Selective White Matter Involvement in a Patient with LateOnset Krabbe Disease: MR, MR Spectroscopy,and Diffusion Tensor Study

Andrea Romano, MD, Roberto De Simone, MD, Fabrizio Fasoli, MD, Michele Ferrante, MD,Valentina Cipriani, MD, Luigi Maria Fantozzi, MD, Alessandro Bozzao, MDFrom the Department of Neuroradiology, S. Andrea Hospital, University “La Sapienza”, Rome, Italy (AR, FF, MF, VC, LMF, AB); Department of Neurology, S. Eugenio Hospital,Rome, Italy (RDS).

keywords: Late onset Krabbe disease,MR spectroscopy, MRI diffusion tensor.

Acceptance: Received February 9,2008, and in revised form January 11,2008; February 9, 2008. Accepted forpublication February 17, 2008.

Correspondence: Address correspon-dence to Andrea Romano, MD, Depart-ment of Neuroradiology, S. Andrea Hos-pital, Via di Grottarossa 1035, 00189Rome, Italy. E-mail: andrea.romano@uniroma1.it

J Neuroimaging 2009;19:191-193.DOI: 10.1111/j.1552-6569.2008.00258.x

A B S T R A C TThe most frequent type of Krabbe disease has an infantile onset. Unusual slowly progres-sive adult forms have also been described. We described a different involvement of whitematter tracts where magnetic resonance signal alterations were evident in a case of apatient affected by late-onset form of disease.

Case ReportA 42-year-old woman was affected by progressive gait distur-bance after reaching 38 years of age. Neurological examinationshowed spastic paraparesis with increased muscle tone in thelegs.

A demyelinating sensorimotor neuropathy was observedduring electromyography. Enzyme galactocerebrosidase activ-ity was absent in leukocytes (.22 nmol h-1 mg-1 protein, <10%of the normal mean). Visual evoked potentials showed slightalterations. Magnetic resonance spectroscopy (MRS), diffusiontensor imaging (DTI), and conventional sequences were per-formed using a 1.5-T MR system (Sonata; Siemens, Erlan-gen, Germany), all with the same orientation. Two-dimensionalspectroscopic volumes were obtained using Chemical Shift spinecho sequence (TR/TE-1500/135), centered on the centrumsemiovale and on the subcortical parieto-occipital white matterwhere signal alterations were evident in fast low-angled inver-sion recovery (FLAIR) images (Figs 1A, C).

As a reference, the white matter of the cingulum (visible atthe level of centrum semiovale), which appeared normal onFLAIR images, was considered as well.

Metabolite ratios obtained were compared to 10 adult nor-mal controls. MRS revealed (without differences between brainhemispheres) increased Cho/Cr resonance intensities in vox-els located inside and at the border of the magnetic reso-nance imaging (MRI) signal alterations (inside mean valueCho/Cr: 1.25; at the border Cho/Cr: 1.09) (Figs 1 A–C, E),without significant alterations in white matter of cingulum(Cho/Cr: 0.83) (Fig 1E) (Cho/Cr: 0.95 in controls). DTI wasperformed by means of diffusion measurements in 12 non-

collinear directions (TR/TE/slices/thickness/FOV/b/matrix=6600/91/42/3/230/1000/128 × 128) and postprocessed usingDTI-Studio software (Processing Tools and Environment forDiffusion Tensor Imaging, Version 2, H. Jiang and S. Mori,Radiology Dept., Johns Hopkins University, Baltimore, MD)(Fractional Anisotropy (FA) threshold of 0.20, fiber angulationof up to 70◦).

