The Association between Exposure to Fine Particulate Matter and MRI-Assessed Locus Coeruleus Integrity in the Vietnam Era Twin Study of Aging (VETSA)

Abstract

Background: Increased exposure to ambient air pollution, especially fine particulate matter $\le 2.5\mu m$ (${\mathrm{PM}}_{2.5}$) is associated with poorer brain health and increased risk for Alzheimer's disease (AD) and related dementias. The locus coeruleus (LC), located in the brainstem, is one of the earliest regions affected by tau pathology seen in AD. Its diffuse projections throughout the brain include afferents to olfactory areas that are hypothesized conduits of cerebral particle deposition. Additionally, extensive contact of the LC with the cerebrovascular system may present an additional route of exposure to environmental toxicants.

Objective: Our aim was to investigate if exposure to ${\mathrm{PM}}_{2.5}$ was associated with LC integrity in a nationwide sample of men in early old age, potentially representing one pathway through which air pollution can contribute to increased risk for AD dementia.

Methods: We examined the relationship between ${\mathrm{PM}}_{2.5}$ and in vivo magnetic resonance imaging (MRI) estimates of LC structural integrity indexed by contrast to noise ratio (${\text{LC}}_{\text{CNR}}$) in 381 men [$\text{mean age}=67.3$; standard deviation $\left(\text{SD}\right)=2.6$] from the Vietnam Era Twin Study of Aging (VETSA). Exposure to ${\mathrm{PM}}_{2.5}$ was taken as a 3-year average over the most recent period for which data were available (average of 5.6 years prior to the MRI scan). We focused on ${\text{LC}}_{\text{CNR}}$ in the rostral-middle portion of LC due to its stronger associations with aging and AD than the caudal LC. Associations between ${\mathrm{PM}}_{2.5}$ exposures and LC integrity were tested using linear mixed effects models adjusted for age, scanner, education, household income, and interval between exposure and MRI. A co-twin control analysis was also performed to investigate whether associations remained after controlling for genetic confounding and rearing environment.

Results: Multiple linear regressions revealed a significant association between ${\mathrm{PM}}_{2.5}$ and rostral-middle ${\text{LC}}_{\text{CNR}}$ ($\beta =-0.16$; $p=0.02$), whereby higher exposure to ${\mathrm{PM}}_{2.5}$ was associated with lower ${\text{LC}}_{\text{CNR}}$. A co-twin control analysis found that, within monozygotic pairs, individuals with higher ${\mathrm{PM}}_{2.5}$ exposure showed lower ${\text{LC}}_{\text{CNR}}$ ($\beta =-0.11$; $p=0.02$), indicating associations were not driven by genetic or shared environmental confounds. There were no associations between ${\mathrm{PM}}_{2.5}$ and caudal ${\text{LC}}_{\text{CNR}}$ or hippocampal volume, suggesting a degree of specificity to the rostral-middle portion of the LC.

Discussion: Given previous findings that loss of LC integrity is associated with increased accumulation of AD-related amyloid and tau pathology, impacts on LC integrity may represent a potential pathway through which exposure to air pollution increases AD risk. https://doi.org/10.1289/EHP14344.

Figure 1.

Regression plot showing the association between rostral-middle ${\text{LC}}_{\text{CNR}}$ and ${\mathrm{PM}}_{2.5}$ exposure in the VETSA MRI sample ($n=381$). The predicted values (i.e., regression slope) for the association between 3-year average ${\mathrm{PM}}_{2.5}$ exposure and rostral-middle ${\text{LC}}_{\text{CNR}}$ obtained from a linear mixed-effects model (Table 2; Table S1). Twin pair ID was included as a random intercept to account for correlated outcomes. Covariates included scanner and age at time of MRI scan, as well as lifetime education, household income during the period that air pollution was measured, and interval between air pollution assessment and MRI scan. Data points represent partial residuals from the regression model adjusting for included covariates. The shaded band represents the 95% confidence interval. All continuous variables were standardized to z-score units using sample means and standard deviations. Note: ${\text{LC}}_{\text{CNR}}$, locus coeruleus contrast-to-noise ratio; MRI, magnetic resonance imaging; ${\mathrm{PM}}_{2.5}$, fine particulate matter $\le 2.5\mathrm{\mu }\mathrm{m}$ in diameter; VETSA, Vietnam Era Twin Study of Aging.