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Neurobiol Aging. 2014 Apr;35(4):757-68. doi: 10.1016/j.neurobiolaging.2013.10.081. Epub 2013 Oct 18.

Functional connectivity and graph theory in preclinical Alzheimer's disease.

Author information

1
Program in Neuroscience, Division of Biological and Biomedical Science, School of Medicine, Washington University in St. Louis, St. Louis, MO, USA.
2
Department of Neurology, School of Medicine, Washington University in St. Louis, St. Louis, MO, USA.
3
Department of Neurology, School of Medicine, Washington University in St. Louis, St. Louis, MO, USA; Hope Center for Neurological Disorders, Washington University in St. Louis, St. Louis, MO, USA; Knight Alzheimer's Disease Research Center, Washington University in St. Louis, St. Louis, MO, USA.
4
Department of Neurology, School of Medicine, Washington University in St. Louis, St. Louis, MO, USA; Knight Alzheimer's Disease Research Center, Washington University in St. Louis, St. Louis, MO, USA; Department of Psychology, Washington University in St. Louis, St. Louis, MO, USA.
5
Department of Radiology, School of Medicine, Washington University in St. Louis, St. Louis, MO, USA; Knight Alzheimer's Disease Research Center, Washington University in St. Louis, St. Louis, MO, USA.
6
Department of Neurology, School of Medicine, Washington University in St. Louis, St. Louis, MO, USA; Knight Alzheimer's Disease Research Center, Washington University in St. Louis, St. Louis, MO, USA.
7
Department of Neurology, School of Medicine, Washington University in St. Louis, St. Louis, MO, USA; Hope Center for Neurological Disorders, Washington University in St. Louis, St. Louis, MO, USA; Knight Alzheimer's Disease Research Center, Washington University in St. Louis, St. Louis, MO, USA; Department of Biomedical Engineering, Washington University in St. Louis, St. Louis, MO, USA. Electronic address: ancesb@neuro.wustl.edu.

Abstract

Alzheimer's disease (AD) has a long preclinical phase in which amyloid and tau cerebral pathology accumulate without producing cognitive symptoms. Resting state functional connectivity magnetic resonance imaging has demonstrated that brain networks degrade during symptomatic AD. It is unclear to what extent these degradations exist before symptomatic onset. In this study, we investigated graph theory metrics of functional integration (path length), functional segregation (clustering coefficient), and functional distinctness (modularity) as a function of disease severity. Further, we assessed whether these graph metrics were affected in cognitively normal participants with cerebrospinal fluid evidence of preclinical AD. Clustering coefficient and modularity, but not path length, were reduced in AD. Cognitively normal participants who harbored AD biomarker pathology also showed reduced values in these graph measures, demonstrating brain changes similar to, but smaller than, symptomatic AD. Only modularity was significantly affected by age. We also demonstrate that AD has a particular effect on hub-like regions in the brain. We conclude that AD causes large-scale disconnection that is present before onset of symptoms.

KEYWORDS:

Alzheimer's disease; Biomarker; Functional connectivity; Graph theory; Resting-state

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