Evaluation of novel data-driven metrics of amyloid deposition for longitudinal PET studies

Purpose: Positron emission tomography (PET) provides in vivo quantification of amyloid-beta (A beta) pathology. Established methods for assessing A beta burden can be affected by physiological and technical factors. Novel, data-driven metrics have been developed to account for these sources of variability. We aimed to evaluate the per-formance of four of these amyloid PET metrics against conventional techniques, using a common set of criteria.Methods: Three cohorts were used for evaluation: Insight 46 (N=464, [18F]florbetapir), AIBL (N=277, [18F] flutemetamol), and an independent test-retest data (N=10, [18F]flutemetamol). Established metrics of amyloid tracer uptake included the Centiloid (CL) and where dynamic data was available, the non-displaceable binding potential (BPND). The four data-driven metrics computed were the amyloid load (A beta load), the A beta-PET pathology accumulation index (A beta index), the Centiloid derived from non-negative matrix factorisation (CLNMF), and the amyloid pattern similarity score (AMPSS). These metrics were evaluated using reliability and repeatability in test-retest data, associations with BPND and CL, variability of the rate of change and sample size estimates to detect a 25% slowing in A beta accumulation.Results: All metrics showed good reliability. A beta load, A beta index and CLNMF were strong associated with the BPND. The associations with CL suggest that cross-sectional measures of CLNMF, A beta index and A beta load are robust across studies. Sample size estimates for secondary prevention trial scenarios were the lowest for CLNMF and A beta load compared to the CL.Conclusion: Among the novel data-driven metrics evaluated, the A beta load, the A beta index and the CLNMF can provide comparable performance to more established quantification methods of A beta PET tracer uptake. The CLNMF and A beta load could offer a more precise alternative to CL, although further studies in larger cohorts should be conducted.