Influence of cerebrovascular disease on brain networks in prodromal and clinical Alzheimer’s disease

Brain, Nov 2017

Network-sensitive neuroimaging methods have been used to characterize large-scale brain network degeneration in Alzheimer’s disease and its prodrome. However, few studies have investigated the combined effect of Alzheimer’s disease and cerebrovascular disease on brain network degeneration. Our study sought to examine the intrinsic functional connectivity and structural covariance network changes in 235 prodromal and clinical Alzheimer’s disease patients with and without cerebrovascular disease. We focused particularly on two higher-order cognitive networks—the default mode network and the executive control network. We found divergent functional connectivity and structural covariance patterns in Alzheimer’s disease patients with and without cerebrovascular disease. Alzheimer’s disease patients without cerebrovascular disease, but not Alzheimer’s disease patients with cerebrovascular disease, showed reductions in posterior default mode network functional connectivity. By comparison, while both groups exhibited parietal reductions in executive control network functional connectivity, only Alzheimer’s disease patients with cerebrovascular disease showed increases in frontal executive control network connectivity. Importantly, these distinct executive control network changes were recapitulated in prodromal Alzheimer’s disease patients with and without cerebrovascular disease. Across Alzheimer’s disease patients with and without cerebrovascular disease, higher default mode network functional connectivity z-scores correlated with greater hippocampal volumes while higher executive control network functional connectivity z-scores correlated with greater white matter changes. In parallel, only Alzheimer’s disease patients without cerebrovascular disease showed increased default mode network structural covariance, while only Alzheimer’s disease patients with cerebrovascular disease showed increased executive control network structural covariance compared to controls. Our findings demonstrate the differential neural network structural and functional changes in Alzheimer’s disease with and without cerebrovascular disease, suggesting that the underlying pathology of Alzheimer’s disease patients with cerebrovascular disease might differ from those without cerebrovascular disease and reflect a combination of more severe cerebrovascular disease and less severe Alzheimer’s disease network degeneration phenotype.

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Influence of cerebrovascular disease on brain networks in prodromal and clinical Alzheimer’s disease

Received March Influence of cerebrovascular disease on brain networks in prodromal and clinical Alzheimer's disease Joanna Su Xian Chong 2 8 Siwei Liu 2 8 Yng Miin Loke 2 8 Saima Hilal 0 1 8 Mohammad Kamran Ikram 0 6 8 Xin Xu 0 1 8 Boon Yeow Tan 5 8 Narayanaswamy Venketasubramanian 4 8 Christopher Li-Hsian Chen 0 1 8 Juan Zhou 2 3 8 0 Memory Ageing and Cognition Centre, National University Health System , Singapore 1 Department of Pharmacology, Clinical Research Centre, National University Health System, National University of Singapore , Singapore 2 Centre for Cognitive Neuroscience, Neuroscience and Behavioural Disorders Programme, Duke-National University of Singapore Medical School , Singapore 3 Clinical Imaging Research Centre, The Agency for Science, Technology and Research and National University of Singapore , Singapore 4 Raffles Neuroscience Centre, Raffles Hospital , Singapore 5 St. Luke's Hospital , Singapore 6 Duke-National University of Singapore Medical School , Singapore 7 06-15 , Singapore 169857 8 Centre for Cognitive Neuroscience, Neuroscience and Behavioural Disorders Programme, Duke-NUS Medical School , Singapore 8 College Road Network-sensitive neuroimaging methods have been used to characterize large-scale brain network degeneration in Alzheimer's disease and its prodrome. However, few studies have investigated the combined effect of Alzheimer's disease and cerebrovascular disease on brain network degeneration. Our study sought to examine the intrinsic functional connectivity and structural covariance network changes in 235 prodromal and clinical Alzheimer's disease patients with and without cerebrovascular disease. We focused particularly on two higher-order cognitive networks-the default mode network and the executive control network. We found divergent functional connectivity and structural covariance patterns in Alzheimer's disease patients with and without cerebrovascular disease. Alzheimer's disease patients without cerebrovascular disease, but not Alzheimer's disease patients with cerebrovascular disease, showed reductions in posterior default mode network functional connectivity. By comparison, while both groups exhibited parietal reductions in executive control network functional connectivity, only Alzheimer's disease patients with cerebrovascular disease showed increases in frontal executive control network connectivity. Importantly, these distinct executive control network changes were recapitulated in prodromal Alzheimer's disease patients with and without cerebrovascular disease. Across Alzheimer's disease patients with and without cerebrovascular disease, higher default mode network functional connectivity z-scores correlated with greater hippocampal volumes while higher executive control network functional connectivity z-scores correlated with greater white matter changes. In parallel, only Alzheimer's disease patients without cerebrovascular disease showed increased default mode network structural covariance, while only Alzheimer's disease patients with cerebrovascular disease showed increased executive control network structural covariance compared to controls. Our findings demonstrate the differential neural network structural and functional changes in Alzheimer's disease with and without cerebrovascular disease, suggesting that the underlying pathology of Alzheimer's disease patients with cerebrovascular disease might differ from those without cerebrovascular disease and reflect a combination of more severe cerebrovascular disease and less severe Alzheimer's disease network degeneration phenotype. Introduction Alzheimer’s disease is a neurodegenerative disorder associated with large-scale brain functional and structural network dysfunctions (Seeley et al., 2009) . Using intrinsic functional connectivity approaches that measure correlated spontaneous activity between brain regions under task-free conditions, several intrinsic connectivity networks have been consistently identified in healthy individuals (Biswal et al., 1995; Fox and Raichle, 2007) and demonstrated to show aberrant changes in Alzheimer’s disease and its prodrome. Of these, decreased functional connectivity in the default mode network (DMN) is the most prominent in patients with Alzheimer’s disease (Greicius et al., 2004; Seeley et al., 2009; Zhou et al., 2010) . More recently, aberrant loss of functional connectivity in other intrinsic connectivity networks has also been documented in Alzheimer’s disease patients, including the frontoparietal executive control network (ECN) (Brier et al., 2012; Wang et al., 2015) . In patients with mild cognitive impairment, reduced connectivity in the DMN has also been reported (Rombouts et al., 2005; Bai et al., 2008; Zhou et al., 2008) , with some evidence of increased frontoparietal connectivity that may be suggestive of a compensatory mechanism (Qi et al., 2010). Structural brain networks have been characterized by analysing the co-varying grey mat (...truncated)


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Chong, Joanna Su Xian, Liu, Siwei, Loke, Yng Miin, Hilal, Saima, Ikram, Mohammad Kamran, Xu, Xin, Tan, Boon Yeow, Venketasubramanian, Narayanaswamy, Chen, Christopher Li-Hsian, Zhou, Juan. Influence of cerebrovascular disease on brain networks in prodromal and clinical Alzheimer’s disease, Brain, 2017, pp. 3012-3022, Volume 140, Issue 11, DOI: 10.1093/brain/awx224