Network analysis of intrinsic functional brain connectivity in Alzheimer's disease.
- Authors
- Supekar, Kaustubh; Menon, Vinod; Rubin, Daniel; Musen, Mark; Greicius, Michael D
- Year
- 2008
- Journal
- PLoS computational biology
- PMID
- 18584043
- DOI
- 10.1371/journal.pcbi.1000100
- PMCID
- PMC2435273
Functional brain networks detected in task-free ("resting-state") functional magnetic resonance imaging (fMRI) have a small-world architecture that reflects a robust functional organization of the brain. Here, we examined whether this functional organization is disrupted in Alzheimer's disease (AD). Task-free fMRI data from 21 AD subjects and 18 age-matched controls were obtained. Wavelet analysis was applied to the fMRI data to compute frequency-dependent correlation matrices. Correlation matrices were thresholded to create 90-node undirected-graphs of functional brain networks. Small-world metrics (characteristic path length and clustering coefficient) were computed using graph analytical methods. In the low frequency interval 0.01 to 0.05 Hz, functional brain networks in controls showed small-world organization of brain activity, characterized by a high clustering coefficient and a low characteristic path length. In contrast, functional brain networks in AD showed loss of small-world properties, characterized by a significantly lower clustering coefficient (p<0.01), indicative of disrupted local connectivity. Clustering coefficients for the left and right hippocampus were significantly lower (p<0.01) in the AD group compared to the control group. Furthermore, the clustering coefficient distinguished AD participants from the controls with a sensitivity of 72% and specificity of 78%. Our study provides new evidence that there is disrupted organization of functional brain networks in AD. Small-world metrics can characterize the functional organization of the brain in AD, and our findings further suggest that these network measures may be useful as an imaging-based biomarker to distinguish AD from healthy aging.
Graph metricsβdegree, Ξ» (L/Lran), Ξ³ (C/Cran), Ο (Ξ³/Ξ»), for the AD group (Ξ) and the control group (β) at three frequency intervalsβ0.01 to 005 Hz (green), 0.06 to 0.12 Hz (blue), and 0.13 to 0.25 Hz (red).(A) For both groups, the mean degreeβa measure of network connectivity is highest at Scale 3 for a wide range of correlation thresholds (0.01<R<0.7), (B) The mean characteristic path length (Ξ») is low (1<Ξ»<1.27) and shows similar trends at all the scales (C) The clustering coefficient (Ξ³) for both groups is highest at Scale 3. (D) Due to higher mean Ξ³ values, the small-world measure Ο (Ξ³/Ξ») is highest at Scale 3 for both groups. The small-world property (Ο>1) showed a linear increase in small-worldness as the threshold increased (degree decreased). Ο values for higher correlation thresholds are hard to interpret as at higher threshold values graphs of functional brain networks have fewer edges (smaller degree) and tend to split into isolated sub-graphs.
Small-world properties for networks derived by thresholding the correlation matrices such that the network has Kβ² edges.Error bars represent values two standard deviations from the mean. (A) Mean Ξ» (L/Lran) values for the AD group and the control group. No significant differences in the mean Ξ» values are observed. (B) Mean Ξ³ (C/Cran) values for the AD group and the control group. Ξ³ values in AD group were significantly lower (indicated by *) than that in the control group (p<0.01). (C) Mean Ο (Ξ³/Ξ») values for the AD group and the control group. Ο values in AD group were significantly lower (indicated by *) than that in the control group (p<0.01).
Global efficiency of whole-brain functional connectivity network.(A) Global efficiency measure (Eglobal), for the AD group (Ξ) and the control group (β) at three frequency intervalsβ0.01 to 005 Hz (green), 0.06 to 0.12 Hz (blue), and 0.13 to 0.25 Hz (red). The mean Eglobal value is low (0.78<Ξ»<1) and shows similar trends at all the scales. (B) For the frequency interval 0.01 to 005 Hz (green)βmean Eglobal values for the AD group and the control group for networks derived by thresholding the correlation matrices such that the network has Kβ² edges. No significant differences in the mean Eglobal values were observed. Error bars represent values two standard deviations from the mean.
