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

帕金森病早期中枢嗅觉系统不对称神经变性

基本信息

批准号：
9384491
负责人：
Jianli Wang
金额：
$ 48.9万
依托单位：
PENNSYLVANIA STATE UNIV HERSHEY MED CTR
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-06-01 至 2022-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9384491
关键词：
Address Affect Age Anterior Anterior nares Atrophic Autopsy Back Biological Markers Brain Cerebral hemisphere Chickens Clinical Clinical assessments Cognitive Detection Deterioration Development Diagnosis Disease Disease Marker Disease Progression Early Diagnosis Evaluation Follow-Up Studies Foundations Functional Magnetic Resonance Imaging Functional disorder Goals Magnetic Resonance Imaging Morphology Movement Disorders Nerve Degeneration Odors Olfactory Cortex Olfactory Pathways Onset of illness Outcome Study Outcomes Research Parkinson Disease Pathologic Pathology Patients Process Prospective cohort study Psychophysics Research Risk Sampling Severities Side Signs and Symptoms Site Smell Perception Societies Stage at Diagnosis Staging Structure Substantia nigra structure Symptoms Techniques Testing Time base biomarker development cohort dopaminergic neuron early detection biomarkers early onset egg experience imaging biomarker improved in vivo motor deficit motor symptom neuron loss novel olfactory bulb olfactory nuclei patient oriented research potential biomarker pre-clinical sex

项目摘要

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.

抽象的：目前，帕金森病（PD）的病理学研究表明，临床早期诊断时事实上，处于病理晚期阶段，实体中多达 50-70% 的多巴胺能神经元被耗尽因此，迫切需要能够检测病理变化的生物标志物。然而，当开始解决这个问题时，首先必须能够识别出一群高危人群。最终将发展为帕金森病的临床前受试者，如果没有这样的早期标记，这是不可能的。 “先有鸡还是先有蛋”的问题极大地阻碍了 PD 研究。该应用程序是基于以下三个方面构思的。有据可查的发现：1) PD 中普遍存在嗅觉功能障碍，中枢嗅觉系统高度受PD病理影响，比黑质早约4年2）临床症状为在诊断 H&Y I 期早发型 PD 时，以及随着疾病进展至 II 期，总是不对称的几年之内，身体的无症状一侧不可避免地会出现运动症状；3) 死后病理学和我们最近的体内 MRI 研究证明了病理学的不对称性结合这些发现和事实，可以得出两个半球在疾病早期的状态。这是克服识别临床前帕金森病受试者挑战的独特机会，因为无症状患者 I 期 PD 的半球提供了“临床前”阶段和临床阶段之间过渡阶段的样本，中枢嗅觉系统的早期病理学为帕金森病的潜在生物标志物提供了场所。研究表明，临床上无症状的 I 期 PD 半球正处于过渡阶段 “临床前”和临床阶段，大脑半球的功能缺陷存在不对称性在我们的初步研究中，我们使用一种新颖的功能磁共振成像技术对现阶段患者的初级嗅觉皮层（POC）进行了研究。在对 I 期早发型 PD 的研究中，我们发现 POC 时气味相关激活缺陷存在显着的不对称性。在本申请中，我们提出了一项针对认知正常的 I 期早发 PD 患者的前瞻性队列研究嗅觉功能磁共振成像、嗅球 (OB) 和 POC 的形态学 MRI、气味的心理物理学评估我们的目标是了解运动缺陷的潜在机制。 PD 中的嗅觉缺陷及其与疾病进展的关系将通过以下方法实现。以下三个具体目标：具体目标 1 将检验以下假设：大脑半球不对称 H&Y I 期 PD 中 POC 的功能缺陷将检验存在以下假设： H&Y I 期 PD 中 OB 和 POC 形态变化的半球不对称性；检验以下假设：POC 的功能缺陷以及 OB 和 POC 的萎缩随着该研究的成功结果将为帕金森病早期阶段的疾病进展提供必要的条件。为开发 PD 进展嗅觉后果的生物标志物奠定了基础，并且还有潜力用于早期检测 PD 进展的替代成像标记物。