Eur Radiol (2008) 18: 331–336DOI 10.1007/s00330-007-0740-9 NEURO

Andrea RomanoFabrizio FasoliMichele FerranteLuigi FerranteLuigi Maria FantozziAlessandro Bozzao

Received: 12 October 2006Revised: 6 June 2007Accepted: 20 July 2007Published online: 25 September 2007# Springer-Verlag 2007

Fiber density index, fractional anisotropy,adc and clinical motor findings in the whitematter of patients with glioblastoma

Abstract Whether fractionalanisotropy (FA), apparent diffusioncoefficient (ADC), and fiber densityindex (FDi) values differ in the whitematter close to glioblastomas of bothsymptomatic and asymptomaticpatients was investigated. Twentypatients with glioblastomas underwentmagnetic resonance imaging study.The FDi, FA and ADC values werecalculated in areas of white matter inclose proximity to the tumor (perWM)and encompassing fibers of cortico-spinal tract and in the contralateralnormal-appearing white matter(nWM). The clinical compromise ofthe cortico-spinal tract was gradedusing Brunnstrom’s criteria. FA andFDi were significantly decreased andADC increased in perWM comparedwith the contralateral. Mean FDi, FA,

and ADC values comparing perWMand nWM in symptomatic patientsshowed similar differences. Compar-ing the perWM of symptomatic andasymptomatic patients, mean FDi andADC values were lower in symptom-atic patients than in asymptomaticones. A positive correlation was foundbetween the clinical score (CS) and,separately, FDi, FA and ADC per WMvalues. In a multiple stepwise regres-sion among the same factors, only theADC of perWM values showed apositive correlation with the CS. Anincreased ADC plays a major role inreducing the number of fibers (re-duced FDi) in symptomatic patients.

Keywords Diffusion tensorimaging . Fiber tracking .Glioblastoma multiforme

Introduction

Currently, diffusion tensor tractography (DTT) is the onlyimaging technique with the potential to generate realisticfiber-tract trajectories in the white matter (WM) of the brainin vivo [1–3]. Diffusion tensor imaging (DTI) is presentlyused to document the presence of WM tracts and definetheir location with respect to the tumor.

Brain tumors may alter WM fibers in several ways: inparticular, WM tracts may be displaced, infiltrated bytumor or edema, or destroyed [4].

Previous studies [5–7] have demonstrated that fractionalanisotropy (FA) decreases in the WM close to brain tumors.It is still unclear whether this is due to edema or tumorinfiltration and, consequently, whether FA decrease trulyreflects a reduced number of axons [8]. Roberts et al. [8]

introduced a quantitative description of WM fiber attenu-ation, the fiber density index (FDi), in patients withglioblastoma. This measure is an index derived from thequantitative analysis of the number of fibers passingthrough a region of interest (ROI) and showed an inversecorrelation with FA. In this study, FDi and FA wereevaluated by means of ROIs placed in the WM close to thebrain tumor and generally encompassing the fibers of thecortico-spinal and cortico-pontine tracts. Since this was notthe aim of their research, the authors did not mention if thepatients were symptomatic for cortico-spinal tract (CST)involvement.

In the present study, we tried to validate the results ofRoberts and co-workers, but also considered whether FA,apparent diffusion coefficient (ADC), and FDi values differin the WM close to glioblastomas of both symptomatic and

A. Romano (*) . F. Fasoli .M. Ferrante . L. M. Fantozzi .A. BozzaoDepartment of Neuroradiology,S. Andrea Hospital,University “La Sapienza”,Via di Grottarossa 1035,00189 Rome, Italye-mail: andrea.romano@uniroma1.itTel.: +39-06-33775384Fax: +39-06-33775613

L. FerranteDepartment of Neurosurgery, S. AndreaHospital, University “La Sapienza”,Rome, Italy

asymptomatic patients. This was done to determine thosedifferences able to discriminate between tumor infiltrationand peritumoral edema in these two sub-groups of patients.

