Neuroimaging for Early Diagnosis of Manganese Toxicity in Humans and Rodents

描述（由申请人提供）：由于职业环境导致的锰（Mn）过量暴露可导致神经系统损伤。锰中毒（锰中毒）的症状与特发性帕金森病（IPD）相似，通常会进行性和不可逆，因此早期诊断对于预防职业和环境中的锰中毒至关重要。因此，拟议工作的主要目标是使用新的神经影像学技术，发现和建立一个非侵入性的诊断工具，早期检测锰诱导的帕金森病在人类，并进一步探讨锰神经毒性的动物模型的潜在机制。对啮齿动物和人类的研究表明，锰暴露增加与基底神经节脑区神经递质3-氨基丁酸（GABA）含量的变化有关，这与运动障碍中发现的变化相似。然而，这些改变的剂量依赖性、特异性和机制尚不清楚。磁共振波谱（MRS）中的新方法将用于检测脑GABA以及N-乙酰天冬氨酸（NAA）（神经元完整性的标志物）的体内浓度变化，[11 C]CFT PET将用于评估多巴胺（DA）神经变性。将检验以下三个假设：（1）锰中毒的症状前发作可通过选定脑区中GABA水平升高和NAA水平降低以及脑Mn和Fe水平检测，（2）Mn诱导的纹状体GABA水平变化与纹状体DA神经元变性无关，（3）Mn诱导的GABA和NAA变化可在多个脑区检测到。建立GABA/NAA变化、累积锰暴露、内暴露参数之间的独特关系（如脑、血和尿锰水平）和锰诱导的运动缺陷，一项纵向研究（4年内的两个时间点）将在中国锰暴露受试者的成熟队列中建立（低、高锰作业工人各24名，对照组24名，锰中毒患者15名）。一组24名IPD患者将用作运动障碍中GABA变化的阳性对照。为了确定Mn诱导的帕金森综合征和IPD之间的差异，我们将在目标2中通过在相同动物（每组N=10）中进行连续MRS和PET成像来探索两种Mn暴露水平和药物诱导的（6-OHDA）PD啮齿动物模型中GABA和多巴胺之间的机制关系。最后，我们将通过使用我们目前正在开发的快速3D光谱成像（MRSI）技术，研究当地印第安纳州焊工队列（N=30，15名对照）中由于低水平慢性锰暴露而导致的GABA和NAA变化的空间分布。我们当地的扫描仪。从这项工作中获得的知识将导致对锰诱导的神经毒性的机制和剂量效应的新见解，并可能导致一种诊断工具，允许锰诱导的帕金森病的早期症状前诊断。 公共卫生相关性：在合金和钢铁工业中，过量的锰职业暴露会导致帕金森样症状，即使在停止暴露后也会继续发展。迄今为止，既没有用于早期、症状前诊断的生物标志物，也没有有效的治疗选择。利用磁共振波谱和正电子发射断层扫描等新的非侵入性神经成像技术来测量锰暴露改变的脑神经递质水平的变化，并研究这种变化的剂量-效应关系，将为锰诱导的神经毒性机制提供关键的见解，并将有利于早期临床诊断。

DESCRIPTION (provided by applicant): Excess exposure to manganese (Mn) due to occupational settings can cause damage to the nervous system. Symptoms of Mn intoxication ("manganism") resemble those in idiopathic Parkinson's disease (IPD) and usually become progressive and irreversible, making early diagnosis crucial for prevention of Mn intoxication in the occupational and environmental setting. Therefore the primary objective of the proposed work is to use novel neuroimaging techniques to discover and establish a noninvasive diagnostic tool for early detection of Mn-induced Parkinsonism in humans, and to further explore the underlying mechanism of Mn neurotoxicity in an animal model. Studies on rodents and humans have linked increased Mn exposure with alterations in the content of the neurotransmitter 3-aminobutyric acid (GABA) in the basal ganglia brain region, similar to those found in movement disorders. However the dose-dependency, specificity and the mechanism underlying these alterations is unknown. Novel approaches in magnetic resonance spectroscopy (MRS) will be used to detect in vivo concentration changes of brain GABA as well as N- acetylaspartate (NAA), a marker of neuronal integrity, and [11C]CFT PET will be used to assess dopamine (DA) neurodegeneration. The following three hypotheses will be tested: (1) pre-symptomatic onset of manganism can be detected by increased GABA and decreased NAA levels in selected brain regions in combination with brain Mn and Fe levels, (2) Mn-induced changes of striatal GABA levels are independent of degeneration of striatal DA neurons and (3) Mn-induced GABA and NAA changes are detectable in multiple brain areas. To establish a unique relationship between GABA/NAA changes, cumulative Mn exposure, internal exposure parameters (such as brain, blood and urine Mn levels), and Mn-induced motor deficits, a longitudinal study (two time points over 4 years) will be established on a well-established cohort of Mn-exposed subjects in China (24 workers with low and with high Mn exposure each, 24 control subjects and 15 manganism patients). A group of 24 IPD patients will be used as positive controls for GABA changes in movement disorders. To define the difference between Mn-induced parkinsonism and IPD, we will explore the mechanistic relationship between GABA and dopamine in two levels of Mn-exposure and a drug-induced (6-OHDA) PD rodent model by consecutive MRS and PET imaging in the same animals (N=10 per group) in Aim 2. Finally, we will investigate the spatial distribution of GABA and NAA changes due to low-level chronic Mn exposure in a local Indiana welder cohort (N=30, 15 controls) by using our fast 3D spectroscopic imaging (MRSI) technique currently under development on our local scanner. The knowledge to be gained from this work will lead to new insights about the mechanism and dose-effect of Mn-induced neurotoxicity and potentially result in a diagnostic tool allowing for early, pre-symptomatic diagnosis of Mn induced Parkinsonism. 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 neuroimaging techniques such as magnetic resonance spectroscopy and positron-emission tomography to measure the changes in brain neurotransmitter levels altered by manganese exposure, and studying the dose-effect relationship of such changes, will provide critical insight to the mechanism of manganese- induced neurotoxicity and will benefit early clinical diagnosis.