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Grey and white matter abnormalities inchronic obstructive pulmonary disease: acaseecontrol study

Haiyan Zhang,1 Xiaochuan Wang,2 Jianzhong Lin,3 Yinchuan Sun,1

Yongxia Huang,1 Tianhe Yang,3 Shili Zheng,4 Ming Fan,5 Jiaxing Zhang1

ABSTRACTObjectives: The irreversible airflow limitationcharacterised by chronic obstructive pulmonarydisease (COPD) causes a decrease in the oxygensupply to the brain. The aim of the present study wasto investigate brain structural damage in COPD.

Design: Retrospective caseecontrol study. Patientswith COPD and healthy volunteers were recruited. Thetwo groups were matched in age, gender andeducational background.

Setting: A hospital and a number of communities: theyare all located in southern Fujian province, China.

Participants: 25 stable patients and 25 controls wereenrolled from December 2009 to May 2011.

Methods: Using voxel-based morphometry and tract-based spatial statistics based on MRI to analyse greymatter (GM) density and white matter fractionalanisotropy (FA), respectively, and a battery ofneuropsychological tests were performed.

Results: Patients with COPD (vs controls) showeddecreased GM density in the limbic and paralimbicstructures, including right gyrus rectus, left precentralgyrus, bilateral anterior and middle cingulate gyri,bilateral superior temporal gyri, bilateral anterior insulaextending to Rolandic operculum, bilateral thalamus/pulvinars and left caudate nucleus. Patients with COPD(vs controls) had decreased FA values in the bilateralsuperior corona radiata, bilateral superior and inferiorlongitudinal fasciculus, bilateral optic radiation,bilateral lingual gyri, left parahippocampal gyrus andfornix. Lower FA values in these regions wereassociated with increased radial diffusivity and nochanges of longitudinal diffusivity. Patients with COPDhad poor performances in the Mini-Mental StateExamination, figure memory and visual reproduction.GM density in some decreased regions in COPD hadpositive correlations with arterial blood Po2, negativecorrelations with disease duration and also positivecorrelations with visual tasks.

Conclusion: The authors demonstrated that COPDexhibited loss of regional GM accompanied byimpairment of white matter microstructural integrity,which was associated with disease severity and mayunderlie the pathophysiological and psychologicalchanges of COPD.

INTRODUCTIONChronic obstructive pulmonary disease (COPD)continues to be a major cause of morbidity andmortality. It is increasingly recognised thatCOPD extends beyond the lung.1 The irrevers-ible airflow limitation characterised by COPDusually develops arterial oxygen desaturation,which could subsequently result in a decrease inoxygen transport to the brain. Hypoxia duringCOPD has been previously proven to inducecerebral perfusion decline2 and metabolicchanges.3e6 Moreover, systematic inflamma-tion1 may also cause neuronal damages inthe brain of patients with COPD. In patientswith COPD, clinical symptoms such asneuropsychological deficits,7 depression andanxiety,1 and physical disability1 have beenwell documented. Taken together, thesedata suggest the presence of brain structuralalteration. However, until now, it remainslargely uninvestigated.Voxel-based morphometry (VBM) and

Tract-Based Spatial Statistics (TBSS)8 basedon MRI were adopted to measure greymatter (GM) density and white matter (WM)fibrous microstructure properties in tracts,

ARTICLE SUMMARY

Article focus- Decreased oxygen supply to brain may cause

neuronal damage in COPD. However, the damageremains largely uninvestigated.

Key messages- We found that COPD extends to the brain, with

the loss of regional cortical grey matter accom-panied by impairment in the white mattermicrostructural integrity.

- Our findings would be help for clinical therapy ofCOPD.

Strengths and limitations of this study- Multiple analyses were used based on MR

images. The statistic power for FA analysis wasweak.

To cite: Zhang H, Wang X,Lin J, et al. Grey and whitematter abnormalities inchronic obstructivepulmonary disease:a caseecontrol study. BMJOpen 2012;2:e000844.doi:10.1136/bmjopen-2012-000844

< Prepublication history forthis paper is available online.To view these files pleasevisit the journal online (http://dx.doi.org/10.1136/bmjopen-2012-000844).

HZ and XW contributedequally to this work.

