Discordance in amyloid positivity between visual reads and Centiloids: Impact of white matter uptake

The visual interpretation of amyloid PET scans, or visual read (VR), is the most common technique used in clinical practice to identify the presence of cerebral amyloid plaques. Amyloid status (positive or negative) determined by VR or using a Centiloid (CL) cut-off shows high overall concordance. However, discordant cases can occur where the VR is positive, but the CL is below the positivity cut-off, or vice versa.

The objective of this analysis was to evaluate the rate of discordance and explore potential causes, particularly the role of amyloid tracer uptake in the white matter (WM), when determining amyloid status using VR and CL in screening for the elenbecestat phase 3 studies in early Alzheimer's disease (AD).

Amyloid PET scans using either Florbetapir (Amyvid™), Florbetaben (Neuraceq™) or Flutemetamol (Vizamyl™) from 3,232 participants (1507 VR- and 1725 VR+) with cognitive impairment screened for the elenbecestat phase 3 studies in early AD were visually interpreted at screening by trained neuroradiologists and quantified using CL values.

Academic and clinical centers INTERVENTION/MEASUREMENTS: Quantitatively, amyloid positivity was defined as CL > 32.21. The number of positive cortical regions was determined by counting the number of regions with a standardized uptake value ratio (SUVr) that exceeded 1.17. PET SUVr levels in the cerebral WM were measured using an eroded WM region of interest (ROI). Statistical tests were conducted to detect differences among the four concordance groups, defined by the relationship of VR and CL status (positive or negative). Additionally, tests examined the relationship between uptake in the WM and rates and type of discordance. Receiver operating characteristic (ROC) analysis and DeLong's test were also used to examine the effect of different tracers on the discordant rates.

Discordance was observed in 6.53% of cases (n=211), with VR+/CL- in 4.61% (n=149) and VR-/CL+ in 1.92% (n=62). VR+/CL- discordant cases had significantly fewer amyloid-positive cortical regions compared to both VR+/CL+ and VR-/CL+ cases. VR-/CL+ cases had a significantly higher WM uptake than VR-/CL- and VR+/CL- cases. Our findings revealed a relationship between WM uptake and rates and types of discordance. High WM uptake can erroneously lead to CL+, due to gray matter (GM) contamination from the WM, and VR- status, due to reduced contrast between WM and GM, resulting in VR-/CL+ cases. Conversely, low WM uptake can result in an underestimation of CL values, inaccurately classifying a scan as CL-, and at the same time, the increased contrast may result in a VR+, thereby increasing the occurrence of discordant VR+/CL- cases.

Variations in WM uptake significantly contribute to discordances by introducing positive or negative bias in CL values and altering the GM to WM contrast, which forms the basis of the VR. Nevertheless, the rates of discordant cases are low and VR represents a robust and validated method to determine the presence of amyloid deposition. VR enables enrolling patients with amyloid beta pathology, as seen on amyloid PET scans, whereas CL scaling was developed to provide standardized units that more consistently characterize longitudinal amyloid‑β change. These findings reflect the complementary roles of VR and CL in amyloid PET evaluation, with implications for refining diagnostic accuracy and disease monitoring in AD clinical trials and practice.