Spatially constrained kinetic modeling with dual reference tissues improves 18F-flortaucipir PET in studies of Alzheimer disease

Eur J Nucl Med Mol Imaging. 2021 Sep;48(10):3172-3186. doi: 10.1007/s00259-020-05134-w. Epub 2021 Feb 18.


Purpose: Recent studies have shown that standard compartmental models using plasma input or the cerebellum reference tissue input are generally not reliable for quantifying tau burden in dynamic 18F-flortaucipir PET studies of Alzheimer disease. So far, the optimal reference region for estimating 18F-flortaucipir delivery and specific tau binding has yet to be determined. The objective of the study is to improve 18F-flortaucipir brain tau PET quantification using a spatially constrained kinetic model with dual reference tissues.

Methods: Participants were classified as either cognitively normal (CN) or cognitively impaired (CI) based on clinical assessment. T1-weighted structural MRI and 105-min dynamic 18F-flortaucipir PET scans were acquired for each participant. Using both a simplified reference tissue model (SRTM2) and Logan plot with either cerebellum gray matter or centrum semiovale (CS) white matter as the reference tissue, we estimated distribution volume ratios (DVRs) and the relative transport rate constant R1 for region of interest-based (ROI) and voxelwise-based analyses. Conventional linear regression (LR) and LR with spatially constrained (LRSC) parametric imaging algorithms were then evaluated. Noise-induced bias in the parametric images was compared to estimates from ROI time activity curve-based kinetic modeling. We finally evaluated standardized uptake value ratios at early phase (SUVREP, 0.7-2.9 min) and late phase (SUVRLP, 80-105 min) to approximate R1 and DVR, respectively.

Results: The percent coefficients of variation of R1 and DVR estimates from SRTM2 with spatially constrained modeling were comparable to those from the Logan plot and SUVRs. The SRTM2 using CS reference tissue with LRSC reduced noise-induced underestimation in the LR generated DVR images to negligible levels (< 1%). Inconsistent overestimation of DVR in the SUVRLP only occurred using the cerebellum reference tissue-based measurements. The CS reference tissue-based DVR and SUVRLP, and cerebellum-based SUVREP and R1 provided higher Cohen's effect size d to detect increased tau deposition and reduced relative tracer transport rate in CI individuals.

Conclusion: Using a spatially constrained kinetic model with dual reference tissues significantly improved quantification of relative perfusion and tau binding. Cerebellum and CS are the suggested reference tissues to estimate R1 and DVR, respectively, for dynamic 18F-flortaucipir PET studies. Cerebellum-based SUVREP and CS-based SUVRLP may be used to simplify 18F-flortaucipir PET study.

Keywords: 18F-Flortaucipir PET; Alzheimer disease; Dual reference tissues; Logan plot; SRTM; SUVR; Spatially constrained kinetic modeling.

MeSH terms

  • Alzheimer Disease* / diagnostic imaging
  • Brain / diagnostic imaging
  • Brain / metabolism
  • Carbolines
  • Humans
  • Positron-Emission Tomography
  • tau Proteins / metabolism


  • Carbolines
  • tau Proteins
  • 7-(6-fluoropyridin-3-yl)-5H-pyrido(4,3-b)indole