Visualizing modules of coordinated structural brain atrophy during the course of conversion to Alzheimer's disease by applying methodology from gene co-expression analysis

Kenichiro Sato; Tatsuo Mano; Hiroshi Matsuda; Michio Senda; Ryoko Ihara; Kazushi Suzuki; Hiroyuki Arai; Kenji Ishii; Kengo Ito; Takeshi Ikeuchi; Ryozo Kuwano; Tatsushi Toda; Takeshi Iwatsubo; Atsushi Iwata; Japanese Alzheimer's Disease Neuroimaging Initiative

doi:10.1016/j.nicl.2019.101957

Visualizing modules of coordinated structural brain atrophy during the course of conversion to Alzheimer's disease by applying methodology from gene co-expression analysis

Neuroimage Clin. 2019:24:101957. doi: 10.1016/j.nicl.2019.101957. Epub 2019 Jul 25.

Authors

Affiliations

¹ Department of Neurology, Graduate School of Medicine, University of Tokyo, Japan. Electronic address: kenisatou-tky@umin.ac.jp.
² Department of Neurology, Graduate School of Medicine, University of Tokyo, Japan.
³ National Center for Neurology and Psychiatry, Kodaira, Japan.
⁴ Kobe City Medical Center General Hospital, Kobe, Japan.
⁵ Department of Neurology, Graduate School of Medicine, University of Tokyo, Japan; Unit for Early and Exploratory Clinical Development, The University of Tokyo Hospital, Tokyo, Japan.
⁶ Department of Geriatrics & Gerontology, Division of Brain Science, Institute of Development, Aging and Cancer (IDAC), Tohoku University, Japan.
⁷ Tokyo Metropolitan Institute of Gerontology, Tokyo, Japan.
⁸ National Center for Geriatrics and Gerontology, Obu, Japan.
⁹ Niigata University, Niigata, Japan.
¹⁰ Unit for Early and Exploratory Clinical Development, The University of Tokyo Hospital, Tokyo, Japan; Department of Neuropathology, Graduate School of Medicine, University of Tokyo, Japan.
¹¹ Department of Neurology, Graduate School of Medicine, University of Tokyo, Japan. Electronic address: iwata@m.u-tokyo.ac.jp.

Abstract

Objective: We aimed to identify modularized structural atrophy of brain regions with a high degree of connectivity and its longitudinal changes associated with the progression of Alzheimer's disease (AD) using weighted gene co-expression network analysis (WGCNA), which is an unsupervised hierarchical clustering method originally used in genetic analysis.

Methods: We included participants with late mild cognitive impairment (MCI) at baseline from the Japanese Alzheimer's Disease Neuroimaging Initiative (J-ADNI) study. We imputed normalized and Z-transformed structural volume or cortical thickness data of 164 parcellated brain regions/structures based on the calculations of the FreeSurfer software. We applied the WGCNA to extract modules with highly interconnected structural atrophic patterns and examined the correlation between the identified modules and clinical AD progression.

Results: We included 204 participants from the baseline dataset, and performed a follow-up with 100 in the 36-month dataset of MCI cohort participants from the J-ADNI. In the univariate correlation or variable importance analysis, baseline atrophy in temporal lobe regions/structures significantly predicted clinical AD progression. In the WGCNA consensus analysis, co-atrophy modules associated with MCI conversion were first distributed in the temporal lobe and subsequently extended to adjacent parietal cortical regions in the following 36 months.

Conclusions: We identified coordinated modules of brain atrophy and demonstrated their longitudinal extension along with the clinical course of AD progression using WGCNA, which showed a good correspondence with previous pathological studies of the tau propagation theory. Our results suggest the potential applicability of this methodology, originating from genetic analyses, for the surrogate visualization of the underlying pathological progression in neurodegenerative diseases not limited to AD.

Keywords: Alzheimer's disease module; Brain atrophy; Connectivity; Hierarchical clustering; Mild cognitive impairment.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Aged
Alzheimer Disease / genetics
Alzheimer Disease / pathology*
Atrophy / genetics
Atrophy / pathology
Brain / pathology*
Cognitive Dysfunction / genetics
Cognitive Dysfunction / pathology*
Connectome / methods*
Disease Progression
Female
Follow-Up Studies
Gene Expression Profiling / methods*
Gene Regulatory Networks
Humans
Image Interpretation, Computer-Assisted / methods
Longitudinal Studies
Male
Middle Aged