Receiver operating characteristic curve, plot of the sensitivity vs. (1-specificity) for distinguishing AD participants from controls as a function of varying normalized clustering coefficient (Ξ³) threshold.Using a cut-off value of 1.57, Ξ³ correctly classified 14 out of 18 controls and 15 of 21 AD subjects yielding 72% sensitivity and 78% specificity. The Area under the curve was 0.754 (95% CI Area 0.602 to 0.906).
Small-world property Ξ³ (C/Cran), the normalized clustering coefficient, for four regions of interestβleft hippocampus (Hippocampus - Left), right hippocampus (Hippocampus - Right), left precentral gyrus (Precentral Gyrus - Left), right precentral gyrus (Precentral Gyrus - Right)βfor the AD group (red) and the control group (blue) as a function of the correlation threshold.In the left and the right hippocampus, for threshold values from 0.1 to 0.6, the clustering coefficient values in the AD group were significantly lower (p<0.01) than in the control group, while for the left and the right precentral gyrus, no significant differences in the clustering coefficient values were observed at any correlation threshold.
| Name | Type |
|---|---|
| 90 anatomical regions of interest local | anatomy |
| 90 cortical regions network local | anatomy |
| Acetylcholinesterase inhibitor local | drug |
| AD patients | cohort |
| AD subjects | cohort |
| age | phenotype |
| age-matched controls local | cohort |
| Age-matched controls local | cohort |
| alcohol dependence | phenotype |
| Alzheimer's disease local | cohort |
| Alzheimer's disease | phenotype |
| amygdala | anatomy |
| anatomical region | anatomy |
| angular gyrus | anatomy |
| anterior cingulate cortex | anatomy |
| anterior commissure | anatomy |
| apoE | gene |
| APOE 4 allele local | variant |
| APOE Ξ΅4 allele | gene |
| brain | anatomy |
| brain networks | anatomy |
| calcarine fissure local | anatomy |
| caudate nucleus | anatomy |
| characteristic path length | phenotype |
| Clustering coefficient local | drug |
| cognitive decline | phenotype |
| cognitive domains local | phenotype |
| cognitive reserve local | phenotype |
| control | cohort |
| control group | cohort |
| controls | cohort |
| control subjects | cohort |
| corpus striatum region local | anatomy |
| cortex | anatomy |
| default mode network | anatomy |
| default-mode network | anatomy |
| dorsal striatum | anatomy |
| dysfunctional brain connectivity local | anatomy |
| EEG | phenotype |
| efficiency | phenotype |
| episodic memory | phenotype |
| fMRI signal local | drug |
| focal regions of abnormal brain function local | anatomy |
| frontal cortex | anatomy |
| frontal lobe - corpus striatum connectivity local | anatomy |
| frontal-prefrontal local | anatomy |
| fronto-corpus striatum local | anatomy |
| functional brain network local | drug |
| functional connectivity | phenotype |
| fusiform gyrus | anatomy |
| Global functional brain organization local | anatomy |
| global functional organization local | anatomy |
| gyrus rectus | anatomy |
| Healthy aging local | phenotype |
| Healthy human subjects local | cohort |
| heschl gyrus | anatomy |
| hippocampus | anatomy |
| human brain | anatomy |
| inferior frontal gyrus | anatomy |
| inferior occipital gyrus | anatomy |
| inferior parietal lobule | anatomy |
| inferior temporal gyrus | anatomy |
| intrafrontal local | anatomy |
| intratemporal local | anatomy |
| lateral temporoparietal cortices local | anatomy |
| left precentral gyrus | anatomy |
| Less impaired MCI patients local | cohort |
| lingual gyrus | anatomy |
| long-range connectivity local | phenotype |
| Macaque cortex local | anatomy |
| magnetoencephalogram | drug |
