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

功能性大脑网络：解决帕金森病临床挑战的新方法

• 批准号: 8332351
• 负责人: DAVID EIDELBERG
• 金额: $ 187.35万
• 依托单位: FEINSTEIN INSTITUTE FOR MEDICAL RESEARCH
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-30 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8332351
• 关键词: Address; Adverse effects; Affect; Algorithms; Animal Model; Animals; Area; Arts; Authorship; Autopsy; Back; Basal Ganglia; Basic Science; Behavior assessment; Behavioral; Bioinformatics; Biological Markers; Biological Process; Biomedical Research; Biometry; Blood - brain barrier anatomy; Blood flow; Brain; Brain imaging; Brain region; Caring; Cells; Cerebrovascular Circulation; Cerebrum; Clinic; Clinical; Clinical Research; Cognition; Cognitive; Collaborations; Comorbidity; Complex; Complication; Corpus striatum structure; Data; Development; Diagnostic; Differential Diagnosis; Disadvantaged; Disease; Dissociation; Doctor of Philosophy; Dopamine; Dopamine Agonists; Dyskinetic syndrome; Early Diagnosis; Endothelium; Event; Experimental Animal Model; Functional Imaging; Functional disorder; Funding; Future; Genes; Goals; Growth; Health; Health Benefit; Human; Image; Image Analysis; Imaging Device; Imaging Techniques; Impaired cognition; Individual; Individual Differences; Informatics; Institutes; Investigation; Knowledge; Lead; Leadership; Learning; Levodopa; Magnetic Resonance Imaging; Maps; Measurement; Measures; Mediating; Medical Research; Medicine; Memory; Metabolism; Methods; Mission; Modeling; Molecular; Molecular Medicine; Mood Disorders; Motor; Movement Disorders; Nafion; Nerve Degeneration; Network-based; Neurodegenerative Disorders; Neurology; Neurosciences; Noise; Outcome; Parkinson Disease; Parkinsonian Disorders; Pathogenesis; Pathway Analysis; Pathway interactions; Patients; Pattern; Peripheral; Permeability; Pharmaceutical Preparations; Physicians; Population; Principal Investigator; Process; Property; Psychometrics; Psychophysics; Publications; Radiochemistry; Rattus; Recruitment Activity; Research; Research Infrastructure; Research Personnel; Residencies; Rest; Rewards; Rodent Model; Role; Rubidium; Scientist; Signal Transduction; Sorting - Cell Movement; Staging; Sweden; Symptoms; System; Systems Biology; Testing; Time; Tracer; Training; Training Support; Training and Education; Translating; Translational Research; Translations; Twin Multiple Birth; United States National Institutes of Health; Universities; Validation; Vasomotor; Work; angiogenesis; authority; base; bench to bedside; career; clinical practice; clinically relevant; cognitive change; cognitive neuroscience; computer science; data sharing; effective therapy; experience; follower of religion Jewish; graduate student; hemodynamics; high risk; human disease; improved; indexing; innovation; insight; instrument; interdisciplinary collaboration; medical schools; medical specialties; member; neuroimaging; new therapeutic target; north shore long island; novel; novel strategies; patient oriented; patient oriented research; patient population; programs; public health relevance; relating to nervous system; research study; response; success; tool; translational approach; treatment response; vasculogenesis

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.

