Comparing ATN-T designation by tau PET visual reads, tau PET quantification, and CSF PTau181 across three cohorts

Abstract

Purpose: To compare rates of tau biomarker positivity (T-status) per the 2018 Alzheimer's Disease (AD) Research Framework derived from [¹⁸F]flortaucipir (FTP) PET visual assessment, FTP quantification, and cerebrospinal fluid (CSF) phosphorylated Tau-181 (PTau181).

Methods: We included 351 subjects with varying clinical diagnoses from three cohorts with available FTP PET and CSF PTau181 within 18 months. T-status was derived from (1) FTP visual assessment by two blinded raters; (2) FTP standardized uptake value ratio (SUVR) quantification from a temporal meta-ROI (threshold: SUVR ≥1.27); and (3) Elecsys® Phospho-Tau (181P) CSF (Roche Diagnostics) concentrations (threshold: PTau181 ≥ 24.5 pg/mL).

Results: FTP visual reads yielded the highest rates of T+, while T+ by SUVR increased progressively from cognitively normal (CN) through mild cognitive impairment (MCI) and AD dementia. T+ designation by CSF PTau181 was intermediate between FTP visual reads and SUVR values in CN, similar to SUVR in MCI, and lower in AD dementia. Concordance in T-status between modality pairs ranged from 68 to 76% and varied by clinical diagnosis, being highest in patients with AD dementia. In discriminating Aβ + MCI and AD subjects from healthy controls and non-AD participants, FTP visual assessment was most sensitive (0.96) but least specific (0.60). Specificity was highest with FTP SUVR (0.91) with sensitivity of 0.89. Sensitivity (0.73) and specificity (0.72) were balanced for PTau181.

Conclusion: The choice of tau biomarker may differ by disease stage and research goals that seek to maximize sensitivity or specificity. Visual interpretations of tau PET enhance sensitivity compared to quantification alone, particularly in early disease stages.

Keywords: Alzheimer’s disease; Biomarkers; CSF; Flortaucipir; PET; Tau.

Fig. 1

Rating scheme for visual assessment of FTP pattern of binding to define T-status. Normal pattern of binding and non-AD-like pattern (for example, mild-to-moderate signal in the frontal white matter) were assigned T-status. Classic AD-like pattern following Braak and Braak distribution extending beyond the temporal lobes, and mild temporal binding (confluent binding restricted to the temporal lobes) were assigned T+ status

Fig. 2

Percentage of T+ by modality, clinical diagnosis, and amyloid status. CN, cognitively normal; MCI, mild cognitive impairment; AD_c, Alzheimer’s disease dementia; non-AD, non-AD disorders

Fig. 3

Examples of discordant T-status between FTP visual assessment, SUVR quantification, and CSF PTau181. Selected axial slices of FTP are shown. Amyloid status is based on PET. Clinical diagnosis is indicated in parentheses. bvFTD, behavioral variant frontotemporal dementia; CBS, corticobasal syndrome

Fig. 4

Inter-modality overall percent agreement between modalities by clinical diagnosis. CN, cognitively normal; MCI, mild cognitive impairment; AD_c, Alzheimer’s disease dementia; non-AD, non-AD disorders

Fig. 5

Scatterplot of CSF PTau181 and FTP SUVR values in T+ and T− patients by FTP visual assessment. Dotted lines show threshold of positivity for CSF PTau181 and FTP temporal meta-ROI SUVR. Insert in the top right corner shows percentage of T+ cases by visual assessment for each quadrant of the scatterplot