Characterizing the propagation pathway of neuropathological events of Alzheimer's disease using harmonic wavelet analysis.

Empirical imaging biomarkers such as the level of the regional pathological burden are widely used to measure the risk of developing neurodegenerative diseases such as Alzheimer's disease (AD). However, ample evidence shows that the brain network (wirings of white matter fibers) plays a vital role in the progression of AD, where neuropathological burdens often propagate across the brain network in a prion-like manner. In this context, characterizing the spreading pathway of AD-related neuropathological events sheds new light on understanding the heterogeneity of pathophysiological mechanisms in AD. In this work, we propose a manifold-based harmonic network analysis approach to explore a novel imaging biomarker in the form of the AD propagation pattern, which eventually allows us to identify the AD-related spreading pathways of neuropathological events throughout the brain. The backbone of this new imaging biomarker is a set of region-adaptive harmonic wavelets that represent the common network topology across individuals. We conceptualize that the individual's brain network and its associated pathology pattern form a unique system, which vibrates as do all natural objects in the universe. Thus, we can computationally excite such a brain system using selected harmonic wavelets that match the system's resonance frequency, where the resulting oscillatory wave manifests the system-level propagation pattern of neuropathological events across the brain network. We evaluate the statistical power of our harmonic network analysis approach on large-scale neuroimaging data from ADNI. Compared with the other empirical biomarkers, our harmonic wavelets not only yield a new imaging biomarker to potentially predict the cognitive decline in the early stage but also offer a new window to capture the in-vivo spreading pathways of neuropathological burden with a rigorous mathematics insight.