Disrupted Small-World Brain Networks in Moderate Alzheimer’s Dia:A Resting-State fMRI Study
Xiaohu Zhao1.,Yong Liu2.,Xiangbin Wang1,Bing Liu2,Qian Xi1,Qihao Guo3,Hong Jiang1,
Tianzi Jiang2,4,5*,Peijun Wang1*
1Imaging Department,TongJi University,TongJi Hospital Shanghai,China,2LIAMA Center for Computational Medicine,National Laboratory of Pattern Recognition, Institute of Automation,the Chine Academy of Sciences,Beijing,China,3State Key Laboratory of Medical Neurobiology,Department of Neurology,Institute of Neurology,Huashan Hospital,Shanghai Medical College,Fudan University,Shanghai,China,4Key Laboratory for NeuroInformation of Ministry of Education,School of Life Science and Technology,University of Electronic Science and Technology of China,Chengdu,China,5The Queensland Brain Institute,The University of Queensland, Brisbane,Australia
Abstract
The small-world organization has been hypothesized to reflect a balance between local processing and global integration in the human brain.Previous multimodal imaging studies have consistently de
monstrated that the topological architecture of the brain network is disrupted in Alzheimer’s dia(AD).However,the studies have reported inconsistent results regarding the topological properties of brain alterations in AD.One potential explanation for the inconsistent results lies with the diver homogeneity and distinct progressive stages of the AD involved in the studies,which are thought to be critical factors that might affect the results.We investigated the topological properties of brain functional networks derived from resting functional magnetic resonance imaging(fMRI)of carefully lected moderate AD patients and normal controls (NCs).Our results showed that the topological properties were found to be disrupted in AD patients,which showing incread local efficiency but decread global efficiency.We found that the altered brain regions are mainly located in the default mode network,the temporal lobe and certain subcortical regions that are cloly associated with the neuropathological changes in AD.Of note,our exploratory study revealed that the ApoE genotype modulates brain network properties,especially in AD patients.
Citation:Zhao X,Liu Y,Wang X,Liu B,Xi Q,et al.(2012)Disrupted Small-World Brain Networks in Moderate Alzheimer’s Dia:A Resting-State fMRI Study.PLoS ONE7(3):e33540.doi:10.1371/journal.pone.0033540日文
Editor:Olaf Sporns,Indiana University,United States of America
Received November30,2011;Accepted February10,2012;Published March23,2012
Copyright:ß2012Zhao et al.This is an open-access article distributed under the terms of the Creative Commons Attribution Licen,which permits unrestricted u,distribution,and reproduction in any medium,provided the original author and source are credited.
Funding:This work was partially supported by the National High Technology Rearch and Development Program of China(863Program,Grant No.2009AA02Z302),the National Key Basic Rearch and Development Program(973,Grant2011CBA00408),the Natural Science Foundation of China(Grant Nos.60831004,30970818,30770615,30970770).The funders had no role in study design,data collection and analysis,decision to publish,or preparation of the manuscript.
Competing Interests:Tianzi Jiang is an Academic Editor for PLoS ONE-no additional competing interests exist.
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*E-mail:jiangtz@nlpr.ia.ac(TJ);tongjipjwang@(PW)
.The authors contributed equally to this work.
Introduction
Alzheimer’s dia(AD)is the leading cau of intellectual impairment in the elderly worldwide[1,2,3].In its early stages,the most commonly recognized symptom is an inability to acquire new memories,such as difficulty in recalling recently obrved facts, which is commonly referred to as the loss of episodic memory.As the dia progress,extensive cognitive impairments begin to manifest,including language breakdown and long-term memory loss.Eventually,most brain functions deteriorate,ultimately leading to death.The neural basis underlying the functional damage is not yet fully understood.Recent studies bad on multimodal imaging have provided evidence supporting the notion of AD as a disconnection syndrome[4,5,6].
Information interactions between interconnected brain regions are believed to be a basis of human cognitive process[7,8]. Networks have been ud to model the brain and provide a new tool for understanding functional integration and gregation in the human brain and also the pathogenesis and treatment of neurological disorders[8,9,10,11].Elucidation of the complexity of brain networks will offer fundamental new insights into the general organizational principles of neurological functions from both global and integrative perspectives[8,12,13,14].Character-izing the underlying architecture of brain networks is an important issue in neuroscience.
