e u r o p e a n j o u r n a l o f p a e d i a t r i c n e u r o l o g y 1 8 ( 2 0 1 4 ) 1 5 0 e1 5 6

Official Journal of the European Paediatric Neurology Society

Original article

Novel diffusion tensor imaging findings in Krabbe disease Andrea Poretti a,*, Avner Meoded a, Martin Bunge b, Ali Fatemi c,d, Paul Barrette e, Thierry A.G.M. Huisman a, Michael S. Salman f a

Section of Pediatric Neuroradiology, Division of Pediatric Radiology, The Russell H. Morgan Department of Radiology and Radiological Science, The Johns Hopkins School of Medicine, Baltimore, MD, USA b Department of Radiology, Faculty of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada c Kennedy Krieger Institute, Baltimore, MD, USA d Department of Neurology, The Johns Hopkins School of Medicine, Baltimore, MD, USA e Department of Diagnostic Imaging, Health Sciences Centre, Winnipeg, Manitoba, Canada f Section of Pediatric Neurology, Department of Pediatrics and Child Health, Faculty of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada

article info

abstract

Article history:

Background: Krabbe disease is a lysosomal disorder that primarily affects myelin. Diffusion

Received 20 March 2013

tensor imaging (DTI) provides quantitative information about the white matter organiza-

Received in revised form

tion and integrity. Radial diffusivity (RD) reflects myelin injury selectively.

12 September 2013

Purpose: To report on quantitative DTI findings (including axial diffusivity (AD) and RD, not

Accepted 30 September 2013

previously reported) in two children with Krabbe disease compared to controls. Methods: A quantitative region of interest (ROI) based DTI analysis was performed for the

Keywords:

patients and age- and gender-matched controls. Fractional anisotropy (FA), mean diffu-

Krabbe disease

sivity, AD and RD values as well as variation ratios between the patients’ and controls’

Magnetic resonance imaging

values were calculated for nine brain regions.

Diffusion tensor imaging

Results: Two boys with Krabbe disease were included in this study. DTI data were acquired

Radial diffusivity

at the ages of 6.25 years and 6.5 months. For all regions, FA ratios were negative, while RD and MD ratios positive. The most elevated variation ratios were found for RD. Variation ratios were greater in the centrum semiovale, corpus callosum, and middle cerebellar peduncles than in other anatomical regions, especially in the older patient in comparison with the younger patient. The AD ratios, however, were much lower and close to zero. Conclusions: DTI allows a quantitative evaluation of white matter damage in Krabbe disease. RD seems to be the most sensitive DTI parameter in agreement with the histopathological findings in Krabbe disease, a primary myelin disorder. This may be important in the early detection of the onset of demyelination. ª 2013 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.

* Corresponding author. Section of Pediatric Neuroradiology, Division of Pediatric Radiology, The Russell H. Morgan Department of Radiology and Radiological Science, The Johns Hopkins School of Medicine, Sheikh Zayed Tower, Room 4174, 1800 Orleans Street, Baltimore, MD 21287, USA. Tel.: þ1 4109556454; fax: þ1 4105023633. E-mail address: [email protected] (A. Poretti). 1090-3798/$ e see front matter ª 2013 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.ejpn.2013.09.008

e u r o p e a n j o u r n a l o f p a e d i a t r i c n e u r o l o g y 1 8 ( 2 0 1 4 ) 1 5 0 e1 5 6

1.