Materials and methods

Between January and May 2006, 20 patients (eight womenand 12 men; age range: 42–71 years) with histologicallyconfirmed glioblastoma multiforme underwent a compre-hensive magnetic resonance imaging (MRI) examinationbefore and after administration of paramagnetic contrastmedium (gadolinium tetra-azacyclododecanetetracetic acid;Dotarem, Guerbet, Aulnay-sous-bois, France), includingDTI and DTT, in our institution.

Only those tumors located close to the CST but withoutinvolvement of the motor cortex on conventional MRIwere included. All the tumors affected a single hemisphere.

CST clinical involvement was graded by a neurologistusing the Brunnstrom’s scale [9]. This clinical score isusually used in the evaluation stroke patients, consideringboth arm and foot motor functions. This scale ranges from1 to 6, where 6 represents the absence of symptoms. Themean score of arm and foot clinical evaluation for eachpatient was obtained and correlated with different diffusiontensor parameters.

Thirteen patients were symptomatic for CST involve-ment, while seven did not show any clinical motorsymptoms (Table 1). The mean age (58 vs 57 years) didnot differ between symptomatic and asymptomatic patients.

The Institutional Review Board approval was obtainedfor the study.

MRI acquisition

MRI was performed by means of a 1.5-T MR system(Sonata; Siemens, Erlangen, Germany). Conventional MRIwas carried out with T2-weighted imaging, and conven-tional spin-echo, non-enhanced and gadolinium-enhanced,T1-weighted imaging prior to the diffusion tensor protocol.All the patients underwent single-shot echo-planar se-quences, with the following parameters:

TR=TE=slices=thickness=gap=FOV=averages=matrix=¼ 6600=91=42=3=0=230=2=128� 128:

DTI was performed by means of a 12 non-collineardirection of diffusion sensitization, with one b value of1,000 s/mm2 and one without diffusion-weighted imaging(DWI).

Twelve-DWI sets as well as b=0 image sets werespatially recorded and post-processed using the DTI-Studiosoftware (Processing Tools and Environment for DiffusionTensor Imaging, ver. 2, H. Jiang and S. Mori, Radiology

Dept., Johns Hopkins University, Baltimore, Md.) [10] togenerate pixel-wise FA maps.

Fiber tracking using the fiber assignment by continuoustracking algorithm was then performed, reconstructing allthe possible fibers through the image set from all the pixelsabove an FA threshold of 0.25, thus allowing for a fiberangulation of up to 70°, as suggested by other authors [8].

A single ROI—used to calculate FA, ADC and FDi—was positioned on color maps (blue area) close to thetumor, at the level of the internal capsule (Fig. 1a). toconfirm its exact positioning at the level of the CST, thiswas reconstructed by the conventional approach with thefiber tracking initiated from two user-defined seedingareas. Seeding areas were placed in the midbrain and at thelevel of the motor cortex (Fig. 1b). In all cases, the ROIpositioned on color maps encompassed the CST (Fig. 1c).

No significant T2 signal alterations were evident insidethe ROI positioned for FA measurements. ROIs of the samesize (ranging from 50 to 60 pixels) were placed in thehomologous area of the contralateral hemisphere. As in thestudy by Roberts and co-workers, the FA mean value andthe number of WM fiber paths passing through the ROIs’values were obtained. Then, FDi was calculated as thenumber of fiber paths passing through theROI/area of ROI (inpixels). Mean ADC inside the ROIs was calculated as well.

ROIs were placed blindly by two readers and the meanvalue of observations was considered. Concordancebetween raters for each quantity was assessed using theintraclass correlation coefficient.

Data were analyzed using the Statistical Package forSocial Sciences (SPSS forWindows Package 10.0, Chicago,Ill.). Two-sample t-test and linear and multiple stepwiseregression were performed. First, FDi, FA, ADC, andclinical score (CS) in the affected versus the unaffectedside of all the patients were compared; second, the sameevaluation was performed between symptomatic andasymptomatic patients.

