Multi-scale functional connectivity in preclinical models of Parkinson's disease

帕金森病临床前模型的多尺度功能连接

• 批准号: 10543831
• 负责人: Ashley M Stokes
• 金额: $ 39.94万
• 依托单位: ST. JOSEPH'S HOSPITAL AND MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-01 至 2026-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10543831
• 关键词: Acute; Back; Basal Ganglia; Behavioral; Biochemical; Biological Markers; Blood Vessels; Brain; Chronic; Clinical; Clinical Trials; Contrast Sensitivity; Control Groups; Coupled; Coupling; Detection; Development; Disease; Disease Progression; Disease model; Dopamine; Dorsal; Early Diagnosis; Etiology; Functional Magnetic Resonance Imaging; Functional disorder; Future; Genetic; Genetic Techniques; Goals; Healthcare; Imaging Techniques; Intervention; L-DOPA induced dyskinesia; Levodopa; Link; Magnetic Resonance Imaging; Measures; Methods; Modality; Modeling; Motor; Nature; Neurodegenerative Disorders; Neurons; Neurotransmitters; Oxidopamine; Parkinson Disease; Parkinsonian Disorders; Pathologic; Patients; Perfusion; Play; Population; Pre-Clinical Model; Progressive Disease; Research; Rest; Rodent Model; Role; Sensitivity and Specificity; Signal Transduction; Structure; Techniques; Technology; Testing; Therapeutic; Time; Translations; Validation; alpha synuclein; base; clinical phenotype; clinical translation; diagnostic value; dopaminergic neuron; genetic manipulation; imaging biomarker; imaging modality; improved; insight; locus ceruleus structure; magnetic resonance imaging biomarker; motor symptom; network dysfunction; neuronal circuitry; neuropathology; neurophysiology; neurovascular coupling; non-motor symptom; noradrenergic; novel; pharmacologic; potential biomarker; pre-clinical; pre-formed fibril; preclinical study; prognostic value; receptor; side effect; standard care; synuclein; synucleinopathy; translational therapeutics

PROJECT SUMMARY / ABSTRACT: Parkinson’s disease is a progressive neurodegenerative disorder and is associated with significant motor and non-motor symptoms, traceable to the loss of nigral dopamine neurons in addition to widespread circuit dysfunction extending beyond the dying nigrostriatal tract. Imaging-based biomarkers play a critical role in assessing Parkinson’s-related pathological changes, but current biomarkers are limited in their diagnostic and prognostic ability, particularly in early disease stages when intervention would be most beneficial. Functional magnetic resonance imaging (fMRI) enables the study of brain activation and has been widely used to study global functional network changes in Parkinson’s disease. However, standard fMRI is limited in its ability to robustly measure subtle changes with disease, in part due to low sensitivity and specificity; furthermore, interpretation of standard fMRI is challenging due to the indirect link between neuronal function and MRI signal change. This lack of robust direct biomarkers is a critical gap that ultimately limits our ability to understand the underlying pathological changes, as well as evaluate emerging therapies. To overcome these limitations, we propose to leverage an advanced multi-contrast fMRI method that provides high contrast sensitivity, as well as distinct microvascular sensitivity. By coupling this method with pharmacological and chemogenetic manipulations, a direct link between fMRI-based functional networks and underlying neuronal function can be inferred. More specifically, this project aims to a) characterize multi-contrast (total vascular and microvascular) functional connectivity networks in two complementary preclinical models that recapitulate classic hallmarks of Parkinson’s disease - the progressive PFF synucleinopathy model and the acute 6-OHDA model; b) assess the effect of pharmacological dopamine modulation on functional networks, using both acute and chronic treatment paradigms, analogous to the standard treatment paradigm; and c) investigate the effect of endogenous modulation of the dorsal raphe serotonergic circuit and the locus coeruleus noradrenergic circuit – both of which are proposed to be involved in certain non-motor symptomology – on functional networks using chemogenetic methods. These studies will provide insight into functional network changes that occur over different vascular scales and via different neurotransmitter populations. The development of robust MRI biomarkers that relate to dopaminergic, serotonergic, and noradrenergic circuit function and dysfunction may also provide insight into the multifaceted nature of Parkinson’s disease that contributes to both motor and non-motor symptoms. As functional brain network dysfunction is widely observed in Parkinson’s disease, this integrative approach will enable the development of robust biomarkers of Parkinson’s disease with well-characterized pathophysiological origins, which is a critical shortcoming of current technologies.

项目摘要/摘要： 帕金森病是一种进行性神经退行性疾病，与显着的运动和运动障碍有关。 非运动症状，除了广泛的回路外，还可以追溯到黑质多巴胺神经元的丧失 基于成像的生物标志物在 评估帕金森病相关的病理变化，但目前的生物标志物在诊断和治疗方面有限 预后能力，特别是在疾病早期阶段，此时干预是最有益的。 磁共振成像（fMRI）能够研究大脑激活，并已广泛用于研究 然而，标准功能磁共振成像的能力有限。 稳健地测量疾病的细微变化，部分原因是灵敏度和特异性较低； 由于神经功能和 MRI 信号之间的间接联系，标准功能磁共振成像的解释具有挑战性 缺乏强有力的直接生物标志物是一个关键差距，最终限制了我们理解这一变化的能力。 潜在的病理变化，以及评估新兴疗法，以克服这些局限性。 建议利用先进的多对比功能磁共振成像方法，该方法提供高对比灵敏度，以及 通过将该方法与药理学和化学遗传学相结合，获得独特的微血管敏感性。 通过操作，基于功能磁共振成像的功能网络和潜在神经功能之间的直接联系可以 更具体地说，该项目旨在 a) 表征多重对比（总血管和微血管） 两个互补的临床前模型中的功能连接网络概括了经典特征 帕金森病 - 进行性 PFF 突触核蛋白病模型和急性 6-OHDA 模型 b) 评估 使用急性和慢性治疗的药物多巴胺调节对功能网络的影响 范式，类似于标准治疗范式；c) 研究内源性治疗的效果； 中缝背侧血清素能回路和蓝斑去甲肾上腺素能回路的调节——两者 被提议参与某些非运动症状学——在使用化学遗传学的功能网络上 这些研究将深入了解不同血管上发生的功能网络变化。 规模和通过不同的神经递质群体开发与相关的强大的 MRI 生物标志物。 多巴胺能、血清素能和去甲肾上腺素能回路的功能和功能障碍也可以提供对 帕金森病具有多方面的性质，可导致运动和非运动症状。 脑网络功能障碍在帕金森病中广泛观察到，这种综合方法将使 开发具有明确病理生理学起源的帕金森病的强大生物标志物， 这是当前技术的一个严重缺陷。