Decomposing the effect of normal aging and Alzheimer's disease in brain morphological changes via learned aging templates

Alzheimer's disease (AD) subjects usually show more profound morphological changes with time compared to cognitively normal (CN) individuals. These changes are the combination of two major biological processes: normal aging and AD pathology. Investigating normal aging and residual morphological changes separately can increase our understanding of the disease. This paper proposes two scores, the aging score (AS) and the AD-specific score (ADS), whose purpose is to measure these two components of brain atrophy independently. For this, in the first step, we estimate the atrophy due to the normal aging of CN subjects by computing the expected deformation required to match imaging templates generated at different ages. We used a state-of-the-art generative deep learning model for generating such imaging templates. In the second step, we apply deep learning-based diffeomorphic registration to align the given image of a subject with a reference imaging template. Parametrization of this deformation field is then decomposed voxel-wise into their parallel and perpendicular components with respect to the parametrization of the expected atrophy of CN individuals in one year computed in the first step. AS and ADS are the normalized scores of these two components, respectively. We evaluated these two scores on the OASIS-3 dataset with 1,014 T1-weighted MRI scans. Of these, 326 scans were from CN subjects, and 688 scans were from subjects diagnosed with AD at various stages of clinical severity, as defined by clinical dementia rating (CDR) scores. Our results reveal that AD is marked by both disease-specific brain changes and an accelerated aging process. Such changes affect brain regions differently. Moreover, the proposed scores were sensitive to detect changes in the early stages of the disease, which is promising for its potential future use in clinical studies. Our code is freely available at https://github.com/Fjr9516/DBM_with_DL.