Abstract
There is striking overlap between the spatial distribution of amyloid-β pathology in patients with Alzheimer's disease and the spatial distribution of high intrinsic functional connectivity in healthy persons. This overlap suggests a mechanistic link between amyloid-β and intrinsic connectivity, and indeed there is evidence in patients for the detrimental effects of amyloid-β plaque accumulation on intrinsic connectivity in areas of high connectivity in heteromodal hubs, and particularly in the default mode network. However, the observed spatial extent of amyloid-β exceeds these tightly circumscribed areas, suggesting that previous studies may have underestimated the negative impact of amyloid-β on intrinsic connectivity. We hypothesized that the known positive baseline correlation between patterns of amyloid-β and intrinsic connectivity may mask the larger extent of the negative effects of amyloid-β on connectivity. Crucially, a test of this hypothesis requires the within-patient comparison of intrinsic connectivity and amyloid-β distributions. Here we compared spatial patterns of amyloid-β-plaques (measured by Pittsburgh compound B positron emission tomography) and intrinsic functional connectivity (measured by resting-state functional magnetic resonance imaging) in patients with prodromal Alzheimer's disease via spatial correlations in intrinsic networks covering fronto-parietal heteromodal cortices. At the global network level, we found that amyloid-β and intrinsic connectivity patterns were positively correlated in the default mode and several fronto-parietal attention networks, confirming that amyloid-β aggregates in areas of high intrinsic connectivity on a within-network basis. Further, we saw an internetwork gradient of the magnitude of correlation that depended on network plaque-load. After accounting for this globally positive correlation, local amyloid-β-plaque concentration in regions of high connectivity co-varied negatively with intrinsic connectivity, indicating that amyloid-β pathology adversely reduces connectivity anywhere in an affected network as a function of local amyloid-β-plaque concentration. The local negative association between amyloid-β and intrinsic connectivity was much more pronounced than conventional group comparisons of intrinsic connectivity would suggest. Our findings indicate that the negative impact of amyloid-β on intrinsic connectivity in heteromodal networks is underestimated by conventional analyses. Moreover, our results provide first within-patient evidence for correspondent patterns of amyloid-β and intrinsic connectivity, with the distribution of amyloid-β pathology following functional connectivity gradients within and across intrinsic networks.
Highlights
Alzheimer’s disease is tightly associated with amyloid-b pathology
Our findings indicate that the negative impact of amyloid-b on intrinsic connectivity in heteromodal networks is underestimated by conventional analyses
Patients showed a gradient of plaque deposition across networks [F(6,132) = 3.83, P = 0.001], with the highest Pittsburgh Compound B (PiB)-uptake in the posterior default mode network (DMN) [significantly increased compared to left attentional networks (ATN) and right ATN, all t(22) 4 3.12, corrected P 5 0.035], and strong trends compared to anterior DMN [t(22) = 2.95, corrected P = 0.052], and to posterior auditory cortex network [t(22) = 2.77, corrected P = 0.078]
Summary
Alzheimer’s disease is tightly associated with amyloid-b pathology. Aberrant clearance of amyloid-b precursor protein is thought to be a critical initial event in the disease’s pathogenesis, leading to amyloid-b peptide accumulation and plaque formation 20 to 30 years before cognitive symptoms arise (Selkoe, 2002; Jack et al, 2010; Bateman et al, 2012). The deposition of plaques has been associated with the default mode network (DMN; Buckner et al, 2005; Sperling et al, 2009), a set of frontal and parietal midline structures with high metabolic activity that are coupled through high intrinsic functional connectivity (i.e. synchronous ongoing activity, where regions that are more strongly synchronized will exhibit higher connectivity). This association is mostly due to the apparent spatial overlap between the DMN and the average deposition of amyloid across the cortex
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Disclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.