Results

Mean FA and ADC values were significantly different inperitumoral WM (perWM) compared with the correspondingcontralateral normal-appearing WM (nWM). In perWM, FAhad decreased (0.53±0.11 vs 0.65±0.1; P=0.001) and ADChad increased (0.83±0.1 vs 0.72±0.03; P=6.07×10−5).Similarly, the FDi showed a significant reduction in thesame areas (3.76±0.88 vs 6.67±1.42; P=2.25×10−9) (Fig. 2).

Mean FDi, FA, and ADC values comparing perWM andnWM in symptomatic patients showed similar differences(FDi: 3.36±0.57 vs 6.37±1.35; P=1.24×10−8; FA: 0.50±0.11 vs 0.65±0.11; P=0.001; ADC: 0.87±0.1 vs 0.73±0.04; P=7. 97×105). In asymptomatic patients, there wereno statistically significant differences between perWMand nWM for FA, while FDi and ADC were still differentin the two sides (FDi: 4.89±1.06 vs 6.40±1.59; P=0.05;

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FA: 0.59±0.05 vs 0.63±0.08; P=0.32; ADC: 0.77±0.02 vs0.72±0.01; P=0.0005) (Table 2).

Comparing the perWM of symptomatic and asymptom-atic patients, mean FDi and ADC values in the ROIsadjacent to the tumor were lower in symptomatic patientsthan in asymptomatic ones (FDi: P=0.005; ADC: P=0.002). The FAvalue did not reach significance in the samegroups (P=0.065) (Fig. 3).

A positive correlation was found between the CS and,separately, FDi, FA andADC perWM values (FDi vs CS:P=0.035, Rsq=0.345; FA vs CS: P=0.011, Rsq=0.455; ADCvs CS: P=0.001, Rsq=0.668). In a multiple stepwise re-

gression between the same factors, only the ADC of perWMvalues showed a positive correlation with the CS (P=0.001,Rsq=0.668) (Fig. 4).

A strong correlation across the values of FDi, AD,C andFA of the raters was found (intraclass correlation coef-ficients 0.74 for FDi, 0.71 for ADC, and 0.62 for FA).

Discussion

In a recent paper, Roberts et al. [8] reported a quantitativedescription of WM fiber attenuation-the so-called FDi-in

Fig. 1a–c Representative ex-ample of ROI positioning in apatient (no. 11) with a rightglioblastoma. a ROIs are placedat the level of the internal cap-sule on the blue area of colormaps close to the tumor. b Toverify ROIs correct position,CSTs were subsequently recon-structed from two seeding areasin the midbrain and the motorcortex. c Note the exact positionof the ROIs over the CST

Table 1 Glioblastoma GBM location and clinical evaluation of all patients

Hemiparesis (Bruunstrom’s grading score)a

Patient GBM location GBM position vs internal capsule Hemiparesis symptoms Arm Foot Mean score

1 Right temporo-occipital lobe Posterior Y 5 5 5

2 Left fronto-temporal lobe Anterior Y 4 3 3.5

3 Left fronto-temporal lobe Anterior Y 2 3 2.5

4 Right fronto-temporal lobe Anterior Y 3 3 3

5 Left frontal lobe Anterior Y 2 3 2.5

6 Left temporal lobe Lateral Y 3 5 4

7 Left temporo-parietal lobe Lateral Y 2 2 2

8 Left fronto-parietal lobe Anterior Y 3 3 3

9 Right fronto-parietal lobe Anterior Y 2 4 3

10 Left fronto-parietal lobe Lateral Y 2 2 2

11 Right temporal lobe Lateral Y 2 2 2

12 Right temporal lobe Lateral Y 5 5 5

13 Left temporal lobe Lateral Y 5 5 5

14 Left temporo-parietal lobe Lateral N 6 6 6

15 Left temporal lobe Lateral N 6 6 6

16 Left frontal lobe Anterior N 6 6 6

17 Left temporal lobe Lateral N 6 6 6

18 Left fronto-parietal lobe Lateral N 6 6 6

19 Left temporal lobe Lateral N 6 6 6

20 Left temporo-parietal lobe Posterior N 6 6 6aY indicates presence of symptoms, N absence of symptoms. In Bruunstrom’s scale, 6 indicates no symptoms, 1 maximum impairment

