White matter abnormalities in HIV1 infection: A diffusion tensor imaging study

Ž .Psychiatry Research: Neuroimaging Section 106 2001 15�24

White matter abnormalities in HIV-1 infection:A diffusion tensor imaging study

Nunzio Pomaraa,b, David T. Crandalla, Steven J. Choia, Glyn Johnsonb,Kelvin O. Lima,b,�

aNathan S. Kline Institute for Psychiatric Research, 140 Old Orangeburg Road, Orangeburg, NY 10962, USAbNew York Uni�ersity School of Medicine, New York, NY 10016, USA

Received 19 May 2000; received in revised form 1 November 2000; accepted 19 November 2000

Abstract

Diffuse white matter pallor is the most frequent neuropathological feature of HIV-1 infection and has been foundto be particularly prominent in the advanced stages of the disease. The purpose of this study was to determinewhether subtle white matter abnormalities can be detected in medically stable, ambulatory HIV-1 patients, in vivo,

Ž . Ž .using diffusion tensor imaging DTI . DTI is a magnetic resonance imaging MRI technique that is uniquely suitedfor the study of subtle white matter abnormalities. DTI was performed in six HIV-1 patients and nine controls. Thetwo groups were similar in age. Abnormal fractional anisotropy was found in the white matter of the frontal lobesand internal capsules of the HIV-1 patients, in the absence of group differences in mean diffusivity, computed protondensity, and computed T2. DTI may be more sensitive than conventional MRI methods for detecting subtle whitematter disruptions in HIV-1 disease. � 2001 Elsevier Science Ireland Ltd. All rights reserved.

Keywords: Magnetic resonance imaging; Diffusion tensor imaging; AIDS; Frontal lobe; Internal capsule

1. Introduction

Diffuse damage to cerebral white matter, asevidenced by pallor, is one of the most frequentneuropathological features of HIV-1 infection andhas been found to be particularly prominent in

Žthe advanced stages of the disease Price et al.,

� Corresponding author. Tel.: �1-845-398-5471; fax: �1-845-398-5472.

Ž .E-mail address: [email protected] K.O. Lim .

.1988; Gray et al., 1996 . The white matter pallorhas been found to be more prevalent and severe

Žin patients with HIV-1 associated dementia Gray.et al., 1996 . Immunohistochemical and in situ

hybridization studies of HIV encephalitis haverevealed that HIV-1 infected macrophages andmultinucleated giant cells preferentially invadethe white matter of cerebral hemispheres, corpus

Žcallosum and internal capsule Gosztonyi et al.,.1994 . Axonal damage, as suggested by increased

immunoreactivity to �-amyloid precursor protein,

0925-4927�01�$ - see front matter � 2001 Elsevier Science Ireland Ltd. All rights reserved.Ž .PII: S 0 9 2 5 - 4 9 2 7 0 0 0 0 0 8 2 - 2

( )N. Pomara et al. � Psychiatry Research: Neuroimaging 106 2001 15�2416

has been reported in all stages of HIV-1 infectionŽ .An et al., 1997; Raja et al., 1997 . Additionally,widespread increases in perivascular macrophagesand hypertrophy of astrocytes and microglia havebeen reported in the white matter, as well as graymatter, in HIV-1 infected brains, independent of

Ž .the presence of dementia Power et al., 1993 . Incontrast, virus-infected oligodendrocytes and

Ž .frank myelin loss Bell, 1998 have been foundprimarily in cases with HIV-1 encephalitis andmulti-nucleated giant cells.

Ž .Magnetic resonance imaging MRI studieshave provided in vivo evidence of white matterabnormalities in HIV-1. White matter hyperin-

Ž .tensities Olsen et al., 1988 and reduced cerebralŽ .white matter volume Jernigan et al., 1993 have

been reported in advanced HIV-1 disease, andMRI white matter lesions have been associatedwith the development of AIDS dementia complexŽ .Pedersen et al., 1991 . In the earlier stages ofHIV-1, however, structural MRI methods used todate have not reliably detected white matter

Ž .abnormalities Chang, 1995 , whereas protonŽ .magnetic resonance spectroscopy MRS studies

have demonstrated white matter metaboliteabnormalities in asymptomatic HIV-1 patientsŽ .Wilkinson et al., 1997 .

