Functional brain architecture is associated with the rate of tau accumulation in Alzheimer’s disease

Initiative, Alzheimer’s Disease Neuroimaging

doi:10.1038/s41467-019-14159-1

Cited by 203 publications

(178 citation statements)

References 71 publications

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“…Regions we observed changing in asymmetry were predominantly located in higher-order association cortex, which has been found to exhibit less average interhemispheric connectivity 38 in favour of more lateralized within-hemisphere interactions 10 -supporting notions of hemispheric specialization 9,12 . Speculatively, our observation that thicker homotopic cortex thins faster may be in line with contemporary evidence indicating that age pathologies propogate transneuronally though synaptic connections 39,40 which may precipitate faster degeneration of the hemisphere with more cortico-cortical connections 41 . As evidence suggests cortical thinning partly reflects synaptic loss [42][43][44] , critical questions for future research concern the underlying neurobiological mechanisms, exact functional consequences, and indeed whether the principle that thicker cortex thins faster only applies to homotopy.…”

Section: Discussionsupporting

confidence: 89%

Asymmetric thinning of the cerebral cortex across the adult lifespan is accelerated in Alzheimer’s Disease

Roe

Vidal-Piñeiro

Sørensen

et al. 2020

Preprint

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Normal aging and Alzheimer's Disease (AD) are accompanied by large-scale alterations in brain organization that undermine brain function. Although hemispheric asymmetry is a global organizing feature of cortex thought to promote brain efficiency, current descriptions of cortical thinning in aging and AD have largely overlooked cortical asymmetry. Consequently, the foundational question of whether and where the cerebral hemispheres change at different rates in aging and AD remains open. First, applying vertex-wise data-driven clustering in a longitudinal discovery sample (aged 20-89; 2577 observations; 1851 longitudinal) we identified cortical regions exhibiting similar age-trajectories of asymmetry across the adult lifespan. Next, we sought replication in 4 independent longitudinal aging cohorts. We show that higher-order regions of cortex that exhibit pronounced asymmetry at age ~20 also show asymmetry change in aging. Results revealed that both leftward and rightward asymmetry is progressively lost on a similar time-scale across adult life. Hence, faster thinning of the (previously) thicker homotopic hemisphere is a feature of aging. This simple organizational principle showed high consistency across multiple aging cohorts in the Lifebrain consortium, and both the topological patterns and temporal dynamics of asymmetry-loss were markedly similar across replicating samples. Finally, we show that regions exhibiting gradual asymmetry-loss over healthy adult life exhibit faster asymmetry-change in AD.Overall, our results suggest a system-wide breakdown in the adaptive asymmetric organization of cortex across adult life which is further accelerated in AD, and may implicate thickness asymmetry as a viable marker for declining hemispheric specialization in aging and AD. The brain becomes progressively disorganized with age, and brain alterations accelerated in Alzheimer's disease may occur gradually over the lifespan. Although hemispheric asymmetry aids efficient network organization, efforts to identify structural markers of age-related decline have largely overlooked cortical asymmetry. Here we show the hemisphere that is thicker when younger, thins faster. This leads to progressive system-wide loss of regional thickness asymmetry across life. In multiple aging cohorts, asymmetry-loss showed high reproducibility topologically across cortex and similar timing-of-change in aging. Asymmetry-change was further accelerated in AD. Our findings uncover a new principle of brain aging -thicker homotopic cortex thins faster -and suggest we may have unveiled a structural marker for a widely-hypothesized decline in hemispheric specialization in aging and AD.

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Section: Discussionsupporting

confidence: 89%

Asymmetric thinning of the cerebral cortex across the adult lifespan is accelerated in Alzheimer’s Disease

Roe

Vidal-Piñeiro

Sørensen

et al. 2020

Preprint

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“…Based on prior longitudinal flortaucipir studies ( Jack et al , 2018 b ; Cho et al , 2019 ; Pontecorvo et al , 2019 ; Sintini et al , 2019 ; Franzmeier et al , 2020 ) we expected that both baseline tau and amyloid PET would be independent predictors of tau accumulation rates in the impaired group as a whole. While the point estimates of effect sizes of these variables were very similar, only amyloid-β was significant ( Fig.…”

