Affiliations: [a] Department of Physics and Astronomy, University of British Columbia, Vancouver, BC, Canada
Department of Nuclear Medicine and Molecular Imaging, University of Groningen, University Medical Centre Groningen, Groningen, The Netherlands
Pacific Parkinson’s Research Centre, University of British Columbia, Vancouver, BC, Canada
| [d] TRIUMF, Vancouver, BC, Canada
Department of Pathology, University of British Columbia, Vancouver, BC, Canada
Department of Medical Genetics, Centre for Applied Neurogenetics, University of British Columbia, Vancouver, BC, Canada
Department of Medicine, Division of Neurology, University of British Columbia, Vancouver, BC, Canada
Correspondence to: Dr. Vesna Sossi, Department of Physics and Astronomy, G343 Koerner Pavillion, University of British Columbia, Vancouver, BC, V6T 2B5, Canada. E-mail: email@example.com.
Note:  These authors contributed equally to this work.
Note:  Current Address: Radiation Physics and Protection, Oxford University Hospitals NHS Foundation Trust, Oxford OX3 7LE, UK.
Abstract: Background: Leucine-rich repeat kinase 2 (LRRK2) mutations are the most common genetic risk factor for Parkinson’s disease (PD). While the corresponding pathogenic mechanisms remain largely unknown, LRRK2 has been implicated in the immune system. Objective: To assess whether LRRK2 mutations alter the sensitivity to a single peripheral inflammatory trigger, with ultimate impact on dopaminergic integrity, using a longitudinal imaging-based study design. Methods: Rats carrying LRRK2 p.G2019S and non-transgenic (NT) littermates were treated peripherally with lipopolysaccharide (LPS). They were monitored over 10 months with PET markers for neuroinflammation and dopaminergic integrity, and with behavioral testing. Tyrosine hydroxylase and CD68 expression were assessed postmortem, 12 months after LPS treatment, in the striatum and substantia nigra. Results: Longitudinal [11C]PBR28 PET imaging revealed that LPS treatment caused inflammation in the brain, increasing over time, as compared to saline (corrected p = 0.008). LPS treated LRRK2 animals exhibited significantly increased neuroinflammation in the cortex and ventral-regions compared to saline treated animals (LRRK2 and NT) at 10 months post treatment, with the increase in [11C]PBR28 binding from baseline averaging 0.128±0.045 g/mL. For LPS treated NT animals, the increase was not significant. CD68 immunohistochemistry data supported the imaging results, but without reaching statistical significance. No dopaminergic degeneration was observed. Conclusion: A single peripheral inflammatory trigger elicited long lasting, progressive neuroinflammation. A trend for an exacerbated inflammatory response in LRRK2 animals compared to NT controls was observed. Translationally, this implies that repeated exposure to inflammatory triggers may be needed for LRRK2 mutation carriers to develop active PD.
Keywords: LPS, LRRK2 G2019S, neuroinflammation, Parkinson’s disease, PET imaging