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

多项研究表明，有机磷（OP）杀虫剂暴露与 帕金森氏病（PD）在成人中，但几乎没有研究探索的迹象，致病过程， 早在运动症状出现之前就开始了。显然需要进行前瞻性研究，包括 暴露的生物标志物和基于大脑的测量，以证实因果关系， 随着时间的推移帕金森症的发展。我们有机会获得一个特征良好的社区样本， 城市少数民族出生队列已随访18年，产前血液生物标志物暴露于 一种常见的有机磷农药，毒死蜱（CPF），以及定期评估神经发育，包括 12-14岁和18岁时的多模式脑部扫描。在这个队列中，我们已经表明，产前CPF暴露是 与2-3岁时的运动延迟有关，11- 15岁时持续的大脑、行为和微妙的运动影响， 12岁我们现在有一个独特的机会来研究临床前/非运动性 该队列中18-20岁的PD风险指标。我们建议测试新的假设，产前 CPF暴露具有长期的运动后果，包括神经系统体征和基于脑的生物标志物， 在确定临床确认的PD之前，在致病过程早期可测量的PD风险 症状或诊断。我们的目标是：（1）进行单波神经和脑成像评估 （使用成人人群中PD风险的已知指标）在18-20岁的队列亚组（n=200）中。 我们假设，那些产前CPF水平较高的人与那些水平较低的人相比， 早期PD风险的迹象明显更多，如（a）临床前锥体外系的患病率较高 运动功能障碍（肌张力障碍、运动迟缓、手臂震颤）;（B）非运动症状（REM）的更高患病率 睡眠行为障碍、自主神经功能障碍、嗅觉缺陷）;和（c）前驱运动标志物增加 (gait可变性，不一致的行走模式，手臂摆动不对称和较低的轴向旋转平滑度）;（2） 进行神经黑色素的结构MRI，以确定这些患者中黑质受累（PD的生物标志物）。 同样的主题。我们假设，与产前CPF水平较低的人相比， 水平将显示黑质参与显着增加，其标志是 神经黑色素含量;（3）采用创新的统计程序，使用大量的功能和 根据先前在12-14岁和18岁时收集的多模态成像数据， 以确定是否存在跨模态的神经缺陷的与神经缺陷相关的模式（神经缺陷的潜在生物标志物）， PD）可以在我们的年轻队列中检测到。我们假设产前CPF水平较高的受试者， 与那些水平较低的人相比，将显示出不同模式的大脑异常， 时间这项研究有可能将研究范式从专注于神经退行性过程转变为 在PD纳入神经发育的角度来看，与未来的干预措施的潜在影响。

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.