Alzheimer's Imaging Consortium

Background: Florzolotau (APN-1607) tau-PET has shown distinct patterns of binding in patients with AD and 4-repeat tauopathies. We aimed to establish disease-specific tau covariance patterns in AD and PSP/CBS and validate them as user-independent quantitative biomarkers for reference-region-free evaluation of tau-PET in an independent clinical cohort.

Method: We analyzed Florzolotau PET data from four different cohorts. The derivation dataset included 30 Aß- healthy controls (HC) and 30 patients each with Aß+ AD and PSP with Richardson's syndrome (PSP-RS). The validation dataset included 44, 51, 6, 15, and 17 patients with AD, PSP/CBS, MSA, LBD, and FTD, respectively. First, we applied scaled sub-profile modelling principal components analysis to the derivation dataset to define the AD- and PSP-RS-related covariance patterns. Second, the topographic profile rating algorithm was applied to each scan to calculate AD- and PSP-RS-related pattern scores.

Result: The AD- and PSP-RS-related patterns are described in Figures 1 and 2. In the derivation dataset, the AD- and PSP-RS-scores showed strong increases compared to HC (both p<0.001,AUC-ROC = 0.994 and 0.898, respectively). AD-scores showed a significant negative association with age (r = -0.66,p<0.001) and MMSE (r = -0.64,p<0.001) in AD, while PSP-RS-scores correlated with the PSP rating scale (r = 0.43,p = 0.018) in PSP-RS. In the validation dataset (Figure 3), AD-scores were highest in AD (p<0.001 vs. all other, AUC-ROC[AD vs. all other] = 0.946) and were negatively associated with age and MMSE in AD (r = -0.62,p<0.001 and r = -0.49,p = 0.002, respectively). PSP-RS-scores were highest in the PSP/CBS (p<0.001 vs. all other [at least p<0.05 vs. each group], AUC-ROC[PSP/CBS vs. all other] = 0.734), though also relatively increased in FTD and MSA. UPDRS-III scores (off-state) were available in 23 PSP/CBS patients and significantly associated with PSP-RS-scores (r = 0.60,p = 0.002).

Conclusion: Modelling with principal components analysis allows for reference-region-free quantification of tau imaging data by constructing disease-specific covariance patterns. When applied to Florzolotau, AD- and PSP-RS-related patterns showed high discrimination power in both the derivation and the clinically heterogeneous validation cohorts. PSP-RS-related pattern expression in FTD and MSA may be related to PSP pathology and known striatal off-target binding, respectively. Strong association with respective disease severity scores further advocates for use of AD- and PSP-RS-related patterns as potential quantitative biomarkers of tau pathology.