COMPARISON OF BRAIN METABOLITE CHANGES IN MANGANESE-EXPOSED WELDERS AND SMELTERS

poster abstractExcessive manganese (Mn) exposure is known to cause cognitive, psychiatric and motor deficits. Mn overexposure occurs in different occupational settings, where the type and level of exposure may vary. Magnetic resonance imaging (MRI) and spectroscopy (MRS) can be used to evaluate brain Mn accumulation and to measure Mn-induced metabolite changes non-invasively. The aim of this study was to compare metabolite changes among different brain regions of welders and smelters following occupational Mn exposure. Nine Mn-exposed smelters, 14 Mn-exposed welders and 23 male matched controls were recruited from a cohort of workers from two factories in China (mean airborne Mn level: 0.227 and 0.025 mg/m3 for smelters and welders, respectively). Short-echo-time 1H MRS spectra were acquired in each subject from four volumes of interest: the frontal cortex, posterior cingulate cortex, hippocampus, and thalamus. We found that 1) in the frontal cortex, significantly decreased creatine (Cr), glutamate (Glu) and glutathione (GSH) were found in welders, whereas decreased Glu was found in smelters as compared to controls. 2) In the thalamus, reduced myo-inositol was found in both smelters and welders, while Glu and GSH were decreased in welders. These results suggest that Mn-induced brain metabolite changes may be regional in nature and more extensive in welders than in smelters. The frontal cortex seems to show a more profound change than the other brain areas tested among Mn exposed subjects. Further studies are needed to investigate the effects of exposure type and length on the mechanism of Mn neurotoxicity. (Supported by NIH/NIEHS R21 ES-017498, National Science Foundation of China Grant #81072320 and 30760210)

Neuroimaging Studies of Essential Tremor: How Well Do These Studies Support/Refute the Neurodegenerative Hypothesis?

Background: Tissue‐based research has recently led to a new patho‐mechanistic model of essential tremor (ET)—the cerebellar degenerative model. We are not aware of a study that has reviewed the current neuroimaging evidence, focusing on whether the studies support or refute the neurodegenerative hypothesis of ET. This was our aim. Methods: References for this review were identified by searches of PubMed (1966 to February 2014). Results: Several neuroimaging methods have been used to study ET, most of them based on magnetic resonance imaging (MRI). The methods most specific to address the question of neurodegeneration are MRI‐based volumetry, magnetic resonance spectroscopy, and diffusion‐weighted imaging. Studies using each of these methods provide support for the presence of cerebellar degeneration in ET, finding reduced cerebellar brain volumes, consistent decreases in cerebellar N‐acetylaspartate, and increased mean diffusivity. Other neuroimaging techniques, such as functional MRI and positron emission tomography (PET) are less specific, but still sensitive to potential neurodegeneration. These techniques are used for measuring a variety of brain functions and their impairment. Studies using these modalities also largely support cerebellar neuronal impairment. In particular, changes in 11C‐flumazenil binding in PET studies and changes in iron deposition in an MRI study provide evidence along these lines. The composite data point to neuronal impairment and likely neuronal degeneration in ET. Discussion: Recent years have seen a marked increase in the number of imaging studies of ET. As a whole, the combined data provide support for the presence of cerebellar neuronal degeneration in this disease

Reproducibility and effect of tissue composition on cerebellar GABA MRS in an elderly population.

Magnetic resonance spectroscopy (MRS) provides a valuable tool to non-invasively detect brain gamma-amino butyric acid (GABA) in vivo. GABAergic dysfunction has been observed in the aging cerebellum. Studying cerebellar GABA changes is of considerable interest in understanding certain age-related motor disorders. However, little is known about the reproducibility of GABA MRS in an aged population. Therefore, this study aimed to explore the feasibility and reproducibility of GABA MRS in the aged cerebellum at 3.0 Tesla and to examine the effect of differing tissue composition on GABA measurements. MRI and 1H MRS exams were performed on 10 healthy elderly volunteers (mean age 75.2 years ± 6.5 years) using a 3.0 Tesla Siemens Tim Trio scanner. Among them, 5 subjects were scanned twice to assess short-term reproducibility. The MEGA-PRESS J-editing sequence was used for GABA detection in two volumes of interest (VOIs) in left and right cerebellar dentate. MRS data processing and quantification were performed with LCModel 6.3-0L using two separate basis sets, generated from density matrix simulations using published values for chemical shifts an

Thalamic GABA levels and Occupational Manganese Neurotoxicity: Association with Exposure Levels and Brain MRI