描述（由申请人提供）：帕金森氏病（PD）的特征是运动症状和非运动症状（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，该疾病的表现不能归因于基底神经节的孤立功能障碍。相反，高度局部的多巴胺细胞的局部损失与涉及涉及皮质 - 纹状体 - 甲状腺皮质皮质皮质（CSPTC）环路的宽阔，空间分布的功能异常相关。通过量化空间分布的（大尺度）功能性脑网络的活性，包括多个相互连接的大脑区域，基于图像的分析的现代技术可以提供有关神经退行性疾病基于PD等神经退行性疾病的广泛电路异常的有价值信息。由Eidelberg博士领导的Feinstein Institute神经科学中心的研究者开创了功能性脑成像和网络分析的使用，用于研究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，我们从统计和经验的角度强调了对疾病相关功能模式的严格验证。实际上，在定量网络措施被视为疾病过程的潜在生物标志物及其对治疗的反应之前，需要高水平的测量精度。 在此提案中，我们试图通过使用严格验证的与PD相关的网络来解决许多重要问题，这些问题对当今的PD患者的护理产生了严重影响，将这种方法提高到了新的水平。项目1解决了左旋多巴引起的运动障碍的严重临床问题，最终影响了几乎所有PD患者。项目2研究了对多巴胺能治疗的认知反应中个体差异的网络基础，以预测哪些患者在不同的治疗条件下会发展出不良的认知副作用。 Project 3旨在建立一种新的基于网络的算法的可行性，以提供比目前可能的更早，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PD的运动症状非常有效，因此至少在早期，很容易忽略最终出现的真正问题：左旋多巴引起的发育不良障碍以及某些患者的认知和行为改变。了解这些现象不仅应帮助我们改善患者的生活，而且还将为PD的病理生理以及其他神经退行性疾病提供独特的见解。同样，基于模式的自动诊断方法的验证将有助于简化PD新疗法以及非典型帕金森氏综合症的新疗法。 项目1 首席研究员：David Eidelberg和Angela Cenci 标题：帕金森氏病的微血管变化：与左旋多巴的关系 描述（由申请人提供）：多巴胺前体左旋多巴是可用于治疗帕金森氏病（PD）的最有效的药物，但最终会导致绝大多数患者的左旋多巴引起的运动障碍（LID）。啮齿动物模型中的实验研究表明，涂有盖子的动物的纹状体多巴胺水平（DA）的外围左旋武器施用后，纹状体多巴胺水平（DA）较大。由于左旋多巴通过血脑屏障（BBB）的通过受到严格调节，因此需要彻底研究神经血管的改变，作为盖子中可能的促成因素。为此，我们将扩大我们最近在PD患者中的观察结果，即左旋多巴对区域脑代谢和血流有不同的影响，并且局部流动代谢分离的幅度（治疗中介导的介导的介导指数的定量指标）在LID患者中比具有不合时宜的治疗反应的患者更大。 在特定的目标1中，我们将使用[18F] -FDG PET（用于脑代谢），[150] -H20 PET（用于脑血流）和[82RB] -rubidium PET（用于BBB PERIDECTIAD CHARMIET PRECERIEN CHAIMIT ack acke clange clange Levoda），使用[18F] -FDG PET（用于脑新陈代谢），[150] -H20 PET（用于脑血液流动）[150] -H20 PET（用于脑血液流动）[150] -H20 PET（用于脑血液流动），使用[18F] -FDG pET（用于脑新陈代谢），[150] -H20 PET（用于脑血液流动）[150] -h20 PET（用于脑血液流动）。在特定的目标2中，我们将确定药物不良的PD患者中是否存在局部血管舒缩和/或BBB变化，以及在用左旋多巴进行一年治疗后而不是多巴胺激动剂治疗后流量代谢解离。在特定目标3中，我们将使用盖子模型来确定局部脑血流的变化是否与受影响区域的微脉管系统的结构改变和BBB渗透性有关。该动物模型的先前研究确实表明，基底神经节的血管生成和BBB渗透性增加。 鉴于最近在人类PD大脑的基底神经节中注意到了类似的变化，因此该项目为面对PD患者及其护理人员面临的重大挑战的转化研究提供了独特的机会。 公共卫生相关性：帕金森氏病（PD）中左旋多巴引起的运动障碍（LID）的发展知之甚少。使用转化方法，该项目将进一步了解这种潜在的治疗副作用的病理生理学，并应为开发新的盖子疗法开发途径。此外，对血管生成和血脑屏障在PD中的作用的了解也可能与其他神经退行性疾病有关。