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patients with glioblastomas. They found this index to bereduced in peritumoral WM (compared with the contralat-eral side) and significantly correlated with FA. With thesame method, we tried to clarify the relationships betweenFDi, FA, and ADC of the CST, by considering bothsymptomatic and asymptomatic patients for its involve-ment by glioblastoma. The objective of our study was todetermine which differences are able to discriminate be-tween tumor infiltration and peritumoral edema in patientswith and without preoperative motor deficits.

As described by Roberts et al. [8], we found a reducedquantity of FDi in the WM close to glioblastomas. FAwassignificantly reduced in peritumoral WM as well, and ADCwas increased.

These data are in agreement with those recently reportedby Stadlbauer et al. [11]. These authors found a reducednumber of fibers and FA close to brain neoplasms; in thesame regions, mean diffusivity had increased.

By correlating DTI results with MR spectroscopy,Stadlbauer and co-workers suggested that the increasedextracellular water—not detectable by conventional T2-weighted MRI—might be responsible for the aforemen-tioned changes.

Based on the assumption that, in those patients symp-tomatic for CST involvement, this tract should be moreimpaired than in asymptomatic ones, we analysed DTIchanges in these two sub-groups and tried to correlate themwith the clinical compromise.

In our experience, in symptomatic patients the fiberdensity per voxel of CST (FDi) had statistically reducedwhile ADC had increased; FA was not different in the twosub-groups.

A fiber reduction in symptomatic patients comparedwith asymptomatic ones was not recorded in the study byStadlbauer et al. [11]. These authors found the amount offibers to be reduced only by comparing ipsilateral andcontralateral sides of both symptomatic and asymptomaticcases.

In our opinion, there are at least two possible explana-tions for this observation.

First, the amount of extracellular water—expressed asADC in our study and as mean diffusivity (MD) in thestudy by Stadlbauer and co-workers—was higher in ourpatients. This is immediately evident by considering theP values when comparing ADC and MD of ipsilateral sidesin both symptomatic and asymptomatic patients (PADC=0.002 vs PMD=0.026). We think this is likely to be relatedto the type of neoplasms considered. In our study, we aredealing with a homogeneous group of glioblastomas,whereas II- to IV-grade gliomas were considered in thestudy by Stadlbauer and co-workers.

Furthermore, there is a higher standard deviation in thevalues of fiber count (expressed as “Fiber per Voxel”, FpV)in the study by Stadlbauer and co-workers related to thedifferent location of the ROI considered to evaluate DTIparameters. In our cases, ROIs were always placed in theinternal capsule, thus obtaining a more homogeneousevaluation of CST fibers.

In our study, FA was not different when comparing theipsilateral sides of symptomatic and asymptomatic pa-tients, but it was statistically decreased in the ipsilateralside of symptomatic patients compared with the contra-lateral side. This finding was not recorded in the asymp-tomatic group. The correlation between FA values andsymptoms was partially addressed by Laundre et al. [4].These authors used the FA to monitor the patients’ clinicalmotor function before and after the surgical resection ofspace-occupying lesions, thus identifying CST involve-ment from anisotropy and directional color maps. Althoughthe number of observations in this study is limited, theunderlying pathologies observed are different from ours(low-grade gliomas), and FA was not quantified, the datafrom the study by Laundre and co-workers seem to indicate

Fig. 2 Box-plots of FDi (a), FA (b) and ADC (c) values of peritumoral and normal WM assessed in he contralateral hemisphere of all thepatients. Overlaid are the P values calculated from two-sample t-test

Table 2 P values for t-tests between ipsilateral and contralateralparameters and for subgroups of patients (NS not significant)

Motor deficits FDi FA ADC

Yes (n=13) 1.24×10−8 0.001 797×10−5

No (n=7) 0.05 NS 0.0004

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that FA is decreased in the CST of symptomatic patientsand can be either normal or reduced in asymptomatic ones.