Section: Discussionmentioning

confidence: 99%

Predicting future rates of tau accumulation on PET

Jack

Wiste

Weigand

et al. 2020

Brain

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Clinical trials with anti-tau drugs will need to target individuals at risk of accumulating tau. Our objective was to identify variables available in a research setting that predict future rates of tau PET accumulation separately among individuals who were either cognitively unimpaired or cognitively impaired. All 337 participants had: a baseline study visit with MRI, amyloid PET, and tau PET exams, at least one follow-up tau PET exam; and met clinical criteria for membership in one of two clinical diagnostic groups: cognitively unimpaired (n = 203); or cognitively impaired (n = 134, a combined group of participants with either mild cognitive impairment or dementia with Alzheimer’s clinical syndrome). Our primary analyses were in these two clinical groups; however, we also evaluated subgroups dividing the unimpaired group by normal/abnormal amyloid PET and the impaired group by clinical phenotype (mild cognitive impairment, amnestic dementia, and non-amnestic dementia). Linear mixed effects models were used to estimate associations between age, sex, education, APOE genotype, amyloid and tau PET standardized uptake value ratio (SUVR), cognitive performance, cortical thickness, and white matter hyperintensity volume at baseline, and the rate of subsequent tau PET accumulation. Log-transformed tau PET SUVR was used as the response and rates were summarized as annual per cent change. A temporal lobe tau PET meta-region of interest was used. In the cognitively unimpaired group, only higher baseline amyloid PET was a significant independent predictor of higher tau accumulation rates (P < 0.001). Higher rates of tau accumulation were associated with faster rates of cognitive decline in the cognitively unimpaired subgroup with abnormal amyloid PET (P = 0.03), but among the subgroup with normal amyloid PET. In the cognitively impaired group, younger age (P = 0.02), higher baseline amyloid PET (P = 0.05), APOE ε4 (P = 0.05), and better cognitive performance (P = 0.05) were significant independent predictors of higher tau accumulation rates. Among impaired individuals, faster cognitive decline was associated with faster rates of tau accumulation (P = 0.01). While we examined many possible predictor variables, our results indicate that screening of unimpaired individuals for potential inclusion in anti-tau trials may be straightforward because the only independent predictor of high tau rates was amyloidosis. In cognitively impaired individuals, imaging and clinical variables consistent with early onset Alzheimer’s disease phenotype were associated with higher rates of tau PET accumulation suggesting this may be a highly advantageous group in which to conduct proof-of-concept clinical trials that target tau-related mechanisms. The nature of the dementia phenotype (amnestic versus non-amnestic) did not affect this conclusion.

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“…We have listed each region and its community label in Supplementary Table 3, and the HCP-MMP atlas is available online (https://balsa.wustl.edu/study/show/RVVG, (44)). Task fMRI studies that use group-level analyses can use the group-level characterization of cortico-hippocampal networks reported here in order to rigorously test hypotheses about the functions of these networks and how they may be implicated in memory disorders, as resting connectivity has shown to predict spread of pathology in Alzheimer's (99), and DMN subnetwork perturbation has been demonstrated in MTL amnesia (100).…”

Section: Discussionmentioning

confidence: 99%

Organization of cortico-hippocampal networks in the human brain

Barnett

Reilly

Dimsdale-Zucker

et al. 2020

Preprint

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Episodic memory is thought to depend on interactions between the hippocampus and a set of closely interconnected regions that comprise the default mode network (DMN)-a large-scale network that has been identified with resting-state fMRI. Here, using data-driven analyses of resting-state fMRI data to characterize cortico-hippocampal network connectivity, we identified a discrete set of subnetworks that interact with the hippocampus. Specifically, we found that the hippocampus closely affiliated with the DMN and with a "Medial Temporal Network" (MTN) that included regions in the medial temporal lobe and retrosplenial cortex. The DMN could be further subdivided into three subnetworks: a "Posterior Medial" Subnetwork comprised of regions in the posterior cingulate, lateral parietal, and dorsal prefrontal cortex, an "Anterior Temporal" Subnetwork comprised of regions in the temporopolar, lateral orbitofrontal, and dorsal medial prefrontal cortex, and a "Medial Prefrontal" Subnetwork comprised of regions in the ventral medial prefrontal, and entorhinal cortex. These cortico-hippocampal networks vary in their functional connectivity along the hippocampal long-axis, and analyses of an independent task-fMRI dataset revealed that the three DMN subnetworks represent different kinds of information during memory-guided decision-making. Finally, a data-driven meta-analysis of functional imaging studies of cognition suggests new hypotheses regarding the functions of the MTN and DMN subnetworks, thus providing a framework to guide future research on the neural architecture of episodic memory. Significance StatementNetwork neuroscience has identified large-scale networks across the human brain, but this literature focuses almost exclusively on cortical regions, with sparse characterization of subcortical regions like the hippocampus. The hippocampus is critical for encoding and retrieving episodic memories, but it is currently unclear how the hippocampus interacts with distributed networks in the brain. Here, we used network neuroscience techniques to identify and characterize cortico-hippocampal networks. We find that these cortico-hippocampal networks can be differentiated on the basis of functional connectivity along the hippocampal long-axis, information represented in an independent task-fMRI dataset, and in a meta-analysis of task fMRI studies. Our work demonstrates that the functional organization of memory processes may be determined by the network topology of the human brain.Episodic memory allows us to relive past events that happened at a particular place and time (1). Most research investigating the neurobiology of episodic memory retrieval has focused on the hippocampus and medial temporal lobe (MTL) cortex (perirhinal, parahippocampal, and entorhinal cortex) highlighting the interactions among these regions (2-4). It is generally assumed, however, that the hippocampus supports memory by integrating information represented across distributed areas in the neocortex (5). Consistent with this idea, fMRI studies of memor...

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Functional brain architecture is associated with the rate of tau accumulation in Alzheimer’s disease

Cited by 203 publications

References 71 publications

Asymmetric thinning of the cerebral cortex across the adult lifespan is accelerated in Alzheimer’s Disease

Asymmetric thinning of the cerebral cortex across the adult lifespan is accelerated in Alzheimer’s Disease

Predicting future rates of tau accumulation on PET

Organization of cortico-hippocampal networks in the human brain

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