Microglial CSF1R radioligand [(11)C]CPPC as a marker of disease severity in early Parkinson’s disease: a pilot study

BACKGROUND: Enhanced innate immune response is detected in autopsy studies of Parkinson’s disease (PD) but the role of microglia in early pathophysiology is unclear. While the translocator protein 18 kDa (TSPO) that marks glial activation may be high in PD, TSPO expression is not limited to microglia, and ligand binding affinity for newer generation radiotracers for imaging TSPO with PET varies across individuals due to a common single nucleotide polymorphism in TSPO. Imaging the colony stimulating factor 1 receptor (CSF1R) with [(11)C]CPPC PET offers an opportunity to image a complementary in vivo marker of microglial number and/or activity in early PD. OBJECTIVE: To determine whether the binding of [(11)C]CPPC differs across the brains of healthy controls and patients with early PD, and to test for correlation between binding and disease severity in early PD. METHODS: Healthy controls and persons with PD of ≤2 years disease duration and Hoehn & Yahr <2.5 were enrolled. Each participant underwent motor and cognitive ratings, and then completed [(11)C]CPPC dynamic PET with serial arterial blood sampling. The total volume of tissue distribution (V(T)) in PD-relevant regions of interest was compared between groups (healthy controls, mild versus moderate PD) based on disability from motor symptoms (MDS-UPDRS Part II) and also was regressed with MDS-UPDRS Part II as a continuous measure. Correlations between V(T) and cognitive measures were explored. RESULTS: PET imaging showed higher [(11)C]CPPC binding in multiple regions in patients with more motor disability than those with less motor disability and compared to healthy controls. In patients with mild cognitive impairment (PD-MCI), higher CSF1R binding by [(11)C]CPPC was associated with worse cognitive function on Montreal Cognitive Assessment (MoCA). This inverse correlation was also found between [(11)C]CPPC V(T) and verbal fluency across the entire PD cohort. CONCLUSIONS: Even at early stages of disease, [(11)C]CPPC that binds the CSF1R, a direct marker of microglial density and activation, correlates with motor disability in PD and cognitive function.