Ž .Diffusion tensor imaging DTI , an MRImethod, is uniquely suited to the study of subtlewhite matter abnormalities in vivo. DTI can beused to quantify the magnitude and directionality

Ž .of tissue water mobility i.e. self-diffusion in threedimensions. Barriers to water self-diffusion, suchas myelin sheaths, membranes, or white mattertracts, result in greater self-diffusion along theaxis of the barrier and reduced self-diffusion per-pendicular to the axis. This type of restrictedself-diffusion is termed ‘anisotropic.’ Fractional

Ž .anisotropy FA is a scalar measure derived fromthe diffusion tensor that assesses the degree of

Ž .anisotropic self-diffusion Basser, 1995 .The degree of anisotropy in a voxel is de-

termined by microstructural features of the tissuein that particular voxel, such as fiber diameterand density, as well as the degree of myelinationŽ .Basser, 1995 . Also, macrostructural features,such as intravoxel fiber-tract coherence or organi-zation, influence the degree of anisotropy in a

Ž .voxel Pierpaoli and Basser, 1996 . Tissue withhighly regular fibers, e.g. white matter, shouldhave higher FA compared with less constrainedtissues, e.g. gray matter and cerebrospinal fluid.However, where white matter fiber tracts withdifferent orientations merge, low FA can occur inspite of a high degree of fiber coherence within

Ž .each fiber tract Pierpaoli and Basser, 1996 .Our previous DTI studies have demonstrated

the sensitivity of this method in detecting subtlewhite matter alterations. For instance, we foundreduced white matter FA despite normal white

Žmatter volume in patients with schizophrenia Lim.et al., 1999 . Consistent with other findings

Ž .Klingberg et al., 1999; Virta et al., 1999 , we havealso detected age-related changes in white matter

Ž .FA Pfefferbaum et al., 2000b . Moreover, re-duced white matter anisotropy has been reportedin various patient populations, including

Ž .Alzheimer’s disease Buchsbaum et al., 1999 , is-Ž .chemic leukoaraiosis Jones et al., 1999 , and

Ž .multiple sclerosis Werring et al., 1999 . An ab-stract has reported the observation that whitematter anisotropy decreased with increasing viral

Ž .load in HIV-1 patients Ulug et al., 2000 . Todate, however, DTI has not been applied in acontrolled study of white matter pathology inHIV-1 disease.

In this study, we examined whether subtle whitematter abnormalities can be detected in vivo us-ing DTI in non-demented HIV-1 infected patients.We hypothesized that HIV-1 patients would showabnormal white matter FA. We also investigatedwhether these abnormalities can be detected us-

Ž . Žing mean diffusivity Trace�3 Basser and Pier-.paoli, 1996 , calculated proton density, and calcu-

lated T2 relaxation.

2. Method

2.1. Subjects

This study was approved by the InstitutionalReview Boards of the Nathan S. Kline Institute

Ž .for Psychiatric Research NKI in Orangeburg,NY and the New York University�Bellevue Med-ical Center in New York, NY. HIV-1 seropositive

( )N. Pomara et al. � Psychiatry Research: Neuroimaging 106 2001 15�24 17

subjects were recruited through the BellevueAIDS Clinical Trials Unit and the community.Healthy control subjects were recruited locally.All study volunteers signed informed consent toparticipate. Patients also signed informed consentfor the release of medical records.

Exclusion criteria were: age less than 18, acutemedical illness, history of non-HIV related neuro-logic disease, current DSM-IV Axis I diagnoses,

Ž .history of psychosis, loss of consciousness LOCgreater than 30 min or any LOC with neurologi-cal sequelae, and current alcohol or substanceabuse.

Sixteen HIV-1 subjects signed informed con-sents to participate in the study. Two subjectswere excluded due to a history of LOC followinghead trauma. Two subjects were unable to bescanned because of claustrophobia. Imaging datafrom six subjects were unusable because of agradient hardware problem. As such, a total of sixHIV-1 subjects were included in the analyses. Ofthe 12 controls who consented to participate, twowere not scanned due to claustrophobia, and onesubject was excluded because of a history of psy-chosis. This left a total of nine controls for analy-ses.

