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

• 批准号: 9884829
• 负责人: Jianli Wang
• 金额: $ 48.83万
• 依托单位: PENNSYLVANIA STATE UNIV HERSHEY MED CTR
• 依托单位国家: 美国
• 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/9884829
• 关键词: Address; Affect; 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; Lewy body pathology; 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; programmed cell death protein 1; sex

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 黑质。因此，迫切需要一种能够检测病理变化的生物标志物 早些时候。然而，当开始解决这个问题时，我们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，如果没有早期标志物，这是不可能的。这样一个 “先有鸡还是先有蛋”的问题极大地阻碍了PD研究。这个应用程序是基于三个 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）临床症状是 在诊断 H&Y I 期早发型 PD 时，以及当疾病进展到 II 期时，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；和 3) 尸检病理学和我们最近的体内 MRI 研究已经证明了病理学的不对称性。 疾病早期两个半球的状态。结合这些发现和事实创建了一个 这是克服识别临床前 PD 受试者挑战的独特机会，因为无症状 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。我们 假设临床上无症状的 I 期 PD 半球处于过渡阶段 “临床前”和临床阶段，大脑半球的功能缺陷存在不对称性 此阶段患者的初级嗅觉皮层（POC）。在我们的初步研究中使用一种新颖的功能磁共振成像技术 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 功能和运动缺陷的临床评估。我们的目标是了解潜在的机制 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 将检验以下假设：大脑半球不对称 H&Y I 期 PD 中 POC 功能缺陷；具体目标 2 将检验以下假设： H&Y I 期 PD OB 和 POC 形态变化半球不对称；具体目标 3 将 检验以下假设：POC 的功能缺陷以及 OB 和 POC 的萎缩随着 疾病在 PD 早期阶段进展。这项研究的成功结果将为 开发 PD 进展嗅觉后果的生物标志物的基础，也是潜在的 用于早期检测 PD 进展的替代成像标记物。