RESEARCH ARTICLE Directed Network Motifs in Alzheimer’s Disease and Mild Cognitive Impairment

Directed network motifs are the building blocks of complex networks, such as human brain networks, and capture deep connectivity information that is not contained in standard net-work measures. In this paper we present the first application of directed network motifs in vivo to human brain networks, utilizing recently developed directed progression networks which are built upon rates of cortical thickness changes between brain regions. This is in contrast to previous studies which have relied on simulations and in vitro analysis of non-human brains. We show that frequencies of specific directed network motifs can be used to distinguish between patients with Alzheimer’s disease (AD) and normal control (NC) sub-jects. Especially interesting from a clinical standpoint, these motif frequencies can also dis-tinguish between subjects with mild cognitive impairment who remained stable over three years (MCI) and those who converted to AD (CONV). Furthermore, we find that the entropy of the distribution of directed network motifs increased from MCI to CONV to AD, implying that the distribution of pathology is more structured in MCI but becomes less so as it pro-gresses to CONV and further to AD. Thus, directed network motifs frequencies and distribu-tional properties provide new insights into the progression of Alzheimer’s disease as well as new imaging markers for distinguishing between normal controls, stable mild cognitive im-pairment, MCI converters and Alzheimer’s disease