Received 12 January 2012Accepted 6 March 2012

This final article is availablefor use under the terms ofthe Creative CommonsAttribution Non-Commercial2.0 Licence; seehttp://bmjopen.bmj.com

For numbered affiliations seeend of article.

Correspondence toDr Jiaxing Zhang;[email protected]

Zhang H, Wang X, Lin J, et al. BMJ Open 2012;2:e000844. doi:10.1136/bmjopen-2012-000844 1

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respectively. VBM is an automatic quantitative volumetrictechnique over the whole brain using voxel by voxelanalysis without prior specification of regions-of-interestfor analysis, and it does not rely on arbitrarily predefinedstructures. Recently, the preprocessing steps of VBMhave been improved with the Diffeomorphic AnatomicalRegistration Through Exponentiated Lie algebra(DARTEL) registration method,9 which can achievemore accurate intersubject registration of brain images.

TBSS is a recently introduced method, which uses diffu-sion tensor MR imaging (DTI) to measure differences infractional anisotropy (FA) between groups. TBSS increasesthe sensitivity and the interpretability of the resultscompared with voxel-based approaches based purely onnon-linear registration.8 Moreover, diffusion tensoreigenvalues were also included in the analysis since theycan help interpret FA changes in WM tracts by providinginformation regarding likely alterations in the propor-tion of longitudinally versus obliquely aligned myelin-ated fibres. The VBM and TBSS methods have beenextensively applied in clinical researches, including theevaluation of morphological characteristics of high-alti-tude residents in our previous study.10

Dyspnoea is the most common complaint and mostdisabling symptom in patients with COPD. FunctionalMRI studies on breathlessness, air hunger and inspira-tory loaded breathing have revealed that a large numberof brain regions, including the frontal cortex, parietalcortex, temporal cortex, limbic cortex, cerebellar cortexand brainstem were activated by dyspnoea.11 Thesedyspnoea-activated brain regions have been shown to beimpaired in patients with congenital central hypo-ventilation syndrome,12 in patients with obstructive sleepapnoea13 and in high-altitude residents.10 We thereforehypothesised that patients with COPD would havesimilar cerebral impairment.

METHODSSubjectsTwenty-five patients were enrolled from December 2009to May 2011. All patients had undergone a period of

Table 1 Demographic characteristics of the patients withCOPD and healthy volunteers

Patientswith COPD Controls p Value

Number of subjects 25 25Gender (female), % 16 16Age (years),mean6SD (range)

69.268.1(58e84)

67.9668.0(57e86)

0.59

Education (years),mean6SD

6.763.9 7.565.0 0.53

Family history ofCOPD, %

4 e

Disease duration(years)

7.065.7 e

Actual smokers, % 44 40 0.86

COPD, chronic obstructive pulmonary disease.

Table 2 Physiological and psychological characteristics

Patients withCOPD Controls p Value

BMI (kg/m2) 20.863.9 22.662.6 0.081ADL 20.166.5 14.661.5 <0.001Heart rate 92.4616.2 70.968.9 <0.001Blood pressure (mm Hg)

Systolic pressure 136.1619.1 136.5618.0 0.940Diastolic pressure 81.8610.7 77.5614.5 0.307

Haematological measurementsSao2, % 94.064.2 97.061.3 0.003Po2 (mm Hg) 79.9623.3 98.5611.3 0.006Pco2 (mm Hg) 48.166.0 39.863.0 <0.001pH 7.3760.1 7.460.01 0.731

Pulmonary function testingRespiratory rate(breaths/min)

23.566.0 16.965.5 0.003

FVC (% predicted) 66.6617.2 96.1614.7 <0.001FEV1 (% predicted) 43.4616.4 97.5616.9 <0.001FEV1/FVC, % 50.3610.7 80.068.3 <0.001

Cognitive testsMMSE 23.363.4 25.862.1 0.021Digit spanForward task 7.061.6 7.761.4 0.125Backward task 4.161.9 4.361.5 0.612

Visual reproduction 8.263.4 10.363.0 0.031Figure memory 10.563.0 12.461.9 0.010

Data are presented as mean 6 SD.ADL, activities of daily living; BMI, body mass index; COPD,chronic obstructive pulmonary disease; FVC, forced vital capacity;FEV1, forced expired volume in one second; MMSE, Mini-MentalState Examination.