Previous brain network studies of AD patients have revealed that their cognitive functional deficits m
ay be due to abnormalities in the connectivity between different brain areas,although there is no connsus as to what the alteration pattern is[15,16,17, 18,19,20,21].In2007,using EEG data,Stam and colleagues found that although the network clustering coefficient was unchanged in AD patients,the patients displayed a longer characteristic path length[19].However,in2008,using fMRI data,Supekar and colleagues found that AD patients had a lower clustering coefficient and no change in characteristic path length [20].In a structural imaging study the same year,He and colleagues found a higher clustering coefficient and longer characteristic path length in the brain structural networks of AD patients[17].In2009,using MEG data,Stam and colleagues found a lower clustering coefficient and higher characteristic path length in the brain network in AD patients[21].Furthermore,in 2010,using resting-state fMRI data,Sanz-Arigita and colleagues
found the clustering coefficient to be unchanged but a lower average shortest path in AD patients[18].In the same year,using structural MRI data,Yao and colleagues found a higher clustering coefficient and longer average shortest path length in AD patients; the authors also found that network topological measures in mild cognitive impairment(MCI)patients were between tho of AD and NC groups[15].It should be noted that until now,studies of the altered brain network pattern in AD patients have not produced consistent results.With the studies,rearchers do not obtain consi
stent results which may ari from the differences in the groups of subjects,different measurements and the image modalities ud.As previously established,patients at different stages may manifest different behavioral symptoms with distinct underlying neural mechanisms[22,23,24].Thus,a study focud on a group of subjects with a specific dia stage(for example, mild,moderate or vere AD)will help us understand the network alteration in AD.In addition,the apolipoprotein E(ApoE)gene, located on chromosome19,is a major susceptibility gene and is most clearly linked to late-ont AD.ApoE4is the risk allele of the ApoE gene in AD[25].An increasing amount of evidence has indicated that ApoE4modulates the brain activity of both normal aging and AD patients as measured by fMRI[26,27,28,29]. However,to our knowledge,the question of whether the ApoE gene affects the topological properties of AD in the brain has not yet been studied.
In the current study,we specifically focud on moderate AD patients to directly investigate the hypothesis that the brain network of AD is characterized by the disruption of efficient small-world topological properties bad on resting-state fMRI data. First,binary brain networks of individual brains were constructed with90brain regions as nodes extracted by an automated anatomical labeling(AAL)template[30]with inter-regional functional connectivity as edges.Second,the topological param-eters of the brain network(clustering coefficient,shortest path length,global efficiency and local
浙大录取分数线efficiency)were evaluated at different connection densities.Third,statistical differences be-tween the AD and NC groups were evaluated at both global and nodal levels.Finally,to evaluate the effects of genotype on global network properties,we compared network properties between NCs without ApoE4and ApoE42and ApoE4+AD patients. Materials and Methods
Subjects
Only moderate AD patients and the age and education matched NC were included in the prent study.All subjects gave voluntary and informed connts according to the standards t by the Ethics Committee of Tongji Hospital.The cognitive and neuropsychol-ogy tests were administered to each participant individually by a professional apprair in the neuropsychological rearch center. The cognitive abilities of the AD patients and controls were determined by Mini-Mental State Examination(MMSE)and Mattis Dementia Rating Scale(DRS)equivalent to that of the age-matched cognition level.The AD patients met the criteria for dementia as described by the National Institute of Neurological and Communicative Disorders and Stroke/Alzheimer Dia and Related Disorders Association(NINCDS-ADRDA)[31].The subjects were assd clinically with the Clinical Dementia Rating (CDR)scale[32]and categorized as non-demented normal controls(NCs)(CDR=0)and tho with moderate stages of AD (CDR=2).The inclusion criteria for both the normal controls and AD patie
nts were as follows:1)no anxiety or depressive disorders within a month;2)normal vision and hearing;3)cooperation with the cognitive tests;4)age50–85years old with no constraints on education level;5)no diagnod stroke history;6)no more than one lacunar infarction and no patchy or diffu leukoaraiosis as determined by MRI examination.
