Neuropathologically validated MRI to tau PET synthesis via Covariate-modulated attention networks

Tau PET is a powerful tool to assess tau pathology in vivo; however, in comparison to MRI, its development is more recent, is rarely available at scale, and substantially more difficult to acquire. Here, we present Covariate-Modulated Attention UNet (CoMA-UNet) to synthesize subject-specific 3D tau PET from T1 MRI while incorporating in the synthesis procedure readily available covariates. Across six external validation datasets, CoMA-UNet reproduced regional patterns of tau PET uptake showing strong agreement with true PET that was generalizable across tracers. Next, we submitted the synthetic tau PET to a series of downstream clinically relevant tasks. First, MMSE associations between the synthetic tau PET were statistically indistinguishable from true PET. Second, the synthetic tau PET achieved out-of-sample diagnostic classification of dementia with an AUROC=0.99. Third, in two independent autopsy cohorts, voxel wise synthetic tau PET images closely followed neuropathologically defined Braak-stages. Fourth, when fine-tuned on a small subset of atypical presentations of AD, CoMA-UNet preserved phenotype-relevant tau topographies and recovered clinically meaningful structure across atypical clinical phenotypes. These findings demonstrate that the novel CoMA-UNet MRI-based synthesis augmented with covariate information can approximate tau PET with sufficient accuracy for downstream scientific and clinical applications.