Biomarkers.

Background: 18F-flortaucipir allows in-vivo visualization of tau tangles in Alzheimer's disease (AD) with a standardized definition of tau-PET positivity. However, semi-quantification is often used in research and in therapeutic trials and plays an important role in the AT(N) framework. This work aims to determine quantitative positivity thresholds and compare semi-quantification to visual interpretation.

Method: N=189 flortaucipir scans from A05 (NCT02016560) study were included (15 young-controls (YC), 48 elderly cognitively unimpaired (eCU), 85 MCIs, and 41 with AD) (Table 1), wherein the scans were visually interpreted as either T+/T-. Using a PET-only tau quantification software, volume-weighted SUVRs were calculated on Braak I-II, Braak III-IV, Braak V-VI, and temporal-meta region (TMR) (Figure 3). Three methods to calculate T+ cut-points were used: (T1) Youden-index (MCI/AD vs. Aβ- eCU), (T2) mean+2SDs of Aβ- eCU, and (T3) mean+2SDs of YC SUVRs. Using calculated cut-points, a subject is hierarchically assigned to a Braak stage if they are T+ at that stage and at all previous stages, otherwise, the subject is Braak-staging discordant.

Result: Patients characteristics and visual A+/T+ proportions are summarized in Table 1. T1-derived thresholds are: 1.26 (Braak I-II), 1.18 (Braak III-IV), 1.17 (Braak V-VI), and 1.29 (TMR) (Table 2). TMR-based T+ threshold using T2 was 1.30. Overall, the concordance of visual read with TMR-based quantification was 92%, 93%, and 88.4%, and only 8/189 (4.2%), 6/189 (3.2%), and 0% subjects were Braak staging discordant, using thresholding methods T1, T2, and T3, respectively (Figure 2b). Braak staging was associated with cognitive decline (MMSE and ADAS-Cog-11), and with increase in A+/T+ proportions. All Braak V-VI subjects had a T+ visual read. These subjects were also all Aβ+ MCI/ADs. However, 80% (8/10) of Braak III-IV, 26.9% (7/26) of Braak I-II, and 86% (44/51) of TMR+ subjects, using T1-derived thresholds, had a T+ read, whereas 95.7% (44/46) of TMR+ subjects who were also Aβ+ had a T+ read.

Conclusion: Using the temporal-meta region, visual read and SUVR were highly concordant. Visual T+ aligns more with amyloid positivity. Hierarchical Braak staging was associated with cognitive performance and amyloid load and its concordance with visual interpretation was moderate-to-high for the limbic and neocortical stages.