Declining functional connectivity and changing hub locations in Alzheimer's disease: an EEG study.
BACKGROUND
EEG studies have shown that patients with Alzheimer's disease (AD) have weaker functional connectivity than controls, especially in higher frequency bands. Furthermore, active regions seem more prone to AD pathology. How functional connectivity is affected in AD subgroups of disease severity and how network hubs (highly connected brain areas) change is not known. We compared AD patients with different disease severity and controls in terms of functional connections, hub strength and hub location.


METHODS
We studied routine 21-channel resting-state electroencephalography (EEG) of 318 AD patients (divided into tertiles based on disease severity: mild, moderate and severe AD) and 133 age-matched controls. Functional connectivity between EEG channels was estimated with the Phase Lag Index (PLI). From the PLI-based connectivity matrix, the minimum spanning tree (MST) was derived. For each node (EEG channel) in the MST, the betweenness centrality (BC) was computed, a measure to quantify the relative importance of a node within the network. Then we derived color-coded head plots based on BC values and calculated the center of mass (the exact middle had x and y values of 0). A shifting of the hub locations was defined as a shift of the center of mass on the y-axis across groups. Multivariate general linear models with PLI or BC values as dependent variables and the groups as continuous variables were used in the five conventional frequency bands.


RESULTS
We found that functional connectivity decreases with increasing disease severity in the alpha band. All, except for posterior, regions showed increasing BC values with increasing disease severity. The center of mass shifted from posterior to more anterior regions with increasing disease severity in the higher frequency bands, indicating a loss of relative functional importance of the posterior brain regions.


CONCLUSIONS
In conclusion, we observed decreasing functional connectivity in the posterior regions, together with a shifted hub location from posterior to central regions with increasing AD severity. Relative hub strength decreases in posterior regions while other regions show a relative rise with increasing AD severity, which is in accordance with the activity-dependent degeneration theory. Our results indicate that hubs are disproportionally affected in AD.
Alzheimer Center and Department of Neurology, Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, The Netherlands. mm.engels@vumc.nl.
Marjolein M A
MM
Engels
Department of Clinical Neurophysiology and MEG center, Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, The Netherlands. cj.stam@vumc.nl.
Cornelis J
CJ
Stam
Alzheimer Center and Department of Neurology, Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, The Netherlands. wm.vdflier@vumc.nl.|Department of Epidemiology and Biostatistics, Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, The Netherlands. wm.vdflier@vumc.nl.
Wiesje M
WM
van der Flier
Alzheimer Center and Department of Neurology, Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, The Netherlands. p.scheltens@vumc.nl.
Philip
P
Scheltens
Alzheimer Center and Department of Neurology, Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, The Netherlands. h.dewaal@vumc.nl.
Hanneke
H
de Waal
Department of Clinical Neurophysiology and MEG center, Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, The Netherlands. i.vanstraaten@vumc.nl.|Nutricia Advanced Medical Nutrition, Nutricia Research, Utrecht, The Netherlands. i.vanstraaten@vumc.nl.
Elisabeth C W
EC
van Straaten
D000368:Aged; D000544:Alzheimer Disease / Q000503:physiopathology*; D001921:Brain / Q000503:physiopathology*; D016022:Case-Control Studies; D004569:Electroencephalography; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009434:Neural Pathways / Q000503:physiopathology*; D012720:Severity of Illness Index