Huiling Nie

Cumulative lead exposure and cognitive performance among elderly men.

Background: Recent evidence suggests that cumulative lead exposure among adults in nonoccupational settings can adversely affect cognitive function. Which cognitive domains are affected has not been explored in detail. Methods: We used nonlinear spline regressions and linear repeated-measures analysis to assess the association between scores on a battery of cognitive tests over time and both blood and bone lead concentrations in the Normative Aging Study, a cohort of community-dwelling elderly men. Bone lead was measured from 1991 through 1999 with K-shell x-ray fluorescence. A total of 1089 men with a mean (±standard deviation) age of 68.7 (±7.4) years with blood lead measurements, 761 of whom also had valid bone lead measurements, completed at least one of a battery of cognitive tests. Approximately 3.5 years later, 69% of the men had at least one repeat test. Cognitive testing was performed from 1993 through 2001. Results: On a cross-sectional basis, there was little association between blood or bone lead and cognitive test scores. Change in performance over time on virtually all tests worsened as bone lead increased, with the most robust effects on performance and reaction time scores on visuospatial/visuomotor tests. Conclusions: Low-level cumulative exposure to lead in nonoccupational settings may adversely affect cognitive function, particularly in the visuospatial/visuomotor domain.

A Prospective Study of Bone Lead Concentration and Death From All Causes, Cardiovascular Diseases, and Cancer in the Department of Veterans Affairs Normative Aging Study

Background— Blood lead concentration has been associated with mortality from different causes in several studies. Many effects of lead exposure that might increase risk of death are likely to result from cumulative exposure, for which bone lead is a better biomarker than blood lead. The association between bone lead levels and mortality has not been explored. Methods and Results— We prospectively assessed the association between both blood lead and bone lead, analyzed with the use of K-shell x-ray fluorescence, and mortality among 868 men in the Normative Aging Study. We identified 241 deaths over an average of 8.9 (SD=3.9) years of follow-up. We calculated adjusted hazard ratios and 95% confidence intervals using Cox proportional hazards. Compared with the lowest tertile of patella bone lead, the fully adjusted hazard ratios in the highest tertile for all-cause, cardiovascular (n=137 deaths), and ischemic heart disease (n=62 deaths) mortality were 1.25 (95% confidence interval, 0.82 to 1.92), 1.42 (95% confidence interval, 0.80 to 2.51), and 1.87 (95% confidence interval, 0.77 to 4.53), respectively. Results were similar for tibia lead. Bone lead was not associated with cancer, and blood lead was not associated with any mortality category. Conclusions— We found bone lead to be associated with a slight increase in all-cause and cardiovascular mortality in an environmentally exposed population with low blood lead levels, but this did not reach statistical significance. This study suggests that cumulative lead exposure from prior decades of high environmental exposures may affect risk of death despite recent declines in environmental lead exposure, but studies with more follow-up are needed.

Association of cumulative lead exposure with Parkinson's disease.

Background Research using reconstructed exposure histories has suggested an association between heavy metal exposures, including lead, and Parkinson’s disease (PD), but the only study that used bone lead, a biomarker of cumulative lead exposure, found a nonsignificant increase in risk of PD with increasing bone lead. Objectives We sought to assess the association between bone lead and PD. Methods Bone lead concentrations were measured using 109Cd excited K-shell X-ray fluorescence from 330 PD patients (216 men, 114 women) and 308 controls (172 men, 136 women) recruited from four clinics for movement disorders and general-community cohorts. Adjusted odds ratios (ORs) for PD were calculated using logistic regression. Results The average age of cases and controls at bone lead measurement was 67 (SD = 10) and 69 (SD = 9) years of age, respectively. In primary analyses of cases and controls recruited from the same groups, compared with the lowest quartile of tibia lead, the OR for PD in the highest quartile was 3.21 [95% confidence interval (CI), 1.17–8.83]. Results were similar but slightly weaker in analyses restricted to cases and controls recruited from the movement disorders clinics only (fourth-quartile OR = 2.57; 95% CI, 1.11–5.93) or when we included controls recruited from sites that did not also contribute cases (fourth-quartile OR = 1.91; 95% CI, 1.01–3.60). We found no association with patella bone lead. Conclusions These findings, using an objective biological marker of cumulative lead exposure among typical PD patients seen in our movement disorders clinics, strengthen the evidence that cumulative exposure to lead increases the risk of PD.

