Advanced MRI studies of cerebrovascular and lymphatic abnormalities in LRRK2 mouse models of Parkinson's disease

摘要：帕金森病(PD)是第二常见的神经退行性疾病。目前在那里 是没有根治方法的。帕金森病的临床评估仅限于心理物理评估，即 关于脑神经病理异常的主观性和非信息性。开发生物标记物用于 早期诊断和治疗评估对疾病预后至关重要。帕金森病患者脑部表现 导致多巴胺能丧失的脑血管、淋巴系统和结构异常 神经元和运动障碍。小软脑膜动脉和小动脉是局部脑的主要控制 组织灌流提供营养和氧气，以满足神经元和其他细胞的新陈代谢需求， 而淋巴管在清除脑组织中的废物方面起着至关重要的作用。动脉 来自小血管的脉搏波是淋巴管内液体的主要驱动力， 血管周围空间。两个系统之间相互作用的不平衡可能会对帕金森病产生影响 发病机制。我们最近开发了几种新的MRI(磁共振成像)技术，可以 用于测量人类和动物的脑血管和淋巴系统的异常 模特们。我们建议检验脑微血管和淋巴管的异常可以 通过PD的发展和进展通过新的MRI技术进行测量，这些异常 可作为致病过程和治疗评估的潜在指标。LRRK2基因突变 (富含亮氨酸的重复酶2)可引起遗传性帕金森病，并导致散发性帕金森病。我们最近生成了一个 LRRK2小鼠模型表现出强健的PD样表型，为MRI提供了一个很好的模型 评估。在LRRK2小鼠模型中，MRI测量可以通过侵入性技术进行验证 组织学方法。纵向研究和治疗试验可以在较短的时间内完成 这些小鼠的经期。我们的初步研究发现突变的G2019S-LRRK2小鼠表现出脑血管 异常现象。因此，我们建议使用新的mri方法来研究脑部的病理生理变化。 应用LRRK2小鼠模型建立帕金森病的脑血管和淋巴管 毒素加速疾病进展)和内毒素(一种前炎性介质)通过结合 行为测试和脑组织化学研究。目标1.我们将评估脑内少量血液的异常 LRRK2小鼠模型中的血管。目的2.我们将评估血管周围间隙和大脑的异常 LRRK2小鼠模型的脑内淋巴管。目标3.我们将描述 脑微血管和淋巴管之间的相互作用，并评估脑血管和淋巴管 淋巴指标可用于评价L多巴、LRRK2K和GTP结合的疗效 抑制剂。这些研究将促进我们对帕金森病背后的神经病理变化的理解 发病机制，这可能有助于开发用于诊断和帕金森病干预的生物标志物。

Abstract: Parkinson’s disease (PD) is the second-most common neurodegenerative disease. Currently there is no curative therapy. Clinical evaluation of PD has been limited to psychophysical assessment, which is subjective and uninformative with regard to brain neuropathological abnormalities. Developing biomarkers for early diagnostics and treatment evaluation is critical for disease prognosis. PD cases display brain cerebrovascular, lymphatic system and structural abnormalities which contribute to the loss of dopaminergic neurons and movement disorders. Small pial arteries and arterioles are the primary controls of local brain tissue perfusion for delivery of nutrients and oxygen to supply the metabolic needs of neurons, and other cells, while lymphatic vessels play a crucial role in the clearance of waste products from brain tissues. The arterial pulsation wave from small blood vessels is the primary driving force for the fluid in lymphatic vessels and the perivascular space. Imbalance in the interaction between the two systems may have implications for PD pathogenesis. We recently developed several new MRI (Magnetic resonance imaging) techniques that can be used to measure brain cerebrovascular and lymphatic system abnormalities in both humans and animal models. We propose to test the hypothesis that abnormalities in brain microvascular and lymphatic vessels can be measured by novel MRI techniques through PD development and progression, and that those abnormalities can serve as potential indicators for pathogenic processes and treatment evaluation. Mutations in LRRK2 (Leucine Rich Repeat Kinase 2) cause genetic PD and contribute to sporadic PD. We recently generated a LRRK2 mouse model that displayed a robust PD-like phenotype and provided an excellent model for MRI assessment. MRI measures can be validated with invasive techniques in LRRK2 mouse models using histological methods. The longitudinal study and therapeutic testing can be done in a relatively short time period in these mice. Our pilot study found that mutant G2019S-LRRK2 mice display cerebrovascular abnormalities. Thus, we propose to use new MRI methods to study brain pathophysiological changes in cerebrovascular and lymphatic vessels underlying PD using LRRK2 mouse models with or without MPTP (a toxin to speed disease progression) and lipopolysaccharide (a preinflammatory agent) challenge by combining behavioral testing and brain histochemical studies. Aim 1. We will assess abnormalities in brain small blood vessels in LRRK2 mouse models. Aim 2. We will assess abnormalities in the perivascular space and cerebral lymphatic vessels in the brain in LRRK2 mouse models. Aim 3. We will characterize the abnormalities in the interactions between brain microvascular and lymphatic vessels, and assess whether cerebrovascular and lymphatic measures can be used to evaluate treatment efficacy of L-DOPA, LRRK2 kinase and GTP binding inhibitors. These studies will advance our understanding of the neuropathological changes underlying PD pathogenesis, which may facilitate the development of biomarkers for diagnostics and PD intervention.