Introduction

Krabbe disease or globoid cell leukodystrophy (OMIM 245200) is a progressive, autosomal recessive, lysosomal storage disorder affecting the white matter of the central and peripheral nervous systems.1 The primary defect in Krabbe disease is a deficiency of galactocerebrosidase due to mutations within the GALC gene on chromosome 14q31. This leads to impaired degradation of galactosylceramide, infiltration of globoid cells, accumulation of psychosine, and results in the apoptosis of myelin-forming cells.2 Depending on age at onset and rate of clinical deterioration, a number of clinical phenotypes can be distinguished. The early-infantile subtype is the most common one and affected children present with developmental stagnation, irritability, stiffness, and periods of fever followed by rapid and severe motor and cognitive deterioration.3 The late-infantile, juvenile, and adolescent-adult types are less common.3 Diffusion tensor imaging (DTI) is an advanced MR technique that provides qualitative and quantitative information about the microscopic structural organization of the white matter, changes in cell density and myelination.4 Therefore, DTI is a suitable MR tool to study the normal development of the white matter and acquired or inherited white matter diseases.5 DTI has been previously performed to study children with Krabbe disease.6e9 In asymptomatic and symptomatic patients, significantly lower FA values were found in several white matter structures including frontal and occipital white matter, centrum semiovale, and corpus callosum. In this article, we report on clinical, conventional neuroimaging, and quantitative DTI findings in two children with Krabbe disease including fractional anisotropy (FA) as well as mean (MD), axial (AD), and radial (RD) diffusivity. Because Krabbe disease is a primary myelin disorder and RD reflects selective myelin injury, we hypothesized that RD values will show the greatest variation between patients and controls.

2.

Materials and methods

Two boys with Krabbe disease were included in this study. Clinical, conventional MR, 1H-MRS, laboratory, and genetic findings of patient 1 were previously reported in detail.10 In summary, patient 1 presented with irritability and poor feeding at the age of 5 months with rapid progression over the following two years. He had an unusual prolonged survival and at the age of 8 years he is alive. Patient 2 was admitted to the hospital at the age of 6.5 months with a history of irritability, macrocephaly, poor feeding, failure to thrive, and loss of milestones. He was born at term to non-consanguineous parents after a prenatal diagnosis of macrocephaly. The family history was unremarkable. Since the age of four months, the infant did not gain weight and had a progressive macrocephaly. Two weeks before admission and after a viral illness, he lost previously acquired developmental milestones: He was not able to lift his head, reach for toys, and babble. He smiled and tracked visually only intermittently. Additionally, he became very irritable and inconsolable. On examination at 6.5 months of age, his head circumference was 47 cm (1 cm

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above the 95th centile). He was able to visually track only briefly and inconsistently, had a head lag, and was unable to sit with support. He had normal limb movements and peripheral muscle tone. The truncal tone was mildly decreased, but he developed an opisthotonic posturing when agitated or picked up. Deep tendon reflexes were normal. The diagnosis of Krabbe disease was made by an abnormally low galactocerebrosidase activity in peripheral leukocyte in both children (0.01 nmol/h/kg for patient 2, normal range 0.9e4.4 nmol/h/kg) and confirmed by molecular genetic analysis in the older patient. Five age- and gender-matched controls for each patient were selected from our pediatric MR database using the following criteria: (1) normal brain anatomy, (2) absence of neurological disorders, and (3) availability of DTI raw data. The MRI studies of patient 1 and 2 were acquired on a 3.0 and 1.5 T clinical MR scanner, respectively (Verio and Avanto, Siemens, Erlangen, Germany) using the standard departmental protocols including multiplanar T1- and T2-weighted sequences, an axial fluid attenuated inversion recovery (FLAIR) sequence, and a single voxel, long-echo 1H magnetic resonance spectroscopy (MRS) of the basal ganglia and posterior centrum semiovale. Additionally, for both patients a single shot spin-echo, echo-planar (EPI) axial DTI sequence was acquired. For patient 1, balanced pairs of diffusion gradients were applied along 30 orthogonal directions; a b value of 0 and 800 s/mm2 was used; TR ¼ 4000 ms, TE ¼ 95 ms, slice thickness: 4.0 mm, field of view (FOV): 230  230 mm; matrix: 128  128. For patient 2, balanced pairs of diffusion gradients were applied along 20 orthogonal directions, a b value of 0 and 800 s/mm2 was used; TR ¼ 8500 ms, TE ¼ 86 ms, slice thickness: 2.0 mm, FOV : 192  192 mm; matrix: 192  192. DTI data of the patients and age- and gender-matched controls were transferred to an off-line workstation for further post processing. DtiStudio, DiffeoMap, and RoiEditor software (available at http://www.MriStudio.org/) were used. FA, vector maps, and color-coded maps were generated after rigid transformation for adjustment of the position and the rotation of images. MD, AD, and RD were also calculated. The regions of interest (ROI) were drawn manually on the bilateral anterior and posterior centrum semiovale, genu and splenium of the corpus callosum, posterior limbs of the internal capsule, cerebral peduncles, pontine corticospinal tracts and medial lemnisci, and middle cerebellar peduncles (MCP). For the identification of each structure, color-coded FA maps were used in comparison to the MRI atlas by Oishi et al.11 Each ROI was drawn as large as possible while care was given not to include cerebrospinal fluid along the margin of the structure on color-coded images. FA map and B0 map were also referred to, if needed. All ROI were set by a single operator (AP). We evaluated FA, MD, AD, and RD of each structure. Variation ratios between patients and the median value of the five gender- and age-matched controls were calculated (ratio ¼ (patient value  controls’ median value)/controls’ median value). Variation ratios were calculated to show differences in DTI parameters between patients and controls better.12,13

