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)的特点是运动症状(包括步态)对多巴胺能药物治疗的反应性处于“蜜月期”。进展性帕金森病与轴向运动障碍相关，如步态冻结(FOG)，在超过50%的患者中，多巴胺反应性降低甚至难治性。多巴胺抵抗步态问题的处理是帕金森病最重要的未得到满足的需求。目前，帕金森病患者中还没有雾的生物标志物，这是因为缺乏对雾的多巴胺无反应的机制的了解。我们以前已经发现胆碱能去神经是帕金森病患者跌倒和步态减慢的一个显著因素。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，而且与帕金森病患者的姿势不稳定和步态困难有关。在这项建议中，我们提出的初步数据表明，雾与PD的胆碱病、淀粉样变性或两者都有关联。我们建议检验这一新的假说，即共病的淀粉样变性可能是进展性帕金森病中雾对多巴胺能治疗反应差的一个可能的机制因素。相反，孤立性胆碱病可能与雾的多巴胺反应性保留有关。为此，我们建议进行详细的运动，包括雾化，测试帕金森病患者“开”和“关”他们的多巴胺能药物，并将其与多巴胺能11C-DTBZ，囊泡乙酰胆碱转运体18F-FEOBV和β-淀粉样蛋白11C-PIB在有雾和无雾的帕金森病患者进行脑正电子发射计算机断层扫描。此外，基于最近的临床观察，即5-羟色胺能药物，如广受欢迎的抗抑郁药物SSRI，与老年人群中β-淀粉样斑块的建立显著降低有关，并且基于我们随后观察到的β-淀粉样斑块沉积与帕金森病患者纹状体5-羟色胺能终末之间有趣的相反关系，我们提议进行一项探索性的分研究来测试一项新的假说，即与没有雾的PD患者相比，有雾的PD患者不仅表现出更高的纹状体β-淀粉样蛋白，而且还表现出更低的纹状体5-羟色胺能神经支配(如11C-DASB正电子发射计算机断层扫描所确定的)。如果得到证实，这项研究中的积极发现将使我们能够识别不同的帕金森病亚型(个性化药物)，例如存在淀粉样变性或胆碱病，以选择患者进行有针对性的药物治疗，以潜在地防止雾的发展(抗淀粉样蛋白，如5-羟色胺能药物)或管理其临床表现(胆碱能增强疗法)，以保持和维持患有帕金森病的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.