Cumulative Exposure to Lead in Relation to Cognitive Function in Older Women

Background Recent data indicate that chronic low-level exposure to lead is associated with accelerated declines in cognition in older age, but this has not been examined in women. Objective We examined biomarkers of lead exposure in relation to performance on a battery of cognitive tests among older women. Methods Patella and tibia bone lead—measures of cumulative exposure over many years—and blood lead, a measure of recent exposure, were assessed in 587 women 47–74 years of age. We assessed their cognitive function 5 years later using validated telephone interviews. Results Mean ± SD lead levels in tibia, patella, and blood were 10.5 ± 9.7 μg/g bone, 12.6 ± 11.6 μg/g bone, and 2.9 ± 1.9 μg/dL, respectively, consistent with community-level exposures. In multivariable-adjusted analyses of all cognitive tests combined, levels of all three lead biomarkers were associated with worse cognitive performance. The association between bone lead and letter fluency score differed dramatically from the other bone lead-cognitive score associations, and exclusion of this particular score from the combined analyses strengthened the associations between bone lead and cognitive performance. Results were statistically significant only for tibia lead: one SD increase in tibia lead corresponded to a 0.051-unit lower standardized summary cognitive score (95% confidence interval: −0.099 to −0.003; p = 0.04), similar to the difference in cognitive scores we observed between women who were 3 years apart in age. Conclusions These findings suggest that cumulative exposure to lead, even at low levels experienced in community settings, may have adverse consequences for women’s cognition in older age.

Stress as a potential modifier of the impact of lead levels on blood pressure: the normative aging study.

Background Lead exposure and psychological stress have been independently associated with hypertension in various populations, and animal studies suggest that when they co-occur, their effects may be exacerbated. Objectives We examined whether psychological stress modifies the impact of cumulative lead exposure (measured as bone lead levels) on hypertension and blood pressure in Boston-area community–exposed men participating in the Normative Aging Study. Methods We evaluated the modifying effect of stress on lead exposure on baseline hypertension status (513 participants) and on blood pressure in those without hypertension (237 participants), cross-sectionally. In baseline nonhypertensives, we examined the same risk factors in relation to prospective risk of developing hypertension. Results Cross-sectional analysis revealed a positive interaction between stress and tibia lead on systolic blood pressure, after adjusting for age, body mass index, family history of high blood pressure, education, smoking, alcohol consumption, physical activity, and nutritional factors. In prospective multivariate analyses, high stress also modified the effect of tibia lead and patella lead on the risk of developing hypertension. Those reporting high stress had 2.66 [95% confidence interval (CI), 1.43–4.95] times the risk of developing hypertension per standard deviation increase in tibia lead and had 2.64 (95% CI, 1.42–4.92) times the risk per standard deviation increase in patella lead. Conclusion To our knowledge, these are the first analyses to look at interactive effects of stress and lead on hypertension in humans. These results suggest that the effect of lead on hypertension is most pronounced among highly stressed individuals, independent of demographic and behavioral risk factors.

Low-Level Lead Exposure, Metabolic Syndrome, and Heart Rate Variability: The VA Normative Aging Study

Background Altered heart rate variability (HRV), a marker of poor cardiac autonomic function, has been associated with sudden cardiac death and heart failure. Objective We examined the association of low-level lead exposure measured in bone by K-X-ray fluorescence with alterations in HRV, and whether metabolic syndrome (MetS) or its individual components modify those associations. Methods HRV measures [power in high-frequency (HFnorm) and low-frequency (LFnorm) in normalized units, and LF/HF] were taken among 413 elderly men from the Normative Aging Study. MetS was defined as subjects having three or more of the following criteria: abdominal obesity, hypertriglyceridemia, low high-density lipoprotein, high blood pressure, and high fasting glucose. Results Of the subjects, 32% were identified as having MetS. Inverse but nonstatistically significant associations of both tibia and patella lead levels with HFnorm and nonstatistically significant positive relations with LFnorm and LF/HF were found in the entire cohort. There was a graded, statistically significant reduction in HFnorm and increases in LFnorm and LF/HF in association with an increase in patella lead as the number of metabolic abnormalities increased. We also observed that higher patella lead was consistently associated with lower HFnorm and higher LFnorm and LF/HF among subjects with MetS or its individual components. No statistically significant interaction between MetS and tibia lead was observed. Conclusion The results suggest that elderly men with MetS were more susceptible to autonomic dysfunction in association with chronic lead exposure as measured in patella. The modification by MetS is consistent with a role for oxidative stress in lead toxicity on the cardiovascular system.

Lead Levels and Ischemic Heart Disease in a Prospective Study of Middle-Aged and Elderly Men: the VA Normative Aging Study

Background Lead exposure has been associated with higher blood pressure, hypertension, electrocardiogram abnormalities, and increased mortality from circulatory causes. Objective We assessed the association between bone lead—a more accurate biomarker of chronic lead exposure than blood lead—and risk for future ischemic heart disease (IHD). Methods In a prospective cohort study (VA Normative Aging Study), 837 men who underwent blood or bone lead measurements at baseline were followed-up for an ischemic heart disease event between 1 September 1991 and 31 December 2001. IHD was defined as either a diagnosis of myocardial infarction or angina pectoris that was confirmed by a cardiologist. Events of fatal myocardial infarction were assessed from death certificates. Results An IHD event occurred in 83 cases (70 nonfatal and 13 fatal). The mean blood, tibia, and patella lead levels were higher in IHD cases than in noncases. In multivariate Cox-proportional hazards models, one standard deviation increase in blood lead level was associated with a 1.27 (95% confidence interval, 1.01–1.59) fold greater risk for ischemic heart disease. Similarly, a one standard deviation increase in patella and tibia lead levels was associated with greater risk for IHD (hazard ratio for patella lead = 1.29; 95% confidence interval, 1.02–1.62). Conclusions Men with increased blood and bone lead levels were at increased risk for future IHD. Although the pathogenesis of IHD is multifactorial, lead exposure may be one of the risk factors.

