Asymmetric neurodegeneration of central olfactory system in early-stage Parkinsons disease

摘要： 目前，帕金森病(PD)的病理研究表明，临床早期诊断 事实上，处于病理晚期，脑实质中多达50%-70%的多巴胺能神经元耗尽。 黑。因此，迫切需要一种能够很好地检测病变的生物标志物。 早些时候。然而，在开始解决这一问题时，人们必须首先能够确定一群处于危险之中的人 临床前受试者最终将发展为帕金森病，如果没有早期的标志物，这是不可能的。这样的一个 “先有鸡还是先有蛋”的问题严重阻碍了PD的研究。这个应用程序是基于三个基础构思的 研究发现：1)嗅觉功能障碍在帕金森病患者中普遍存在，中枢嗅觉系统高度发达 受帕金森病病理影响，大约比黑质早4年；2)临床症状为 在诊断H&Y期早发性帕金森病时总是不对称的，当疾病进展到II期时 在几年内，身体的无症状一侧不可避免地会出现运动症状；以及 身体病理和我们最近的活体核磁共振研究已经证明了病理上的不对称性 在疾病早期的两个半球的状态。将这些发现和事实结合起来，就产生了一个 克服识别临床前PD受试者的挑战的独特机会，因为无症状的 第一阶段中的半球PD提供了处于临床前阶段和临床阶段之间过渡阶段的样本， 中央嗅觉系统的早期病理为帕金森病的潜在生物标志物提供了一个场所。我们 假设临床上无症状的帕金森病患者大脑半球处于 临床前期和临床期，并存在半球不对称的功能缺陷。 这一阶段患者的初级嗅皮层(POC)。使用一种新的功能磁共振成像技术在我们的初步研究中 在对I期早发性帕金森病的研究中，我们发现POC的气味相关激活缺陷存在显著的不对称性。 在这项应用中，我们提出了一项认知正常的I期早发性帕金森病患者的前瞻性队列研究。 用嗅觉功能磁共振成像、嗅球形态磁共振成像(OB)和POC、嗅觉的心理物理评估 功能和运动缺陷的临床评估。我们的目标是了解其潜在的机制 帕金森病患者的嗅觉缺陷及其与疾病进展的关系。这一目标将通过 以下三个具体目标：特定目标1将检验假设，即存在半球不对称 H&Y阶段POC的功能缺陷-I PD；特定目标2将检验以下假设 H&Y阶段OB和POC形态变化的半球不对称性--I PD；特定目标3将 测试POC功能缺陷以及OB和POC萎缩的假设 疾病在帕金森病的早期发展。这项研究的成功结果将提供必要的 帕金森病进展的嗅觉后果生物标记物的开发基础，以及潜在的 替代成像标记物早期检测帕金森病进展。

Abstract: At present, pathology studies of Parkinson's disease (PD) have shown that the clinical early stage at diagnosis is, in fact, at a pathologically late stage with up to 50-70% of dopaminergic neurons depleted in the substantia nigra. Therefore, there is a critical need for a biomarker capable of detecting pathological changes much earlier. However, when beginning to address this issue, one must first be able to identify a cohort of at-risk preclinical subjects who will eventually develop PD, which is not possible without an early marker. Such a “chicken-and-egg” problem holds back PD research significantly. This application is conceived based on three well-documented findings: 1) Olfactory dysfunction is prevalent in PD, and central olfactory system is highly affected by PD pathology, approximately 4 years earlier than the substantia nigra; 2) The clinical symptoms are always asymmetric at the diagnosis of H&Y stage-I early onset PD, and as the disease progresses to stage II within a few years, the asymptomatic side of the body inevitably develops motor symptoms; and 3) Postmortem pathological and our recent in vivo MRI studies have demonstrated the asymmetry of pathological status in the two hemispheres at the early stage of disease. Combining these findings and facts creates a unique opportunity to overcome the challenge of identifying preclinical PD subjects, because the asymptomatic hemisphere in stage-I PD offers a sample at a transitional stage between “preclinical” stage and clinical stage, and early pathology in the central olfactory system offers a site for potential biomarkers for PD. We hypothesize that the clinically asymptomatic hemisphere of stage-I PD is at a transitional stage between “preclinical” and clinical stage, and there is hemispheric asymmetry in functional deficits in the primary olfactory cortex (POC) of patients at this stage. Using a novel fMRI technique in our preliminary study of stage-I early onset PD, we have found significant asymmetry in odor-related activation deficit at POC. In this application, we propose a prospective cohort study of cognitively-normal stage-I early onset PD patients with olfactory fMRI, morphological MRI of the olfactory bulb (OB) and POC, psychophysical evaluation of smell functions, and clinical assessment of motor deficits. Our goal is to understand the underlying mechanisms of olfactory deficit in PD, and its relationship to disease progression. This goal will be accomplished with the following three specific aims: Specific Aim 1 will test the hypothesis that there is a hemispheric asymmetry in functional deficit in the POC in H&Y stage-I PD; Specific Aim 2 will test the hypothesis that there is a hemispheric asymmetry in morphological change of the OB and POC in H&Y stage-I PD; Specific Aim 3 will test the hypothesis that the functional deficit in the POC and the atrophy of the OB and POC worsen as the disease progresses in the early stages of PD. A successful outcome of this research will provide the necessary foundation for the development of biomarkers for olfactory consequences of PD progression, and also potential surrogate imaging markers for the early detection of PD progression.