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.

Contributions of connectional pathways to shaping Alzheimer’s disease pathologies

“…1B for the structural and functional connectomes. In agreement with studies of the structural network diffusion model, we found that the diffusion clusters of our structural connectome captured left–right gradients 78 , 79 and that the diffusion mode showed strong involvement of medial and lateral temporal lobes 7 ( Fig. 1B , left).…”

Contributions of connectional pathways to shaping Alzheimer’s disease pathologies

“…1B for the structural and functional connectomes. In agreement with studies of the structural network diffusion model, we found that the diffusion clusters of our structural connectome captured left–right gradients 78 , 79 and that the diffusion mode showed strong involvement of medial and lateral temporal lobes 7 ( Fig. 1B , left).…”

Connectome architecture for gray matter atrophy and surgical outcomes in temporal lobe epilepsy

“…Our group-level modeling identified ipsilateral hippocampus and its adjacent temporo-limbic regions as the primary sources of GMV changes in patients with TLE. This finding is consistent with a previous study 18 and aligns with our network-based diffusion model, 33 which simulates the dynamic process of spatiotemporal pathological propagation from an initial seed to connected regions. The mesial temporal structures, especially the hippocampus, play a key role in the generation and propagation of epileptic activities.…”

Individual brain metabolic connectome indicator based on Kullback-Leibler Divergence Similarity Estimation predicts progression from mild cognitive impairment to Alzheimer’s dementia

“…Network properties in metabolic connectivity in precuneus, middle frontal region, and temporal pole appeared to change progressively in our cross-sectional comparison of HC, sMCI, pMCI, and AD groups. The results are in accord with previous MRI studies showing analogous network changes in MCI conversion [27,28].…”

Contributions of connectional pathways to shaping Alzheimer’s disease pathologies

“…1B for the structural and functional connectomes. In agreement with studies of the structural network diffusion model, we found that the diffusion clusters of our structural connectome captured left–right gradients 78 , 79 and that the diffusion mode showed strong involvement of medial and lateral temporal lobes 7 ( Fig. 1B , left).…”

Connectome architecture for gray matter atrophy and surgical outcomes in temporal lobe epilepsy

“…Our group-level modeling identified ipsilateral hippocampus and its adjacent temporo-limbic regions as the primary sources of GMV changes in patients with TLE. This finding is consistent with a previous study 18 and aligns with our network-based diffusion model, 33 which simulates the dynamic process of spatiotemporal pathological propagation from an initial seed to connected regions. The mesial temporal structures, especially the hippocampus, play a key role in the generation and propagation of epileptic activities.…”

Individual brain metabolic connectome indicator based on Kullback-Leibler Divergence Similarity Estimation predicts progression from mild cognitive impairment to Alzheimer’s dementia

“…Network properties in metabolic connectivity in precuneus, middle frontal region, and temporal pole appeared to change progressively in our cross-sectional comparison of HC, sMCI, pMCI, and AD groups. The results are in accord with previous MRI studies showing analogous network changes in MCI conversion [27,28].…”

Contributions of connectional pathways to shaping Alzheimer’s disease pathologies

“…1B for the structural and functional connectomes. In agreement with studies of the structural network diffusion model, we found that the diffusion clusters of our structural connectome captured left–right gradients 78 , 79 and that the diffusion mode showed strong involvement of medial and lateral temporal lobes 7 ( Fig. 1B , left).…”

Connectome architecture for gray matter atrophy and surgical outcomes in temporal lobe epilepsy

“…Our group-level modeling identified ipsilateral hippocampus and its adjacent temporo-limbic regions as the primary sources of GMV changes in patients with TLE. This finding is consistent with a previous study 18 and aligns with our network-based diffusion model, 33 which simulates the dynamic process of spatiotemporal pathological propagation from an initial seed to connected regions. The mesial temporal structures, especially the hippocampus, play a key role in the generation and propagation of epileptic activities.…”

Individual brain metabolic connectome indicator based on Kullback-Leibler Divergence Similarity Estimation predicts progression from mild cognitive impairment to Alzheimer’s dementia

“…Network properties in metabolic connectivity in precuneus, middle frontal region, and temporal pole appeared to change progressively in our cross-sectional comparison of HC, sMCI, pMCI, and AD groups. The results are in accord with previous MRI studies showing analogous network changes in MCI conversion [27,28].…”