Analysis of Olfactory Dysfunction for Early Diagnosis of Parkinson's Disease

100多万美国人患有帕金森氏症，其中至少有8万人 退伍军人。虽然目前帕金森病的诊断是基于运动体征，但这些症状是先行的。 持续几年到几十年的时间，在此期间神经退化扩散到大脑的许多区域。这个 我们越早发现帕金森病，在出现残疾症状之前治疗它的机会窗口就越长。 学习如何预防致残症状需要识别标记物，这些标记物不仅能够准确地及早 同时也增进了对疾病发病机制的认识，为疾病的发展铺平了道路 早期使用治疗疾病的药物进行干预。嗅觉是帕金森病的第一个受害者。尽管这种可能性 近年来，嗅觉作为帕金森病的生物标志物引起了越来越多的兴趣，这将是唯一可能的 一旦我们对这种嗅觉丧失的机制及其因果有了更好的了解 与-突触核蛋白病理的关系，这是帕金森病的一个标志。 我们的总体假设是，帕金森病患者的嗅觉损害是与上游直接相关的早期事件。 突触核蛋白毒性和基于具有可测量的功能影响的特定神经解剖学变化。通过 利用一种成熟的转基因小鼠模型在小鼠体内过表达人野生型-突触核蛋白 脑中，我们在我们目前的vamr中显示了脑血流量中-突触核蛋白病理的病因作用。 帕金森病的缺陷和嗅觉功能障碍。进一步开发嗅觉功能障碍的潜力作为一个多方面的 BioMarker，我们寻求深入了解CBF改变在嗅觉功能障碍中的作用，包括其 与-突触核蛋白病理学的机制关系。使用-突触核蛋白转基因小鼠，我们将评估 -突触核蛋白的渐进性积累导致细胞之间的反调节机制中断 脑内肾素-血管紧张素系统(RAS)和多巴胺导致局部RAS和DA异常上调 CBF赤字。此外，我们还将阐明进行性-突触核蛋白在代谢中的作用。 调节失调，能量平衡改变，线粒体功能障碍，氧化应激和神经炎症， 以及这些过程与CBF缺陷和嗅觉功能障碍的关系。我们的方法具有以下特点 免疫组织化学、生物化学、行为评估和高级神经成像方式(动脉 自旋标记磁共振成像、扩散张量成像和功能磁共振成像)，患者可以很容易地翻译。 关注4个月、9个月和16个月大的转基因小鼠的进行性-突触核苷酸病 帕金森病的前驱、临床前和临床阶段，我们的具体目标是： 1.阐明帕金森病患者-突触核蛋白聚集异常与脑血流量异常的关系 嗅觉功能障碍； 2.了解-突触核蛋白过度表达诱导氧化应激和 神经炎症，导致脑血流量不足和嗅觉受损；以及 3.探讨-突触核蛋白聚集异常与能量调节失调的关系 帕金森病相关嗅觉功能障碍的动态平衡。 这些研究意义重大，因为其结果将极大地增强对这一机制的理解 帕金森病患者嗅觉丧失、脑血流量不足和-突触核变性之间的关系，从而加速努力 将急需的早期诊断转移到临床现实中。我们的方法是创新的，因为他们利用了切割- 边缘无创多模式磁共振成像，可以很容易地转换到临床上。由于我们的 调查团队在嗅觉、帕金森病、神经退行性变、氧化应激、炎症、 神经行为测试和先进的成像技术，以及11.7特斯拉的独特优势 磁体用于高分辨率磁共振成像的研究具有很高的可行性。

More than one million Americans suffer from Parkinson’s disease (PD), of whom at least 80,000 are Veterans. Although PD is currently diagnosed on the basis of motor signs, these manifestations are preceded by a period that lasts several years to decades, in which neurodegeneration spreads to many brain regions. The earlier we can detect PD, the longer the window of opportunity to treat it before disabling symptoms appear. Learning how to prevent disabling symptoms will require identifying markers that not only enable accurate early diagnosis, but also enhance understanding of disease pathogenesis, paving the way for the development of early intervention with disease-modifying drugs. Sense of smell is the first casualty of PD. Although the possibility of using olfaction as a biomarker for PD has garnered increased interest in recent years, it will only be possible once we have achieved a better understanding of the mechanisms of this olfactory loss and its cause-and-effect relationship to -synuclein pathology, a hallmark of PD. Our over-arching hypothesis is that olfactory damage in PD is an early event directly linked to upstream - synuclein toxicity and based on specific neuroanatomical changes with measurable functional impact. By capitalizing on a well-established transgenic mouse model overexpressing human wild-type -synuclein in the brain, we showed in our current VAMR a causative role for -synuclein pathology in cerebral blood flow (CBF) deficit and olfactory dysfunction in PD. To develop further the potential of olfactory dysfunction as a multi-faceted biomarker, we seek in-depth understanding of the role of CBF alterations in olfactory dysfunction, including its mechanistic relationship to -synuclein pathology. Using the -synuclein transgenic mouse, we will assess how progressive accumulation of -synuclein leads to disruption of the counter-regulatory mechanism between the brain renin-angiotensin system (RAS) and dopamine, leading to abnormal local upregulation of the RAS and deficits in CBF. In addition, we will elucidate the role of progressive -synuclein accumulation in metabolic dysregulation, altered energy homeostasis, mitochondrial dysfunction, oxidative stress, and neuroinflammation, as well as the relationships of these processes to CBF deficit and olfactory dysfunction. Our approach features immunohistochemistry, biochemistry, behavioral assessments, and advanced neuroimaging modalities (arterial spin-labeling MRI, diffusion tensor imaging, and fMRI) that are readily translatable to patients. Focusing on progressive -synucleinopathy in transgenic mice at 4, 9, and 16 months of age, representing prodromal, preclinical, and clinical stages of PD, respectively, our specific objectives are: 1. To elucidate the relationship between abnormal-synuclein aggregation and CBF deficit in PD-related olfactory dysfunction; 2. To understand the mechanism of -synuclein overexpression-induced oxidative stress and neuroinflammation, leading to CBF deficit and impaired sense of smell; and 3. To explore the relationship between abnormal -synuclein aggregation and the dysregulation of energy homeostasis in PD-related olfactory dysfunction. These studies are significant, as the results will substantially enhance understanding of the mechanistic relationships among olfactory loss, CBF deficit, and -synucleinopathy in PD, thereby accelerating efforts to move much-needed early diagnosis to clinical reality. Our approaches are innovative since they exploit cutting- edge non-invasive multimodal MRI in a fashion that could be readily translated to the clinic. Owing to our investigative team’s in-depth expertise in olfaction, PD, neurodegeneration, oxidative stress, inflammation, neurobehavioral testing, and advanced imaging technologies, along with the unique advantage of an 11.7 Tesla magnet for high-resolution MRI, the proposed studies have high feasibility.