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  • Review Article
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Spreading of pathology in neurodegenerative diseases: a focus on human studies

Key Points

  • Many neurodegenerative diseases share a common pathological hallmark: the accumulation of characteristic proteins into insoluble aggregates in vulnerable neurons and glial cells.

  • Converging lines of evidence from cell culture studies and animal models indicate that progression of these diseases is driven by the template-directed misfolding, seeded aggregation and cell-to-cell transmission of characteristic disease-related proteins.

  • Although such mechanisms of propagation are similar to prions, important differences to prions exists, namely the lack of inter-individual infectivity and the lack of zoonoses.

  • Neuropathological studies in humans identified stereotypical patterns of pathology in various neurodegenerative diseases, and progression of these patterns can be correlated with increasing severity of the clinical phenotype, enabling the development of staging systems for these diseases.

  • Human tissue pathology-staging studies are limited by the relative lack of early (prodromal) cases and by the fact that the resulting neuropathological data are, by definition, cross-sectional.

  • Imaging biomarkers specific to the different disease proteins are necessary to validate the sequential involvement of different CNS regions proposed by human autopsy studies. Currently, the most promising markers are positron emission tomography ligands that should enable the in vivo detection and monitoring of the spread of protein pathology in longitudinal studies.

Abstract

The progression of many neurodegenerative diseases is thought to be driven by the template-directed misfolding, seeded aggregation and cell–cell transmission of characteristic disease-related proteins, leading to the sequential dissemination of pathological protein aggregates. Recent evidence strongly suggests that the anatomical connections made by neurons — in addition to the intrinsic characteristics of neurons, such as morphology and gene expression profile — determine whether they are vulnerable to degeneration in these disorders. Notably, this common pathogenic principle opens up opportunities for pursuing novel targets for therapeutic interventions for these neurodegenerative disorders. We review recent evidence that supports the notion of neuron–neuron protein propagation, with a focus on neuropathological and positron emission tomography imaging studies in humans.

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Figure 1: Hypothetical molecular mechanisms of prion-like disease protein transmission in neurodegenerative diseases.
Figure 2: Sequential topographical dissemination of non-prion proteins in neurodegenerative diseases.

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Acknowledgements

The authors thank H. Braak for reviewing the manuscript and M. Leonhard for help with designing the figures.

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Glossary

Sequential spreading

The staged spatial dissemination of intracellular or extracellular protein aggregate pathology in neurodegenerative diseases.

Skein-like inclusions

Elongated filamentous intraneuronal inclusions of neurodegenerative disease proteins.

Cross-seeding

A process whereby seeds of one pathological protein cause the aggregation of another protein.

Exosomes

Cell-derived vesicles that are released from the plasma membrane and could thus constitute a mechanism of disease-protein release in neurodegenerative diseases.

Chronic traumatic encephalopathy

A form of neurodegeneration that occurs in individuals who have sustained multiple concussions or injuries to the brain.

Rigidity

Stiffness and resistance to limb movement due to increased muscle tone. It is a key clinical symptom of Parkinson disease and can be uniform (known as lead-pipe rigidity) or ratchety (known as cogwheel rigidity).

Hyposmia

A reduced ability to smell and detect odours. This deficit can be due to any of a wide range of causes, including neurodegenerative diseases such as Parkinson disease or Alzheimer disease.

Dual-hit theory

The proposal that α-synuclein pathology in Parkinson disease starts in two different locations: the lower brainstem (dorsal motor nucleus of the vagus nerve) and the olfactory bulb.

Pretangles

Early intracellular aggregates of hyperphosphorylated tau protein that develop into filamentous neurofibrillary tangles.

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Brettschneider, J., Tredici, K., Lee, VY. et al. Spreading of pathology in neurodegenerative diseases: a focus on human studies. Nat Rev Neurosci 16, 109–120 (2015). https://doi.org/10.1038/nrn3887

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