Air Pollution and Heart Rate Variability : Effect Modification by Chronic Lead Exposure

Background: Outdoor air pollution and lead exposure can disturb cardiac autonomic function, but the effects of both these exposures together have not been studied. Methods: We examined whether higher cumulative lead exposures, as measured by bone lead, modified cross-sectional associations between air pollution and heart rate variability among 384 elderly men from the Normative Aging Study. We used linear regression, controlling for clinical, demographic, and environmental covariates. Results: We found graded, significant reductions in both high-frequency and low-frequency powers of heart rate variability in relation to ozone and sulfate across the quartiles of tibia lead. Interquartile range increases in ozone and sulfate were associated respectively, with 38% decrease (95% confidence interval = −54.6% to −14.9%) and 22% decrease (−40.4% to 1.6%) in high frequency, and 38% decrease (−51.9% to −20.4%) and 12% decrease (−28.6% to 9.3%) in low frequency, in the highest quartile of tibia lead after controlling for potential confounders. We observed similar but weaker effect modification by tibia lead adjusted for education and cumulative traffic (residuals of the regression of tibia lead on education and cumulative traffic). Patella lead modified only the ozone effect on heart rate variability. Conclusions: People with long-term exposure to higher levels of lead may be more sensitive to cardiac autonomic dysfunction on high air pollution days. Efforts to understand how environmental exposures affect the health of an aging population should consider both current levels of pollution and history of lead exposure as susceptibility factors.

Interaction of stress, lead burden, and age on cognition in older men: the VA Normative Aging Study.

Background Low-level exposure to lead and to chronic stress may independently influence cognition. However, the modifying potential of psychosocial stress on the neurotoxicity of lead and their combined relationship to aging-associated decline have not been fully examined. Objectives We examined the cross-sectional interaction between stress and lead exposure on Mini-Mental State Examination (MMSE) scores among 811 participants in the Normative Aging Study, a cohort of older U.S. men. Methods We used two self-reported measures of stress appraisal—a self-report of stress related to their most severe problem and the Perceived Stress Scale (PSS). Indices of lead exposure were blood lead and bone (tibia and patella) lead. Results Participants with higher self-reported stress had lower MMSE scores, which were adjusted for age, education, computer experience, English as a first language, smoking, and alcohol intake. In multivariable-adjusted tests for interaction, those with higher PSS scores had a 0.57-point lower (95% confidence interval, −0.90 to 0.24) MMSE score for a 2-fold increase in blood lead than did those with lower PSS scores. In addition, the combination of high PSS scores and high blood lead categories on one or both was associated with a 0.05–0.08 reduction on the MMSE for each year of age compared with those with low PSS score and blood lead level (p < 0.05). Conclusions Psychological stress had an independent inverse association with cognition and also modified the relationship between lead exposure and cognitive performance among older men. Furthermore, high stress and lead together modified the association between age and cognition.

Modifying effects of the HFE polymorphisms on the association between lead burden and cognitive decline.

Background As iron and lead promote oxidative damage, and hemochromatosis (HFE) gene polymorphisms increase body iron burden, HFE variant alleles may modify the lead burden and cognitive decline relationship. Objective Our goal was to assess the modifying effects of HFE variants on the lead burden and cognitive decline relation in older adults. Methods We measured tibia and patella lead using K-X-ray fluorescence (1991–1999) among participants of the Normative Aging Study, a longitudinal study of community-dwelling men from greater Boston. We assessed cognitive function with the Mini-Mental State Examination (MMSE) twice (1993–1998 and 1995–2000) and genotyped participants for HFE polymorphisms. We estimated the adjusted mean differences in lead-associated annual cognitive decline across HFE genotype groups (n = 358). Results Higher tibia lead was associated with steeper cognitive decline among participants with at least one HFE variant allele compared with men with only wild-type alleles (p interaction = 0.03), such that a 15 μg/g increase in tibia lead was associated with a 0.2 point annual decrement in MMSE score among HFE variant allele carriers. This difference in scores among men with at least one variant allele was comparable to the difference in baseline MMSE scores that we observed among men who were 4 years apart in age. Moreover, the deleterious association between tibia lead and cognitive decline appeared progressively worse in participants with increasingly more copies of HFE variant alleles (p-trend = 0.008). Results for patella lead were similar. Conclusion Our findings suggest that HFE polymorphisms greatly enhance susceptibility to lead-related cognitive impairment in a pattern consistent with allelelic dose.