Brain functional network integrity sustains cognitive function despite atrophy in presymptomatic genetic frontotemporal dementia

Tsvetanov, Kamen A.; Gazzina, Stefano; Jones, P Simon; Swieten, John van; Borroni, Barbara; Sánchez‐Valle, Raquel; Moreno, Fermín; Laforce, Robert; Graff, Caroline; Synofzik, Matthis; Galimberti, Daniela; Masellis, Mario; Tartaglia, Maria Carmela; Finger, Elizabeth; Vandenberghe, Rik; Mendonça, Alexandre de; Tagliavini, Fabrizio; Santana, Isabel; Ducharme, Simon; Butler, Chris; Gerhard, Alexander; Danek, Adrian; Levin, Johannes; Otto, Markus; Frisoni, Giovanni B.; Ghidoni, Roberta; Sorbi, Sandro; Rohrer, Jonathan D.; Rowe, James B.; Initiative, Genfi Genetic Ftd

doi:10.1002/alz.12209

Cited by 42 publications

(45 citation statements)

References 69 publications

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“…We identified significant whole group effects across all grey matter voxels (Figure 2e). In addition, there was a widespread age‐related decrease in GMV, in bilateral temporal lobes, bilateral prefrontal, middle and superior frontal areas, bilateral medial occipital areas, cerebellum, and subcortical areas including thalamus, caudate, and putamen (Figure 2f), consistent with previous reports (Mohajer et al., 2020; Peelle et al., 2012; Tsvetanov et al., 2020).…”

Section: Resultssupporting

confidence: 91%

The effects of age on resting‐state BOLD signal variability is explained by cardiovascular and cerebrovascular factors

et al. 2020

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Accurate identification of brain function is necessary to understand neurocognitive aging, and thereby promote health and well-being. Many studies of neurocognitive aging have investigated brain function with the blood-oxygen level-dependent (BOLD) signal measured by functional magnetic resonance imaging. However, the BOLD signal is a composite of neural and vascular signals, which are differentially affected by aging. It is, therefore, essential to distinguish the age effects on vascular versus neural function. The BOLD signal variability at rest (known as resting state fluctuation amplitude, RSFA), is a safe, scalable, and robust means to calibrate vascular responsivity, as an alternative to breath-holding and hypercapnia. However, the use of RSFA for normalization of BOLD imaging assumes that age differences in RSFA reflecting only vascular factors, rather than age-related differences in neural function (activity) or neuronal loss (atrophy). Previous studies indicate that two vascular factors, cardiovascular health (CVH) and cerebrovascular function, are insufficient when used alone to fully explain age-related differences in RSFA. It remains possible that their joint consideration is required to fully capture age differences in RSFA. We tested the hypothesis that RSFA no longer varies with age after adjusting for a combination of cardiovascular and cerebrovascular measures. We also tested the hypothesis that RSFA variation with age is not associated with atrophy. We used data from the population-based, lifespan Cam-CAN cohort. After controlling for cardiovascular and cerebrovascular estimates alone, the residual variance in RSFA across individuals was significantly associated with age. However, when controlling for both cardiovascular and cerebrovascular estimates, the variance in RSFA was no longer associated with age. Grey matter volumes did not explain age differences in RSFA, after controlling for CVH. The results were consistent between voxel-level analysis and independent component analysis. Our findings indicate that cardiovascular and cerebrovascular signals are together sufficient predictors of age differences in RSFA. We suggest that RSFA can be used to separate vascular from neuronal factors, to characterize neurocognitive aging. We discuss the implications and make recommendations for the use of RSFA in the research of aging. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

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Section: Resultssupporting

confidence: 91%

The effects of age on resting‐state BOLD signal variability is explained by cardiovascular and cerebrovascular factors

et al. 2020

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“…Ageing is also associated with decline of other aspects of motor performance such as psychomotor slowing and reduced fine motor skills (Salthouse, 2000;Seidler et al, 2010). A contributor to age-related performance decline is loss of grey matter volume (Draganski, Lutti, & Kherif, 2013) with evidence from functional neuroimaging studies for adaptive plasticity paralleling structural decline (Tsvetanov et al, 2020). Consequently, older adults may display more widespread brain activation, weaker segregation of local networks and weaker interhemispheric connectivity (Rowe et al, 2006;Chan, Park, Savalia, Petersen, & Wig, 2014;Geerligs, Renken, Saliasi, Maurits, & Lorist, 2014;Tsvetanov et al, 2016).…”

