Brain and Behavioral Indicators of Risk for Parkinsonism among Adolescents with Early Pesticide Exposure

早期接触农药的青少年帕金森病风险的大脑和行为指标

• 批准号: 10321251
• 负责人: F. DuBois Bowman
• 金额: $ 56.61万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-01-15 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10321251
• 关键词: 12 year old; 18 year old; 20 year old; Adolescent; Adult; Age; Age-Years; Appearance; Autonomic Dysfunction; Base of the Brain; Behavioral; Biological Markers; Birth; Blood; Bradykinesia; Brain; Brain imaging; Brain scan; Characteristics; Child; Chlorpyrifos; Clinical; Cognitive deficits; Cohort Studies; Communities; Data; Development; Diagnosis; Dystonia; Early identification; Environmental Exposure; Environmental Health; Environmental Risk Factor; Etiology; Exposure to; Functional disorder; Future; Gait; High Prevalence; Image; Individual; Insecticides; Intervention; Life; Magnetic Resonance Imaging; Measures; Modality; Modeling; Motor; Multimodal Imaging; Nerve Degeneration; Neurologic; Neurologic Signs; Occupational; Organophosphates; Parkinson Disease; Parkinsonian Disorders; Participant; Pathogenicity; Pattern; Persons; Pesticides; Population; Prevalence; Prevention strategy; Procedures; Process; Prospective Studies; Public Health; REM Sleep Behavior Disorder; Reporting; Research; Risk; Role; Rotation; Sampling; Signal Transduction; Societies; Substantia nigra structure; Symptoms; Testing; Time; Toxic Environmental Substances; Tremor; Umbilical Cord Blood; Walking; Work; age related neurodegeneration; arm; base; behavior measurement; behavior test; cohort; disorder risk; early detection biomarkers; high risk; inner city; innovation; member; minority children; motor disorder; motor symptom; multimodality; neural patterning; neurodevelopment; neuroimaging; neuromelanin; non-motor symptom; novel; novel marker; novel strategies; pesticide exposure; potential biomarker; pre-clinical; prenatal; prenatal exposure; progressive neurodegeneration; sex; urban minority; virtual

Multiple studies have demonstrated an association between organophosphate (OP) insecticide exposure and Parkinson's Disease (PD) in adults, but virtually no studies have explored signs of the pathogenic process that begins long before the appearance of motor symptoms. There is a clear need for prospective studies, including biomarkers of exposure and brain-based measures, to substantiate a cause-effect relationship and the development of parkinsonism over time. We have access to a well-characterized community sample—an urban minority birth cohort that has been followed for 18 years, with a prenatal blood biomarker of exposure to a common OP pesticide, chlorpyrifos (CPF), and regular assessments of neurodevelopment, including multimodal brain scans at 12-14 and 18 years. In this cohort, we have shown that prenatal CPF exposure is associated with motor delay at 2-3 years, and persistent brain, behavioral and subtle motor effects through 11- 12 years of age. We now have a unique opportunity to study the emergence of pre-clinical/non-motor indicators of PD risk at 18-20 years of age in this cohort. We propose to test the novel hypothesis that prenatal CPF exposure has long-term motor consequences, including neurological signs and brain-based biomarkers of PD risk that are measureable early in the pathogenic process, prior to the identification of clinically confirmed symptoms or diagnosis. We aim to: (1) conduct a single wave of neurological and brain imaging assessment (using known indicators of PD risk in adult populations) in a subset of the cohort (n=200) at 18-20 years of age. We hypothesize that those with higher prenatal CPF levels as compared to those with lower levels will show significantly more signs of early PD risk, as indicated by (a) higher prevalence of pre-clinical extrapyramidal motor dysfunction (dystonia, bradykinesia, arm tremor); (b) higher prevalence of non-motor symptoms (REM sleep behavior disorder, autonomic dysfunction, olfactory deficits); and (c) increased prodromal motor markers (gait variability, inconsistent walking pattern, arm swing asymmetry and lower axial rotation smoothness); (2) conduct structural MRI for neuromelanin to identify substantia nigra involvement (a biomarker of PD) in these same subjects. We hypothesize that those with higher prenatal CPF levels as compared to those with lower levels will show significantly greater substantia nigra involvement marked by a greater decrease in neuromelanin content; (3) employ an innovative statistical procedure using a vast number of functional and structural brain characteristics, based on multi-modal imaging data previously collected at 12-14 and 18 years, to determine whether an exposure-related pattern of neural deficits across modalities (a potential biomarker for PD) can be detected in our young cohort. We hypothesize that subjects with higher prenatal CPF levels as compared to those with lower levels will show a distinctive pattern of brain anomalies across modalities and time. This study has the potential to shift the research paradigm from a focus on neurodegenerative processes in PD to incorporate a neurodevelopmental perspective, with potential implications for future interventions.

多项研究表明有机磷酸盐（OP）杀虫剂暴露与 帕金森氏病（PD）成人，但实际上没有研究探讨了病原过程的迹象 早在出现运动症状之前就开始了。明确需要前瞻性研究，包括 暴露和基于大脑的措施的生物标志物，以证实因果关系和 随着时间的流逝，帕金森主义的发展。我们可以访问一个特征良好的社区样本 - 一个 城市少数族裔出生队列已有18年了，带有产前血液生物标志物 一种常见的农药，毒性里利（CPF）和对神经发育的定期评估，包括 多模式的脑扫描在12 - 14年和18年。在此队列中，我们已经证明了产前CPF的暴露是 与2 - 3年的运动延迟相关，以及通过11-- 12岁。我们现在有一个独特的机会来研究临床前/非运动前的出现 该队列中18-20岁的PD风险指标。我们建议测试产前的新假设 CPF暴露具有长期运动后果，包括神经系统体征和基于大脑的生物标志物 在临床确认之前，在病原过程中测量的PD风险是在病原过程中测量的 症状或诊断。我们的目的是：（1）进行一波神经和脑成像评估 （使用已知的成人人群中PD风险的已知指标）在18-20岁时的一部分（n = 200）中。 我们假设那些与水平较低的人相比具有较高产前CPF水平的人将显示 早期PD风险的迹象明显更多，如（a）较高的临床前锥体外体患病率所表明 运动功能障碍（肌张力障碍，Bradykinesia，手臂震颤）； （b）非运动症状的较高患病率（REM） 睡眠行为障碍，自主功能障碍，嗅觉定义）； （c）前驱电机标记增加 （步态变异性，步行模式不一致，手臂不对称和较低的轴向旋转平滑度）； （2） 进行神经苯胺的结构MRI以鉴定nigra参与（PD的生物标志物） 相同的主题。我们假设那些与较低的产前CPF水平较高的人 水平将显示出明显更大的基本NIGRA，标志着更大的下降 神经苯胺含量； （3）使用大量功能和 基于先前在12 - 14年和18年收集的多模式成像数据的结构性大脑特征， 确定是否跨模态的神经脱发的暴露相关模式（一种潜在的生物标志物 可以在我们的年轻队列中检测到PD）。我们假设具有较高产前CPF水平的受试者为 与水平较低的人相比，将显示出跨模态和脑异常的独特模式 时间。这项研究有可能将研究范式从关注神经退行性过程的关注中转移 在PD中融合了神经发育的观点，对将来的干预措施产生了潜在影响。