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Fig. 1 e Infratentorial (A) T2-weighted, (B) FLAIR images, and (C) FA maps of patient 2 at 6.5 months of age show a symmetric T2- and FLAIR-hyperintense signal abnormality of the lateral/dorsal extension of the middle cerebellar peduncles (arrows in A, B) with matching reduced assigned intensity in the FA map (arrows in C) representing decreased FA values. Additionally, there is a symmetric T2- and FLAIR-hyperintense signal abnormality in the center of the dentate nuclei (arrowheads in A, B). Supratentorial (D) T2-weighted, (E) FLAIR images, and (F) FA maps of the same child at the level of the centrum semiovale reveal a symmetric T2- and FLAIR-hyperintense signal abnormality of periventricular white matter involving predominantly the posterior regions with matching reduced hyperintense signal in the FA map (arrows in F) representing decreased FA values. Additionally, a moderate volume loss of the cerebral hemisphere with secondary ventriculomegaly is noted.

3.

Results

The first MRI of patient 1 at the age of 8.5 months showed T2and FLAIR-hyperintense signal in the periventricular white matter, centrum semiovale, dentate nuclei, cerebellar white matter, and splenium of the corpus callosum. Enlargement of the optic nerves and chiasm were also present. 1H-MRS revealed elevated choline/creatine and myoinositol/creatine ratios and decreased N-acetyl aspartate (NAA)/creatine ratio. DTI data were acquired at the age of 6.25 years. A qualitative evaluation of the FA maps revealed a decrease FA of the periventricular white matter, centrum semiovale, cerebellar white matter, and corpus callosum (not shown). Patient 2 had a brain MRI at birth that showed a mild isolated ventriculomegaly. A brain MRI was repeated at 6.5 months of age and revealed an abnormal T2- and FLAIR-hyperintense signal

within the center of the dentate nuclei, cerebellar white matter (Fig. 1AeB), cerebral peduncles, periventricular white matter and centrum semiovale with a predominant involvement of the parietal regions (Fig. 1DeE). On T1-weighted images, the thalami were hyperintense (not shown). A moderate volume loss of the cerebral hemisphere was present with ventriculomegaly (Fig. 1DeE). Finally, the optic nerves, chiasm, and tracts were enlarged (Fig. 2AeB). 1H-MRS showed a markedly elevated choline/creatine ratio and decreased NAA/creatine ratio (not shown). A qualitative evaluation of the FA maps revealed a decrease FA of the involved white matter (Fig. 1C and F). DTI data of patient 1 and 2 were acquired at the age of 6.25 years and 6.5 months, respectively. The raw data of FA, MD, AD, and RD of the patients and the median values of the five age- and gender-matched controls for each structure are shown in Table 1. Variation ratios of the DTI scalars between