Section: Discussionmentioning

confidence: 99%

Prefrontal cortical connectivity mediates locus coeruleus noradrenergic regulation of inhibitory control in older adults

Tomassini

Hezemans

et al. 2021

Preprint

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Response inhibition is a core executive function enabling adaptive behaviour in dynamic environments. Human and animal models indicate that inhibitory control and control networks are modulated by noradrenaline, arising from the locus coeruleus. The integrity (i.e., cellular density) of the locus coeruleus noradrenergic system can be estimated from magnetization transfer sensitive magnetic resonance imaging, in view of neuromelanin present in noradrenergic neurons of older adults. Noradrenergic psychopharmacological studies indicate noradrenergic modulation of prefrontal and frontostriatal stopping-circuits in association with behavioural change. Here we test the noradrenergic hypothesis of inhibitory control, in healthy adults. We predicted that locus coeruleus integrity is associated with age-adjusted variance in response inhibition, mediated by changes in connectivity between frontal inhibitory control regions. In a preregistered analysis, we used magnetization transfer MRI images from N=63 healthy adults aged above 50 years who performed a stop-signal task, with atlas-based measurement of locus coeruleus contrast. We confirm that better response inhibition is correlated with locus coeruleus integrity and stronger connectivity between pre-supplementary motor area and right inferior frontal gyrus, but not volumes of the cortical regions. We confirmed a significant role of prefrontal connectivity in mediating the effect of individual differences in the locus coeruleus on behaviour, whereby this effect was moderated by age, over and above adjustment for the mean effects of age. Our results support the hypothesis that in normal populations, as in clinical settings, the locus coeruleus noradrenergic system regulates inhibitory control.

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“…Current models of neurovascular ageing [25,301] provide an array of biological pathways leading to global brain tissue loss/atrophy and cognitive deficits, mainly in agerelated neurodegeneration. However, such models are suboptimal for characterizing healthy and successful ageing, where cognitive function is maintained in the presence of brain atrophy [302]. In addition, the link between age-related changes in brain tissue and cognition is surprisingly weak, and it has proven difficult to establish region-by-region correlations between brain structure and cognitive function [303].…”

Section: Towards Neuro-vascular Integrationmentioning

confidence: 99%

Separating vascular and neuronal effects of age on fMRI BOLD signals

Tsvetanov

Henson

Rowe

2020

Phil. Trans. R. Soc. B

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Accurate identification of brain function is necessary to understand the neurobiology of cognitive ageing, and thereby promote well-being across the lifespan. A common tool used to investigate neurocognitive ageing is functional magnetic resonance imaging (fMRI). However, although fMRI data are often interpreted in terms of neuronal activity, the blood oxygenation level-dependent (BOLD) signal measured by fMRI includes contributions of both vascular and neuronal factors, which change differentially with age. While some studies investigate vascular ageing factors, the results of these studies are not well known within the field of neurocognitive ageing and therefore vascular confounds in neurocognitive fMRI studies are common. Despite over 10 000 BOLD-fMRI papers on ageing, fewer than 20 have applied techniques to correct for vascular effects. However, neurovascular ageing is not only a confound in fMRI, but an important feature in its own right, to be assessed alongside measures of neuronal ageing. We review current approaches to dissociate neuronal and vascular components of BOLD-fMRI of regional activity and functional connectivity. We highlight emerging evidence that vascular mechanisms in the brain do not simply control blood flow to support the metabolic needs of neurons, but form complex neurovascular interactions that influence neuronal function in health and disease. This article is part of the theme issue ‘Key relationships between non-invasive functional neuroimaging and the underlying neuronal activity’.

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Brain functional network integrity sustains cognitive function despite atrophy in presymptomatic genetic frontotemporal dementia

Cited by 42 publications

References 69 publications

The effects of age on resting‐state BOLD signal variability is explained by cardiovascular and cerebrovascular factors

The effects of age on resting‐state BOLD signal variability is explained by cardiovascular and cerebrovascular factors

Prefrontal cortical connectivity mediates locus coeruleus noradrenergic regulation of inhibitory control in older adults

Separating vascular and neuronal effects of age on fMRI BOLD signals

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