Olfaction as a Biomarker for Parkinson's Disease

描述（由申请人提供）：有令人信服的证据表明，帕金森病（PD）患者的气味检测能力下降，表明气味检测可以用作帕金森病的生物标志物。免疫组化研究表明，嗅觉区有极高表达的代谢性谷氨酸5受体（mGluR5）。嗅觉是识别气味的一个区域。我们已经开发了高水平的成像仪器和技术以及独特的配体来进行多巴胺能和谷氨酸能神经功能的定量体内成像研究。现在，我们建议使用该成像电池和高水平的体外终点分析措施来研究MPTP（1-甲基-4-苯基-1,2,3,6-四氢吡啶）PD小鼠模型中使用两种不同气味的进行性变性过程中的嗅觉；柠檬和牛至。为了研究嗅觉的潜在机制及其与pd样进行性变性的关系，我们将使用[11C]CFT （[n-甲基-11C]-2- -碳甲氧基-3- -（4-氟苯基）tropane）和[11C]M-PEPy (2-（2-（5-[11C]甲氧基吡啶-3-基）乙基）吡啶对多巴胺能功能进行纵向微pet成像研究。平行研究将在MPTP和对照小鼠中进行，并相应给予生理盐水。这些研究将通过行为分析和终点免疫组织化学、免疫印迹和酶学研究来完成。通过这些研究，我们将探讨：1)用微pet和[11C]CFT测量嗅球是否有进行性多巴胺能变性；2)气味诱导的嗅球mGluR5功能反应是否与进行性变性过程中纹状体多巴胺能变性有关；3)气味刺激对mGluR5功能的影响是否与行为措施相关；4)如果气味致敏取决于气味分子的分子结构或大小；5)嗅球、纤毛或鼻粘液中mGluR5表达或碳酸酐酶VI或腺苷酸环化酶的气味诱导挑战是否可以作为pd样变性的生物标志物？有令人信服的证据表明，帕金森病（PD）患者的气味检测能力下降，表明气味检测可以作为帕金森病的生物标志物。为了研究嗅觉及其与PD样进行性变性的关系，我们将在MPTP小鼠PD模型中进行纵向体内成像研究，并结合体外终点测量分析。

DESCRIPTION (provided by applicant): There is compelling evidence that the ability of odor detection has declined in Parkinson's disease (PD) patients indicating that odor detection could be used as a biomarker for Parkinson's disease. Immunohistochemical studies have shown that olfactory area has extremely high expression of metabotropic glutamate 5 receptors (mGluR5). Olfactory is an area, where recognition of odors is done. We have developed high level imaging instrumentation and techniques as well as unique ligands to conduct quantitative in vivo imaging studies of dopaminergic and glutamatergic neurofunction. Now, we propose to use this imaging battery with high level in vitro analysis of endpoint measures to investigate olfaction during progressive degeneration in a MPTP (1- methyl-4-phenyl-1,2,3,6-tetrahydropyridine) mouse model of PD using two different odors; lemon and oregano. To investigate underlying mechanisms of olfaction and relation to PD-like progressive degeneration we will conduct longitudinal microPET imaging studies of dopaminergic function with [11C]CFT ([N-methyl-11C]-2-¿-carbomethoxy-3- ¿ -(4-fluorophenyl)tropane ) and mGluR5 function with [11C]M-PEPy (2-(2-(5-[11C]methoxypyridin-3-yl)ethynyl)pyridine). Parallel studies will be conducted in MPTP and control mice, correspondingly administered with saline. These studies will be completed with behavior analyses and end point immunohistochemical, Western Blot and enzymatic studies. With these studies we will investigate, 1) if olfactory bulb has progressive dopaminergic degeneration measured by microPET and [11C]CFT; 2) if odor induced response on mGluR5 function in olfactory bulb has correlation to dopaminergic degeneration measured in striatum during progressive degeneration; 3) if odor induced challenge on mGluR5 function has correlation to behavioral measures; 4) if odor sensitization depends on molecular structure or size of the odor molecule; and 5) if odor induced challenge on mGluR5 expression or carbo anhydrase VI or adenylyl cyclase measured from olfactory bulb, cilia or nasal mucus can be used as a biomarker for PD-like degeneration? Abstract There is compelling evidence that the ability of odor detection has declined in Parkinson's disease (PD) patients indicating that odor detection could be used as a biomarker for PD. To investigate olfaction and its relation to PD-like progressive degeneration we will conduct longitudinal in vivo imaging studies combined with in vitro analysis of endpoint measures in a MPTP mouse model of PD.