Progress Report
  • 2011 Progress Report
  • 2012 Progress Report
  • 2013 Progress Report
  • Final Report

  • Main Center Abstract and Reports:

    R834798    Air Pollution Mixtures: Health Effects across Life Stages

    Subprojects under this Center: (EPA does not fund or establish subprojects; EPA awards and manages the overall grant for this center).
    R834798C001 Relative Toxicity of Air Pollution Mixtures
    R834798C002 Cognitive Decline, Cardiovascular Changes, and Biological Aging in Response to Air Pollution
    R834798C003 Identifying the Cognitive and Vascular Effects of Air Pollution Sources and Mixtures in the Framingharn Offspring and Third Generation Cohorts
    R834798C004 Longitudinal Effects of Multiple Pollutants on Child Growth, Blood Pressure and Cognition
    R834798C005 A National Study to Assess Susceptibility, Vulnerability, and Effect Modification of Air Pollution Health Risks