Neurodegenerative diseases are a group of chronic, progressive disorders that are characterized by the gradual loss of neurons in various areas of the central nervous system. The onset and progression of neurodegeneration are closely linked to brain network degeneration via demyelination, axonal degeneration, and dendrite retraction. The pathophysiology is also characterized by “prion-like” abnormal protein aggregation and its propagation along neural connections. Connectomic analysis, the comprehensive mapping of neural connections within the brain, may thus provide novel ways to characterize neurodegenerative diseases. Here, we introduce the clinical application of connectomics in neurodegenerative diseases including Alzheimer’s and Parkinson’s.
What is a Connectome?
A connectome is a comprehensive map of neural connections within the brain1. Attempts to comprehensively map the connectome have been promoted by the notion that individual brain functions are not solely based on the properties of individual brain regions but rather on the interactions within networks. Elucidating the connectome of the human brain has become a new national project in the United States, Europe, Japan, and other countries.
The connectome can be examined at different scales that correspond with the various spatial resolutions used in brain imaging techniques2. The scales can be roughly categorized into the microscale, mesoscale, and macroscale2. The microscale (micrometer resolution) connectome corresponds with individual neurons and their synaptic connections; the mesoscale connectome corresponds with anatomically and/or functionally distinct populations of neurons (e.g., cortical columns) and their local circuits; and the macroscale (cubic centimeter or larger) corresponds with cortical areas and their white matter connections. Among these scales, researches at the macroscale are conducted for clarifying the relationships between the connectome and normal brain function or the pathophysiology of various brain diseases.
How do we measure a connectome?
Although various modalities can be used for evaluating the macroscale connectome, magnetic resonance imaging (MRI) is the most popular tool because of its safety, availability, and spatial resolution. Recent advances in MRI allow for in vivo imaging and quantification of both the structural and functional connections of the large-scale neural system across the entire brain. Macroscale connections can be evaluated by analyzing multi-modal MRI data (e.g., by measuring the correlations of time courses from functional MRI data), associations of brain morphometry can be obtained from structural MRI, and the properties of white matter tracts can be derived from diffusion MRI. In this lecturewe focus on diffusion MRI-based connectomics study.
How do we characterize a connectome?
The human connectome is a conceptually and mathematically complex object; thus, it is challenging to visually or intuitively understand the connectome. A formal description of a neural network is needed to characterize its local and global properties. A connectome can be expressed using graph theory as comprising a collection of nodes (i.e., brain regions) and edges (i.e., interactions between nodes)3. Using such descriptions, graph theory can provide metrics to characterize a network’s architecture. This lecture will briefly describe the representative graph theoretical measures to introduce to the clinical application of connectome analysis.
Clinical application of diffusion MRI-based connectomics in neurodegenerative diseases
Structural connectomics is already being applied to clarify the pathophysiology of neurodegenerative diseases4,5. Neurodegenerative diseases are a group of chronic, progressive disorders characterized by the gradual loss of neurons in various areas of the central nervous system. The onset and progression of neurodegeneration is closely linked to brain network degeneration via demyelination and axonal degeneration, secondary Wallerian degeneration, the loss of signaling, and axonal and dendrite retraction6. “Prion-like” abnormal protein aggregation and its propagation along neural connections also characterize this pathophysiology. The use of connectomics could thus provide new ways of characterizing neurodegenerative diseases. In this presentation, we introduce the clinical application of connectomics to study neurodegenerative diseases such as Alzheimer’s and Parkinson’s.