Mapping Neurodegenerative Disease Onset and Progression

Abstract

Brain networks have been of long-standing interest to neurodegeneration researchers, including but not limited to investigators focusing on conventional prion diseases, which are known to propagate along neural pathways. Tools for human network mapping, however, remained inadequate, limiting our understanding of human brain network architecture and preventing clinical research applications. Until recently, neuropathological studies were the only viable approach to mapping disease onset and progression in humans but required large autopsy cohorts and laborious methods for whole-brain sectioning and staining. Despite important advantages, postmortem studies cannot address in vivo, physiological, or longitudinal questions and have limited potential to explore early-stage disease except for the most common disorders. Emerging in vivo network-based neuroimaging strategies have begun to address these issues, providing data that complement the neuropathological tradition. Overall, findings to date highlight several fundamental principles of neurodegenerative disease anatomy and pathogenesis, as well as some enduring mysteries. These principles and mysteries provide a road map for future research.

Figure 1.

Neurodegenerative syndromes reflect degeneration within large-scale networks. (A) Five clinical neurodegeneration syndromes showed distinct atrophy patterns, with atrophy maxima highlighted with white circles. Regions circled in A were used as seed regions of interest (ROIs) for task-free functional magnetic resonance imaging (fMRI) analysis (B) and structural covariance mapping (C) in healthy controls. Both approaches showed that the connectivity of the healthy brain mirrored the five atrophy patterns. These data showed that each syndrome was anatomically linked to a specific large-scale network that could be detailed in the healthy brain with connectivity-based methods. (Reproduced, with permission, from Seeley 2016, © 2016 Oxford University Press; www.oup.com.)

Figure 2.

Neurodegenerative disease onset and progression. What is the relationship between disease onset and progression? After a first locus of onset, progression to other regions could involve (1) connectivity-based spread alone, (2) secondary sites of onset within or outside the target network, or (3) a combination of these models. (Reproduced, with permission, from Seeley 2016, © 2016 Oxford University Press; www.oup.com.)

Figure 3.

Clinicoanatomical convergence may occur at the neuronal, nodal, or network levels. Diseases that cause each syndrome may converge at multiple levels to create the syndrome. Convergence at the level of specific neuronal types (not shown) or even specific network nodes (left) would be expected to create nearly identical patterns of network impairment. Alternatively, convergence could occur at the level of the overall network (right), with each disease targeting different nodes but, nonetheless, manifesting as the same (or nearly the same) syndrome. Circles represent network nodes (brain regions), lines represent edges (connections between two nodes), and shorter edges indicate tighter connections between node pairs. Color shading indicates the severity of predicted regional impairment based on the onset nodes (“epicenters”) indicated by arrows. (Reproduced, with permission, from Seeley 2016, © 2016 Oxford University Press; www.oup.com.)

Figure 4.

Phenotypic diversity suggests that most diseases can produce multiple clinical syndromes, reflecting a small portfolio of candidate onset regions (“epicenters,” E). The heterogeneity of clinical manifestations for each disease is illustrated here at the network level, where onset within epicenters (E¹, E², or E³) that anchor distinct networks gives rise to three different clinicoanatomical presentations. Network depictions follow Figure 3.