Olfaction as a Biomarker for Parkinson's Disease

描述(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已经下降，这表明气味检测可以作为帕金森病的生物标记物。免疫组织化学研究表明，嗅区具有极高的代谢性谷氨酸5受体(MGluR5)表达。嗅觉是对气味进行识别的区域。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和谷氨酸能神经功能的体内定量成像研究。现在，我们建议使用这种具有高水平终点措施的体外成像电池来研究MPTP(1-甲基-4-苯基-1，2，3，6-四氢吡啶)小鼠PD模型在进行性退化过程中的嗅觉，使用两种不同的气味：柠檬和牛至。为了研究嗅觉的潜在机制及其与帕金森样进行性变性的关系，我们将用[11C]CFT([N-甲基-11C]-2-β-甲氧基-3-(4-氟苯基)托烷)和[11C]M-Pepy(2-(2-(5-[11C]methoxypyridin-3-yl)ethynyl)pyridine).对多巴胺能功能和mGluR5功能进行纵向microPET成像研究将在MPTP和对照组小鼠中进行平行研究，相应地给予生理盐水。这些研究将通过行为分析和终点免疫组织化学、Western Blot和酶研究来完成。通过这些研究，我们将调查：1)通过microPET和[11C]CFT测量嗅球是否有进行性多巴胺能变性；2)嗅球对mGluR5功能的气味诱导反应是否与进行性变性期间在纹状体测量的多巴胺能变性相关；3)气味诱导对mGluR5功能的挑战是否与行为测量相关；4)气味敏化是否取决于气味分子的分子结构或大小；5)如果气味诱导对mGluR5表达的挑战或从嗅球测量的碳水解酶VI或腺酰环化酶，纤毛或鼻腔粘液是否可用作PD样变性的生物标志物？摘要有令人信服的证据表明，帕金森病(PD)患者的气味检测能力已经下降，这表明气味检测可以作为PD的生物标志物。为了研究嗅觉及其与帕金森病样进行性变性的关系，我们将在MPTP小鼠帕金森病模型中进行纵向的体内成像研究，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.