Figure 1 A statistical parametric map for grey matter densityreduced in patients with chronic obstructive pulmonary diseaseversus healthy controls (pFDR_corrected <0.01) overlaid onthe Montreal Neurological Institute template.

2 Zhang H, Wang X, Lin J, et al. BMJ Open 2012;2:e000844. doi:10.1136/bmjopen-2012-000844

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30e45 days of in-hospital rehabilitation following anacute exacerbation of COPD. At the time of data collec-tion, patients were in stable condition. Among thesepatients, 12 discharged patients were recruited duringtheir rest at home and 13 patients were recruited whenthey were awaiting discharge from hospital. Patients werediagnosed in Zhongshan Hospital (Xiamen, China)according to the diagnostic criteria of Global Initiativefor Chronic Obstructive Lung Disease.14 Twenty-fivehealthy volunteers, with comparable age, gender andeducational background, comprised the control group.All the subjects were free from a known history of cere-brovascular accident, heart failure, neurological disor-ders, obstructive sleep apnoea, coronary artery disease,diabetes or other diseases known to affect cognition.Patients were provided with therapy including inhaledipratropium bromide, bricanyl, ventoline and budeso-nide. Demographic characteristics of the patients andhealthy volunteers were listed in table 1. Procedures werefully explained, and all subjects were provided written

informed consent before participating in the study. Theexperimental protocol was approved by the ResearchEthics Review Board of Xiamen University.

Physiological and neuropsychological testsPhysiological and neuropsychological tests and activitiesof daily living (ADL) (score range 14e56)15 wereconducted 1 day before the MRI scan. Physiological testsinclude pulse rate and arterial blood pressure measures,arterial blood gas analysis and pulmonary functionmeasure. Blood samples were taken in the morningbetween 07:00 and 07:30 h. The neuropsychological testsinclude (1) the Chinese version of the Mini-Mental StateExamination (MMSE) that measured the generalcognitive function and (2) the visual reproduction test,figure memory test and digital span forward and back-ward tasks, which, taken from the Chinese revisedversion of the Wechsler Memory Scale, were used tomeasure visual construction ability, visuospatial memoryand short-term working memory, respectively.16 All data

Figure 2 Grey matter densitydecrease in patients with chronicobstructive pulmonary diseaseversus healthy controls.Three-dimensional slicesdepicting regions showingreduced grey matter in the rightgyrus rectus, left precentral gyrus,left Rolandic operculum andsuperior temporal gyrus overlaidon a T1-weighted MRI anatomicalimage in the MontrealNeurological Institute template.




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were analysed using SPSS V.19.0. Independent t testmeasured between-group differences. Statistical signifi-cance was set at p<0.05.

MRI data acquisitionImages were acquired on a Siemens Trio Tim 3.0T(Erlangen, Germany) at MRI Research Center (Zhong-shan Hospital). A three-dimensional (3D) structuralMRI was acquired from each subject using a T1--weighted MPRAGE sequence (TR/TE¼1900 ms/2.48 ms, FOV¼25325 cm2, NEX¼1, matrix¼5123256,slice thickness¼1.0 mm). Conventional two-dimensionalT1 and T2 images were also acquired and examined forany incidental findings. A DTI pulse sequence withsingle shot diffusion-weighted echo planar imaging(TR/TE¼3600/95 ms, FOV¼24324 cm2, NEX¼2,matrix¼1283128, slice thickness¼4.5 mm) was ap-plied sequentially in 30 non-collinear directions(b-value¼1000 s/mm2) with one scan without diffusionweighting (b¼0s/mm2). The following data analyses were

conducted by two researchers who were blinded to thestatus of subjects.

VBM analysis of 3D T1 imagesThe 3D T1 images were used for GM analysis usingVBM8 toolbox implemented in SPM8 (WellcomeDepartment of Imaging Neuroscience, UniversityCollege London, London, UK). The followingprocessing steps were carried out: (1) the images wereinspected and set at the anterior commissure. Eachreorientated image was segmented into GM, WM andcerebrospinal fluid in native space, and procrustesaligned GM images were generated by a rigid trans-formation. (2) The DARTEL registration method wasused to create a study-specific template by using thealigned images from all the patients and controls toimprove intersubject registration of structural images.9

The procedure implicated in six iterations, which beganwith the averaging of aligned data to generate an orig-inal template. Then, the first iteration of the registration

Figure 3 Grey matter densitydecrease in patients with chronicobstructive pulmonary diseaseversus healthy controls. Three-dimensional slices depictingregions showing reduced greymatter in the bilateral anterior andmiddle cingulate gyri overlaid ona T1-weighted MRI anatomicalimage in the MontrealNeurological Institute template.