The fiber density index (FDi), FA, and apparent diffusioncoefficient (ADC) were calculated. FDi measure, introduced byRoberts et al.,1 expresses the number of white matter fiberspassing through a ROI. Position of ROIs (size 50 pixels) on thecolor maps is shown in Figs 1F–H. FDi values obtained werecompared to 10 adult normal controls (the same ones previouslydescribed for MRS). The mean FDi of both cortico spinal tract(CST) in Krabbe patient (4.7) differed from the mean FDi incontrols (7.0), indicating reduction of fiber density (about 33%).In optic radiations (OR) the FDi values (4.4 vs. 5.6 in normalcontrols) indicated a reduction of 22%. No differences were seenwhen the analysis of mean FDi was performed in cingulum (6.2vs. 5.9 in normal controls). The mean FA value showed the samemodifications (Krabbe disease OR .51; CST .46; cingulum .46)(controls OR .61; CST .65; cingulum .47). No significantdifferences were appreciated between patient and controls forADC.

DiscussionThe most frequent form of Krabbe disease is the infantile vari-ant. The late onset type is rare and its clinical progression isslower. Unusual slowly progressive adult forms have also been

Copyright ◦C 2008 by the American Society of Neuroimaging 191

Fig. 1. Both the MRS acquired in parieto-occipital white matter (A-B) and in centrum semiovale (E) demonstrate an increased Choline/Creatineratio in voxels located inside and at the border the MRI lesions. In (C) and (D) the spectroscopic grid is placed on a region encompassing thewhite matter of CST (blue) and cingulum (green). No significant metabolic alterations are evident in voxels located inside the white matter ofcingulum, whereas increased Choline/Creatine ratio is clearly evident in voxels located inside and at the borders of CST (white circles) (E). In(F), (G), and (H), ROIs placement on color maps in areas encompassing the cortico-spinal tract (blue, F), the cingulum (green, G), and theoptic radiation (green, H) used to calculate the Fiber Density index are represented.

described being characterized by spastic paraparesis and MRIfindings of bilateral CST demyelization.2,3 Visual dysfunctionsand extra pyramidal motor disability are reported as well.4,5

D’Agostino et al.6 reported, from autopsy studies, 4 stages ofthe disease based on the degree of demyelination progressingto a final stage consisting of astrocytic gliosis with loss of myelinand preservation of only few axons. Loes et al. suggest thatpyramidal tract involvement is the most characteristic findingin both early and late-onset Krabbe disease.7 The most commonimaging findings in late onset-type include T2 hyperintensity in-volving pyramidal tract, corpus callosum and parieto-occipitalwhite matter, and cerebral atrophy. Metabolite concentrationsin white matter of patients with late-onset type is debated, rang-ing from values close to normal8 to increased values.9,10 The in-creased Cho/Cr ratio observed, although not specific of Krabbedisease,9 could be related to active myelin breakdown. Thereis a general agreement that metabolic changes may involvethe white matter beyond the T2 signal alterations. De Stefanoet al.10 showed spectroscopic alterations inside, at the borderand outside (even if milder) the MRI lesions along the pyra-

midal tracts suggesting the hypothesis of a diffuse white matterpathology.

In our patient the observed metabolic alterations might sug-gest a selective vulnerability of white matter tracts. This vul-nerability seems to be higher in CST and to a lesser degree inOR and it could be possibly due to the greater myelin turnoverof these fibers compared to others. This concept was alreadyproposed by Satoh et al.2 indicating that the selective vulnera-bility of the CST in patients with late-onset Krabbe disease maydepend on their myelin metabolism.

The selective decrease of FA and fiber density, demon-strated by the FDi values, should be considered, in our opin-ion, in the same way. The FDi, proposed by Roberts,5 is anindicator of number of fibers, as assessed by diffusion ten-sor imaging, in a specific area. In our patients FDi and FAvalues were found to be reduced, compared to normal con-trols, in regions encompassing the CST and OR. This re-duction was more marked at the level of CST than in OR.As expected, non significant differences emerged about ADCvalues.

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The patient showed clinical symptoms referable to CST in-volvement while only slight alterations of visual potential andno objective visual symptoms were observed.

Our hypothesis is that metabolism alterations, associatedwith a possible mild gliosis, differently involve myelin tracts,leading to loss of fibers and, eventually, to clinical symptomswhen below a specific threshold.

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