Functional connectivity associated with tau levels in ageing, Alzheimer’s, and small vessel disease

Franzmeier, Nicolai; Rubinski, Anna; Neitzel, Julia; Kim, Yeshin; Damm, Alexander; Na, Duk L.; Kim, Hee Jin; Lyoo, Chul Hyoung; Cho, Hanna; Finsterwalder, Sofia; Duering, Marco; Seo, Sang Won; Ewers, Michael

doi:10.1093/brain/awz026

Cited by 185 publications

(203 citation statements)

References 72 publications

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“…We observed phospho-tau spreading from 3 to 10 months in 3xTg AD model mice and found that this was associated with long-range connectivity deficits in young model animals. This supports the notion of a tight coupling between functional connectivity and tau progression 35 , supported by molecular work by others 43 . The seeding hypothesis can be further connected to other models of axonal degeneration and inflammatory response 44 and, thus, provides a coherent description of the pathophysiology process taking place in AD.…”

Section: Discussionsupporting

confidence: 82%

“…Moreover, regions highlighted in the pair-wise correlation analysis were also found to be enriched in tau aggregates within the AD-like disease progression (amygdala and hippocampus, Supplementary Fig. 2), consistent with tau dispersions across functionally connected networks 35 .…”

Section: Local Functional Connectivity Deficits Translate Into Whole-supporting

confidence: 64%

“…This hyperexcitable neuronal profile may, thus, support the network dysfunction observed, through compensatory mechanisms in response to the compromised functional connectivity reported at rest. Additionally, the Input/Output curve (IOC) analysis for synaptic strength revealed a quadruple interaction effect between ROIs, age, genotype, and stimulation amplitude: F (35,32) = 108.31, p < 0.001. Within the BLA, 3xTgAD mice did not show significant differences compared to controls at 3 months, whereas, there was a significantly larger response at 6 months for all stimulus intensities, e.g.…”

Section: Local Functional Connectivity Deficits Translate Into Whole-mentioning

confidence: 99%

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The lateral entorhinal cortex is a hub for local and global dysfunction in pre-tauopathy states

Mandino

Yeow

et al. 2020

Preprint

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Functional activity alterations are one of the earliest hallmarks of Alzheimer's disease (AD), already detected prior to beta-amyloid plaque and tau-tangle accumulation. To reveal the physiological basis underpinning these changes at the onset of the pathology, we leveraged fMRI in the 3xTgAD mouse model for AD. Resting-state fMRI revealed functional connectivity loss within areas homologous to the human temporal lobe, particularly the entorhinal cortex. Optogenetic activation of the entorhinal cortex results, instead, in enhanced fMRI signal, thus denoting an increase in metabolic demand under load. This is corroborated by synaptic hyperexcitability in the highlighted projection targets, reported with electrophysiological recordings. Thus, 3xTgAD mice reveal a dichotomic behavior between resting and evoked states, resulting in a functional brain-wide reorganization with local underpinnings, which reconciles evidence from the human literature. The 3xTgAD tauopathy profile resembles that in AD patients closely, suggesting that similar pathophysiological mechanisms might underlie network dysfunction in clinical cases. Results Phosphorylated tau in ventral-amygdaloid-striatal networks precedes amyloid depositionTo determine the pathological state, brain slices from 3xTgAD and control animals aged 3, 6, and 10 months were examined for immunoreactivity to 6e10 (targeting the N-terminus of beta-amyloid, Aβ) and AT8 (targeting phospho-tau (Ser202, Thr205)). Consistent with previous description 9,16 , no immunoreactivity was observed to 6e10 at 3 and 6 months of age ( Supplementary Fig. 1), while AT8 binding was revealed in the amygdala at 3 months, spreading to the hippocampus at 6 and 10 months ( Fig. 1d, Supplementary Fig. 2). Only at 10 months of age did 3xTgAD exhibit the immunoreactivity patterns attributable to neurofibrillary tangles ( Supplementary Fig. 2c).We confirmed these results with ELISA performed on brain tissue homogenate. Soluble Aβ1-40 levels in 3xTgAD were of comparable magnitude (~12000/~16000 pg/mg) to that of age-matched control animals at 3 months of age; a difference of 1.7-fold in soluble Aβ1-40 was seen between controls (~9000 pg/ml) and 3xTgAD (~16000 pg/ml) at 6 months of age. No difference was reported for insoluble Aβ1-40 at both age points. Furthermore, 3xTgAD mice showed an increase in total tau of several orders of magnitude compared to age-matched controls at both age points, e.g., 20-fold increment at 6 months of age. We conclude that 3xTgAD mice aged 3 and 6 months represent a preplaque and pre-tangle stage of AD-like pathology. The 3-and 6-months age points were, therefore, examined in the remainder of this study. The ventral-amygdaloid-striatal network is affected during tauopathy in mice and humansTo examine spontaneous fluctuations in brain activity, we recorded rsfMRI in male 3xTgAD and wildtype control mice on the same background strain (129sv/c57bl6) at 3 (N3xTgAD = 19, Ncontrols = 10) and 6 months of age (N3xTgAD = 13, Ncontrols = 10), longitudinally. The rsfMRI protocol empl...

