In Vivo Measurement of Brain GABA Concentrations by Magnetic Resonance Spectroscopy in Smelters Occupationally Exposed to Manganese

Abstract

BackgroundExposure to excessive levels of manganese (Mn) is known to induce psychiatric and motor disorders, including parkinsonian symptoms. Therefore, finding a reliable means for early detection of Mn neurotoxicity is desirable.ObjectivesOur goal was to determine whether in vivo brain levels of γ-aminobutyric acid (GABA), N-acetylaspartate (NAA), and other brain metabolites in male smelters were altered as a consequence of Mn exposure.MethodsWe used T1-weighted magnetic resonance imaging (MRI) to visualize Mn deposition in the brain. Magnetic resonance spectroscopy (MRS) was used to quantify concentrations of NAA, glutamate, and other brain metabolites in globus pallidus, putamen, thalamus, and frontal cortex from a well-established cohort of 10 male Mn-exposed smelters and 10 male age-matched control subjects. We used the MEGA-PRESS MRS sequence to determine GABA levels in a region encompassing the thalamus and adjacent parts of the basal ganglia [GABA-VOI (volume of interest)].ResultsSeven of 10 exposed subjects showed clear T1-hyperintense signals in the globus pallidus indicating Mn accumulation. We found a significant increase (82%; p = 0.014) in the ratio of GABA to total creatine (GABA/tCr) in the GABA-VOI of Mn-exposed subjects, as well as a distinct decrease (9%; p = 0.04) of NAA/tCr in frontal cortex that strongly correlated with cumulative Mn exposure (R = −0.93; p < 0.001).ConclusionsWe demonstrated elevated GABA levels in the thalamus and adjacent basal ganglia and decreased NAA levels in the frontal cortex, indicating neuronal dysfunction in a brain area not primarily targeted by Mn. Therefore, the noninvasive in vivo MRS measurement of GABA and NAA may prove to be a powerful tool for detecting presymptomatic effects of Mn neurotoxicity.

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“…Indeed, the dramatic increment of metal ranged between 16-68 folds in acute and 4-93 folds in chronic metal intoxication (Table 1). These observations mirror metal accumulation data in vivo in PD and Parkinsonism patients (Zecca et al 2005;Berg 2006;Dydak et al 2011) and poor clinical scores (Atasoy et al 2004). …”

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“…In another study, reduced NAA : Cr was found only in the frontal cortex of Mn-exposed smelters, but not in the thalamus, putamen, or globus pallidus. 11 Additionally, a significant increase in GABA level, similar to the report of elevated GABA in globus pallidus tissue by Zwingmann et al, 84 was observed in a larger thalamus-centered volume of interest in the same study. 11 This finding of increased thalamic GABA has been reproduced in additional populations of smelters and welders in different countries and settings; 88-90 moreover, thalamic GABA levels were recently found to predict fine motor performance in Mn-exposed workers.…”

“…11 Additionally, a significant increase in GABA level, similar to the report of elevated GABA in globus pallidus tissue by Zwingmann et al, 84 was observed in a larger thalamus-centered volume of interest in the same study. 11 This finding of increased thalamic GABA has been reproduced in additional populations of smelters and welders in different countries and settings; 88-90 moreover, thalamic GABA levels were recently found to predict fine motor performance in Mn-exposed workers. 89 Finally, Long et al also reported reduced Glu in the frontal cortex of Mn-exposed smelters and welders vs. matched controls, as well as reduced mI in the thalamus and posterior cingulate cortex.…”

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“…Prior to Fourier transformation of the MRS signal, 3 Hz exponential line broadening was applied. The difference-edited GABA signal at 3 ppm and the Cr peak from the unsuppressed MEGA-PRESS signal were fit with Gaussian and Lorentzian models, respectively (r > 0.95), and the area under these model fits was calculated to determine the GABA to total Cr ratio (GABA/Cr) (Edden and Barker 2007;Dydak et al 2011;Zhu et al 2011;Edden et al 2014).…”