Computational modeling of tau pathology spread reveals patterns of regional vulnerability and the impact of a genetic risk factor

Cornblath, Eli J.; Li, Howard L.; Changolkar, Lakshmi; Zhang, Bin; Brown, Hannah J.; Gathagan, Ronald J.; Olufemi, Modupe F.; Trojanowski, John Q.; Bassett, Danielle S.; Lee, Virginia M.‐Y.; Henderson, Michael X.

doi:10.1126/sciadv.abg6677

Cited by 38 publications

(49 citation statements)

References 61 publications

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“…This suggests a network-spreading phenomenon where focal pathology or perturbation propagates to connected regions, resulting in cortical abnormality that is correlated with the underlying connection patterns 14 . This interaction between local vulnerability and connectomic vulnerability has previously been reported in neurodegenerative syndromes where the trans-synaptic spreading of misfolded proteins appears to be guided and amplified by local gene expression 10,[71][72][73][74] . In other words, the poorer performance of connectivity predictors does not suggest that the white-matter architecture is less relevant to disease progression.…”

Section: Discussionsupporting

confidence: 60%

Local molecular and global connectomic contributions to cross-disorder cortical abnormalities

et al. 2022

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Numerous brain disorders demonstrate structural brain abnormalities, which are thought to arise from molecular perturbations or connectome miswiring. The unique and shared contributions of these molecular and connectomic vulnerabilities to brain disorders remain unknown, and has yet to be studied in a single multi-disorder framework. Using MRI morphometry from the ENIGMA consortium, we construct maps of cortical abnormalities for thirteen neurodevelopmental, neurological, and psychiatric disorders from N = 21,000 participants and N = 26,000 controls, collected using a harmonised processing protocol. We systematically compare cortical maps to multiple micro-architectural measures, including gene expression, neurotransmitter density, metabolism, and myelination (molecular vulnerability), as well as global connectomic measures including number of connections, centrality, and connection diversity (connectomic vulnerability). We find a relationship between molecular vulnerability and white-matter architecture that drives cortical disorder profiles. Local attributes, particularly neurotransmitter receptor profiles, constitute the best predictors of both disorder-specific cortical morphology and cross-disorder similarity. Finally, we find that cross-disorder abnormalities are consistently subtended by a small subset of network epicentres in bilateral sensory-motor, inferior temporal lobe, precuneus, and superior parietal cortex. Collectively, our results highlight how local molecular attributes and global connectivity jointly shape cross-disorder cortical abnormalities.

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Section: Discussionsupporting

confidence: 60%

Local molecular and global connectomic contributions to cross-disorder cortical abnormalities

et al. 2022

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“…Since these initial studies in non-transgenic mice, work has continued aiming to further characterise the patterns of spread. Recently, Cornblath and colleagues injected tau from AD brains into the brains of non-transgenic mice, and showed with network modelling analysis that diffusion through the connectome is the best predictor for tau pathology pattern, corroborating previous findings from others in the field [ 108 ]. This study also showed that retrograde, rather than anterograde spread, seems to dominate the spread of tau in the mouse brain [ 108 ].…”

Section: Tausupporting

confidence: 66%

Propagation of tau and α-synuclein in the brain: therapeutic potential of the glymphatic system

Lopes

Llewellyn

Harrison

2022

Transl Neurodegener

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Many neurodegenerative diseases, including Alzheimer’s disease and Parkinson’s disease, are characterised by the accumulation of misfolded protein deposits in the brain, leading to a progressive destabilisation of the neuronal network and neuronal death. Among the proteins that can abnormally accumulate are tau and α-synuclein, which can propagate in a prion-like manner and which upon aggregation, represent the most common intracellular proteinaceous lesions associated with neurodegeneration. For years it was thought that these intracellular proteins and their accumulation had no immediate relationship with extracellular homeostasis pathways such as the glymphatic clearance system; however, mounting evidence has now suggested that this is not the case. The involvement of the glymphatic system in neurodegenerative disease is yet to be fully defined; however, it is becoming increasingly clear that this pathway contributes to parenchymal solute clearance. Importantly, recent data show that proteins prone to intracellular accumulation are subject to glymphatic clearance, suggesting that this system plays a key role in many neurological disorders. In this review, we provide a background on the biology of tau and α-synuclein and discuss the latest findings on the cell-to-cell propagation mechanisms of these proteins. Importantly, we discuss recent data demonstrating that manipulation of the glymphatic system may have the potential to alleviate and reduce pathogenic accumulation of propagation-prone intracellular cytotoxic proteins. Furthermore, we will allude to the latest potential therapeutic opportunities targeting the glymphatic system that might have an impact as disease modifiers in neurodegenerative diseases.

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“…For example, it has been recently shown that the tau accumulation rate in animal models is more related to local amplification than seed spreading ( 22 ). In this sense, several studies have suggested a specific cellular/molecular vulnerability driving (or modulating) the downstream neurodegeneration (and tau spreading) process ( 13 , 23 , 24 ). However, most studies have only assessed whether local regional vulnerability, such as the study of the cellular composition, genetic, and molecular environment for a specific region, present such selectivity to accumulate tau.…”

Section: Discussionmentioning

confidence: 99%

Network Tau spreading is vulnerable to the expression gradients of APOE and glutamatergic-related genes

et al. 2022

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A key hallmark of Alzheimer’s disease (AD) pathology is the intracellular accumulation of tau protein in the form of neurofibrillary tangles across large-scale networks of the human brain cortex. Currently, it is still unclear how tau accumulates within specific cortical systems and whether in situ genetic traits play a role in this circuit-based propagation progression. In this study, using two independent cohorts of cognitively normal older participants, we reveal the brain network foundation of tau spreading and its association with using high-resolution transcriptomic genetic data. We observed that specific connectomic and genetic gradients exist along the tau spreading network. In particular, we identified 577 genes whose expression is associated with the spatial spreading of tau. Within this set of genes, APOE and glutamatergic synaptic genes, such as SLC1A2 , play a central role. Thus, our study characterizes neurogenetic topological vulnerabilities in distinctive brain circuits of tau spreading and suggests that drug development strategies targeting the gradient expression of this set of genes should be explored to help reduce or prevent pathological tau accumulation.

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Computational modeling of tau pathology spread reveals patterns of regional vulnerability and the impact of a genetic risk factor

Cited by 38 publications

References 61 publications

Local molecular and global connectomic contributions to cross-disorder cortical abnormalities

Local molecular and global connectomic contributions to cross-disorder cortical abnormalities

Propagation of tau and α-synuclein in the brain: therapeutic potential of the glymphatic system

Network Tau spreading is vulnerable to the expression gradients of APOE and glutamatergic-related genes

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