All subjects were medically stable, ambulatoryand functioning independently. The two groups

Žwere similar in age t��1.056, d.f.�13, P�. Ž .0.310 . The average ages S.D. of HIV-1 patients

Ž . Ž .and controls were 40.09 5.80 and 43.19 5.42years, respectively. There were four males in theHIV-1 group and seven males in the controlgroup. In the HIV-1 group, the probable mode ofHIV-1 infection was sexual contact for five

Ž .patients and intravenous drug use IVDU forone patient. Four patients had a history of oppor-tunistic infections and�or CD4� T-lymphocytecounts below 200 cells�� l, meeting the CDC

Žsurveillance case definition for AIDS Center for.Disease Control and Prevention, 1992 . Recent

CD4 cell counts, assessed within 3 months of theŽ .scan mean�S.D.: 288.67�94.40 , revealed that

two patients had CD4� T cell counts below 200.Five patients were receiving highly active anti-

Ž .retroviral treatment HAART ; one patient wasnot receiving any antiretroviral treatment.

Except for the presence of peripheral neuropa-

thy in three HIV subjects, there was no documen-tation indicating the presence of any other neuro-logical symptoms or disease. The assessment ofdementia in the HIV-1 patients was based on apsychiatric evaluation using DSM-IV criteria. The

Ž . Ž .mean S.D. Mini-Mental Status Exam MMSEŽ .score was 28.5 1.87 , with a range of 25�30. The

Ž .mean S.D. Wechsler Memory Scale-RevisedŽ .General Memory Index WMS-R GMI was 93.67

Ž .21.09 , ranging from 69 to 120. No clinicallyŽsignificant levels of anxiety mean�SD: 1.17�

. Ž .1.17 or depression 0.17�0.41 were found inthe HIV-1 patients, as assessed by Hamilton

Ž . ŽDepression Hamilton, 1960 and Anxiety Ham-.ilton, 1959 Rating Scales.

2.2. Procedures

The study was conducted at NKI, where allsubjects were screened for medical and psychi-atric history and underwent MRI. For the HIV-1patients, a brief neurocognitive screening batterywas administered, which included the MMSE andWMS-R. Psychiatric evaluation and medicalrecord review were also performed to assess thefunctional status of the HIV-1 patients.

The MRI procedures began with a sagittal lo-Žcalizer TR�15 ms, TE�6 ms, 15 slices, 5 mm

.thick, skip�0, FOV�30 cm, 256�256 matrix ,from which the anterior and posterior commis-

Ž .sures AC�PC were identified and used to posi-tion the next sequence. A proton density and

ŽT2-weighted dual spin echo sequence TR�2500,TE�20�80, 26 slices, 5 mm thick, skip�0, FOV�24 cm, 256�256 matrix, acquisition time 8 min

.34 s was acquired in the oblique axial planeparallel to the AC�PC plane. DTI data wereacquired using a double echo pulsed gradientecho planar imaging method to reduce eddy cur-

Žrent effects TR�6 s, TE�100 ms, FOV�24cm; 128�128 matrix reconstructed to 256�256,b�900 s�mm2, six non-collinear gradient orien-

.tations, NEX�4, acquisition time 2 min 36 sŽ .Heid, 2000 ; the dual echo method greatly re-duces eddy currents, obviating the need for post-acquisition eddy current distortion correction. Anacquisition with no diffusion gradients was col-

Ž .lected b�0, two averages , followed by acquisi-


Ž .tions where gradients b�900, four averageswere applied in six non-collinear directions with

Ž . �Ž . Ž .the following pattern Gx,Gy,Gz : 1,1,0 , 0,1,1 ,Ž . Ž . Ž . Ž .41,0,1 , �1,1,0 , 0,�1,1 , 1,0,�1 . The DTIdata were collected in oblique slices correspond-ing to the same thickness, spacing and locationsas for the spin echo MRI.

Ž .Fractional anisotropy FA and mean diffusivityŽ .MD were computed from the DTI data set.

Ž .Estimates of proton density PD and T2 werecomputed using a two-point fit of the anatomicaldual echo image data. Images were processed byan experimenter blind to subject identity, usingsoftware developed at NKI.

