Optimized reference region and the effect on test-retest reliability and sensitivity to differences between...

[¹¹C]UCB-J is a radioligand targeting synaptic vesicle glycoprotein 2A, used to image synaptic density. For quantification, a small-volume centrum semiovale area was previously optimized as a [¹¹C]UCB-J reference region (CS2mL); however, due to its small volume, its high variability resulted in reduced reliability. Herein, we evaluated an alternative reference region method to assess longitudinal test-retest reliability and detection of Parkinson's disease (PD). For estimating distribution volume ratio (DVR), CS2mL and eleven white matter (WM) reference regions (range: 0.5-200 mL) were generated. Same-day and longitudinal test-retest variability (TRV) were assessed (24 healthy subjects (HS); n = 10 same-day and n = 20 longitudinal scans, range: 7-1028 days). Each reference region was used to evaluate the substantia nigra (SN) and caudate DVRs in HS (n = 25) and PD (n = 20); 10 mL was the optimal reference region volume, yielding [¹¹C]UCB-J DVR measurements with reduced variability in TRV (same-day: 10 mL: 1.2 ± 5.7%, same-day: CS2mL: -0.9 ± 9.2% longitudinal: 10 mL: 1.5 ± 7.0%, CS2mL: 1.6 ± 11.9%), while maintaining <10% volume of distribution difference, compared to CS2mL. Further, a significant difference between PD and HS groups in SN and caudate DVRs was found using 10 mL, with greater effect size (Cohen's d 0.61 for SN and 0.66 for caudate) compared to CS2mL (0.38 for SN and 0.43 for caudate).