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Fig. 2 e (A) Axial T2- and (B) sagittal T1-weighted images demonstrate symmetric enlargement of the optic nerves (black arrows in A, white arrow in B).

the patients and the median value of the controls of each structure are shown in Fig. 3. The FA ratio was negative in both patients and in every structure. This means that FA values are lower in patients compared to controls. The reduction is especially prominent in the older patient (advanced stage of disease) and regions located in the upper brain (centrum semiovale and corpus callosum), with the exception of the MCP. A similar trend was also found for the increase in MD and RD: less pronounced for MD, but higher for RD than the change in FA. The AD ratios, however, were much lower and close to zero indicating similar values to controls.

4.

Discussion

Neuroimaging plays a key role in the diagnosis of Krabbe disease. Conventional MRI shows characteristic findings.14 On T2-weighted images, the corticospinal tracts and the deep cerebral white matter are abnormally hyperintense. Signal abnormalities involve particularly the posterior frontal and anterior parietal lobes and may extend into the splenium of the corpus callosum. The subcortical U-fibers are, however, relatively spared. Additionally, in early-onset Krabbe disease, the thalami are abnormally bright on T1-weighted images, the cerebellar white matter and the center of the deep cerebellar nuclei show a hyperintense signal on T2-weighted images, and in some children, the optic nerves and chiasm are enlarged.15,16 Finally, diffuse cranial nerves and cauda equina nerve roots enhancement has been reported after intravenous injection of Gadolinium based contrast agent, presumably due to myelin breakdown and associated inflammatory response.17 Advanced MR techniques may further enhance the diagnostic sensitivity and specificity of neuroimaging by providing additional information about the pathological process. Diffusion-weighted imaging (DWI) may show restricted diffusion during the active demyelinating process in the early stage of the disease.18 This is most likely due to intramyelin

edema. In subsequent stages of the disease, the DWIhyperintense signal of the white matter changes into a DWIhypointensity due to complete loss of myelin.18 1H-Magnetic resonance spectroscopy (1H-MRS) was reported to show marked increase of choline (marker of membrane turnover) and myoinositol and moderate to marked reduction of NAA (neuronal marker).19e21 The findings are due to changes in glial membrane composition and microglia activation for synthesis of phospholipid membrane.19e21 In our investigations, we focus on the complementary diagnostic role of DTI in Krabbe disease. Four parameters are typically used currently to quantify white matter structural properties using DTI: FA, MD, AD, and RD. FA represents the degree of anisotropic diffusion which is believed to be related to the degree of white matter tract packing and myelination. Accordingly, decreased FA values are seen in areas of white matter injury with loss of anisotropic diffusion resulting from disorganized or disrupted myelin sheaths. MD describes the overall diffusion and is calculated as the mean of the three eigenvalues (l1, l2, l3) of the diffusion tensor. Changes in MD are related to variation in diffusivity of water molecules in the extracellular space. In chronic white matter injuries, diffusivity of water molecules in the extracellular spaces typically increases resulting in increased MD values. The analysis of AD and RD allows a more detailed study of the local tissue integrity. AD is defined as the eigenvalue of the primary eigenvector (l1) and is predominantly modified by acute axonal damage. An increase in AD suggests an increased axonal diameter. RD is defined as the mean of the eigenvalues of the second and third eigenvectors (l2 and l3) and may reflect selective myelin injury. An increase in RD seems to represent disordered myelin sheaths or increased astrogliosis and giant cells. Hence, AD and RD may detect and differentiate between axonal and myelin damage, respectively.22e24 DTI has been previously performed in children with Krabbe disease.6e9 In the first study, eight children with Krabbe disease and eight controls were investigated.6 The authors

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Structure

Anterior CSO Posterior CSO Genu CC Splenium CC PLIC

FA

MD (103 mm2/s)

