Neuroimaging for Early Diagnosis of Manganese Toxicity in Humans and Rodents

描述(由申请人提供)：由于职业环境原因，过量接触锰会对神经系统造成损害。锰中毒(“锰中毒”)的症状与特发性帕金森病(IPD)相似，通常是进行性的和不可逆转的，因此早期诊断对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技术，发现并建立一种非侵入性的早期诊断工具，用于人类锰致帕金森病的早期检测，并在动物模型中进一步探讨锰神经毒性的潜在机制。对啮齿动物和人类的研究发现，接触锰的增加与基底节脑区神经递质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)的新方法将被用来检测体内大脑GABA和N-乙酰天冬氨酸(NAA)的浓度变化，N-乙酰天冬氨酸(NAA)是神经元完整性的标志，[11C]CFT PET将被用于评估多巴胺(DA)神经退行性变。将检验以下三个假设：(1)在特定脑区GABA水平的升高和NAA水平的降低，结合脑中的锰和铁水平，可以检测到症状前锰中毒的发生；(2)锰诱导的纹状体GABA水平的变化与纹状体DA神经元的变性无关；(3)锰诱导的GABA和NAA变化可在多个脑区检测到。为了建立体内暴露参数(脑、血、尿中的锰水平)与锰引起的运动功能障碍之间的独特关系，我们将对中国的一组公认的锰接触者(24名低锰接触者、24名高锰接触者、24名对照组和15名锰中毒患者)进行为期4年的纵向研究。一组24名IPD患者将被用作运动障碍中GABA变化的阳性对照。为了明确锰诱导的帕金森病和IPD之间的区别，我们将在两个水平的锰暴露和药物诱导的(6-OHDA)PD啮齿动物模型(每组10只)中，通过连续的MRS和PET成像来探索GABA和多巴胺之间的机制关系。最后，我们将使用我们的本地扫描仪上正在开发的快速三维光谱成像(MRSI)技术，研究由于低水平慢性锰暴露在印第安纳州当地焊工队列中(N=30，15名对照)GABA和NAA的空间分布。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的见解，并可能导致一种诊断工具，使得能够对锰诱导的帕金森症进行早期、症状前的诊断。 公共卫生相关性：众所周知，在合金和钢铁行业中，职业过量接触锰会导致帕金森样症状，即使在停止接触之后，这种症状也会继续发展。到目前为止，既没有用于早期症状前诊断的生物标记物，也没有有效的治疗选择。利用核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后脑神经递质水平的变化，并研究这种变化的量效关系，将为深入了解锰致神经毒性的机制提供关键的见解，有助于临床的早期诊断。

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.