Dynamic neuroimaging of intranasal-administered radiotracers to assess brain waste clearance

1606 Objectives: Diminished waste clearance from the brain is partially mediated by the glymphatic system (GS) and hypothesized to contribute to protein aggregation, neurotoxicity, and cognitive decline in elderly and dementia patients. The impact of reduced glymphatic efficacy has not been investigated, as clinical methods to evaluate the GS are lacking. A sensitive, non-invasive, and translatable approach was investigated to quantify brain waste clearance following intranasal delivery of 18F-Fluoride and 18F-2-deoxy-2-fluorosorbitol (18F-FDS). Methods: Brain uptake and clearance were measured in rats using a 7T Bruker BioSpec 70/30 MRI with PET insert following intranasal (IN) dosing (0.550 mCi, n=4) or tail vein injection (0.409 mCi, n=6) of 18F-Fluoride. To reduce skull accumulation and spillover into brain tissue, 18F-FDS brain clearance was evaluated following IN (.07 mCi, n=2) or intravenous (IV; .05 mCi, n=2) dosing. PET scans were acquired in 14 frames for 18F-Fluoride scans (5x60 seconds; 9x5 minutes with 5-minute delay between each frame) or three static frames for 18F-FDS (3 5-minute frames at 25-, 105-, and 240-minutes post-dose). Nyquist sampling tested the PET resolution using 0.43 mm cubic voxels spanning an 18F-Fluoride-filled tube. Spillover characterization was used to identify a brain region (“Deep VOI”, VOI: volume of interest) with minimal skull contribution. PET reconstruction was achieved using a MLEM algorithm (12 iterations, 0.75 mm isotropic voxels) following randoms, scatter, dead time, decay, and attenuation correction using MRI-generated attenuation maps for each subject. PET scans were manually registered to a RARE anatomical MRI (TE 72.91 ms; TR 210 ms; echo spacing 9.121 ms; 90-degree excitation angle; 180-degree refocusing angle; 4 averages) for analysis in Pmod 4.1. Brain uptake and clearance were assessed as percent change from baseline, where baseline is the first 5-minute PET frame (25-minutes post-dose). For 18F-FDS scans, analysis was conducted for the whole brain. Results: For both tracers, brain clearance patterns differed between IN and IV dosing. 18F-Fluoride showed high skull accumulation and similar Deep VOI uptake profiles for both IV and IN delivery. After 105 minutes, 18F-Fluoride given IN showed a 57.5% reduction in signal, while IV showed an increase of 36.9%. Skull uptake was absent in 18F-FDS subjects. IN 18F-FDS showed brain uptake and clearance (110% signal reduction after 105 minutes) whereas brain accumulation of IV 18F-FDS only declined from baseline. Conclusions: PET/MRI had sufficient resolution for imaging brain clearance of 18F-Fluoride independent of 18F in adjacent skull. IN delivery of tested tracers was better suited for imaging brain clearance than IV. 18F-FDS may be preferred for future studies due to the lack of skull uptake and spillover, potentially improving sensitivity by analyzing the whole brain.