Abstract
The study aims to assess site assessment of the performance of 18F-PBR-111 as a neuroinflammation marker in the cuprizone mouse model of multiple sclerosis (MS). 18F-PBR-111 PET imaging has not been well evaluated in multiple sclerosis applications both in preclinical and clinical research. This study will help establish the potential utility of 18F-PBR-111 PET in preclinical MS research and future animal and future human applications. 18F-PBR-111 PET/CT was conducted at 3.5 weeks (n = 7) and 5.0 weeks (n = 7) after cuprizone treatment or sham control (n = 3) in the mouse model. A subgroup of mice underwent autoradiography with cryosectioned brain tissue. T2 weighted MRI was performed to obtain the brain structural data of each mouse. 18F-PBR-111 uptake was assessed in multiple brain regions with PET and autoradiography images. The correlation between autoradiography and immunofluorescence staining of neuroinflammation (F4/80 and CD11b) was measured. Compared to control mice, significant 18F-PBR-111 uptake in the corpus callosum (p < 0.001), striatum (caudate and internal capsule, p < 0.001), and hippocampus (p < 0.05) was identified with PET images at both 3.5 weeks and 5.0 weeks, and validated with autoradiography. No significant uptake differences were detected between 3.5 weeks and 5.0 weeks assessing these regions as a whole, although there was a trend of increased uptake at 5.0 weeks compared to 3.5 weeks in the CC. High 18F-PBR-111 uptake regions correlated with microglial/macrophage locations by immunofluorescence staining with F4/80 and CD11b antibodies. 18F-PBR-111 uptake in anatomic locations correlated with activated microglia at histology in the cuprizone mouse model of MS suggests that 18F-PBR-111 has potential for in vivo evaluation of therapy response and potential for use in MS patients and animal studies.
Highlights
Poor imaging outcomes and assessment measures plague the study of prognostic determinants of multiple sclerosis (MS) [1]
In vivo detection of microglia is possible with PET ligands of 18-kDa translocator protein (TSPO), called peripheral benzodiazepine receptor (PBR) [5]
TSPO is a nuclear encoded mitochondrial protein significantly expressed in the MM of MS, the uptake of which correlates with atrophy, a known prognostic indicator in MS [6]
Summary
Poor imaging outcomes and assessment measures plague the study of prognostic determinants of multiple sclerosis (MS) [1]. Insensitive MRI measures that only assess anatomic sequela of the disease processes, but not molecular pathophysiology, are a probable issue. Imaging that assesses cellular activity and molecular information is needed. Microglia/macrophages (MM) provide central nervous system (CNS) immune surveillance influencing inflammatory and reparative processes with shortterm neuroprotective activity. These MM are involved in long-term pro-inflammatory cytokine induced neuronal degeneration and short-term inflammatory response to brain injury/BBB disruption, both processes in MS [2,3]. In vivo imaging of neuroinflammation associated with MM levels would provide a window into patient specific pathophysiology and assist with animal testing. Each non-FDA approved agent requires site-specific validated radiopharmaceutical production and animal assessment prior to human use
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