Functional connectivity and graph theory in preclinical Alzheimer's disease.
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.
Program in Neuroscience, Division of Biological and Biomedical Science, School of Medicine, Washington University in St. Louis, St. Louis, MO, USA.
Matthew R
MR
Brier
Department of Neurology, School of Medicine, Washington University in St. Louis, St. Louis, MO, USA.
Jewell B
JB
Thomas
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.
Anne M
AM
Fagan
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.
Jason
J
Hassenstab
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.
David M
DM
Holtzman
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.
Tammie L
TL
Benzinger
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.
John C
JC
Morris
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.
Beau M
BM
Ances
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology* / Q000523:psychology; D016229:Amyloid beta-Peptides / Q000378:metabolism; D001921:Brain / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology*; D001931:Brain Mapping / Q000379:methods; D003071:Cognition; D005260:Female; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D009415:Nerve Net / Q000473:pathology / Q000503:physiopathology*; D012720:Severity of Illness Index; D016875:tau Proteins / Q000378:metabolism
D016229:Amyloid beta-Peptides; D016875:tau Proteins
Alzheimer's disease; Biomarker; Functional connectivity; Graph theory; Resting-state