Cerebellar cortical amyloid deposition biases 18F-Florbetapir PET quantification with whole cerebellum as reference region

To investigate whether cerebellar cortical amyloid-beta (Aβ) deposition biases 18F-Florbetapir Aβ PET quantification when the whole cerebellum (WC) is used as the reference region, and to identify a stable reference region for quantification. Additionally, to establish an optimal diagnostic threshold for the detection of cerebellar cortical Aβ deposition. This retrospective cohort study enrolled 359 Aβ-positive participants including 52 with and 307 without cerebellar cortical Aβ deposition. All participants underwent 18F-Florbetapir Aβ PET imaging, structural MRI, and cerebrospinal fluid biomarker analysis. Standardized uptake value ratio (SUVR) was derived from the standardized uptake value (SUV) by normalizing to WC, pons, and white matter (WM). Centiloid (CL) values were derived following standardized procedures. Bootstrap resampling was employed for group comparisons. Receiver operating characteristic (ROC) analysis was performed to determine the optimal SUVR threshold for identifying cerebellar cortical Aβ deposition, with validation conducted in an internal validation subset (n = 30). Two patients treated with lecanemab underwent longitudinal Aβ PET follow-up. Individuals classified as cerebellar cortical Aβ-positive exhibited significantly lower CL values than Aβ‑negative individuals (bootstrap P < 0.001). The cerebellar cortical Aβ‑positive group showed elevated SUVWC (bootstrap P = 0.012) and reduced SUVcortex (bootstrap P = 0.008), whereas SUVpons showed no significant differences between groups (bootstrap P = 0.110). SUVWM exhibited a significant intergroup difference (bootstrap P < 0.001), while SUVRWM showed no significant between-group difference (bootstrap P = 0.288). An optimal cerebellar SUVRWM threshold of 0.428 yielded excellent diagnostic performance for identifying cerebellar cortical Aβ deposition, with an area under the curve (AUC) = 0.931, sensitivity 86.5%, specificity 86.3%. Substantial agreement between quantitative and visual assessment was confirmed in the validation subset (Cohen’s kappa = 0.856). In the two cerebellar cortical Aβ-positive lecanemab-treated patients, CL values decreased over time, SUVRWM showed modest alterations, while cerebellar SUVRWM remained above the 0.428 threshold throughout follow-up. Cerebellar cortical Aβ deposition raises WC reference signals and interferes with CL-based 18F-Florbetapir Aβ PET quantification, which systematically underestimates true cerebral Aβ burden. The WM represents a robust reference region, and the cerebellar SUVRWM threshold of 0.428 is reliable and practical for identifying cerebellar cortical Aβ status. Cerebellar cortical Aβ deposition increases tracer uptake in the whole cerebellum reference region, interfering with Centiloid measurement and underestimating cerebral cortical amyloid burden. Compared with the whole cerebellum and pons, white matter is a robust reference region and avoids bias in Aβ PET quantification. A quantitative diagnostic threshold of cerebellar SUVRWM = 0.428 was established and validated for detecting cerebellar cortical Aβ deposition.