| Maximum overlap discrete wavelet transform local | drug |
| MCI patients local | cohort |
| mean Ξ³ local | phenotype |
| mean Ξ» local | phenotype |
| mean Ο local | phenotype |
| medial temporal region local | anatomy |
| median cingulate | anatomy |
| memantine | drug |
| Memory disorder clinics local | cohort |
| middle frontal gyrus | anatomy |
| middle occipital gyrus | anatomy |
| middle temporal gyrus | anatomy |
| Mild cognitive impairment | phenotype |
| MMSE | phenotype |
| neocortical regions | anatomy |
| neurodegenerative disorders | phenotype |
| NMDA-receptor antagonist local | drug |
| Non-AD dementias local | phenotype |
| nonalcoholic | cohort |
| Normal subjects local | phenotype |
| occipital cortex | anatomy |
| occipital lobe region local | anatomy |
| olfactory gyrus local | anatomy |
| other parts of frontal lobe region local | anatomy |
| pallidum | anatomy |
| paracentral lobule | anatomy |
| parahippocampal gyrus | anatomy |
| parietal lobe region local | anatomy |
| postcentral gyrus | anatomy |
| posterior cingulate cortex | anatomy |
| posterior commissure | anatomy |
| precentral gyrus | anatomy |
| precuneus | anatomy |
| prefrontal areas - frontal lobe connectivity local | anatomy |
| prefrontal cortex | anatomy |
| prefrontal lobe region local | anatomy |
| Primate cerebral cortex local | anatomy |
| Primate cortical visual system local | anatomy |
| PSEN1 | gene |
| PSEN2 | gene |
| PSEN2 mutation local | variant |
| putamen | anatomy |
| rest1 dataset local | cohort |
| rest2 dataset local | cohort |
| right cuneus | anatomy |
| right precentral gyrus | anatomy |
| rolandic operculum | anatomy |
| Scale 1 (0.13-0.25 Hz) local | drug |
| Scale 2 (0.06-0.12 Hz) local | drug |
| Scale 3 (0.01-0.05 Hz) local | drug |
| sex | phenotype |
| Small-world architecture local | phenotype |
| Small-world metric local | drug |
| small-world network characteristics local | anatomy |
| Small-world properties | phenotype |
| Stanford University local | cohort |
| sub-cortical regions local | anatomy |
| subjects with AD local | cohort |
| superior frontal cortex | anatomy |
| superior occipital gyrus | anatomy |
| superior parietal cortex | anatomy |
| superior temporal gyrus | anatomy |
| supplementary motor area | anatomy |
| supramarginal gyrus | anatomy |
| Task-free fMRI local | drug |
| task-free functional magnetic resonance imaging local | drug |
| Task-free functional MRI dataset local | cohort |
| temporal | anatomy |
| temporal lobe | anatomy |
| temporal lobe - corpus striatum connectivity local | anatomy |
| temporal lobe - thalamus connectivity local | anatomy |
| temporal pole | anatomy |
| temporo-corpus striatum local | anatomy |
| Temporoparietal junction local | anatomy |
| temporo-thalamus local | anatomy |
| thalamo-frontal local | anatomy |
| thalamo-occipital local | anatomy |
| thalamus | anatomy |
| thalamus - frontal lobe connectivity local | anatomy |
| thalamus - occipital lobe connectivity local | anatomy |
| Tzourio-Mazoyer anatomical template local | anatomy |
| UCSF longitudinal study of normal aging local | cohort |
| University of California San Francisco local | cohort |
| wavelet correlation matrix local | drug |
| Wavelets local | drug |
| whole brain | anatomy |
| whole-brain functional connectivity network local | anatomy |
| whole-brain functional connectivity network local | phenotype |
| Whole-brain functional connectivity network local | anatomy |
| Whole brain functional network local | anatomy |
| years of education | phenotype |
| Ξ³ (normalized clustering coefficient) local | drug |
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