Neuroimaging for Early Diagnosis of Manganese Toxicity in Humans and Rodents

描述（由申请人提供）：由于职业环境过量暴露于锰（Mn）会导致神经系统损伤。锰中毒（“锰中毒”）的症状类似于特发性帕金森病（IPD），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。因此，本研究的主要目的是利用新的神经影像学技术发现并建立一种无创诊断工具，用于早期检测人类Mn诱导的帕金森病，并进一步探索Mn神经毒性在动物模型中的潜在机制。对啮齿动物和人类的研究表明，接触锰的增加与基底神经节脑区神经递质3-氨基丁酸（GABA）含量的改变有关，这与运动障碍中发现的情况类似。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）的新方法将用于检测大脑GABA和N-乙酰天冬氨酸（NAA）的体内浓度变化，NAA是神经元完整性的标志，[11C]CFT PET将用于评估多巴胺（DA）神经变性。本文将检验以下三个假设：(1)锰中毒症状前发作可通过特定脑区GABA水平升高和NAA水平降低结合脑内Mn和Fe水平检测；(2)锰诱导的纹状体GABA水平变化与纹状体DA神经元变性无关；(3)锰诱导的GABA和NAA变化可在多个脑区检测到。为了建立GABA/NAA变化、累积锰暴露、内部暴露参数（如脑、血液和尿液锰水平）和锰诱发运动缺陷之间的独特关系，将在中国建立一个成熟的锰暴露受试者队列（低锰和高锰暴露工人各24名，对照24名，锰中毒患者15名）的纵向研究（超过4年的两个时间点）。一组24名IPD患者将作为运动障碍中GABA变化的阳性对照。为了明确mn诱导的帕金森病和IPD之间的区别，我们将在Aim 2中通过对同一动物（每组N=10）进行连续MRS和PET成像，探索两种mn暴露水平和药物诱导（6-OHDA） PD啮齿动物模型中GABA和多巴胺之间的机制关系。最后，我们将利用我们目前正在开发的快速3D光谱成像（MRSI）技术，研究印第安纳州当地焊工队列（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。从这项工作中获得的知识将导致对Mn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Mn诱导的帕金森病的早期，症状前诊断。

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.