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

摘要： 目前，帕金森病（PD）的病理学研究表明，诊断时的临床早期阶段 事实上，在病理学晚期，在实质中多达50-70%的多巴胺能神经元耗尽， 黑鬼因此，迫切需要一种能够检测病理变化的生物标志物， 之前然而，当开始解决这个问题时，首先必须能够确定一组高危人群， 临床前受试者最终将发展为PD，如果没有早期标志物，这是不可能的。这样的 “先有鸡还是先有蛋”的问题严重阻碍了帕金森病的研究。本申请是基于三个 研究发现：1）嗅觉功能障碍在PD中普遍存在，中枢嗅觉系统高度受损。 受PD病理影响，比黑质早约4年; 2）临床症状 在诊断H&Y I期早发性PD时总是不对称的，并且随着疾病进展到II期， 在几年内，身体的无症状侧不可避免地发展出运动症状;以及3） 尸检病理和我们最近的体内MRI研究表明，病理性 在疾病的早期阶段两个半球的状态。结合这些发现和事实， 这是克服识别临床前PD受试者的挑战的独特机会，因为无症状性PD受试者 I期PD中半球提供了处于“临床前”期和临床期之间的过渡期的样本， 中枢嗅觉系统的早期病理学为PD的潜在生物标志物提供了一个位点。我们 假设I期PD的临床无症状半球处于过渡阶段， “临床前”和临床阶段，并且在大脑中的功能缺陷中存在半球不对称性。 初级嗅觉皮层（POC）的患者在这个阶段。在我们的初步研究中， I期早发性PD研究中，我们发现POC时气味相关激活缺陷的显著不对称性。 在本申请中，我们提出了一个前瞻性队列研究的认知正常的I期早发性PD患者 嗅觉功能磁共振成像，嗅球（OB）和POC的形态学磁共振成像，嗅觉的心理物理评价 功能和运动缺陷的临床评估。我们的目标是了解 PD中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：具体目标1将测试假设，有一个半球不对称， H&Y I期PD中POC的功能缺陷;具体目标2将检验以下假设： 在H&Y I期PD中OB和POC的形态学变化中存在半球不对称性;特异性Aim 3将 检验POC的功能缺陷以及OB和POC的萎缩随着 疾病在PD的早期阶段进展。这项研究的成功结果将提供必要的 为PD进展的嗅觉后果的生物标志物的开发奠定了基础， 用于早期检测PD进展的替代成像标志物。

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.