AD (103 mm2/s)

RD (103 mm2/s)

Pat 1

Controls

Pat 2

Controls

Pat 1

Controls

Pat 2

Controls

Pat 1

Controls

Pat 2

Controls

Pat 1

Controls

Pat 2

Controls

0.093

0.624 (0.600e0.651) 0.616 (0.547e0.628) 0.834 (0.780e0.842) 0.785 (0.713e0.850) 0.705 (0.689e0.741) 0.715 (0.688e0.782) 0.462 (0.405e0.483) 0.502 (0.464e0.578) 0.770 (0.688e0.872)

0.188

0.429 (0.358e0.478) 0.455 (0.429e0.513) 0.666 (0.534e0.691) 0.763 (0.695e0.799) 0.622 (0.612e0.641) 0.579 (0.552e0.609) 0.394 (0.357e0.423) 0.455 (0.448e0.498) 0.726 (0.663e0.773)

0.169

0.080 (0.075e0.084) 0.083 (0.076e0.084) 0.79 (0.077e0.89) 0.086 (0.082e0.089) 0.075 (0.072e0.079) 0.088 (0.078e0.091) 0.075 (0.072e0.083) 0.078 (0.077e0.087) 0.073 (0.63e0.76)

0.115

0.102 (0.096e0.105) 0.103 (0.099e0.109) 0.107 (0.097e0.116) 0.098 (0.096e0.114) 0.086 (0.082e0.089) 0.101 (0.089e0.103) 0.081 (0.076e0.092) 0.082 (0.075e0.085) 0.077 (0.074e0.079)

0.185

0.146 (0.135e0.155) 0.141 (0.139e0.152) 0.184 (0.179e0.193) 0.187 (0.165e0.193) 0.153 (0.142e0.159) 0.172 (0.165e0.179) 0.113 (0.105e0.121) 0.126 (0.123e0.141) 0.148 (0.139e0.172)

0.137

0.152 (0.143e0.155) 0.163 (0.151e0.168) 0.193 (0.189e0.212) 0.218 (0.196e0.242) 0.158 (0.150e0.166) 0.174 (0.158e0.182) 0.114 (0.109e0.137) 0.125 (0.116e0.136) 0.152 (0.147e0.170)

0.161

0.046 (0.045e0.051) 0.049 (0.045e0.150) 0.034 (0.025e0.179) 0.040 (0.027e0.042) 0.039 (0.034e0.042) 0.046 (0.033e0.049) 0.057 (0.053e0.066) 0.056 (0.049e0.061) 0.028 (0.017e0.039)

0.103

0.075 (0.068e0.081) 0.075 (0.069e0.081) 0.059 (0.050e0.077) 0.046 (0.039e0.058) 0.050 (0.048e0.051) 0.063 (0.055e0.066) 0.066 (0.059e0.071) 0.590 (0.054e0.062) 0.036 (0.034e0.042)

0.120 0.157 0.190 0.438

Cerebral peduncle Pontine CST

0.411

Pontine ML

0.446

MCP

0.392

0.273

0.158 0.465 0.363 0.473 0.428 0.335 0.447 0.465

0.186 0.206 0.214 0.108 0.096 0.111 0.098 0.096

0.126 0.128 0.122 0.086 0.095 0.083 0.091 0.092

0.208 0.241 0.260 0.163 0.140 0.144 0.147 0.139

0.147 0.200 0.174 0.136 0.143 0.113 0.140 0.143

0.174 0.188 0.191 0.080 0.075 0.095 0.074 0.075

0.116 0.092 0.096 0.061 0.07 0.067 0.067 0.067

AD, axial diffusivity; CC, corpus callosum; CSO, centrum semiovale; CST, corticospinal tract; DTI, diffusion tensor imaging; FA, fractional anisotropy; MCP, middle cerebellar peduncle; MD, mean diffusivity; ML, medial lemniscus; Pat, patient; RD, radial diffusivity.