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was completed on each subject and a new template wascreated. After this, the second iteration began. When sixiterations were finished, the template was generated,which was the average of the DARTEL registered data.During iterations, all images were warped to thetemplate yielding a series of flow fields that para-meterised deformations. (3) The normalised imageswere transformed into Montreal Neurological Institutespace. These GM images were then smoothed usinga Gaussian kernel of 8 mm full-width at half-maximum.Independent t tests were performed to examinebetween-group differences. The statistical parametricmap was generated with the voxel level threshold att>3.7734 p<0.01 (false discovery rate FDR correctionwith gender, age, education and total intracranialvolume as covariates).To analysed the correlation of GM image values with

cognitive or physiological measurement, the followingsteps were first taken: (1) regions-of-interests werecreated for clusters showing differences between groups

and (2) using these regions-of-interests masks, the GMvalues were extracted from each individual’s normalisedand smoothed GM maps. Then, the correlations wereanalysed using SPSS. Statistical significance was set atp<0.05, with gender, age and education as covariates.

TBSS analysis of DTIDCM2MII was used to convert diffusion tensor imagesfrom the proprietary scanner format to the NIFTIformat. Then, the images were processed using the FSL4.1.5 software package (http://www.fmrib.ox.ac.uk/fsl/).The images were realigned to the b-value (b0) image byaffine transformations using FMRIB’s diffusion toolbox17

to minimise distortions and reduce head motion artefacts.In order to remove non-brain tissue components andbackground noise, a brain mask was created from the firstb0 image and then applied in the DTI to extract brainvoxels using Brain Extraction Tool. After these processes,using DTIFit within the FMRIB’s diffusion toolbox, theimages were calculated to get the FA, l1 (longitudinal

Figure 4 Grey matter densitydecrease in patients with chronicobstructive pulmonary diseaseversus healthy controls. Three-dimensional slices depictingregions showing reduced greymatter in the bilateral insula,bilateral thalamus and left caudatenucleus overlaid on a T1-weightedMRI anatomical image in the MNItemplate.




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diffusivity) (the magnitude of diffusion along the principaldiffusion direction) and l23 (radial diffusivity) (themagnitude of diffusion in the two orthogonal directionsperpendicular to the principal diffusion direction) maps.The whole-brain voxel-wise statistic analysis of the FAimages was performed using TBSS in FSL.8 TBSSprocessing includes the following steps: (1) align the FAimages of all subjects to a template that was arbitrarilyselected from those FA images by non-linear registrations;(2) transform all the aligned FA images into 13131 mm3

MNI152 space by affine registrations to remove the effectof cross-subject spatial variability that remains after thenon-linear registration; (3) create the mean FA imageand filter to retain only the centre of the WM tracts,with the threshold FA$0.20, and successfully excludevoxels, which consisted of GM or cerebrospinal fluid inthe majority of subjects, so as to create the mean FAskeleton8; (4) project individual subjects’ FAs ontomean FA skeleton; (5) following these steps, data werefed into voxel-wise cross-subject statistical analyses. Inall cases, the null distribution was built up over 5000permutations, with significance analysed using inde-pendent t tests at p<0.05 levels, uncorrected formultiple comparisons. We determined the anatomiclocalisation of each cluster by means of the FSL atlastool, which incorporates several anatomic templates,including the Harvard-Oxford Cortical Structural Atlas,Harvard-Oxford Subcortical Structural Atlas, TalairachDaemon Labels and MNI Structural Atlas.Within the cluster of changed FA, mean l1 and l23

values were extracted from each individual’s l1 and l23maps. Values were analysed using SPSS. Analysis of vari-ance statistic was used to identify the group differencesfor these distinct brain locations. Statistical significancewas set at p<0.05.