To avoid registration problems between dif-ferent image acquisition methods, the ROIs forthe DTI-derived measures were placed on the

Ž .T2-weighted image b�0 of the DTI data set.Ž .Circular regions of interest ROIs were posi-

tioned on the images in defined anatomical loca-Ž .tions see Table 1 . The genu, splenium, frontal,

parietal, and internal capsule ROIs were placedon the slice located 10 mm above the anterior

Ž .commissure AC slice. The temporal ROIs wereplaced on the image 10 mm below the AC slice.ROIs were positioned bilaterally for each regionexcept the genu and the splenium, resulting in atotal of 10 measurements. Each ROI contained50 voxels, except for the internal capsules, whichcontained 13 voxels. The 10 ROIs were thenplaced on the identical locations on the earlyecho image from the dual spin echo sequence.Fig. 1 shows examples of ROI positioning on thePD-weighted images, T2-weighted images, andcalculated FA images. The images were reviewed

Ž .qualitatively by one of the authors K.O.L. for

the presence of white matter hyperintensitieswithin the ROIs from the dual echo sequence.

2.3. Analyses

The mean value was calculated within eachROI for the FA, MD, PD and T2. Analysesproceeded with six brain regions for each of thefour dependent measures. To reduce the numberof comparisons, the left and right hemispherevalues of the bilateral regions were averaged.

Ž .Mixed-model analyses of variance ANOVAswere computed for the FA, MD, PD and T2 data

Ž .separately, with Group HIV-1 vs. Controls asŽ .the between-subject factor and Region six ROIs

as the within-subjects factor. Huynh-Feldt epsilonŽ .Huynh and Feldt, 1976 was applied to correctthe degrees of freedom and P-values, when theassumption of sphericity was not met. In thepresence of a significant main effect of Group ora Group�Region interaction, follow-up para-metric or non-parametric comparisons were per-formed between the HIV-1 and control groups

Ž .for each brain region ��0.05, two-tailed . Theanalyses were conducted with and without theone subject who had a history of IVDU. Effect

Ž .sizes d were calculated using pooled standarddeviations.

3. Results

3.1. Fractional anisotropy

The means and standard deviations of whitematter FA, as well as the effect sizes, are pre-sented in Table 2. The mixed-model ANOVA

Table 1Anatomical locations for regions of interest

Brain region Anatomical landmarks on transverse brain images

Genu Anterior corpus callosum, centered on interhemispheric fissureSplenium Posterior corpus callosum, centered on interhemispheric fissureFrontal lobes White matter anterior to frontal horns of lateral ventricles, both hemispheresParietal lobes White matter adjacent to ventricles, aligned with splenium, both hemispheresInternal capsules In the genu of the internal capsule white matter, both hemispheresTemporal lobes White matter, aligned with most lateral point of cerebral peduncle, both hemispheres


Ž . Ž . Ž .Fig. 1. ROI positions on proton density-weighted left , T2-weighted middle and fractional anisotropy right images.

Table 2aFractional anisotropy and diffusivity means �S.D. by group

Ž . Ž . Ž .DTI measures Brain region HIV-1 n�6 Control n�9 Effect size d

Fractional Genu 744.70�69.16 798.57�42.81banisotropy Splenium 818.09�66.50 812.96�85.96 �

�Frontal lobes 399.68�39.01 500.01�81.84 �1.46Parietal lobes 509.32�45.33 476.42�37.63

�Internal capsules 694.52�36.45 648.39�40.09 1.19Temporal lobes 477.48�45.35 523.61�41.88

Mean diffusivity Genu 422.19�89.05 411.52�41.98Ž .Trace�3 Splenium 340.34�18.33 433.71�121.02

Frontal lobes 401.35�12.23 389.32�22.48Parietal lobes 434.52�10.61 461.52�34.33Internal capsules 362.61�20.52 391.98�19.30Temporal lobes 413.56�8.89 424.15�9.44

a Significance: � P�0.05.bSignificant Group�Region interaction.