The meaning of FA reduction in the WM close toglioblastomas was assessed by many studies [12–14]. Apositive correlation between FA and cell density inglioblastomas was clearly demonstrated by Beppu et al.[15]. The same authors described how FA decreases morein the CST of those patients with motor deficits byglioblastomas when three-dimensional anisotropy contrast(3DAC) MR axonography showed obscured dark areas[16]. These authors believe that the darkened regions on3DAC in the involved tract of patients with glioblastomaresult from a large obstruction to water diffusion due toinvasion by tumor cells. In another recent study, Goebellet al. [17] described how, in gliomas, the degree of tissueorganization decreases continuously from the surroundingtissue toward the center of the tumor, accompanied by aconcordant FA and N-acetylaspartate decrease (at spec-troscopy), both reflecting a decreasing integrity of neuronalstructures and fibers.

FA reduction in the CST of symptomatic patients wasobserved also by Stadlbauer et al. [11], but the authors didnot provide an explanation for this finding.

As previously mentioned, ADC values recorded in ourpatients were statistically more increased by comparingNWm and perWm of symptomatic than in the asymptomaticgroup (Table 2), while FA values reached a statisticalsignificance only in symptomatic cases (Table 2). Also,

when comparing ADC and FA of perWm in symptomaticand asymptomatic patients, ADC only turned out to bestatistically increased. It is our opinion that ADC plays amajor role in determining a decrease of FA in symptomaticbut not in asymptomatic patients.

To confirm this hypothesis, we correlated ADC, FA, andFDi values with the CSs as assessed by the Brunnstrom’sscale. Although all these three values showed statisticallysignificant correlations with the CSs (FDi vs CS: P=0.035,Rsq=0.345; FA vs CS: P=0.011, Rsq=0.455; ADC vs CS:P=0.001, Rsq=0.668), only ADC turned out to be sig-nificant at multiple stepwise regression analysis. In ouropinion, this confirms that ADC is a main factor indetermining the onset of clinical symptoms and in causingchanges of both FA and FDi values.

This finding suggests the possible reversibility ofneurologic symptoms as soon as the vasogenic edemaresolves due to treatment. A post-surgical assessment ofthese patients might help to understand whether DTT candifferentiate possible reversible from irreversible WM fiberinvolvement in those patients with reduced FDi and FA,and increased ADC.

Conclusions

FDi was significantly reduced in the CST of the affectedhemisphere of patients harboring glioblastomas. Both ADC

Fig. 3 Box-plots of FDi (a), FA (b) and ADC (c) values of peritumoral WM in with and without motor symptoms. Overlaid are the P valuescalculated from two-sample t-test

Fig. 4 Scatter-plots of FDi (a), FA (b) and ADC (c) values of peritumoral WM against clinical scores, as assessed by Brunnstrom’s criteria.A significant correlation is evident between all the parameters and the CS, with the highest significance for ADC (Rsq=0.668)

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(increased) and FA (decreased) had significantly changed(with a higher statistical significance for ADC) in the CSTas well. By comparing the ipsilateral versus the contralateralside of symptomatic patients, ADC showed the greaterdifference between the two sides, while FA values weresimilar. All DTI values were shown to be correlated with

clinical impairment. In a multiple stepwise analysis, ADCwas only shown to be significantly correlated with the CS.These data indicate that an increased ADC plays a majorrole in reducing the number of fibers (reduced FDi) insymptomatic patients.

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