Excessive occupational exposure to Manganese (Mn) has been associated with clinical symptoms resembling idiopathic Parkinson’s disease (IPD), impairing cognitive and motor functions. Several studies point towards an involvement of the brain neurotransmitter system in Mn intoxication, which is hypothesized to be disturbed prior to onset of symptoms. Edited Magnetic Resonance Spectroscopy (MRS) offers the unique possibility to measure γ-amminobutyric acid (GABA) and other neurometabolites in vivo non-invasively in workers exposed to Mn. In addition, the property of Mn as Magnetic Resonance Imaging (MRI) contrast agent may be used to study Mn deposition in the human brain. In this study, using MRI, MRS, personal air sampling at the working place, work history questionnaires, and neurological assessment (UPDRS-III), the effects of chronic Mn exposure on the thalamic GABAergic system was studied in a group of welders (N = 39) with exposure to Mn fumes in a typical occupational setting. Two subgroups of welders with different exposure levels (Low: N = 26; mean air Mn = 0.13 ± 0.1 mg/m3; High: N = 13; mean air Mn = 0.23 ± 0.18 mg/m3), as well as unexposed control workers (N = 22, mean air Mn = 0.002 ± 0.001 mg/m3) were recruited. The group of welders with higher exposure showed a significant increase of thalamic GABA levels by 45% (p < 0.01, F(1,33) = 9.55), as well as significantly worse performance in general motor function (p < 0.01, F(1,33) = 11.35). However, welders with lower exposure did not differ from the controls in GABA levels or motor performance. Further, in welders the thalamic GABA levels were best predicted by past-12-months exposure levels and were influenced by the Mn deposition in the substantia nigra and globus pallidus. Importantly, both thalamic GABA levels and motor function displayed a non-linear pattern of response to Mn exposure, suggesting a threshold effect

Vulnerability of welders to manganese exposure--a neuroimaging study

Increased manganese (Mn) exposure is known to cause cognitive, psychiatric and motor deficits. Mn exposure occurs in different occupational settings, where the airborne Mn level and the size of respirable particulates may vary considerably. Recently the importance of the role of the cerebral cortex in Mn toxicity has been highlighted, especially in Mn-induced neuropsychological effects. In this study we used magnetic resonance imaging (MRI) to evaluate brain Mn accumulation using T1 signal intensity indices and to examine changes in brain iron content using T2* contrast, as well as magnetic resonance spectroscopy (MRS) to measure exposure-induced metabolite changes non-invasively in cortical and deep brain regions in Mn-exposed welders, Mn-exposed smelter workers and control factory workers with no measurable exposure to Mn. MRS data as well as T1 signal intensity indices and T2* values were acquired from the frontal cortex, posterior cingulate cortex, hippocampus, and thalamus. Smelters were exposed to higher air Mn levels and had a longer duration of exposure, which was reflected in higher Mn levels in erythrocytes and urine than in welders. Nonetheless, welders had more significant metabolic differences compared to controls than did the smelter workers, especially in the frontal cortex. T1 hyperintensities in the globus pallidus were observed in both Mn-exposed groups, but only welders showed significantly higher thalamic and hippocampal T1 hyperintensities, as well as significantly reduced T2* values in the frontal cortex. Our results indicate that (1) the cerebral cortex, in particular the frontal cortex, is clearly involved in Mn neurotoxic effects and (2) in spite of the lower air Mn levels and shorter duration of exposure, welders exhibit more extensive neuroimaging changes compared to controls than smelters, including measurable deposition of Mn in more brain areas. These results indicate that the type of exposure (particulate sizes, dust versus fume) and route of exposure play an important role in the extent of Mn-induced toxic effects on the brain

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

Background: Exposure to excessive manganese (Mn) levels is known to induce psychiatric and motor disorders including parkinsonian symptoms. Therefore finding a reliable means for early detection of Mn neurotoxicity is desirable. Objectives: Our goal was to study whether in-vivo brain levels of gamma-aminobutyric acid (GABA), N-acetylaspartate (NAA) and other brain metabolites in smelters were altered as a consequence of Mn exposure. Methods: T1-weighted MRI was used 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. The MEGA-PRESS MRS sequence was used to determine GABA levels in a region encompassing the thalamus and adjacent parts of the basal ganglia ("GABA-VOI"). Results: Seven out of ten exposed subjects showed clear T1-hyperintense signals in the globus pallidus indicating Mn accumulation. We found a significant increase (82%; p=0.014) of 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 (R= - 0.93, p<0.001) with cumulative Mn exposure. Conclusions: We demonstrated elevated GABA levels in the thalamus and adjacent basal ganglia and decreased frontal cortex NAA levels, indicating neuronal dysfunction in a brain area not primarily targeted by Mn. Therefore, the non-invasive in vivo MRS measurement of GABA and NAA may prove to be a powerful tool for detecting presymptomatic effects of Mn neurotoxicity

In vivo quantification of GABA by magnetic resonance spectroscopy and its applications in panic disorder and manganese neurotoxicity