Fig. 2. Comparison of fractional anisotropy by brain regions between HIV-1 patients and controls.

revealed a significant Group�Region interactionŽ .F�3.695, d.f.�5, P�0.005 , but no main effect

Ž .of Group F�2.505, d.f.�1, P�0.137 .Follow-up analyses of the Group�Region in-

teraction showed that the HIV-1 subjects hadsignificantly decreased FA compared to the

Žhealthy controls in the frontal lobes t��2.775,. Ž .d.f.�13, P�0.016 see Fig. 2 . There were no

significant group differences in FA for the pari-

Ž . Ž .etal lobes P�0.150 , temporal lobes P�0.077 ,Žor the two corpus callosum ROIs genu, P�0.083;

.splenium, P�0.904 .FA was significantly increased in the internal

capsules of the HIV-1 subjects compared to theŽ .controls t�2.260, d.f.�13, P�0.042 . In an

effort to clarify this finding, four additional ROIswere placed bilaterally in the anterior and poste-rior limbs of the internal capsules. These ROIs

Table 3Calculated proton density and T2 means�S.D. by group

Ž . Ž .Dual echo measures Brain region HIV-1 n�6 Control n�9

Proton density Genu 12 869.63�191.37 12 956.80�402.99Splenium 12 658.35�362.04 12 507.97�447.84Frontal lobes 13 139.75�392.55 13 121.42�363.61Parietal lobes 13 219.08�431.22 13 157.73�411.43Internal capsules 13 507.54�466.47 13 318.04�396.90Temporal lobes 13 753.45�294.14 13 696.38�532.35

T2 relaxation Genu 58.53�3.15 59.19�2.83Splenium 65.05�2.78 67.58�3.47Frontal lobes 60.59�2.61 60.23�1.36Parietal lobes 64.30�2.00 65.97�2.65Internal capsules 59.07�1.14 60.45�2.33Temporal lobes 62.22�2.95 62.05�1.21


were located in the regions that bisect the junc-tion of the external�internal capsules and thegenu of the internal capsule. FA in the posteriorlimb of the internal capsule was significantlygreater in the HIV-1 patients relative to controlsŽ t�3.324, d.f.�7.127, P�0.012, unequal vari-

.ances , while no group difference in FA was notedŽin the anterior limb t��0.353, d.f.�9.352, P�

.0.732, unequal variances . There were no groupdifferences in mean diffusivity in the anteriorŽ . Ž .P�0.814 or posterior P�0.124 limbs of theinternal capsule.

3.2. Mean diffusi�ity

The means and standard deviations for MD arepresented in Table 2. Mixed-model ANOVAshowed neither a significant Group� Region

Žinteraction F � 2.251, d.f.� 2.498, P � 0.111,.Huynh�Feldt epsilon corrected nor a main effect

Ž .of Group F�3.979, d.f.�1, P�0.067 .

3.3. Proton density and T2 signal intensity

Qualitative review of the images revealed nosignificant white matter hyperintensities in any ofthe analyzed regions. The means and standarddeviations for calculated PD and T2 are shown inTable 3.

From the mixed-model ANOVA, there was nei-Žther a significant main effect of Group F�0.125,

.d.f.�1, P�0.729 nor a Group�Region inter-Ž .action F�0.649, d.f.�5, P�0.663 for the PD

measures. Similarly for the T2 measures, the mainŽ .effect of Group F�1.511, d.f.�1, P�0.241

Žand the Group�Region interaction F�0.940,d.f.�4.401, P�0.454, Huynh�Feldt epsilon cor-

.rected were not significant.

4. Discussion

To our knowledge, this is the first controlledstudy to employ DTI for the examination of whitematter abnormalities in HIV-1 infection. Reduc-tions in FA were found in the frontal white mat-ter of non-demented HIV-1 patients. The pres-ence of white matter abnormalities in these re-

gions is consistent with findings from proton MRSstudies of HIV-1 disease, in which abnormal

Ž .N-acetyl aspartate NAA , choline and creatinemetabolite ratios were reported in the frontalwhite matter of symptomatic HIV-1 patientsŽ .Lopez-Villegas et al., 1997 . Multivoxel protonMRS studies using absolute metabolite quantita-

Žtion have also shown NAA reductions Barker et. Žal., 1995 and myo-inositol elevations Chang et.al., 1999 in the frontal white matter of HIV-1

patients with mild to moderate neurocognitivedysfunction.

