Neuroinflammatory Biomarkers for Nigrostriatal Injury

摘要。 帕金森病（PD）引起运动和非运动表现。基础病理学包括异常 α-synuclein（α-syn）的沉积始于尾侧脑干（以及嗅结节和内侧 颞区），然后扩散到更多的喙脑干和皮质区。初始运动表现 可能反映黑质纹状体多巴胺能通路的退化，但皮质功能障碍导致 非运动和一些运动表现可能反映直接α-syn参与，神经递质缺乏 由于投射脑干核团的丢失或皮质或皮质下网络的继发性功能障碍。 目前，没有治疗可以延缓PD的无情进展。我们有初步的数据（神经炎症， 非人灵长类动物（NHP）黑质纹状体损伤后活性氧增加，这表明， 皮质功能障碍可由沿着皮质-纹状体神经元的逆行变性沿着而发生。在这里我们将测试 一种抗炎化合物，synoxizyme（以前称为羧基富勒烯或C3），是否会减少 观察到的神经炎症，并防止逆行性皮质损伤作为一个潜在的机制， 会导致PD患者的残疾我们将证实这一发现，并验证体内PET措施， 神经炎症和活性氧。我们还证明了突触合酶可以恢复黑质纹状体 单侧颈内动脉（ic）灌注选择性神经毒素MPTP后功能障碍。Synoxizyme可能起作用 通过减轻神经炎症和减少破坏性的活性氧。另一个目标是 这项研究的目的是确定我们的新PET放射性示踪剂是否可以作为结合酶的靶点。 这些高度新颖的研究将确定非人类灵长类动物中MPTP引起的黑质纹状体损伤是否会导致 皮质功能障碍，这可以为研究皮质功能障碍的另一种机制提供基础。 帕金森病患者的功能障碍此外，我们将验证新的PET措施， 神经炎症和活性氧可能是这些研究的关键。我们将决定 扩散张量成像MR测量平均扩散率可以识别皮质纹状体束功能障碍， 支持黑质纹状体损伤后退行性变的概念。我们还将确定 全身给药的synoxizyme将减弱MPTP的作用，以及这是否对应于 减少MPTP诱导的神经炎症和增加活性氧-这可能是 参与人类PD的发病机制。最后，我们将能够证明PET是否能够测量 可以提供参与synoxizyme的目标的量化，这将是一个关键信息， 随后在人类中进行Synoxizyme或任何其它靶向这些致病性 PD或其他神经退行性疾病的机制。

ABSTRACT. Parkinson disease (PD) causes motor and nonmotor manifestations. Underlying pathology includes abnormal deposition of α-synuclein (α-syn) starting in caudal brainstem (as well as olfactory tubercle and medial temporal areas) and then spreads to more rostral brainstem and cortical areas. Initial motor manifestations likely reflect degeneration to the nigrostriatal dopaminergic pathway but cortical dysfunction leading to nonmotor and some motor manifestations may reflect direct α-syn involvement, neurotransmitter deficiencies due to loss of projecting brainstem nuclei or secondary dysfunction of cortical or subcortical networks. Currently, no treatment delays the relentless progression of PD. We have preliminary data (neuroinflammation, increased reactive oxygen species) after nigrostriatal injury in nonhuman primates (NHPs) that suggests that cortical dysfunction may occur from retrograde degeneration along cortico-striatal neurons. Here we will test whether an anti-inflammatory compound, synoxizyme (previously called carboxyfullerene or C3), will reduce the observed neuroinflammation, and prevent retrograde cortical injury as a potential mechanism which could contribute to disability in people with PD. We will confirm this finding and validate in vivo PET measures of neuroinflammation and reactive oxygen species. We also demonstrated that synoxizyme restores nigrostriatal dysfunction after unilateral internal carotid (ic) infusion of the selective neurotoxin MPTP. Synoxizyme may act through attenuation of neuroinflammation and reduce destructive reactive oxygen species. Another goal of this study is to determine whether our new PET radiotracers can act as targets of engagement for synoxizyme. These highly novel studies will determine whether nigrostriatal injury with MPTP in nonhuman primates leads to cortical dysfunction which could provide the basis for investigations into another mechanism of cortical dysfunction that occurs in people with PD. Furthermore, we will validate new PET measures of neuroinflammation and reactive oxygen species that could be key for such studies. We will determine whether diffusion tensor imaging MR measures of mean diffusivity identify cortical striatal tract dysfunction that could support the notion of retrograde degeneration after nigrostriatal injury. We also will determine whether systemically administered synoxizyme will attenuate the effects of MPTP and whether this corresponds with a reduction in MPTP-induced neuroinflammation and increased reactive oxygen species – which may be involved in the pathogenesis of human PD. Finally, we will be able to demonstrate whether the PET measures may provide quantification of targets of engagement for synoxizyme, which would be critical information for a subsequent clinical trial in humans of synoxizyme or any other treatment targeting these pathogenic mechanisms in PD or other neurodegenerative conditions.