RESULTSPhysiological and behavioural findingsCompared with the controls, independent t test showedthat patients with COPD had significant decreases inarterial blood Sao2 and Po2, and increases in arterialblood Pco2 and heart rate. Patients with COPD hadsignificantly lower values in one second over forced vitalcapacity (FVC), forced expiratory volume (FEV) andFEV1/FVC values and higher respiratory rate. Thedisease staging categories of patients with COPD basedon FEV1% predicted were as follows: FEV1 ¼82%predicted, n¼1; 54.9%#FEV1<78% (64.967.6)predicted, n¼8; 31.9%#FEV1<48.4% (42.065.4)predicted, n¼7; FEV1<29.9% (26.262.9) predicted,n¼9. Patients with COPD had significantly lower scoresin ADL, MMSE test, visual reproduction and figurememory (table 2).

GM densityNo subject from either group showed visible abnormal-ities on T1-weighted structural images. VBM analysisshowed that patients with COPD had decreased GMdensities compared with healthy controls in the rightgyrus rectus, left precentral gyrus, bilateral anterior andmiddle cingulate gyri, bilateral superior temporal gyri,bilateral anterior insula extending to Rolandic oper-culum (base of the pre- and post-central gyri), bilateralthalamus/pulvinars and left caudate nucleus (clustersize >100 voxels) (figures 1e4, table 3).

FA, longitudinal diffusivity and radial diffusivity in relationto COPDWhole-brain voxel-wise statistic analysis showed thatpatients with COPD had significantly lower FA in a broadrange of brain regions compared with controls (figure 5,

Table 3 Regional information of decreased grey matter density (cluster size >100 voxels) in patients with COPD comparedwith healthy controls

Area Volume (mm3) Brodmann areas

MNI coordinate

t-score (peak)x y z

Rectus_R 118 11 9 39 �20 4.31Precentral_L 100 6 �51 �5 33 4.95Cingulum_Ant_R 485 32 8 38 17 5.88Cingulum_Ant_L 212 32 �8 38 18 4.49Cingulum_Mid_R 157 24 6 �9 42 4.87Cingulum_Mid_L 136 24 �6 �9 41 4.91Temporal_Sup_ L 280 22/42 �60 �33 3 4.99Temporal_Sup/Rolandic_Oper _L

837 22 �57 �14 10 4.91

Insula/Temporal_Sup/Rolandic_Oper _R

2821 13/22/47 44 11 �5 5.15

Insula/Temporal_Sup/Rolandic_Oper _L

1551 13/22/47 �33 12 �15 4.48

Thalamus/pulvinar_L 1270 �12 �30 3 6.46Thalamus/pulvinar_R 2210 12 �26 8 5.29Caudate_L 212 �9 14 14 4.19





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table 4). The significantly affected regions (clusters size>40 voxels) included the superior corona radiata(corresponding to bilateral precuneus and bilateralsuperior parietal lobules), superior longitudinal fascic-ulus (bilateral supramarginal gyri), inferior longitudinalfasciculus (left superior temporal gyrus, right middletemporal gyrus and fusiform gyrus), bilateral opticradiation, bilateral lingual gyri, left parahippocampalgyrus and fornix.Lower FA values in these regions were associated with

increased radial diffusivity and no changes of longitu-dinal diffusivity in patients with COPD versus controls(table 4).

Correlations between MRI measurement and diseaseseverityThe correlations were listed in table 5. In patients withCOPD, partial correlation (controlling for disease dura-

tion, FEV1/FVC, age, education and gender) revealed thatthe GM density in the bilateral anterior cingulate cortex,left superior temporal cortex, bilateral insula/superiortemporal/Rolandic operculum, bilateral thalamus/pulvinar and left caudate nucleus had positive correlationswith arterial blood Po2. Partial correlation (controlling forPo2, FEV1/FVC, age, education and gender) revealed thatthe GM density in the bilateral anterior cingulate cortex,right insula/superior temporal/Rolandic operculum andright thalamus/pulvinar had negative correlations withdisease duration. Partial correlation (controlling for age,education and gender) analysis showed that the GMdensity in the left superior temporal lobes and left insula/superior temporal/Rolandic operculum in patients withCOPD was significantly correlated with figure memoryscore and the GM density in left precentral gyrus and leftthalamus/pulvinar in patients with COPD correlatedsignificantly with visual reproduction.

