Effect of Manganese Exposure on GABA and Glutamate in Human Brains by MRS

描述（由申请人提供）：虽然锰（Mn）是一种必需的微量金属，但由于职业环境导致的过量接触会对神经系统造成损害。锰中毒（“锰中毒”）的症状类似于特发性帕金森病，通常是进行性和不可逆转的，因此早期诊断对于预防职业和环境中的锰中毒至关重要。对啮齿动物的研究表明，Mn浓度的增加与基底神经节脑区神经递质含量的改变有关，但这种改变的剂量依赖性存在争议。利用新的、无创的方法检测人脑中神经递质3-氨基丁酸（GABA）和谷氨酸（Glu）的浓度变化，并研究它们与血液、尿液和空气样本等其他锰暴露指标的相关性，可能会对锰中毒的机制有新的认识，并可能产生一种无创的生物标志物，可用于锰中毒的早期、症状前的临床诊断。因此，本研究的主要目的是利用磁共振成像（MRI）和光谱学（MRS）相结合的技术来检测和量化锰暴露受试者大脑几个相关区域中GABA和Glu的变化，并研究它们的剂量依赖性。以下两个假设将被验证：(1)Mn暴露导致丘脑区GABA水平升高，大脑皮质区Glu水平降低，白球区Glu水平升高；(2)这些变化，以及已知的由于Mn沉积在大脑白球区的MRI信号强度增加，与其他外部和内部暴露指数测量的Mn暴露程度相关。研究队列将包括30名mn暴露者和20名对照受试者。暴露组将被细分为10名有锰中毒症状的锰暴露患者，10名来自中国一家铁锰合金制造厂从事已知高锰暴露但无临床症状工作的工人，以及10名来自同一工厂低锰暴露地区的工人。这种细分允许对脑代谢中所寻求的变化的剂量依赖性进行测试。最近发展的MRS技术，允许人脑中GABA和Glu的非侵入性检测和定量，将用于测量这些神经递质和其他脑代谢物在几个不同大脑区域的浓度。为了评估其他外部和内部锰暴露指数(1)将在受试者目前或以前的工作场所采集空气样本，(2)收集尿液和血液样本，(3)每位受试者进行生理检查和神经行为测试。从这项工作中获得的知识可能是第一次在人类研究中得出关于谷氨酸能和gaba能脑系统对Mn的脆弱性的结论，从而有助于推进新的治疗策略。公共卫生相关性：已知在合金和钢铁工业中职业性过量接触锰可引起帕金森样症状，即使在停止接触后仍会恶化。迄今为止，既没有早期症状前诊断的生物标志物，也没有有效的治疗选择。利用磁共振成像和磁共振波谱等新颖的非侵入性技术来测量锰暴露引起的脑代谢变化，并研究这种变化的剂量依赖性，将为锰诱导神经毒性的机制提供关键见解，并有助于早期临床诊断。

DESCRIPTION (provided by applicant): While manganese (Mn) is an essential trace metal, excess exposure due to occupational settings can cause damage to the nervous system. Symptoms of Mn intoxication ("manganism") resemble those in idiopathic Parkinson's disease and usually become progressive and irreversible, making early diagnosis crucial for prevention of Mn intoxication in the occupational and environmental setting. Studies on rodents have linked increased Mn concentrations with alterations in the content of neurotransmitters in the basal ganglia brain region, however the dose-dependency of such alterations is controversial. Using novel, non-invasive approaches to detect concentration changes of the neurotransmitters 3-aminobutyric acid (GABA) and glutamate (Glu) in the human brain and studying their correlation to other Mn exposure indices, such as blood, urine and air samples, may lead to new insights about the mechanism on Mn-induced toxicity and potentially result in a non-invasive biomarker, which may be used for early, pre-symptomatic clinical diagnosis of Mn intoxication. Therefore the primary objective of the proposed work is to use a combined magnetic resonance imaging (MRI) and spectroscopy (MRS) technique to detect and quantify changes of GABA and Glu in several relevant brain regions of Mn-exposed subjects and to study their dose- dependency. The following two hypotheses will be tested: (1) Mn exposure leads to increased GABA levels in the thalamic brain region, to decreased Glu levels in cortical brain regions and to increased Glu levels in the pallidal brain region, and (2) such changes, together with the known MRI signal intensity increase in the globus pallidus due to Mn deposition in this brain region, correlate with the extent of Mn exposure, as measured by other external and internal exposure indices. The study cohort will consist of 30 Mn-exposed and 20 control subjects. The exposed group will be subdivided into 10 Mn-exposed patients with manganism symptoms, 10 workers from a Fe-Mn-alloy manufacture in China performing jobs with known high Mn exposure, but without clinical symptoms, and 10 workers from low Mn-exposure areas in the same factory. This subdivision allows for the testing of the dose dependency of the sought changes in brain metabolism. Recently developed MRS techniques, allowing for the non-invasive detection and quantification of GABA and Glu in the human brain will be used to measure concentrations of these neurotransmitters and other brain metabolites in several different brain areas. To assess other external and internal Mn exposure indices (1) air samples will be taken at the current or former working places of the subjects, (2) urine and blood samples will be collected and (3) each subject will undergo physiological examination and neurobehavioral testing. The knowledge to be gained from this work may for the first time in human studies allow for conclusions on the vulnerability of glutamatergic and GABAergic brain systems to Mn and thus help advance novel therapeutic strategies. PUBLIC HEALTH RELEVANCE: Excessive occupational exposure to manganese in the alloying and steel industry is known to cause Parkinson-like symptoms, which progress even after the cessation of the exposure. Neither a biomarker for early, pre-symptomatic diagnosis, nor effective treatment options exist to date. Using novel, non-invasive techniques such as magnetic resonance imaging and magnetic resonance spectroscopy to measure the changes in brain metabolism caused by manganese exposure, and studying the dose-dependence of such changes, will provide critical insight to the mechanism of manganese-induced neurotoxicity and will benefit early clinical diagnosis.