[11C]dihydrotetrabenazine Positron Emission Tomography in Manganese-Exposed Workers

Abstract

Objective: To understand the neurotoxic effects of manganese (Mn) exposure on monoaminergic function, utilizing [C]dihydrotetrabenazine (DTBZ) positron emission tomography (PET) to measure vesicular monoamine transporter 2 (VMAT2).

Methods: Basal ganglia and thalamic DTBZ binding potentials (BPND) were calculated on 56 PETs from 41 Mn-exposed workers. Associations between cumulative Mn exposure, regional BPND, and parkinsonism were examined by mixed linear regression.

Results: Thalamic DTBZ BPND was inversely associated with exposure in workers with less than 3 mg Mn/m-yrs, but subsequently remained stable. Pallidal DTBZ binding increased in workers with less than 2 mg Mn/m-yrs of exposure, but decreased thereafter. Thalamic DTBZ binding was inversely associated with parkinsonism (P = 0.003).

Conclusion: Mn-dose-dependent associations with thalamic and pallidal DTBZ binding indicate direct effects on monoaminergic VMAT2. Thalamic DTBZ binding was also associated with parkinsonism, suggesting potential as an early biomarker of Mn neurotoxicity.

FIGURE 1.

Thalamic and Pallidal DTBZ Binding in Relation to Cumulative Mn Exposure. (A) The cross-sectional association between cumulative Mn exposure (mg Mn/m³-yrs) and thalamus DTBZ BPND is inverse among those with less than 3 mg Mn/m³-yrs of exposure but relatively stable thereafter. Using two linear splines (not shown) with a knot at 3 mg Mn/m³-yrs, the respective DTBZ BPND estimates per mg Mn/m³-yr of exposure are −0.0268 (95% CI −0.0406, −0.0129) and 0.0121 (95% CI −0.0036, 0.0279). (B) The cross-sectional association between cumulative Mn exposure (mg Mn/m³-yrs) and globus pallidus DTBZ BPND is positive among those with less than 2mg Mn/m³-yrs of exposure and inverse among those with more than or equal to 2mg Mn/m³-yrs of exposure. Using two linear splines (not shown) with a knot at 2mg Mn/m³-yrs, the respective DTBZ BPND estimates per mg Mn/m³-yr of exposure are 0.1054 (95% CI 0.0169, 0.1938) and – 0.0901 (95% CI −0.1430, −0.0373). The lines represent the local polynomial smoother for all participants (solid line) or when restricted to Mn-exposed welders (dashed line). The grey band represents the respective 95% CI for all participants. (Grey triangle = Mn-exposed non-welders; grey dot = Mn-exposed welders).

FIGURE 2.

Baseline UPDRS3 in Relation to Annual Rate of Change in Substantia Nigra DTBZ BPND. Participants who had higher UPDRS3 scores at the baseline examination had a greater reduction in substantia nigra DTBZ BPND over time than participants with lower baseline UPDRS3 scores. The grey band represents annual “changes” in substantia nigra DTBZ BPND of only ±0.02 surrounding a change of zero (horizontal line). Only one participant (an influential point marked as a lighter grey dot) had a greater increase in DTBZ BPND, whereas five participants had greater decrease in DTBZ BPND. All five had a baseline UPDRS3 more than 10 (marked by the vertical line). A local polynomial smoother for all participants is shown (solid line).