Figure 5 Statistical maps ofgroup comparison of fractionalanisotropy (FA) value on a voxel-wise basis (results of Tract-BasedSpatial Statistics). The group’smean FA skeleton (green) wasoverlaid on the MontrealNeurological Institute template.The threshold of mean FAskeleton was set at 0.2. Patientswith chronic obstructive pulmonarydisease show significantly lowerFA value than healthy controls(p<0.05).




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DISCUSSIONOur present study revealed that patients with COPD haddecreased regional GM density confined to the limbicand paralimbic structures. GM density in impairedregions in patients with COPD had significant positivecorrelation with arterial blood Po2 and negative corre-lation with disease duration. The decreased WM FA valuewith increased radial diffusivity value was detectedmainly in the visual cortex of the occipital lobe, theposterior parietal lobe as well as the temporal lobe.Decreased FA was associated with compromised myelinstructure, changes in axonal morphologic structure andaltered interaxonal spacing of fibre bundles.18 Radialdiffusivity measures motion of water molecules perpen-dicular to fibres, and an increase of radial diffusivity isinterpreted as abnormalities in myelinated membranes.19

Consequently, decreased FA and increased radial diffu-sivity in COPD indicated the impairment of WM micro-structural integrity.Previously, Borson et al 6 only measured the volume of

hippocampus in patients with COPD using region-of-interest analysis and did not find any significant change.The impaired brain regions in COPD have also beenfound in other chronic hypoxic diseases. For example,decrease in GM volume/concentration in the gyrusrectus, precentral gyrus, anterior cingulate cortex,multiple sites within the temporal lobes, insular cortex,thalamus and caudate nucleus were detected in patientswith obstructive sleep apnoea.13 Impairments of WMmicrostructure in the temporal lobe, parietal lobe,fornix and corona radiata were found in patients withcongenital central hypoventilation syndrome.12 In ourprevious study, the decrease in GM volume in the ante-rior insula, anterior cingulate cortex and precentralcortex were found in high-altitude residents.10

GM density in impaired regions in patients with COPDhad a strongly positive correlation with the arterial bloodPo2, which suggested that the impairment in GM mayresult from low blood oxygen. Moreover, the GM densityin some impaired regions showed negative correlationswith disease duration. It is already known that hypoxiacan induce metabolic decreases3e5 and cerebral perfu-sion decline2 in COPD. In addition, patients with COPDoften suffer from systemic inflammation, which canexacerbate neuronal injury.1 A greater proportion ofregions showing GM loss located in limbic/paralimbiccortex in patients with COPD may be due to the fact thatphylogenetically older regions of the brain showedsharper vascular responses to hypoxia than evolutionaryyounger regions.20

A larger cortical network including the anterior insulaand anterior cingulate cortex underlie the perception ofdyspnoea,11 and these regions play an important role inregulating the cardiovascular system.21 Posterior thal-amus was implicated in suppressing the ventilatoryresponse to hypoxia.22 Hippocampus has been proved tocontrol arterial pressure and heart rate.23 Thus, themorphological impairments in these regions may playT

able

4Main

regionsshowingFA,l1

andl2

3valuesin

patients

withCOPD

comparedwithhealthycontrols

MNI(peak)

Voxels

(mm

3)

Whitematter

tract

Corresponding

corticalarea

FA

value

l1(3

103mm

2/s)

l23(3

103mm

2/s)

xy

zCOPD

Control

COPD

Control

COPD

Control

110

16

240

Fornix

Fornix

0.248(0.067)

0.289(0.073)

2.586(0.314)

2.406(0.0321)

1.809(0.295)

1.577(0.262)*

�26

�69

1191

Leftlingualgyrus

0.259(0.042)

0.283(0.046)

1.450(0.240)

1.370(0.224)

0.992(0.185)

0.896(0.168)*

27

�53

3147

Lingualgyrus

Rightlingualgyrus

0.265(0.065)

0.290(0.056)

1.381(0.239)

1.346(0.227)

0.955(0.242)

0.891(0.215)*

�23

�19

�24

77

Parahippocampus

LeftParahippocampus

0.268(0.042)

