Evidence of regional associations between age-related inter-individual differences in resting-state functional connectivity and cortical thinning revealed through a multi-level analysis

Normal aging incurs functional and anatomical alterations in the brain. Cortical thinning, age-related alterations in resting-state functional connectivity (RSFC) and reductions in fractional amplitude of low frequency fluctuations (fALFF) are key components of brain aging that can be studied by neuroimaging. However, the level of association between these processes has not been fully established. We performed an analysis at multiple-levels, i.e. region or connection and modality, to investigate whether the evidence for the effect of aging on fALFF, RSFC and cortical thickness are associated in a large cohort. Our results show that there is a positive association between the level of evidence of age-related effects in all three in the brain. We also demonstrate that on a regional basis the association between RSFC alterations and cortical atrophy may be either positive or negative, which may indicate compensatory mechanisms predicted by the Scaffolding Theory of Aging and Cognition (STAC).


Introduction
1 Just like the rest of the human body, the brain ages. Brain aging has 2 been perceived almost as long as physical aging [1]. This phenomenon is 3 measurable at the most diverse levels of cerebral structure and function, 4 largely affecting the way the brain works. Decline of memory and executive 5 functions are among the most prevalent symptoms of brain aging [2]. On 6 the other hand, language is often spared [3] and shows that aging affects 7 different cognitive aspects in a variety of ways. The aging process in the brain 8 is heterogeneous and its symptoms are similar to those of slow progressing 9 neurodegenerative diseases that are also more likely to occur in the elderly 10 [4, 5, 6].

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An extensive literature has developed from the studies of normal brain ag-12 ing using neuroimaging [5,6,7,8]. High resolution neuroanatomical imaging 13 techniques facilitate the study of the brain morphology and how it changes 14 throughout the adult lifespan. Due to its optimal soft-tissue contrast, mag-15 netic resonance imaging (MRI) is today the standard imaging technique in 16 neuroanatomical investigation in vivo. 17 Prominent brainwide age-related cortical thinning has been consistently 18 observed in the literature [4,6,9,10,11,12,13,14].  ing shows this atrophy is not linked to neuronal cell loss, as the number of 20 neuronal cells remains relatively constant throughout the lifespan of adults 21 free of neurocognitive diseases, nor completely explained by the incidence of 22 pre-symptomatic AD markers [15]. Therefore, other factors must account 23 for these age-related changes in cortical morphometry. Changes in synapses 24 and spines and cell body shrinking were hypothesized to cause these phe-  [3]. Neurocognitive scaffolding encompasses increased functional connectiv-52 ity between resting-state networks, a process of dedifferentiation, whereby 53 different regions, due to aging, work more similarly to perform functions 54 that did not require as many resources as before. that support the relationship between changes in structural phenotypes and 99 the brain ability to engage functional networks during the aging process.

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Brain connectivity is fundamentally linked to its structure and function.

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The study of the co-occurrence of age-related alterations in any of the three 102 may help to better characterize the mechanisms of cognition and aging in 103 the brain. Since the neurocognitive scaffolding is supposed to counterbalance 104 neural challenges such as atrophy, we aim to find evidence of co-localization of 105 age-related alterations in cortical thickness, functional connectivity and am-106 plitude of low-frequency oscillations in a large sample of neurotypical adults.

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Employing a multimodal analysis we expect to find positive correlations be-108 tween the regional and global occurrence of cortical atrophy and age-related 109 effects in connectivity and fALFF.

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The methods and data were partially described in Vieira and Garrido 112 Salmon [43], which we reproduce with small adjustments below. The NKI-  Project (FCP) [45].

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The NKI-RS applied several exclusion criteria when recruiting partici-127 pants. Of special interest for our study, these criteria include severe psychi-

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The characteristics of the sample are shown in Table 1.     subject was removed from the study due to faulty structural pre-processing.

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Structural data from 482 subjects were successfully pre-processed.

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Functional scans were pre-processed in the MATLAB toolbox CONN  The association between the t-statistic for the effect of age on cortical 268 thickness and the t-statistic for the effect of age on fALFF is shown in Figure   269 3a

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Our results support the notion that age-related cortical thickness atro-389 phy and age-related differences in functional connectivity are associated. We 390 showed that at the same time that the brain thickness becomes more homoge-391 neous, with cortical atrophy affecting almost the whole brain, age-related ef-   tional connectivity stay significant however. This is shown in Figure S2b