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

MRS 测定锰暴露对人脑 GABA 和谷氨酸的影响

• 批准号: 7708238
• 负责人: Ulrike Dydak
• 金额: $ 22.67万
• 依托单位: PURDUE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-05 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7708238
• 关键词: 3-aminobutyric acid; Air; Alloys; Aminobutyric Acids; Animals; Area; Basal Ganglia; Biological Markers; Blood; Blood specimen; Brain; Brain region; China; Choline; Clinical; Clinical Chemistry; Cohort Studies; Corpus striatum structure; Creatine; Dependence; Dependency; Deposition; Development; Diagnosis; Dopamine; Dose; Early Diagnosis; Evaluation; Exposure to; Globus Pallidus; Glutamates; Human; In Vitro; Industry; Inositol; Intoxication; Knowledge; Lead; Link; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Manganese; Measures; Metabolism; Methods; Motor; N-acetylaspartate; Nature; Nerve Degeneration; Nervous system structure; Neurons; Neurotransmitters; Non-Invasive Cancer Detection; Occupational; Occupational Exposure; Occupations; Outcome; Parkinson Disease; Participant; Patients; Physiological; Prevention; Recording of previous events; Recruitment Activity; Rodent; Severities; Signal Transduction; Spectrum Analysis; Steel; Structure; Symptoms; System; Techniques; Testing; Thalamic structure; Time; Toxic effect; Trace metal; Urine; Work; Workplace; air sampling; brain metabolism; clinical Diagnosis; early onset; effective therapy; gamma-Aminobutyric Acid; in vivo; indexing; innovation; insight; neurobehavioral test; neurotoxicity; novel; novel strategies; novel therapeutics; psychologic; public health relevance

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.

描述（由申请人提供）：虽然锰（MN）是必不可少的痕量金属，但由于职业设置而导致的过多暴露会损害神经系统。 Mn中毒的症状（“锰”）类似于特发性帕金森氏病，通常变得渐进且不可逆，这对于预防在职业和环境环境中预防MN中毒至关重要。关于啮齿动物的研究已将MN浓度与基底神经节脑区域的神经递质含量的改变联系在一起，但是这种改变的剂量依赖性是有争议的。使用新型的非侵入性方法来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，并研究其与其他MN暴露指标的相关性，例如血液，尿液和空气样品，可能会导致对MN诱导的毒性的可能性，并可能导致对MN诱导的毒性的新洞察力，并具有新的毒性，并可能导致毒性的毒性，并可能导致毒性的毒性，并具有不可能的毒性，并且可能会导致毒性的毒性，并可能导致毒性的毒性，并可能导致毒性的毒性，并可能导致毒性的毒性，并可能导致毒性的毒性，并可能引起毒性的毒性。用于早期，症状前临床诊断Mn中毒。因此，提出的工作的主要目的是使用磁共振成像（MRI）和光谱（MRS）技术来检测和量化MN暴露受试者的几个相关大脑区域的GABA和GLU的变化并研究其剂量依赖性。将测试以下两个假设：（1）MN暴露导致丘脑脑区域的GABA水平升高，导致皮质大脑区域的GLU水平降低，并导致颗粒大脑区域的GLU水平和GLU水平增加，（2）此类变化，以及由于MN造成的MRI信号的增加而与MN的ext型相关的MRI信号的增加，而MN的含量与MN的含量相同，并且在MN中占据了MEN，而MEN在MN中的含量，并且在MN中占据了MRI的范围，并且在MN中的含量均与MER隔离，并且在MN中的含量均相互依赖。和内部暴露指数。该研究队列将由30名MN暴露和20名对照受试者组成。暴露的组将分为10名暴露于锰症状的患者，来自中国Fe-MN合金制造的10名工人，具有已知的高MN暴露的工作，但没有临床症状，而在同一工厂中，有10名来自MN较低的工人。该细分允许测试脑代谢所寻求的变化的剂量依赖性。最近开发的MRS技术允许人脑中GABA和GLU的非侵入性检测和定量，用于测量几个不同大脑区域中这些神经递质和其他脑代谢物的浓度。为了评估其他外部和内部MN暴露指数（1）在受试者的当前或以前的工作场所将采集空气样本，（2）将收集尿液和血液样本，（3）每个受试者将接受生理检查和神经行为检查。从这项工作中获得的知识可能首次在人类研究中可以得出关于谷氨酸能和Gabaergic脑系统对MN的脆弱性的结论，从而有助于推进新颖的治疗策略。公共卫生相关性：已知合金和钢铁行业中对锰的职业暴露过多会导致类似帕金森氏症的症状，即使在暴露停止之后，这种症状也会进展。迄今为止，既不存在用于早期，症状诊断的生物标志物，也不是有效的治疗选择。使用新颖的非侵入性技术，例如磁共振成像和磁共振光谱，以测量锰暴露引起的脑代谢的变化，并研究这种变化的剂量依赖性，将为锰诱导的神经毒性的机制提供关键的见解，并将受益于早期临床诊断。