Disruption of Functional Connectivity in Clinically Normal Older Adults Harboring Amyloid Burden

Abstract

Amyloid deposition is present in 20 -50% of nondemented older adults yet the functional consequences remain unclear. The current study found that amyloid accumulation is correlated with functional disruption of the default network as measured by intrinsic activity correlations. Clinically normal participants (n ϭ 38, aged 60 -88 years) were characterized using 11 C-labeled Pittsburgh Compound B positron emission tomography imaging to estimate fibrillar amyloid burden and, separately, underwent functional magnetic resonance imaging (fMRI). The integrity of the default network was estimated by correlating rest-state fMRI time courses extracted from a priori regions including the posterior cingulate, lateral parietal, and medial prefrontal cortices. Clinically normal participants with high amyloid burden displayed significantly reduced functional correlations within the default network relative to participants with low amyloid burden. These reductions were also observed when amyloid burden was treated as a continuous, rather than a dichotomous, measure and when controlling for age and structural atrophy. Whole-brain analyses initiated by seeding the posterior cingulate cortex, a region of high amyloid burden in Alzheimer's disease, revealed significant disruption in the default network including functional disconnection of the hippocampal formation.

The cognitive neuroscience of ageing

“…Several studies have found that the reduction of DN activity during externally-driven cognitive tasks is less pronounced in old adults, relative to young adults 58,[105][106][107][108][109][110][111][112] . Functional connectivity of the DN also is reduced with age during working memory tasks 113 and during periods of rest 105,[114][115][116] . These reductions in task-related deactivation and functional connectivity are seen in the two regions thought to be the major nodes of the DN, the posterior cingulate cortex (PCC) and ventromedial PFC 117 , as well as in other DN regions, such as the MTL and inferior parietal lobes (see Figure 3).…”

Functional brain network centrality is related to APOE genotype in cognitively normal elderly

“…Aβ disrupts synaptic functioning, resulting in aberrant brain connectivity at the synaptic level (Selkoe, 2002; Spires‐Jones & Hyman, 2014), as well as on the whole‐brain connectivity level (Delbeuck, der Linden, & Collette, 2003; Hedden et al., 2009). Although the precise sequence of events caused by Aβ plaques is still being investigated (Altmann, Ng, Landau, Jagust, & Greicius, 2015) and interactions with other agents recognized (Jones et al., 2017), the key role of Aβ in AD pathology is beyond doubt (Jack et al., 2016).…”

“…The default mode network (DMN) and other resting‐state networks, that is, regions with synchronized fMRI activity, have been studied as markers for AD progression (Binnewijzend et al., 2012; Filippini et al., 2009; Sheline et al., 2010). Functional brain connectivity changes in healthy adults are related to amyloid depositions (Hedden et al., 2009; Sperling et al., 2009), and carriers of the APOE‐ε4 allele show increased co‐activation with the DMN in young adults (Bookheimer et al., 2000; Filippini et al., 2009), indicating that functional connectivity is sensitive to AD‐related alterations of the brain. This study extends these previous findings, using a large sample from a population imaging study, combined with comprehensive AD‐related cognitive assessment and genotyping.…”

Quantitative mapping of cerebrovascular reactivity using resting-state BOLD fMRI: Validation in healthy adults

“…The rs-fMRI family of techniques (Biswal et al, 1995;Fox and Greicius, 2010;Hedden et al, 2009;van Dijk et al, 2010) is commonly used to capture intrinsic brain activity. However, the rs-fMRI signal also encompasses substantial non-neural contributions (Biswal and Kannurpatti, 2009;Biswal et al, 2007;Tong and Frederick, 2010), notably through intrinsic physiological processes.…”