Neuroinflammatory Biomarkers for Nigrostriatal Injury

抽象的。 帕金森病(PD)会引起运动和非运动症状。潜在的病理包括异常 α-突触核蛋白(α-SYN)在脑干尾侧(以及嗅结节和内侧)的沉积 颞区)，然后扩散到更多的吻侧脑干和皮质区域。最初的运动表现 可能反映了黑质纹状体多巴胺能通路的变性，但皮质功能障碍导致 非运动性和某些运动性表现可能反映α-SYN直接受累，神经递质缺乏。 由于投射的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，没有任何治疗方法可以延缓帕金森病的持续进展。我们有初步数据(神经炎症， 非人灵长类黑质纹状体损伤后的活性氧增加)，这表明 皮质功能障碍可能发生于沿皮质纹状体神经元的退行性变性。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，并防止逆行皮质损伤作为一种潜在的机制，可以 有助于帕金森病患者的残疾。我们将证实这一发现，并在体内验证PET测量 神经炎症和活性氧。我们还证明了合并素可以恢复黑质纹状体 单侧颈内动脉注射选择性神经毒素mptp后的功能障碍。Synoxizyme可能会行动 通过减轻神经炎症，减少破坏性的活性氧物种。这方面的另一个目标 研究是为了确定我们的新的PET放射性示踪剂是否可以作为突触的靶标。 这些高度新颖的研究将确定MPTP对非人类灵长类黑质纹状体的损伤是否会导致 皮质功能障碍，这可能为研究皮质功能障碍的另一种机制提供基础。 帕金森病患者出现的功能障碍。此外，我们将验证新的PET测量 神经炎症和活性氧可能是这类研究的关键。我们将确定是否 磁共振扩散张量成像的平均弥散系数测量可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。我们还将确定是否 系统给药将减弱MPTP的影响，以及这是否对应于 减少MPTP诱导的神经炎症和增加活性氧物种--这可能是 参与了人类帕金森病的发病机制。最后，我们将能够演示PET是否测量 可以提供融合的参与目标的量化，这将是 随后在人体上进行了针对这些致病因子的合酶或任何其他治疗方法的临床试验 帕金森病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.