A Network Diffusion Model of Disease Progression in Dementia

Abstract

SUMMARY Patterns of dementia are known to fall into dissociated but dispersed brain networks, suggesting that the disease is transmitted along neuronal pathways rather than by proximity. This view is supported by neuropathological evidence for “prion-like” transsynaptic transmission of disease agents like misfolded tau and beta amyloid. We mathematically model this transmission by a diffusive mechanism mediated by the brain’s connectivity network obtained from tractography of 14 healthy-brain MRIs. Subsequent graph theoretic analysis provides a fully quantitative, testable, predictive model of dementia. Specifically, we predict spatially distinct “persistent modes,” which, we found, recapitulate known patterns of dementia and match recent reports of selectively vulnerable dissociated brain networks. Model predictions also closely match T1-weighted MRI volumetrics of 18 Alzheimer’s and 18 frontotemporal dementia subjects. Prevalence rates predicted by the model strongly agree with published data. This work has many important implications, including dimensionality reduction, differential diagnosis, and especially prediction of future atrophy using baseline MRI morphometrics.

A common brain network links development, aging, and vulnerability to disease

“…Deviations from normal trajectories of brain maturation have been identified in developmental disorders (38,48), while some neurodegenerative disorders seem to progress within specific healthy brain networks (23,49). One recent study has also shown that data-driven decomposition of white matter tractograms in healthy young subjects recapitulates the pattern of abnormalities in dementia (50). Here, we show how the symmetric inverted-U component, while derived without any prior hypothesis from healthy subjects' brain structure, (i) spatially recapitulates the structural vulnerability of two etiologically distinct disorders emerging at opposite ends of the life spectrum (schizophrenia-aptly named "dementia praecox" until the mid1950s-and Alzheimer's disease), (ii) accurately discriminates these two disorders from their matched healthy group, and (iii) is associated, in this large-scale lifespan healthy population, with cognitive functions whose impairment are key symptoms of schizophrenia and Alzheimer's disease.…”

Proteopathic tau seeding predicts tauopathy in vivo

“…These disorders feature the accumulation of fibrillar deposits of the microtubule-associated protein tau with progressive deterioration of the central nervous system. Tau pathology and its associated brain atrophy do not appear randomly throughout the brain, but rather progress along distinct neural networks (1)(2)(3)(4)(5). This aspect suggests a role for transcellular spread of a pathogenic agent via neural connections.…”

Transcellular spreading of huntingtin aggregates in theDrosophilabrain

“…Lesions in each of these diseases are initially limited to defined regions of selectively vulnerable neurons, but staging of pathology in Alzheimer's disease (1), Parkinson's disease (2,3), amyotropic lateral sclerosis (4,5), and Huntington's disease (HD) (6) reveal broader deposition of pathological aggregates at more advanced stages of disease progression. The observation that the pathology appeared to progress into regions that were synaptically connected led to the idea that pathology was spreading through neuronal circuits (7,8). Converging lines of evidence demonstrated that aggregates of diseaseassociated misfolded proteins, including α-synuclein, tau, and superoxide dismutase 1, are in fact transmissible from cell to cell and that this transmission propagates throughout the brain (9,10).…”