The exclusion criteria included:1)age under50years old or above85years old;2)the prence of the following dias or dia histories within a year:local brain injury,traumatic brain injury with loss of consciousness,confusion immediately following traumatic brain injury,rious mental dias and alcohol or drug abu;3)obviously incomplete heart,liver,kidney or lung function;blood disorders;endocrine dias;neurosyphilis;4) clinical depression;5)cancer;6)excessive psychotropic drug u. All subjects underwent a complete physical and neurological examination using an extensive battery of neuropsychological asssments and standard laboratory tests.Brain MRI scans of the AD patients showed no abnormalities other than brain atrophy. ApoE genotype
Venous blood samples from all subjects were added to EDTA anticoagulant after fMRI data acquisition.The technicians were blind to the diagnosis of the participants.ApoE genotypes were determined using standard methods[33].
The clinical and demographic data for the age-and gender-matched participants,excluding data from subjects with excessive head motion(e data preprocessing ction),are shown in Table1. Data acquisition
Images were scanned on an American Marconi1.5T EDGE ECLIPSE superconducting MRI system in the department of radiology of Tongji Hospital of Tongji University,Shanghai. Resting-state BOLD-fMRI was collected axially using an echo-planar imaging(EPI)quence with the following parameters: repetition time(TR)=2000ms,echo time(TE)=40ms,flip angle (FA)=90u,field of view(FOV)=24cm624cm,matrix=64664, NEX=1,slices=21,thickness=6mm,gap=1mm.The scan lasted for320conds.The subjects were instructed to keep their Table1.Demographic,clinical and neuropsychological data.
NC(n=20)AD(n=33)P
ApoE2ApoE+ApoE2ApoE+P d
Gender
(M/F)
10/1013/200.57a
10/90/18/115/90.710.61a Age(year)63.065.866.269.60.18b
63.365.85866.969.465.3610.10.640.42c MMSE27.861.315.362.9,0.001b
27.761.32915.363.015.262.90.92,0.001c DRS132.365.096.0610.8,0.001b 132.064.913894.669.997.8612.10.41,0.001c
a Chi-square was ud for gender comparisons.
b Two samples two sides t-test was ud for age and neuropsychological tests comparisons between AD and NC.
c One-way ANOVA was performe
d for ag
e and neuropsychological tests comparisons.
d Two samples two sides t-test was ud for ag
e and neuropsychological tests comparisons between ApoE2and ApoE+in AD group.
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MMSE,Mini-Mental State Examination,DRS,Dementia Rating Scale.
Gray background means the detail statistical of the subject divided by using ApoE genotype.
Demographic,clinical and neuropsychological data in normal control patients (NCs)and Alzheimer’s dia patients(AD).
doi:10.1371/journal.pone.0033540.t001
eyes clod,relax their minds and remain as motionless as possible during the data acquisition.Rubber earplugs were ud to reduce noi,and foam cushioning was ud to fix the head to reduce motion artifacts.
Data preprocessing
Unless specifically stated otherwi,all the preprocessing was carried out using statistical parametric mapping (SPM8,www.fil.ion.ucl.ac.uk/spm).The first 5images were discarded in consideration of magnetization equilibrium.The remaining 155images were corrected for the acquisition time delay
among different slices,and then the images were realigned to the first volume for head-motion correction.The fMRI images were further spatially normalized to the Montreal Neurological Institute (MNI)EPI template and resampled to a 2-mm cubic voxel.Several sources of spurious variance including the estimated motion parameters,the linear drift,and the average time ries in the cerebrospinal fluid and white matter regions were removed from the data through linear regression.Finally,temporal band-pass filtering (0.01#f #0.08HZ)was performed to reduce the effects of low-frequency drift and high-frequency noi [34,35].