Magnetic resonance spectroscopy (MRS) provides a non-invasive tool allowing us to directly detect brain metabolites in vivo. One of the growing research interests is focused on γ-aminobutyric acid (GABA), the major inhibitory neurotransmitter in the human brain. Due to its low concentration and spectral overlapping with other larger resonances, the measurement has been proven to be complicated with standard single voxel MRS techniques. Among methods for reliably detecting GABA, the MEGA-PRESS technique has been most widely used. However the total signal resulting from this approach can be contaminated by macromolecules and homocarnosine. Various acquisition and quantification methods have been reported to minimize the contribution of macromolecules. However, the question as to which quantification method provides the best estimate of pure GABA remains elusive. Therefore, the research presented was designed to the optimize the fitting method using LCModel, and to apply this improved method to quantify in vivo GABA levels in panic disorder (PD) and manganese (Mn) neurotoxicity research. By introducing macromolecule resonances into the fitting model, optimizing fitting parameters and comparing results to an acquisition technique which eliminates co-editing of macromolecules, an optimal LCModel fitting method was found. This GABA MRS technique, together with short echo time MRS, was further used to explore family history effects on metabolic changes of Panic Disorder (PD). A significant decrease in GABA was detected in the anterior cingulate cortex (ACC)/medial prefrontal cortex (mPFC) in PD patients, which tends to be pronounced in patients with a PD family history. Overall, the results indicate that deficits in GABA levels in PD patients vary by brain regions and possibly by family history status. At the same time, the developed technique was used to explore the mechanism of manganese (Mn) neurotoxicity. Firstly, the relationship between occupational Mn exposure, changes in GABA, and motor deficits indicated by the Purdue Pegboard test was studied in Mn-exposed smelters. Increasing GABA in the thalamus of smelters was found to significantly correlate with the duration of exposure. Strong inverse correlations were found between an increase in GABA and decrease in scores of all the Purdue Pegboard tests. Thus, GABA may be a potential biomarker of Mn exposure and motor deficits in smelters. Secondly, metabolite levels including GABA, as well as T1 signal intensity index, a semi-quantitative indicator of Mn accumulation, were compared among different brain regions in Mn-exposed welders and smelters. Although smelters had higher Mn in the erythrocytes and urine than welders, welders showed more significant metabolic changes, especially in the frontal cortex. In addition, welders also showed significantly higher thalamic and hippocampal signal intensity indices. Overall, the frontal cortex appears particularly vulnerable to Mn exposure in terms of metabolite changes. The type of exposure seems to play an important role in the extent of Mn-induced toxic changes and should be carefully investigated in the future

Thalamic GABA predicts fine motor performance in manganese-exposed smelter workers.

Overexposure to manganese (Mn) may lead to parkinsonian symptoms including motor deficits. The main inhibitory neurotransmitter gamma-aminobutyric acid (GABA) is known to play a pivotal role in the regulation and performance of movement. Therefore this study was aimed at testing the hypothesis that an alteration of GABA following Mn exposure may be associated with fine motor performance in occupationally exposed workers and may underlie the mechanism of Mn-induced motor deficits. A cohort of nine Mn-exposed male smelter workers from an Mn-iron alloy factory and 23 gender- and age-matched controls were recruited and underwent neurological exams, magnetic resonance spectroscopy (MRS) measurements, and Purdue pegboard motor testing. Short-echo-time MRS was used to measure N-Acetyl-aspartate (NAA) and myo-inositol (mI). GABA was detected with a MEGA-PRESS J-editing MRS sequence. The mean thalamic GABA level was significantly increased in smelter workers compared to controls (p = 0.009). Multiple linear regression analysis reveals (1) a significant association between the increase in GABA level and the duration of exposure (R(2) = 0.660, p = 0.039), and (2) significant inverse associations between GABA levels and all Purdue pegboard test scores (for summation of all scores R(2) = 0.902, p = 0.001) in the smelter workers. In addition, levels of mI were reduced significantly in the thalamus and PCC of smelter workers compared to controls (p = 0.030 and p = 0.009, respectively). In conclusion, our results show clear associations between thalamic GABA levels and fine motor performance. Thus in Mn-exposed subjects, increased thalamic GABA levels may serve as a biomarker for subtle deficits in motor control and may become valuable for early diagnosis of Mn poisoning

Voxel placement and representative ¹H short-TE and GABA-edited spectra with LCModel fitting.

<p>(A) Volume of interest (VOI) for the thalamus (TH); (B) VOI for the posterior cingulate cortex (PCC); (C) a representative sagittal T1-weighted MRI brain image of a smelter, depicting the hyperintense signal associated with brain manganese deposition, especially in the globus pallidus; (D) a representative short-TE spectrum with LCModel fitting; (E) a representative MEGA-PRESS difference spectrum with LCModel fitting. CC: corpus callosum, Cho: choline, CN: caudate nucleus, Cr: creatine, Glx: combination of glutamate and glutamine, GP: globus pallidus, HCN: head of caudate nucleus, mI: myo-inositol, NAA: N-Acetyl-aspartate, PU: putamen,</p