Amyloidopathy, cholinopathy, dopamine responsiveness and freezing of gait in PD

 描述（由申请人提供）： 早期帕金森病（PD）的特征在于运动症状（包括步态）对多巴胺能药物治疗的反应性方面的“蜜月”期。进展性PD与失能性轴向运动并发症相关，如步态冻结（FoG），超过50%的患者多巴胺反应性降低甚至顽固性。多巴胺抵抗步态问题的管理代表了PD中最重要的未满足需求。目前，PD患者中没有FoG的生物标志物，因为缺乏对FoG的多巴胺无反应性的机制理解。我们以前已经确定胆碱能去神经支配是与PD患者的福尔斯跌倒和步态减慢相关的一个突出因素。我们最近发现，皮质β-淀粉样蛋白沉积不仅与认知能力下降有关，而且与PD患者的姿势不稳定和步态困难有关。在这个建议中，我们提出了初步的数据表明，FoG与PD中的胆固醇病，淀粉样蛋白病或两者兼而有之。我们建议测试新的假设，共病淀粉样病变可能是一个潜在的机制因素，FoG对多巴胺能治疗进展PD的反应差。相比之下，孤立性胆碱能病预计与FoG的多巴胺反应性有关。为此，我们建议在PD患者中进行详细的运动（包括FoG）测试，“开启”和“关闭”其多巴胺能药物，并将其与有和无FoG的PD受试者中的多巴胺能11 C-DTBZ、囊泡乙酰胆碱转运蛋白18F-FEOBV和β-淀粉样蛋白11 C-PIB脑PET成像相关联。此外，基于最近的临床观察，即胆碱能药物，如流行的抗β-SSRI药物，与老年人群中β-淀粉样蛋白斑块的显著较低积聚相关，并且基于我们随后观察到的PD中β-淀粉样蛋白斑块沉积和纹状体胆碱能末端之间有趣的负相关性，我们建议进行一项探索性子研究，以检验一个新的假设，即与没有FoG的PD受试者相比，患有FoG的PD受试者不仅表现出更高的纹状体β-淀粉样蛋白，而且表现出更低的纹状体多巴胺能神经支配（如通过11 C-DASB 5-羟色胺PET成像所确定的）。如果得到证实，本研究中的阳性结果将允许识别不同的PD亚组（“个性化药物”），如存在淀粉样蛋白病或胆碱能病，以选择患者进行靶向药物治疗，以潜在地预防FoG的发展。（抗淀粉样蛋白，如肾上腺素能药物）或控制其临床表现（胆碱能增强治疗），以保持和维持PD退伍军人的良好生活质量。

 DESCRIPTION (provided by applicant): Early stage Parkinson disease (PD) is characterized by a 'honeymoon' phase in terms of responsiveness of motor symptoms, including gait, to dopaminergic pharmacotherapy. Advancing PD is associated with disabling axial motor complications, such as freezing of gait (FoG), with decreased or even refractory dopamine responsiveness in over 50% of patients. The management of dopamine resistant gait problems represents the most important unmet need in PD. At present, there is no biomarker of FoG in patients with PD as there is a lack of mechanistic understanding of dopamine non-responsiveness of FoG. We have previously identified cholinergic denervation as a prominent factor related to both falls and gait slowing in PD. We recently identified that cortical β-amyloid deposition not only associates with cognitive decline but also with postural instability and gait difficulties in PD. In this proposal, we presen preliminary data suggesting that FoG is associated with either cholinopathy, amyloidopathy or both in PD. We propose to test the novel hypothesis that comorbid amyloidopathy may be a possible mechanistic factor underlying the poor response of FoG to dopaminergic therapy in advancing PD. In contrast, isolated cholinopathy would be expected to be associated with preserved dopamine responsiveness of FoG. For this purpose, we propose to perform to perform detailed motor, including FoG, testing in PD patients "on" and "off" their dopaminergic medications and relate this to dopaminergic 11C-DTBZ, vesicular acetylcholine transporter 18F-FEOBV and β-amyloid 11C-PIB brain PET imaging in PD subjects with and without FoG. Furthermore, based on recent clinical observations that serotoninergic drugs, like the popular anti-depressant SSRI drugs, are associated with significantly lower build- up of β-amyloid plaques in the elderly population, and based on our subsequent observation of an intriguing inverse relationship between β-amyloid plaque deposition and striatal serotoninergic terminal in PD, we propose to perform an exploratory sub-study to test a new hypothesis that PD subjects with FoG will exhibit not only higher striatal β-amyloid but also lower striatal serotoninergic innervation (as determined by 11C-DASB serotonin PET imaging) compared to PD subjects without FoG. If confirmed, positive findings in this study would allow the identification of differnt PD subgroups ('personalized medicine'), such as presence amyloidopathy or cholinopathy, to select patients for targeted pharmacotherapies to potentially prevent the development of FoG (anti-amyloid, such as serotoninergic drugs) or manage its clinical manifestation (cholinergic augmentation therapy) in order to preserve and maintain a good quality of life in veterans with PD.