Interaction of Stress, Lead Burden, and Age on Cognition in Older Men: The VA Normative Aging Study

Junenette L. Peters; Marc G. Weisskopf; Avron Spiro III; Joel Schwartz; David Sparrow; Huiling Nie; Howard Hu; Robert O. Wright; Rosalind J. Wright


Environ Health Perspect. 2010;118(4):505-510. 

In This Article

Abstract and Introduction


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.


Cognitive decline has been associated with aging, and as the U.S. population shifts to a more elderly population, there is growing concern about the implications of cognitive dysfunction. However, cognitive decline varies widely across ages, which suggests that it may not be just a natural consequence of aging but may be linked to multiple risk factors (Wright et al. 2005).

The relationship between lead and cognitive impairment has been documented extensively in children and in occupationally exposed populations (e.g., Fiedler et al. 2003; Schwartz et al. 2001, 2005; Stewart et al. 1999; Winker et al. 2006). Previous studies by our group and others have also shown an inverse association in bone lead levels as well as blood lead levels with cognition and changes in cognition over time among nonoccupationally exposed older men and older women (Balbus-Kornfeld et al. 1995; Muldoon et al. 1996; Shih et al. 2007; Weuve et al. 2009). Levels of lead in blood represent acute exposure and levels in bone represent cumulative exposure.

Psychological stress (hereafter referred to as stress) has also been associated with decrements in short-term memory and attention (e.g., Levy et al. 1994; Mahoney et al. 1998; Vitaliano et al. 2005). However, stress itself is not uniformly negative (Cory-Slechta et al. 2008) and, under some conditions, may result in improved learning and memory (Zheng et al. 2007). In general, stressful events may result in negative emotional states, such as depression and anxiety, which in turn may exert lasting effects on physiologic processes that influence disease states or enhance vulnerability to other environmental factors (e.g., lead). The negative emotional response to life events (stressors) results when one perceives or appraises these events as overwhelming their ability to cope (Cohen et al. 1983; Lazarus and Folkman 1984). In response, physiologic systems may operate at higher or lower levels relative to normal homeostasis. The resulting long-term damage of unchecked accommodation of defensive processes (e.g., neural, immune, endocrine) is conceptualized as allostatic load (Lupien et al. 2007; McEwen 2007, 2008).

Exposure to both lead and stress often co-occur and potentially operate through overlapping biologic pathways of action [e.g., the hypothalamic–pituitary–adrenal (HPA) axis with disrupted release of glucocorticoids (e.g., cortisol). Recent laboratory studies have demonstrated that stress (restraint, cold, and novelty) modifies the neurotoxic effects of lead; moreover, lead and stress may have a combined effect in the absence of the effect of each alone (Cory-Slechta et al. 2008; Virgolini et al. 2005, 2008). Laboratory studies also show that the interactive effect is not limited to early development, a finding that indicates longer-term vulnerability (Agrawal and Chansouria 1989; Kim and Lawrence 2000). In a recent human study, Glass et al. (2009) found joint effects between neighborhood psychosocial hazards and cumulative lead exposure on cognitive function in older adults.

In this study, we cross-sectionally examined the modifying potential of psychological stress on the relation of cumulative and acute lead exposures as predictors of cognition in a cohort of older men from the Normative Aging Study (NAS). We previously reported an association between lead and cognition (Weisskopf et al. 2004, 2007; Wright et al. 2003) and an interaction of lead and age on cognition in this cohort (Wright et al. 2003). We hypothesized that high stress would lower the scores on the Mini-Mental State Examination (MMSE; Psychological Assessment Resources, Lutz, FL) and modify the lead-MMSE association and that the combined elevation of lead and stress would modify the relationship between age and cognitive impairment.


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