Functional Brain Networks: A Novel Approach to Address Clinical Challenges in PD

描述（由申请人提供）：帕金森病（PD）的特征是运动和非运动症状（认知障碍、情感障碍和其他临床特征）。来自实验动物模型和PD患者的数据表明，这种疾病的表现不能归因于基底神经节的孤立功能障碍。相反，黑质多巴胺细胞的高度局部化的损失与广泛的，空间分布的功能异常，涉及皮质-纹状体-苍白球-丘脑皮质（CSPTC）环路和相关途径。通过量化空间分布（大规模）功能性脑网络（包括多个相互连接的脑区域）的活动，基于图像的现代分析技术可以提供有关神经退行性疾病（如PD）的广泛电路异常的有价值信息。由Eidelberg博士领导的Feinstein研究所神经科学中心的研究人员率先使用功能性脑成像和网络分析来研究PD和相关的神经退行性疾病。由于这种“小信号”分析中固有的噪声，我们强调从统计和经验的角度严格验证疾病相关的功能模式。事实上，在定量网络测量可以被认为是疾病过程及其对治疗的反应的潜在生物标志物之前，需要高水平的测量精度。 在这项提案中，我们试图通过采用严格验证的PD相关网络来解决一些严重影响当今PD患者护理的重要问题，从而将这种方法提升到一个新的水平。项目1解决了左旋多巴诱导的运动障碍的严重临床问题，这最终影响到几乎所有的PD患者。项目2研究了多巴胺能治疗认知反应个体差异的网络基础，以期预测哪些患者在不同治疗条件下会出现不良认知副作用。项目3旨在建立一种新的基于网络的算法的可行性，以提供比目前更早，更准确的鉴别诊断。 公共卫生相关性：由于多巴胺能治疗通常对帕金森病的运动症状非常有效，至少在早期，很容易忽视最终发展的真实的问题：左旋多巴诱导的运动障碍以及某些患者的认知和行为变化。了解这些现象不仅可以帮助我们改善患者的生活，还可以为PD和其他神经退行性疾病的病理生理学提供独特的见解。同样，基于自动模式的早期诊断方法的验证将有助于简化PD和非典型帕金森综合征新疗法的试验。 项目1 主要研究者：大卫艾德尔伯格和安吉拉Cenci 标题：帕金森病的微血管变化：与左旋多巴诱导的运动障碍的关系 描述（由申请人提供）：多巴胺前体左旋多巴是治疗帕金森病（PD）最有效的药物，但最终在绝大多数患者中导致左旋多巴诱导的运动障碍（LID）。在啮齿动物模型中的实验研究表明，外周左旋多巴给药后，LID动物的纹状体多巴胺水平（DA）出现更大和更快的激增。由于左旋多巴通过血脑屏障（BBB）的通道在内皮水平受到严格调节，因此需要彻底研究神经血管改变作为LID的可能影响因素。为此，我们将扩展我们最近在PD患者中的观察，左旋多巴对局部脑代谢和血流量有不同的影响，局部血流代谢分离的程度，治疗介导的血流动力学改变的定量指标，在LID患者中比那些治疗反应简单的患者大得多。 在具体目标1中，我们将研究两组患者，LID患者和单纯左旋多巴反应患者，使用[18 F]-FDG PET（用于脑代谢）、[150]-H20 PET（用于脑血流量）和[82 Rb]-铷PET（用于BBB渗透性）比较各组间左旋多巴介导的变化。在具体目标2中，我们将确定在药物初治的PD患者中是否存在局部血管扩张和/或BBB变化，以及在使用左旋多巴而不是多巴胺激动剂治疗一年后是否出现血流代谢分离。在具体目标3中，我们将使用LID大鼠模型来确定局部脑血流量的变化是否与受影响区域的微血管结构改变和BBB通透性相关。以前在这种动物模型中的研究确实揭示了基底神经节中血管生成和BBB通透性的增加。 鉴于最近在尸检中在人类PD大脑的基底神经节中发现了类似的变化，该项目为针对PD患者及其护理人员面临的重大挑战进行转化研究提供了一个独特的机会。 公共卫生相关性：对帕金森病（PD）中左旋多巴诱导的运动障碍（LID）的发展知之甚少。使用翻译的方法，该项目将进一步了解这种潜在的禁用治疗副作用的病理生理学，并应开辟新的治疗LID的发展途径。此外，对血管生成和血脑屏障在PD中的作用的更好理解可能也与其他神经退行性疾病有关。

DESCRIPTION (provided by applicant): Parkinson's disease (PD) is characterized by both motor and non-motor symptoms (cognitive impairment, affective disorder, and other clinical features). Data from experimental animal models and patients with PD indicate that the manifestations of this disease cannot be attributed to isolated dysfunction of the basal ganglia. Rather, the highly localized loss of nigral dopamine cells is associated with a broad, spatially distributed set of functional abnormalities involving cortico-striato-pallido-thalamocortical (CSPTC) loops and related pathways. By quantifying the activity of spatially distributed (large-scale) functional brain networks, comprising multiple interconnected brain regions, modern techniques of image-based analysis can provide valuable information concerning the widespread circuit abnormalities that underlie neurodegenerative disorders such as PD. The investigators at the Center for Neurosciences at The Feinstein Institute, led by Dr. Eidelberg, have pioneered the use of functional brain imaging and network analysis for the study of PD and related neurodegenerative diseases. Because of the noise inherent in "small signals" analyses of this sort, we have emphasized rigorous validation of the disease-related functional patterns from both statistical and empiric standpoints. Indeed, high levels of measurement precision are needed before quantitative network measures can be considered as potential biomarkers of the disease process and its response to treatment. In this proposal, we seek to take this approach to a new level by employing rigorously validated PD-related networks to address a number of vital issues that impact heavily on the care of today's PD patients. Project 1 addresses the serious clinical problem of levodopa-induced dyskinesias, which ultimately affect nearly all PD patients. Project 2 examines the network basis for individual differences in the cognitive response to dopaminergic treatment with a view to predicting which patients will develop untoward