Optimal Reference Region to Measure Longitudinal Amyloid-β Change with 18F-Florbetaben PET

J Nucl Med. 2017 Aug;58(8):1300-1306. doi: 10.2967/jnumed.116.187351. Epub 2017 Feb 9.


Accurate measurement of changes in amyloid-β (Aβ) deposition over time is important in longitudinal studies, particularly in anti-Aβ therapeutic trials. To achieve this, the optimal reference region (RR) must be selected to reduce variance of Aβ PET measurements, allowing early detection of treatment efficacy. The aim of this study was to determine the RR that allows earlier detection of subtle Aβ changes using 18F-florbetaben PET. Methods: Forty-five patients with mild cognitive impairment (mean age ± SD, 72.69 ± 6.54 y; 29 men/16 women) who underwent up to 3 18F-florbetaben scans were included. Baseline scans were visually classified as high (Aβ+) or low (Aβ-) amyloid. Six cortical regions were quantified using a standardized region-of-interest atlas applied to the spatially normalized gray matter image obtained from segmentation of the baseline T1-weighted volumetric MRI. Four RRs (cerebellar gray matter [CGM], whole cerebellum [WCER], pons, and subcortical white matter [SWM]) were studied. The SUV ratio (SUVR) for each RR was calculated by dividing cortex activity by RR activity, with a composite SUVR averaged over 6 cortical regions. SUVR increase from baseline to 1 and 2 y, and percentage Aβ deposition per year, were assessed across Aβ+ and Aβ- groups. Results: SUVs for any RR were not significantly different over time. Percentage Aβ accumulation per year derived from composite SUVR was 0.10 ± 1.72 (Aβ-) and 1.36 ± 1.98 (Aβ+) (P = 0.02) for CGM and 0.13 ± 1.47 and 1.32 ± 1.75 (P = 0.01), respectively, for WCER. Compared with baseline, the composite SUVR increase in Aβ+ scans was significantly larger than in Aβ- scans at 1 y (P = 0.04 [CGM]; P = 0.03 [WCER]) and 2 y (P = 0.02 [CGM]; P = 0.01 [WCER]) using these 2 RRs. Significant SUVR changes using the pons as the RR were detected only at 2 y (P = 0.46 [1 y], P = 0.001 [2 y]). SUVR using the SWM as the RR showed no significant differences at either follow-up (P = 0.39 [1 y], P = 0.09 [2 y]). Conclusion: RR selection influences reliable early measurement of Aβ changes over time. Compared with SWM and pons, which do not fulfil the RR requirements and have limited sensitivity to detect Aβ changes, cerebellar RRs are recommended for 18F-florbetaben PET because they allow earlier detection of Aβ accumulation.

Keywords: amyloid beta; florbetaben PET; longitudinal; reference region.

MeSH terms

  • Aged
  • Alzheimer Disease / diagnostic imaging
  • Alzheimer Disease / metabolism
  • Amyloid beta-Peptides / metabolism*
  • Aniline Compounds* / metabolism
  • Biological Transport
  • Female
  • Humans
  • Longitudinal Studies
  • Male
  • Positron-Emission Tomography / standards*
  • Reference Standards
  • Stilbenes* / metabolism


  • Amyloid beta-Peptides
  • Aniline Compounds
  • Stilbenes
  • 4-(N-methylamino)-4'-(2-(2-(2-fluoroethoxy)ethoxy)ethoxy)stilbene