FA in the genu of the internal capsule wasincreased in the HIV-1 patients. Abnormalitywithin the internal capsules of AIDS patients wasconsistent with histopathological evidence of

ŽHIV-1 infection and active viral replication Kure.et al., 1990 in this region. Since anisotropy has

been shown to increase through abnormalities inŽone set of intersecting fiber pathways Pierpaoli

.et al., 1998 , the increased anisotropy in thissample of HIV-1 patients could reflect a disrup-tion of selective internal capsule fibers. Examina-tion of FA in the anterior and posterior limbsseparately revealed that the microstructural whitematter abnormality might be located primarily inthe posterior limb.

Interestingly, frontal white matter FA was re-duced even though most of the HIV-1 patientswere receiving HAART. Preliminary evidencesuggests that treatment with zidovudine may re-sult in at least partial normalization of biochemi-

Žcal abnormalities in white matter Vion-Dury et.al., 1995 and reductions of white matter hyperin-Ž .tensities Luer et al., 1994 . In another MRI

study, patients being treated with protease inhibi-tors were more likely to show decreased periven-tricular white matter hyperintensities, as assessedby qualitative reviews, than those not receiving

Ž .this treatment Filippi et al., 1998 . Although theeffects of HAART on white matter FA cannot bedetermined from this study, the findings suggestthat microstructural abnormalities may persist inwhite matter, at least in some brain regions, de-spite therapeutic antiretroviral treatment.

These abnormalities in white matter FA werefound in HIV-1 patients in the absence of groupdifferences in MD or in calculated PD or T2. This


suggests that FA may be more sensitive thanother MRI approaches to microstructural whitematter abnormalities. In addition, the lack ofsignificant differences in MD suggests that theabnormalities in FA were not simply due togreater restrictions in mean diffusion of water inwhite matter, as might be produced by gliosis.However, the possibility exists that the non-find-ings in MD may be due to small sample size.

The results of this study need to be interpretedwith caution. Our findings were based on a rela-tively small sample. The study also included onesubject with a history of IVDU, for which theeffect on FA is unknown. When this subject wasremoved, however, the overall Group�Region

Žinteraction in FA remained significant F�3.534,.d.f.�5, P�0.007 . Additionally, follow-up analy-

ses continued to show significant FA abnormali-Žties in the frontal lobes t��2.420, d.f.�12,

. ŽP�0.032 and internal capsules t�2.303, d.f.�.12, P�0.040 of HIV-1 patients.

The precise underlying mechanisms for theabnormal white matter FA are not known. Thereis evidence suggesting that microstructural whitematter abnormalities are present in HIV-1patients. Increased immunoreactivity for �-

Ž .amyloid precursor protein �-APP , an es-tablished sensitive marker of axonal damage, has

Ž .been found in the early An et al., 1997 andŽ .advanced Giometto et al., 1997; Raja et al., 1997

Žstages of HIV-1 disease. Frank myelin loss Bell,.1998 , as well as antibodies against myelin basic

Ž .protein Mastroianni et al., 1991 , have also beenreported in AIDS patients. Thus, the abnormali-ties in white matter FA may reflect damage to theaxons and�or the myelin.

A recent study has demonstrated a significantrelationship between abnormal white matter mi-crostructure and neurocognitive functioning in al-

Ž .coholics Pfefferbaum et al., 2000a . The neu-rocognitive effects, if any, of abnormal white mat-ter FA in HIV-1 disease have yet to be investi-gated. Further study is needed to determine therole of HIV-1 related microstructural white mat-ter abnormalities in the manifestation of neu-rocognitive impairment.

In summary, microstructural white matterabnormalities were detected in vivo using FA but

not mean diffusivity in multiple brain regions ofthe HIV-1 patients, even though the vast majorityof them were being treated with HAART. Thefindings also suggest that FA is more sensitive

Ž .than other MRI measures i.e. PD and T2 fordetecting white matter abnormalities. It remainsto be determined how FA derived from DTIcompares with fluid-attenuated inversion recov-ery, a sequence with demonstrated sensitivity inthe detection of white matter pathology. Giventhe apparent sensitivity of FA, future studies areneeded to assess whether this method can detectsubtle white matter abnormalities in earlier dis-ease stages and to determine the potential func-tional implications of microstructural white mat-ter abnormalities in HIV-1 disease.

Acknowledgements

This work has supported in part by the Natio-nal Institutes of Health CMH 56994, MH 53313.

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White matter abnormalities in HIV1 infection: A diffusion tensor imaging study