cognitive side effects under different treatment conditions. Project 3 aims to establish the feasibility of a new network-based algorithm for providing earlier and more accurate differential diagnosis than is currently possible. PUBLIC HEALTH RELEVANCE: Because dopaminergic treatment is generally so effective for the motor symptoms of PD, at least early on, it is easy to dismiss the very real problems that ultimately develop: levodopa-induced dyskinesias and cognitive and behavioral changes for some patients. Understanding these phenomena should not only help us improve the lives of patients, but will provide unique insight into the pathophysiology of PD and perhaps other neurodegenerative disorders. Likewise, the validation of an automated pattern-based method for early diagnosis will help streamline trials of new therapies for PD as well as for atypical parkinsonian syndromes. PROJECT 1 Principal Investigator: David Eidelberg and Angela Cenci Title: Microvascular Changes in Parkinson's Disease: Relationship to Levodopa-lnduced Dyskinesia Description (provided by applicant): The dopamine precursor levodopa is the most effective medication available for the treatment of Parkinson's disease (PD), but eventually it causes levodopa-induced dyskinesias (LID) in the vast majority of the patients. Experimental studies in a rodent model indicate that following peripheral levodopa administration there is a larger and prompter surge in striatal dopamine levels (DA) in animals with LID. Because the passage of levodopa through the blood-brain barrier (BBB) is critically regulated at the level of the endothelium, neurovascular alterations need to be thoroughly investigated as a possible contributing factor in LID. To that end, we will expand upon our recent observation in PD patients, that levodopa has divergent effects on regional cerebral metabolism and blood flow, and that the magnitude of local flow metabolism dissociation, a quantitative index of treatment-mediated hemodynamic alterations, is much greater in patients with LID than those with uncomplicated treatment responses. In Specific Aim 1, we will study two groups of patients, those with LID and those with uncomplicated levodopa responses, using [18F]-FDG PET (for cerebral metabolism), [150]-H20 PET (for cerebral blood flow), and [82Rb]-Rubidium PET (for BBB permeability) to compare levodopa-mediated changes across groups. In Specific Aim 2, we will determine whether localized vasomotor and/or BBB changes exist in drug-naive PD patients and whether flow-metabolism dissociation develops following one year of treatment with levodopa, but not dopamine agonist. In Specific Aim 3, we will use a rat model of LID to determine whether changes in local cerebral blood flow relate to structural alterations of the microvasculature and BBB permeability in the affected regions. Previous studies in this animal model have indeed revealed increased angiogenesis and BBB permeability in the basal ganglia. Given that analogous changes have very recently been noted in the basal ganglia of human PD brains at autopsy, this project provides a unique opportunity for translational investigation directed at a major challenge confronting PD patients and their caretakers. Public Health Relevance: The development of levodopa-induced dyskinesias (LID) in Parkinson's disease (PD) is poorly understood. Using a translational approach, this project will further the understanding of the pathophysiology of this potentially disabling side effect of therapy, and should open avenues for the development of new treatments of LID. Furthermore, improved understanding of the role of angiogenesis and blood-brain barrier in PD is likely also relevant to other neurodegenerative diseases.