The time cour of head motion was obtained by estimating the translations in each direction and the rotations in angular motion about each axis for each of the 155concutive volumes.All the subjects included in this study exhibited a maximum displacement of less than 3mm (smaller than the size of a voxel in plane)at each axis and an angular motion of less than 3u for each axis.Data from two subjects were excluded due to excessive motion.Furthermore,for exclusion the influence of head motion on functional connectivity results,an extra evaluation of the movement parameter between AD and NC group have been performed in line with the procedures described in Van Dijk et al.[36].
Anatomical parcellation
The registered fMRI data were gmented into 90regions (45for each hemisphere,Table S1)using an automated anatomical labeling template [30],which has been ud in veral previous studies [20,35,37,38,39,40].For each subject,a reprentative time ries of each individual region was then obtained by simply averaging the fMRI time ries over all voxels in this region.
Graph theoretical analysis
Brain
network结晶的意思
construction.
The Pearson correlationyuto
coefficients of each area were calculated for each pair of 90functionally connected regions.To simplify the statistical calculation,a Fisher r-to-z transformation was performed to increa the normality of the correlation matrix.Then,the absolute z values were converted into a binary connection matrix to make a graphic model of a brain network.That is,if the absolute z(i,j)(Fisher r-to-z of the partial correlation coefficient)of a pair of brain regions,i and j,exceeds a given threshold T,an
edge is said to exist;otherwi it does not exist.Spar networks of each subject were constructed using a minimum spanning tree method followed by global thresholds [41].
The degree of each node,D i ,is defined as the number of nodes directly connected to the region i.The total number of edges in a graph,divided by the maximum possible number of edges,N(N-1)/2,that is,Cost ~1
N (N {1)
X i [G D i ,is called the connection density or cost of the network,which measures how expensive it is to build the network [42].The graphs were constructed over the whole range of connection densities or costs,from 4%to 40%,at 2%intervals.Global and nodal network properties were evaluated statistically over the range of 4–40%,and nodal properties were
also analyzed at a connection density of 22%,at which the global efficiency showed the largest differences between AD and NC subjects.
Topological properties of the brain functional networks.All other topological properties considered were
calculated using in-hou software (Brat,wwwm/brat).The include the clustering coefficients (C p ),shortest path length (L p ),small-worldness,global efficiency (E global )and local efficiency (E local ),each of which have been described previously and ud in veral prior studies [35,38,39].Table 2provides an overview of the parameters and their meaning in brain functional networks.A detailed description of the parameters can be found in the supplemental material (Text S1).
Statistical analysis
Statistical comparisons of topological measures between the two groups were performed using a two-sample two-tailed t -test for each value over a wide range of connection densities (P ,0.05).We determined the regional distribution of any statistically significant changes in the topological properties found between the two groups.
Exploratory study of gene effect
To investigate the potential effect of ApoE genotype on network topological properties,we evaluated the differences between the NC ApoE42group and the AD ApoE42and ApoE4+groups and tho between the AD ApoE42and ApoE4+groups using a two-sample two-tailed t -test for each value over
a wide range of connection densities (P ,0.05).We determined the regional distribution of any statistically significant changes in the topological properties found between the two groups.
Caret v5.61software was ud to make cortical surface reprentations of the regional distributions of fixed group level network property alterations in the AD groups [43,44].The value plotted at a given point is the value of the template volume at a point below the surface at the level of the cortical layer.
Results
Cognitive and neuropsychology test
There were no significant differences in gender (P =0.591)or age (P =0.182)between the NC and AD groups.The MMSE scores of the NC group averaged 27.861.3,which fits the normal age-matched standard.The MMSE scores of the AD group averaged 15.362.9,which is significantly different from that of the NC group (P ,0.001).The Mattis Dementia Rating Scale (DRS)scores of the NC group averaged 132.3265.0and tho of the AD group averaged 96.00610.8,and the scores also markedly differed from each other (P ,0.001)(Table 1).There was one ApoE4+NC subject,19ApoE42NC subjects,19AD ApoE42subjects and 14AD ApoE4+subjects.There were no significant differences in
either gender or age between the NC ApoE42,AD ApoE42and AD ApoE4+groups (Table 1).In addition,there were no significant differences in MMSE or DRS scores between the ApoE42and ApoE4+AD groups (Table 1).
