Neuroinflammatory Biomarkers for Nigrostriatal Injury

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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.