TY - JOUR T1 - TRACKING INNATE IMMUNE ACTIVATION IN A MOUSE MODEL OF PARKINSON’S DISEASE USING TREM1 AND TSPO PET TRACERS JF - Journal of Nuclear Medicine JO - J Nucl Med DO - 10.2967/jnumed.121.263039 SP - jnumed.121.263039 AU - Katherine Lindsay Lucot AU - Marc Yendall Stevens AU - T. Adam Bonham AU - E. Carmen Azevedo AU - Aisling M. Chaney AU - Ebony Danielle Webber AU - Poorva Jain AU - Jessica Lee Klockow AU - Isaac Mackenzie Jackson AU - Mackenzie Leigh Carlson AU - Edward E. Graves AU - Thomas Jude Montine AU - Michelle Louise James Y1 - 2022/02/01 UR - http://jnm.snmjournals.org/content/early/2022/02/17/jnumed.121.263039.abstract N2 - Parkinson’s disease (PD) is associated with aberrant innate immune responses, including microglial activation and infiltration of peripheral myeloid cells into the central nervous system (CNS). Methods to investigate innate immune activation in PD are limited and have not yet elucidated key interactions between neuroinflammation and peripheral inflammation. Translocator protein 18 kDa (TSPO)-positron emission tomography (PET) is a widely evaluated imaging approach for studying activated microglia and peripheral myeloid lineage cells in vivo, however it is yet to be fully explored in PD. Herein we investigate the utility of TSPO-PET, in addition to PET imaging of triggering receptor expressed on myeloid cells 1 (TREM1) – a novel biomarker of proinflammatory myeloid cells – for detecting innate immune responses in the 6-hydroxydopamine (6-OHDA) mouse model of dopaminergic neuron degeneration. Methods: C57/BL6J and TREM1-knockout mice were stereotaxically injected with 6-OHDA in the left striatum; control mice were saline-injected. At day 7 or 14 post-surgery, mice were administered 18F-GE-180, 64Cu-TREM1-mAb or 64Cu-Isotype control-mAb and imaged by PET/CT. Ex vivo autoradiography (ARG) was performed to obtain high resolution images of tracer binding within the brain. Immunohistochemistry was conducted to verify myeloid cell activation and dopaminergic cell death and quantitative PCR and flow cytometry were completed to assess levels of target in the brain. Results: PET/CT images of both tracers showed elevated signal within the striatum of 6-OHDA-injected mice compared to those injected with saline. ARG afforded higher resolution brain images and revealed significant TSPO and TREM1 tracer binding within the ipsilateral striatum of 6-OHDA- compared to saline-injected mice at both 7- and 14-days post-toxin. Interestingly, 18F-GE-180 enabled detection of inflammation in the brain and peripheral tissues (blood and spleen) of 6-OHDA mice, whereas 64Cu-TREM1-mAb appeared to be more sensitive and specific for detecting neuroinflammation, in particular infiltrating myeloid cells, in these mice, as demonstrated by flow cytometry findings and higher tracer binding signal-to-background ratios in brain. Conclusion: TSPO- and TREM1-PET tracers are promising tools for investigating different cell types involved in innate immune activation in the context of dopaminergic neurodegeneration, thus warranting further investigation in other PD rodent models and human postmortem tissue to assess their clinical potential. ER -