Evaluation of the movement parameter between AD and NC groups
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The displacements of the MAD and NC groups are 0.8960.39mm and 0.8060.60degree,respectively,and the rotations of the MAD and NC groups are 0.6960.33mm and 0.5260.30degree,respectively.No significant differences were found between the experimental groups (two-sample,two-tailed t -test;P =0.51for displacement and P =0.07for rotation).
Direct comparisons between the AD and NC groups The mean functional connectivity matrix of each group was calculated by averaging the N6N(N=90in the prent study) absolute connection matrix of all the subjects within the group.In the normal group,most of the strong functional connectivities(large z-scores)were between inter-hemispheric homogeneous regions, within a lobe,and between anatomically adjacent brain areas(Fig. S1).This functional connectivity pattern is consistent with many previous studies of whole brain functional connectivity in the resting-state[35,38,39,45].The AD group showed a similar functional connectivity pattern to that of the health
y group;however,the correlation strength was significantly altered(F1,51=22.2,P,0.001). Altered topological properties of functional networks in AD subjects
In the range of0.04#Cost#0.4,clustering coefficients(C p), shortest path length(L p),small-worldness,global efficiency(E global) and local efficiency(E local)values for the AD and NC groups were calculated and then compared using a two sample two-tailed t-test. With increasing connection density,C p,E global and E local all incread,whereas L p decread in both the AD and NC groups (Fig.1).Across the entire threshold range,C p and E local values were notably higher in the AD group than in the NC group (P,0.05)(Fig.1A and D).In a wide threshold range(0.04,0.34), the L p of the AD group was also significantly greater than in the normal controls(P,0.05)(Fig.1B),but the E global of the AD group was significantly lower than that of the NC group in this range(P,0.05)(Fig.1C).
The c,l and s(a detailed definition can be found in Table2 and the supplemental material)values of the brain network as a function of connection density within both groups is shown in Fig. 2.Both groups fit c=C p real/C p rand.1and l=L p real/ L p rand<1(Fig.2A and B).Thus,the functional networks of AD patients and NCs fit the definition of small-worldness[46].The c and l values were significantly higher in the AD group over nearly the entire range of connection density(Fig.2A and B).The s values of the AD group were significantly larger than that of the NC group in the range of0.1
4#Cost#0.4(Fig.2C). Distribution of brain regions with altered network properties in AD subjects
Two-sample two-tailed t-tests for each of the90regions was performed to further localize the nodes that demonstrated significant differences between the AD and normal control groups.
Fig.3shows the frequencies of the altered nodes that were found across the19threshold times(P,0.05)in the AD patients (Fig.S2).As shown in Fig.3,the regions showing significant alterations in C p and E local are widely distributed across the brain, especially in the default mode network,which is compod of the right posterior cingulate gyrus(PCC_R),the anterior cingulate and paracingulate gyrus(ACC),the opercular part of the inferior frontal gyrus(IFGoper),the superior frontal gyrus(SFG),regions in the temporal lobe such as the superior temporal gyrus(STG), and regions in the subcortical structure such as the right thalamus (THA_R),left lenticular nucleus pallidum(PAL_L)and right lenticular nucleus putamen(PUT_R).The regions showing significant alterations in E global and L p are distributed primarily in regions of the temporal lobe,such as the middle temporal gyrus temporal pole(MTGp)and right middle temporal gyrus (MTG_R),and nsory motor regions,such as the right supplementary motor area(SMA_R)and right precentral gyrus (PreCG_R).
miss sophieWe further explored the brain regions where the topological parameters were significantly different between AD patients and NCs at the cost of0.22(global efficiency showed the most prominent differences at this connection density).As shown in Fig.4(A/B/D),most of network topological properties(C p,L p and E local)were found to be incread in AD patients relative to controls across widely distributed regions(also e Fig.S3).We generally grouped the altered regions into three clusters.The first cluster is the default mode network(Fig.4);nearly all the regions belonging to a typical default mode network can be identified in our results,such as the ACC,PCC,middle prefrontal cortex (MPFC),hippocampus(HIP)and inferior parietal cortex(IPL). The cond cluster includes parts of the subcortical structure such as the thalamus(THA),lenticular nucleus putamen(PUT)and INS(Fig.4).The third cluster consists of regions of the temporal lobe such as the superior/middle temporal gyrus temporal pole (STGp/MTGp)and the bilateral middle temporal gyrus(MTG), which showed significantly decread E global in AD patients (Fig.4C).E global was also found to be decread in AD patients in motor areas such as SMA_R and PreCG_R.