0.319(0.046)

1.234(0.057)

1.189(0.052)

0.869(0.148)

0.771(0.125)*

38

�24

�24

77

Fusiform

gyrus

Rightfusiform

gyrus

0.231(0.037)

0.248(0.046)

1.053(0.063)

1.094(0.073)

0.774(0.030)

0.723(0.032)*

�10

�91

17

204

Opticradiation

Leftoccipitalcortex

0.234(0.043)

0.277(0.041)

1.037(0.038)

1.020(0.031)

0.752(0.063)

0.693(0.051)*

25

�86

�5200

Opticradiation

Rightoccipitalcortex

0.369(0.099)

0.409(0.122)

1.171(0.014)

1.177(0.171)

0.649(0.057)

0.601(0.071)*

�9�7

245

94

SCR

Leftprecuneus

0.283(0.053)

0.317(0.056)

1.099(0.032)

1.069(0.041)

0.726(0.075)

0.665(0.065)*

9�6

637

57

SCR

Rightprecuneus

0.251(0.030)

0.280(0.044)

1.044(0.032)

1.018(0.023)

0.868(0.073)

0.731(0.084)*

�15

�51

62

57

SCR

Leftsuperiorparietallobule

0.267(0.043)

0.294(0.043)

1.130(0.051)

1.082(0.025)

0.724(0.039)

0.671(0.045)*

16

�45

64

66

SCR

Rightsuperiorparietallobule

0.251(0.043)

0.294(0.051)

1.176(0.117)

1.107(0.094)

0.805(0.056)

0.762(0.056)*

�45

�53

31

44

SLF

Leftsupramarginalgyrus

0.221(0.027)

0.239(0.026)

1.088(0.020)

1.076(0.040)

0.935(0.090)

0.873(0.071)*

37

�68

21

63

SLF

Rightsupramarginalgyrus

0.220(0.025)

0.237(0.025)

1.116(0.039)

1.090(0.052)

0.773(0.076)

0.715(0.007)*

�48

0�1

643

ILF

Leftsuperiortemporalgyrus

0.244(0.013)

0.270(0.021)

1.060(0.030)

0.984(0.015)

0.758(0.025)

0.714(0.037)*

53

�46

�641

ILF

Rightmiddle

temporalgyrus

0.206(0.016)

0.241(0.024)

1.025(0.016)

1.006(0.021)

1.605(0.167)

1.340(0.139)*

Data

are

presentedasmeans(SD).

*p<0.05.

COPD,chronic

obstructivepulm

onary

disease

;FA,fractionalanisotropy;ILF,inferiorlongitudinalfasciculus;SCR,superiorcoronaradiata;SLF,superiorlongitu

dinalfasciculus.




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a role in respiratory and cardiovascular disturbances,such as higher heart rate and higher respiratory rate, inpatients with COPD tested in our study.In the present study, patients with COPD had poorer

performance in MMSE, visuospatial memory and visualconstruction task. These results were consistent with thosefound in previous studies in patients with COPD.7 In linewith the present findings of COPD, we previously foundthat long-time living in mild high-altitude hypoxic envi-ronment only impaired cognitive performances confinedto visual reproduction and short-time complex figurememory.24 In our present study, the decreases in GMdensity in the frontal precentral cortex, insula/superiortemporal cortex/Rolandic operculum and thalamus/pulvinar may be responsible for the performance deficitin visual-related tasks since the GM density in these areasshowed a significant positive correlation with figurememory or visual reproduction score. The following datasupport our findings: (1) recent research has identifiedthe inferior frontal cortex served as a source of topedownmodulation underlying attention to visual features25; (2)studies on patients using fMRI and positron emissiontomography demonstrated Rolandic operculum as one ofthe visual structures26; (3) the pulvinar region of thethalamus is known to project to posterior parietal lobeand inferior temporal lobe. The pulvinar has beenimplicated in various visual functions in lesion studies.27