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Section: Discussionsupporting

confidence: 82%

Section: Local Functional Connectivity Deficits Translate Into Whole-supporting

confidence: 64%

Section: Local Functional Connectivity Deficits Translate Into Whole-mentioning

confidence: 99%

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The lateral entorhinal cortex is a hub for local and global dysfunction in pre-tauopathy states

Mandino

Yeow

et al. 2020

Preprint

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“…Our datadriven approach detected 10 independent spatial patterns of tau across temporal (medial temporal, parahippocampal, lateral temporo-parietal), occipital (left and right inferior occipital), frontal (orbitofrontal, middle frontal, anterior frontal), parietal, and sensorimotor regions. This finding might seem surprising, as several studies have shown that tau is either absent or restricted to temporal regions in cognitively normal individuals [39][40][41]. Our study shows that an unsupervised network approach may reveal additional patterns in tau PET data, which can be used to understand why some individuals, despite being clinically normal, are more prone to accumulate tau in specific brain areas.…”

Section: Discussionmentioning

confidence: 68%

Spatial patterns of tau deposition are associated with amyloid, ApoE, sex, and cognitive decline in older adults

Pereira

Harrison

Joie

et al. 2020

Eur J Nucl Med Mol Imaging

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Purpose The abnormal deposition of tau begins before the onset of clinical symptoms and seems to target specific brain networks. The aim of this study is to identify the spatial patterns of tau deposition in cognitively normal older adults and assess whether they are related to amyloid-β (Aβ), APOE, sex, and longitudinal cognitive decline. Methods We included 114 older adults with cross-sectional flortaucipir (FTP) and Pittsburgh Compound-B PET in addition to longitudinal cognitive testing. A voxel-wise independent component analysis was applied to FTP images to identify the spatial patterns of tau deposition. We then assessed whether tau within these patterns differed by Aβ status, APOE genotype, and sex. Linear mixed effects models were built to test whether tau in each component predicted cognitive decline. Finally, we ordered the spatial components based on the frequency of high tau deposition to model tau spread. Results We found 10 biologically plausible tau patterns in the whole sample. There was greater tau in medial temporal, occipital, and orbitofrontal components in Aβ-positive compared with Aβ-negative individuals; in the parahippocampal component in ε3ε3 compared with ε2ε3 carriers; and in temporo-parietal and anterior frontal components in women compared with men. Higher tau in temporal and frontal components predicted longitudinal cognitive decline in memory and executive functions, respectively. Tau deposition was most frequently observed in medial temporal and ventral cortical areas, followed by lateral and primary areas. Conclusions These findings suggest that the spatial patterns of tau in asymptomatic individuals are clinically meaningful and are associated with Aβ, APOE ε2ε3, sex and cognitive decline. These patterns could be used to predict the regional spread of tau and perform in vivo tau staging in older adults.

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“…Studies decomposing the spatial distribution of tau-PET signal in the human brain have revealed spatial patterns highly reminiscent of brain functional networks [30, 31]. In addition, brain regions with greater functional connections to the rest of the brain tend to have greater tau accumulation [32], and correlations have been found between functional connectivity patterns and tau covariance patterns [33, 34].…”

Section: Introductionmentioning

confidence: 99%

Spread of pathological tau proteins through communicating neurons in human Alzheimer’s disease

Vogel

Iturria-Medina

Strandberg

et al. 2019

Preprint

150

194

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Tau is one of the two pathological hallmarks of Alzheimer's disease, and bears a much closer relationship to local neurodegeneration and cognitive impairment than the other hallmark, β-amyloid. Cell and rodent models have shown evidence that tau spreads from cell to cell through anatomical neuronal connections, and that this process is facilitated by the presence of βamyloid. We test this hypothesis in humans by using an epidemic spreading model (ESM) to simulate the spread of tau over human neuronal connections, and we compare the simulated pattern of progression to the observed pattern measured in the brains of 312 individuals on the Alzheimer's disease spectrum, using PET. Fitting our model, we found that the majority of variance in the overall pattern of tau progression could be explained by diffusion of an agent through the human connectome, measured using either functional connectivity or diffusion tractography. These models far exceeded chance, and outperformed models testing the extracellular spread of tau over Euclidian space. Surprisingly, the ESM predicted the spatial patterns of tau * Corresponding authors: jacob.vogel@mail.mcgill.ca, alan.evans@mcgill.ca * * These authors contributed equally to the work Data used in preparation of this article were obtained from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database (adni.loni.usc.edu). As such, the investigators within the ADNI contributed to the design and implementation of ADNI and/or provided data but did not participate in analysis or writing of this report. A complete listing of ADNI investigators can be found at:irrespective of whether subjects demonstrated evidence for brain β-amyloid. In addition, in β-amyloid-positive subjects only, regions with greater amyloid burden showed greater tau than predicted by connectivity patterns, suggesting a role of amyloid in accelerating the spread of tau in certain isocortical regions. Altogether, our results provide strong evidence that tau spreads through neuronal communication pathways even in normal aging, and that this process is accelerated by the presence of brain β-amyloid.

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Functional connectivity associated with tau levels in ageing, Alzheimer’s, and small vessel disease

Cited by 185 publications

References 72 publications

The lateral entorhinal cortex is a hub for local and global dysfunction in pre-tauopathy states

The lateral entorhinal cortex is a hub for local and global dysfunction in pre-tauopathy states

Spatial patterns of tau deposition are associated with amyloid, ApoE, sex, and cognitive decline in older adults

Spread of pathological tau proteins through communicating neurons in human Alzheimer’s disease

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