Local vulnerability and global connectivity jointly shape neurodegenerative disease propagation

Abstract

It is becoming increasingly clear that brain network organization shapes the course and expression of neurodegenerative diseases. Parkinson's disease (PD) is marked by progressive spread of atrophy from the midbrain to subcortical structures and eventually, to the cerebral cortex. Recent discoveries suggest that the neurodegenerative process involves the misfolding and prion-like propagation of endogenous α-synuclein via axonal projections. However, the mechanisms that translate local "synucleinopathy" to large-scale network dysfunction and atrophy remain unknown. Here we use an agent-based epidemic spreading model to integrate structural connectivity, functional connectivity and gene expression, and to predict sequential volume loss due to neurodegeneration. The dynamic model replicates the spatial and temporal patterning of empirical atrophy in PD and implicates the substantia nigra as the disease epicenter. We reveal a significant role for both connectome topology and geometry in shaping the distribution of atrophy. The model also demonstrates that SNCA and GBA transcription influence α-synuclein concentration and local regional vulnerability. Functional co-activation further amplifies the course set by connectome architecture and gene expression. Altogether, these results support the theory that the progression of PD is a multifactorial process that depends on both cell-to-cell spreading of misfolded proteins and regional vulnerability.Neurodegenerative diseases such as Alzheimer's Disease (AD), Parkinson's Disease (PD), 2 and Amyotrophic Lateral Sclerosis, are a major cause of psychosocial burden and 3 mortality, but lack specific therapy. Until recently, the mechanism of progressive 4 neuronal death in these conditions was unknown. However, converging lines of evidence 5 from molecular, animal and human postmortem studies point to misfolded neurotoxic 6 proteins that propagate through the central nervous system via neuronal 7 connections [1-6]. These pathogenic misfolded disease-specific proteins function as 8 corruptive templates that induce their normal protein counterparts to adopt a similar 9 conformational alteration, analogous to the self-replication process in prion diseases. 10Examples include amyloid β-protein (Aβ) and tau in AD and α-synuclein in PD. The 11 November 1, 2019 1/26 misfolded proteins can deposit into insoluble aggregates and progressively spread to 12 interconnected neuronal populations through synaptic connections. The model of a 13propagating proteinopathy remains controversial however [7], and direct evidence in 14 humans remains mostly circumstantial [8]. 15The prion hypothesis suggests that propagation dynamics in neurodegenerative 16 diseases may be modeled using methods derived from infectious disease epidemiology. 17Just as infectious diseases spread via social contact networks, misfolded proteins 18 propagate via the brain's connectome. There are different approaches for modeling 19 epidemic spread over a network. In simple diffusion models, disease in any region is 20 model...

Topographic gradients of intrinsic dynamics across neocortex

“…More generally, the present findings are part of a larger trend in the field to understand structure-function relationships by considering molecular [4,28,77,107], cellular [3,70,81,83] and physiological [25,82] attributes of network nodes, thereby conceptually linking local and global brain organization [55,89]. In such "annotated networks", macroscale network architecture is thought to reflect similarity in local properties, and vice versa, such that areas with similar properties are more likely to be anatomically connected and to functionally interact with one another [11,42,46,104].…”

Spatial Patterning of Tissue Volume Loss in Schizophrenia Reflects Brain Network Architecture

“…In neurodegenerative diseases, transneuronal transport of toxic misfolded proteins is associated with cell death and atrophy (6,63,64). As a result, patterns of atrophy in neurodegenerative diseases often resemble structural and functional network patterns (65), a result that has been reported in Alzheimer's disease (8,66,67), Parkinson's disease (9,10,68), and amyotrophic lateral sclerosis (69).…”

A meta-analytic approach to mapping co-occurrent grey matter volume increases and decreases in psychiatric disorders

“…By far, most work in this area has focused on understanding GM volume reductions in clinical disease. Not only have several meta-analyses of different diseases shown that such reductions are common (Fornito et al, 2009;Bora et al, 2010Bora et al, , 2011Bora et al, , 2012aFusar-Poli et al, 2011;Hallahan et al, 2011;Linkersdörfer et al, 2012;Du et al, 2012;Li et al, 2014Li et al, , 2018Stoodley, 2014;Cauda et al, 2014;Foster et al, 2015;Lin et al, 2016;Wise et al, 2017;Wu et al, 2018), and other work suggests that anatomically distributed yet coordinated GM reductions are tied to the underlying connectivity between regions (Seeley et al, 2009;Raj et al, 2012;Zhou et al, 2012;Crossley et al, 2014;Iturria-Medina et al, 2014;Zeighami et al, 2015, Cauda et al, 2018aYau et al, 2018;Zheng et al, 2019). In contrast, GM increases are less commonly considered in clinical neuroimaging studies (Cauda et al, 2011(Cauda et al, , 2017(Cauda et al, , 2018bTatu et al, 2018, Cauda et al, 2019bDing et al, 2019;Lu et al, 2019), potentially because they might be a rarer consequence of disease and because they can be difficult to explain in the context of pathology.…”