Accurate measurement of amyloid-beta (Aβ) change is important in anti-Aβ therapeutic trials. Selecting the optimal reference region (RR) is essential to reduce the variance of the Aβ burden PET measurements, allowing early detection of treatment efficacy. The study objective was to determine the RR that allows earlier detection of subtle Aβ changes using 18F-florbetaben (FBB) PET.


      FBB PET scans from 45 mild cognitively impaired (MCI) patients (72.69 ± 6.54 yrs., 29 male/16 female) who underwent three FBB scans were included (baseline (n=45), one-year (n=41) and two-years (n=36)). FBB scans were visually assessed as positive and negative. Cortical regions (frontal, lateral temporal, occipital, parietal, anterior cingulate and posterior cingulate) were quantified using the standardized AAL region-of-interest (ROI) atlas applied to the spatially normalized gray matter PET image obtained from the segmentation of the participant’s baseline T1-weighted volumetric MRI. Four regions of reference (gray matter cerebellum (CGM), whole cerebellum (WCER), pons (PONS) and subcortical white matter (WM)) were studied. Cortical standardized uptake value ratio (SUVR) for each RR was calculated dividing cortex activity by the RR activity. A composite SUVR averaged all cortical regions. T-test was used to compare SUVR at baseline to the SUVR from one- and two-years follow-up scans.


      Both CGM and WCER RRs enabled early detection of cortical SUVR changes that were in concordance with the anticipated pattern of change for the MCI patients. Average percent of Aβ accumulation per year (mean±SD) derived from composite SUVR in negative (-) and positive (+) scans was 0.13±1.68(-)/1.39±2.02(+) for CGM, 0.16 ± 1.43(-)/1.36±1.79(+) for the WCER. Composite SUVR increase in positive scans was significantly larger than those in negative scans between baseline and 1-year follow-up (p(CGM)=0.04, p(WCER)=0.02) and between baseline and 2-years follow-up scans (p(CGM)=0.04, p(WCER)=0.02). PONS detected significant changes only at 2-years follow-up (p(1-yr)=0.71, p(2-yrs)=0.001) while SWM did not show significant difference either follow-up (p(1-yr)=0.50, p(2-yrs)=0.04).


      Reference region selection influences the reliable and early measurement of amyloid-beta changes. Compared with WM or PONS, cerebellar reference regions (CGM and WCER) are recommended as RR for 18F-florbetaben PET since they allow earlier detection of amyloid-beta change.