The ApoE4gene modulates global network properties Compared with the NC ApoE42subjects,the AD patients had significantly higher C p,higher E local,and longer L p,but lower E global(Fig.1,E–H)regardless of their ApoE4status(P,0.05). Relative to the AD ApoE42group,the AD ApoE4+group showed lower C p,lower E local,shorter L p,and higher E global.
Table2.Overview of the measurements and their meaning in brain functional network.
Character Meaning
D p degree of connectivity which evaluates the level of sparness of a network
cost cost of network
C p clustering coefficient which measures the extent of a local cluster of the network
L p path length which measures of the extent of average connectivity of the network
c c=C p real/C p rand,the ratio of the clustering coefficients between real an
d random network l l=L p real/L p rand,th
e ratio o
f the path length between real and random network
s s=c/l,scalar quantitative measurement of the small-wordness of a network
E global a measure of the global efficiency of parallel information transfer in the network
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E local a measure of the fault tolerance of the network
Overview of brain functional network parameters and their meanings.
doi:10.1371/journal.pone.0033540.t002
Although the differences did not reach statistical significance,the trend was clear (Fig.1,E,F,G,H,Fig.2,D,E,F).In addition,the brain regions where the topological parameters significantly differ between the patients carrying and not carrying ApoE4gene were investigated.The AD ApoE42patients displayed higher C p ,higher E local ,and longer L p in the temporal cortex,frontal cortex and medial prefrontal cortex,and they displayed lower E global in the frontal cortex (Fig.5D,E,F,Fig.S4).
Discussion
Our results revealed that the topological properties of the brain networks in the moderate AD group were disrupted compared to tho in the normal controls.Specifically,the altered regions were mainly distributed in the default mode network,the temporal lobe and subcortical structures.More importantl
y,we also evaluated the effects of genotype on network properties,especially in the AD group.
Small-world topology in normal individuals
The human brain is a functionally specialized organ with anatomically distinct structures.Cognition requires a high level of functional interaction between brain regions to support daily activities.Recent studies with noninvasive brain imaging technol-ogies such as MRI,EEG,and MEG have demonstrated that the human brain’s structural and functional networks have small-world properties [9,10,47].The brain networks in NCs and AD
patients fit the features of small-world networks,suggesting that the human brain supports rapid real-time integration of information across gregated nsory brain regions [12,13]to confer resilience against pathological attacks [39]and to maximize efficiency at a minimal cost for effective information processing between different brain regions [38],irrespective of age or illness status.
Altered small-world topology in AD patients
Our investigation revealed that network topological properties are altered in AD patients,consistent with previous studies [15,17,18,19,20,21,48].
C p is a measure of local network connectivity.It reflects the local efficiency and error tolerance [49]of a network.Higher network clustering coefficients indicate more concentrated clus-tering of local connections and stronger local information processing capacity [10].The C p of brain functional networks was found to be higher in A
D patients,indicating that the patients have stronger local information processing capacity.This finding is consistent with previous structural network studies in AD [15,17].
