Longitudinal Relationship Between Brain Atrophy Patterns, Cognitive Decline, and Cerebrospinal Fluid Biomarkers in Alzheimer's Disease Explored by Orthonormal Projective Non-Negative Matrix Factorization

Background: Longitudinal magnetic resonance imaging (MRI) has been proposed for tracking the progression of Alzheimer's disease (AD) through the assessment of brain atrophy. Objective: Detection of brain atrophy patterns in patients with AD as the longitudinal disease tracker. Methods: We used a refined version of orthonormal projective non-negative matrix factorization (OPNMF) to identify six distinct spatial components of voxel-wise volume loss in the brains of 83 subjects with AD from the ADNI3 cohort relative to healthy young controls from the ABIDE study. We extracted non-negative coefficients representing subjectspecific quantitative measures of regional atrophy. Coefficients of brain atrophy were compared to subjects with mild cognitive impairment and controls, to investigate the cross-sectional and longitudinal associations betweenADbiomarkers and regional atrophy severity in different groups. We further validated our results in an independent dataset from ADNI2. Results: The six non-overlapping atrophy components represent symmetric gray matter volume loss primarily in frontal, temporal, parietal and cerebellar regions. Atrophy in these regionswas highly correlated with cognition both cross-sectionally and longitudinally, with medial temporal atrophy showing the strongest correlations. Subjects with elevated CSF levels of TAU and PTAU and lower baseline CSF A beta(42) values, demonstrated a tendency toward a more rapid increase of atrophy. Conclusions: The present study has applied a transferable method to characterize the imaging changes associated with AD through six spatially distinct atrophy components and correlated these atrophy patterns with cognitive changes and CSF biomarkers cross-sectionally and longitudinally, which may help us better understand the underlying pathology of AD.