Neuroimaging for Early Diagnosis of Manganese Toxicity in Humans and Rodents

神经影像学用于人类和啮齿动物锰毒性的早期诊断

• 批准号: 8842130
• 负责人: Ulrike Dydak
• 金额: $ 32.53万
• 依托单位: PURDUE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-12 至 2018-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8842130
• 关键词: 3-aminobutyric acid; Alloys; Aminobutyric Acids; Animal Model; Animals; Area; Basal Ganglia; Biological Markers; Blood; Brain; Brain region; China; Chronic; Clinical; Control Groups; Corpus striatum structure; Data; Dependency; Development; Diagnosis; Diagnostic; Dopamine; Dose; Drug usage; Early Diagnosis; Exhibits; Exposure to; Functional disorder; General Population; Goals; Human; Image; Indiana; Industry; Intoxication; Knowledge; Lead; Link; Literature; Longitudinal Studies; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Manganese; Measurement; Measures; Movement Disorders; N-acetylaspartate; National Institute of Environmental Health Sciences; Nerve Degeneration; Nervous system structure; Neurodegenerative Disorders; Neurons; Neurotransmitters; Occupational; Occupational Exposure; Outcome Study; Oxidopamine; Parkinson Disease; Parkinsonian Disorders; Patients; Pharmaceutical Preparations; Play; Positron-Emission Tomography; Prevention; Reporting; Research; Resolution; Rodent; Rodent Model; Role; Scientist; Secondary to; Severity of illness; Spatial Distribution; Specificity; Steel; Symptoms; Techniques; Technology; Testing; Thalamic structure; Time; Tissues; Toxic effect; United States National Institutes of Health; Urine; Welding; Work; base; brain metabolism; career; clinical Diagnosis; cohort; design; dopaminergic neuron; effective therapy; experience; frontal lobe; gamma-Aminobutyric Acid; human subject; improved; in vivo; insight; magnetic resonance spectroscopic imaging; motor deficit; motor disorder; nerve supply; nervous system disorder; neurochemistry; neuroimaging; neuron loss; neurotoxicity; novel; novel strategies; response; spectroscopic imaging; tool; treatment strategy

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.

描述（由申请人提供）：由于职业设置而导致的锰（MN）过多的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（IPD）的症状，并且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。因此，提出的工作的主要目标是使用新型的神经影像学技术来发现和建立一种无创诊断工具，用于早期发现人类中Mn诱导的帕金森氏症，并进一步探索动物模型中MN神经毒性的潜在机制。关于啮齿动物和人类的研究已将MN暴露与基底神经节脑区域的神经递质3-氨基丁酸（GABA）的含量的改变联系在一起，类似于运动障碍中的介质。然而，这些改变的剂量依赖性，特异性和机制尚不清楚。磁共振光谱（MRS）中的新方法将用于检测脑GABA以及N-乙酰基大赛（NAA）的体内浓度变化（NAA），神经元完整性的标志物，[11C] CFT PET将用于评估多巴胺（DA）神经脱发。 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.为了在GABA/NAA变化，累积MN暴露，内部暴露参数（例如大脑，血液和尿液和尿液MN水平）与MN引起的运动不足之间建立独特的关系，将在中国的MN较高者和24名较高的人（24名工程师）中建立一项纵向研究（4年内的两个时间点）。一组24例IPD患者将用作运动障碍GABA变化的阳性对照。为了定义MN诱发的帕金森氏症和IPD之间的差异，我们将探索两个级别的MN暴露和药物诱导的（6-OHDA）PD啮齿动物模型的GABA和多巴胺之间的机械关系，通过连续的MRS和PET在AIM 2中的同一动物（n = 10）在AIM 2和NA的情况下，我们将在AIM 2和NA中进行调查。在当地的印第安纳州焊工队列（n = 30，15个对照组）中，我们使用我们当地扫描仪正在开发的快速3D光谱成像（MRSI）技术。从这项工作中获得的知识将导致有关MN诱导的神经毒性的机制和剂量效应的新见解，并可能导致诊断工具，从而可以对MN诱导的Parkinsonism进行早期症状的症状诊断。

项目成果

Spatial variability and reproducibility of GABA-edited MEGA-LASER 3D-MRSI in the brain at 3 T.

• DOI: 10.1002/nbm.3613
• 发表时间: 2016-11
• 期刊: NMR IN BIOMEDICINE
• 影响因子: 2.9
• 作者: Hnilicova, Petra;Povazan, Michal;Strasser, Bernhard;Andronesi, Ovidiu C.;Gajdosik, Martin;Dydak, Ulrike;Ukropec, Jozef;Dobrota, Dusan;Trattnig, Siegfried;Bogner, Wolfgang
• 通讯作者: Bogner, Wolfgang

Association of exposure to manganese and fine motor skills in welders - Results from the WELDOX II study.

• DOI: 10.1016/j.neuro.2020.12.003
• 发表时间: 2021-01
• 期刊: Neurotoxicology
• 影响因子: 3.4
• 作者: Lotz A;Pesch B;Casjens S;Lehnert M;Zschiesche W;Taeger D;Yeh CL;Weiss T;Schmidt-Wilcke T;Quetscher C;Gabriel S;Zella MAS;Woitalla D;Dydak U;van Thriel C;Brüning T;Behrens T
• 通讯作者: Behrens T

Striatal and thalamic GABA level concentrations play differential roles for the modulation of response selection processes by proprioceptive information.

• DOI: 10.1016/j.neuroimage.2015.06.066
• 发表时间: 2015-10-15
• 期刊: NeuroImage
• 影响因子: 5.7
• 作者: Dharmadhikari S;Ma R;Yeh CL;Stock AK;Snyder S;Zauber SE;Dydak U;Beste C
• 通讯作者: Beste C

Striatal GABA-MRS predicts response inhibition performance and its cortical electrophysiological correlates.

• DOI: 10.1007/s00429-014-0873-y
• 发表时间: 2015-11
• 期刊: Brain structure & function
• 影响因子: 3.1
• 作者: Quetscher C;Yildiz A;Dharmadhikari S;Glaubitz B;Schmidt-Wilcke T;Dydak U;Beste C
• 通讯作者: Beste C