The average shortest path length (L p )of a network reflects how the network connects internally [46].In brain networks,the shortest path ensures the effective integration and fast transmission of information between distant brain areas.Generally speaking,the integration and transmission of information are the bas of cognitive processing [8,11,13].Our results demonstrate that
the
Figure 1.Change of network parameters as a function of connection density (Cost).Clustering coefficient (A ),shortest path length (B ),global efficiency (C )and local efficiency (D )of the AD (green
line)and NC (red line)groups as a function of Cost.Clustering coefficient (E ),shortest path length (F ),global efficiency (G )and local efficiency (H )of the AD ApoE4+(black line),AD ApoE42(blue line)and NC ApoE42(red line)groups as a function of Cost.The error bars correspond to the standard error of the mean.Blue asterisks indicate where the difference between the NC and AD groups is significant (P ,0.05).Blue circles indicate points where the difference between the AD ApoE42group and the NC ApoE42group is significant (P ,0.05).Blue squares indicate points where the difference between the AD ApoE4+group and the NC ApoE42group is significant (P ,0.05).The difference between the AD ApoE 2group and the AD ApoE +group is not significant at any Cost (P .0.05).doi:10.1371/journal.pone.0033540.g001
average shortest path of the brain functional networks in AD patients was significantly greater than that in NCs,indicating that the long distance information integration and transmission capacity of neurons is reduced in AD patients [15,18,19].Together with the lower global efficiency in AD,the results suggest that information transfer between brain regions is more difficult in AD patients.Our results are consistent with veral studies reporting attenuated long-distance functional connections and incread local functional connections in AD patients [50,51,52].
Altered network properties at the node level in AD subjects
Comparisons of C p ,L p ,E local and E global provided us a perspective with which to investigate differences at the global level,and further nodal level comparisons localized the regions with significantly divergent brain network topological properties.We first explored the brain regions in which AD-related alterations were most likely to occur,and we further investigated the brain regions where the topological properties of AD patients differed significantly from tho of the NCs.Our results revealed nearly overlapping patterns of brain regions (Fig.3and Fig.4)where higher frequency alterations occurred,thereby showing significant differences between the two groups.We generally grouped the regions into three clusters of the default mode network,the subcortical structure and the temporal lobe.The regions had a higher probability of significantly abnormal topological properties in AD patients compared to NCs.
The default mode network has received growing attention over the last decade in neuroimaging studies [53,54]investigating the functions of remembering the past,envisioning future events,and
considering the thoughts and perspectives of other people [55,56,57,58].The relationships between the default mode network and AD and MCI have been extensively investigated using multiple imaging approaches including PET,structural MRI and fMRI [3,53,59].In all instances,from metabolism changes to structural atrophy to functional abnormalities,the multiple modality method
s have consistently revealed abnormal changes in the default mode network of AD patients.For example,previous studies using PET and single photon emission computed tomography techniques found that AD patients had abnormally low cerebral blood flow and low cerebral metabolic rates for gluco in many brain regions,including the parietal,temporal,and prefrontal cortices and the PCC [60,61,62,63,64].Metabolic studies have revealed that the pattern of hypometabolism bears a striking remblance to the regions comprising the default network [65,66].Structural MRI has shown gray matter loss in some regions belonging to the default network [67,68].Several fMRI studies [59,65,69,70]have revealed consistent disruption with metabolic and structural changes in the default mode network in AD patients.Thus,our results complement and extend previous topological studies revealing a disrupted default network in AD patients.
Another important cluster in which the network properties are altered is the subcortical structure,particularly the thalamus and putamen.The thalamus is an important region with complex functions.In particular,every nsory system (with the exception of the olfactory system)includes a thalamic nucleus that receives nsory signals and nds them to the associated primary cortical region.The anterior and dorsal medial nuclei of the thalamus [71]and mammillo-thalamic tract [72]were found to be involved in episodic memory,which is specifically impaired in AD
[73].
自信演讲稿
Figure 2.Change of small-world network definition parameters as a function of connection density (Cost).c (A ),l (B ),and s (C )of the AD (green line)and NC (red line)groups as a function of Cost.c (D ),l (E ),and s (F )of the AD ApoE4+(black line),AD ApoE42(blue line)and NC ApoE42(red line)groups
as a function of Cost.The error bars correspond to the standard error of the mean.Blue asterisks indicate points where the difference between the two groups is significant (P ,0.05).Blue circles indicate points where the difference between the AD ApoE42group and the NC ApoE42groups is significant (P ,0.05).No significant differences were found between the NC ApoE42and AD ApoE4+groups at any threshold (P .0.05)or between the ApoE42and AD ApoE4+groups.doi:10.1371/journal.pone.0033540.g002