Declines in memory and executive function makecontributions to declines in ADL.28 Visual constructiontasks reflect executive function. Therefore, the decreasesin GM density in the above regions that relate to visualconstruction may also be responsible for ADL deficits.Our present study found the impairments of WM

limited to the pathways of visual processing, includingoptic radiation, posterior parietal lobe (superior parietallobule, supramarginal gyrus and precuneus) and theinferior temporal fusiform and lingual gyri. Visual

information enters the primary visual cortex via opticradiation to the visual cortex. Cortical areas along theposterior parietal ‘dorsal stream’ are primarilyconcerned with spatial localisation and directing atten-tion, while cortical areas along the inferior temporal‘ventral stream’ are mainly concerned with the recogni-tion and identification of visual stimuli.29 COPD alsoshowed impaired WM in the middle temporal gyrus.Middle temporal cortex is important for the long-termbuild-up of perceptual memory for ambiguous motionstimuli.30 Based on the above data, our findings in WMmay also clarify the mechanisms underlying the deficit invisual-related tasks. In addition, impaired WM in inputand output fibres of hippocampus (fornix) may berelated to the deficit in MMSE. Previous study onpatients with Alzheimer’s disease found that the volumesof hippocampus were significantly reduced and thevolumes of the left hippocampus correlated significantlywith the MMSE score.31 The limitation of our study is theweak statistical power of FA value analysis because theresults obtained in the TBSS analysis could not survivemultiple comparison correction.

CONCLUSIONSIn summary, we first demonstrated that COPD extendedbeyond the lung to the brain, with the decrease ofregional GM density accompanied by impairment in theWM microstructural integrity. Our findings suggestsignificant participation of these structures inresponding to hypoxic challenges, which includecardiovascular and air-hunger components. The brainstructural changes may also underlie the psychologicaland mood changes of COPD.

Author affiliations1Department of Physiology, Medical College of Xiamen University, Xiamen,China

Table 5 Correlations of grey matter density in impaired regions with Po2, disease duration and cognitive performances inpatients with COPD

Area Po2 (patients)Disease duration(patients)

Cognitive performances (patients + controls)

Figure memory Visual reproduction

Precentral_L r¼0.306, p¼0.0282Cingulum_Ant_R r¼0.530, p¼0.021 r¼�0.471, p¼0.0381Cingulum_Ant_L r¼0.744, p¼0.001 r¼�0.476, p¼0.036Cingulum_Mid_RCingulum_Mid_L11Temporal_Sup_L r¼0.713, p¼0.001 r¼0.511, p¼0.001Temporal_Sup/Rolandic_Oper _L6Insula/Temporal_Sup/Rolandic_Oper _R

r¼0.615, p¼0.007

7Insula/Temporal_Sup/Rolandic_Oper _L

r¼0.656, p¼0.004 r¼0.498, p¼0.001

9Thalamus/pulvinar_L r¼0.487, p¼0.033 r¼�0.474, p¼0.037 r¼0.284, p¼0.0448Thalamus/pulvinar_R r¼0.502, p¼0.028 r¼�0.517, p¼0.0245Caudate_L r¼0.550, p¼0.017





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2Department of Neurology, the Affiliated Hospital of Hangzhou NormalUniversity, Hangzhou, China3Magnetic Resonance Center, Zhongshan Hospital, Medical College of XiamenUniversity, Xiamen, China4Department of Respiratory, Zhongshan Hospital, Medical College of XiamenUniversity, Xiamen, China5Department of Brain Protection and Plasticity, Institute of Basic MedicalSciences, Beijing, China

Contributors HZ contributed to conception and design, the accuracy of thedata analysis, drafting the article and final approval of the version to bepublished. XW contributed to the study design, revising the article critically forimportant intellectual content and final approval of the version to be published.JL, YS, YH, TY, SZ and MF contributed to acquisition of data, revising thearticle critically for important intellectual content and final approval of theversion to be published. JZ contributions to conception and design, acquisitionof data and interpretation of data; drafting the article and revising it criticallyfor important intellectual content; and final approval of the version to bepublished.

Funding This work was supported by National Science Foundation of China(Project No. 31071041; 81171324), Bureau of Science and Technology ofHangzhou (20090833B10) and Health Bureau of Zhejiang Province(2009A168).

Competing interests None.

Patient consent Obtained.

Ethics approval The experimental protocol was approved by the ResearchEthics Review Board of Xiamen University.

Provenance and peer review Not commissioned; externally peer reviewed.

Data sharing statement We are pleased to share our data with otherresearchers. Jiaxing Zhang et al.

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