Propagation of Pathology through Brain Networks in Neurodegenerative Diseases: From Molecules to Clinical Phenotypes

Abstract

The cellular mechanisms underlying the stereotypical progression of pathology in neurodegenerative diseases are incompletely understood, but increasing evidence indicates that misfolded protein aggregates can spread by a self-perpetuating neuron-to-neuron transmission. Novel neuroimaging techniques can help elucidating how these disorders spread across brain networks. Recent knowledge from structural and functional connectivity studies suggests that the relation between neurodegenerative diseases and distinct brain networks is likely to be a strict consequence of diffuse network dynamics. Diffusion tensor magnetic resonance imaging also showed that measurement of white matter tract involvement can be a valid surrogate to assess the in vivo spreading of pathological proteins in these conditions. This review will introduce briefly the main molecular and pathological substrates of the most frequent neurodegenerative diseases and provide a comprehensive overview of neuroimaging findings that support the "network-based neurodegeneration" hypothesis in these disorders. Characterizing network breakdown in neurodegenerative diseases will help anticipate and perhaps prevent the devastating impact of these conditions.

The neuropathological signature of bulbar-onset ALS: A systematic review

“…Currently, the factors that govern dissemination of pathology between segregated regions of the brain are unknown. A predominant theory postulates that propagation occurs within neuronal networks that form functional and structural connectomes, along the axonal wiring structure of the brain (63–67). A recent large-scale brain connectivity study in ALS has shown that abnormal proteins propagate to anatomic regions that are more closely interconnected by WM tracts than regions that are proximally closer, but with lesser connectivity (67).…”

Prion‐like propagation as a pathogenic principle in frontotemporal dementia

“…; Agosta et al . ). For each disease type specific neural networks emerged with their critical center areas and functional and anatomical connectivity profiles resembling disease‐associated atrophy patterns.…”

Charting Frontotemporal Dementia: From Genes to Networks

“…Emerging structural and functional neuroimaging studies have implicated specific large‐scale brain networks in the pathogenesis of FTD syndromes (Fig ), suggesting a new paradigm for explaining the distributed and heterogeneous patterns of regional damage in FTLD . Following this paradigm, the macroscopic topography of network breakdown would direct the development of clinical symptoms.…”

“…By mapping the diffusion profile at each point in the brain, white matter pathways can be reconstructed by following the main diffusion direction between points. In FTLD, anatomical connections are suggested to be a conduit for the physical intra‐brain spreading of misfolded proteins . Although no consensus has been reached yet on the coupling between structural and functional network changes, functional connectivity has been shown to be constrained, to some extent, by structural connectivity (ie, the presence of a direct anatomical connection between two brain areas is associated with stronger functional interaction between these two areas) .…”

“…5 Emerging structural and functional neuroimaging studies have implicated specific large-scale brain networks in the pathogenesis of FTD syndromes (Fig 1), [6][7][8] suggesting a new paradigm for explaining the distributed and heterogeneous patterns of regional damage in FTLD. 9,10 Following this paradigm, the macroscopic topography of network breakdown would direct the development of clinical symptoms. In this review, we briefly summarize the main clinical and genetic features of the FTLD spectrum and report recent neuroimaging research on the study of FTD syndromes, including bvFTD, PPA variants and atypical parkinsonisms, as connectivity disorders.…”