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Table 1 e Raw values of FA, MD, AD, and RD of patients and median values (range) of five age-matched controls for each structure.

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Fig. 3 e Graph displaying the regional variation ratios of DTI parameters for (A) patient 1 and (B) patient 2 in comparison with five age- and gender-matched controls (median values, range). Increased variation ratios have positive values, while decreased variation ratios have negative values. AD, axial diffusivity; CC, corpus callosum; CSO, centrum semiovale; CST, corticospinal tract; FA, fractional anisotropy; MD, mean diffusivity; ML, medial lemniscus; PLIC, posterior limb of internal capsule; RD, radial diffusivity. Note that the y-scale is not the same in A and B.

reported significantly lower FA values in patients in several white matter structures including frontal and occipital white matter, centrum semiovale, and corpus callosum. The authors concluded that FA provides a quantitative measure of abnormal white matter in children with Krabbe disease. Additionally, differences in FA and normalized T2-weighted signal were compared and it was shown FA is more sensitive than T2-weighted images for detecting white matter abnormality in Krabbe disease. In a second study, the same investigators compared FA values of the corticospinal tract between asymptomatic neonates with infantile Krabbe disease, diagnosed through statewide newborn screening program, and controls.9 The authors found significantly lower FA values in asymptomatic neonates with Krabbe disease compared to healthy controls. Finally, in a third study FA values were measured in children with Krabbe disease and early (younger than 1 month of age) or late (at 5e8 months of age) hematopoietic stem cell transplantation, respectively.7 The authors reported smaller decrease in FA in four white matter regions for Krabbe patients with early compared to

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those with late transplantation. The DTI findings correlated relatively well with disease progression assessed by clinical evaluation and conventional neuroimaging. The results of the study suggested improved myelination. Additionally, they demonstrated that DTI is a suitable MR sequence for quantitatively assessing white matter abnormalities in Krabbe disease. Compared to prior studies, we also measured AD and RD. Our study showed that in Krabbe disease, DTI is not only a sensitive tool for evaluation of white matter injury, but can also reveal the underlying pattern of histopathology. This was previously shown in Twicher mice, which mirror the pathology and clinical course of the human infantile form of Krabbe disease.25 In our patients, FA ratios were negative and RD ratios positive. This represents lower FA values and higher RD values in patients compared to controls. Reduced FA and, particularly, increased RD values suggest decreased white matter integrity due to myelin damage.22 Indeed, Krabbe disease is a primary myelin disorder and extensive white matter degeneration with demyelination and gliosis is its characteristic neurohistological finding.26 Although demyelination in Krabbe disease is diffuse throughout the brain, regional variations in its severity have been reported.14 Phylogenetically younger myelinated white matter tracts are affected more severely and include the centrum semiovale, periventricular white matter with a parieto-occipital predominance extending into the corpus callosum, and cerebellar white matter.27 Accordingly, abnormalities of the white matter tracts in the brain stem (corticospinal tracts and medial lemnisci) and posterior limb of the internal capsule (PLIC) were less severe. Our results are consistent with this reported regional variability. For both patients, FA and RD ratios in the centrum semiovale, corpus callosum, and middle cerebellar peduncles were affected more than in the PLIC, cerebral peduncles, and pontine white matter tracts. Although the regional variability of FA and RD ratios in our patients is similar, some differences exist. First, FA and RD ratios are lower in patient 2 compared to patient 1. The most likely explanation is the less advanced stage of disease in patient 2 compared to patient 1. Additionally, in patient 1, RD ratios were higher than FA ratios, while in patient 2, FA and RD ratios were similar. FA depends on several white matter structural components such as number of axons, axonal density, axonal size, packing, and myelin thickness.28 RD, however, is a more specific biomarker of myelin damage.22 The degree of severity of myelin damage has a higher impact on RD than on the FA values. Based on the FA evaluation, DTI was reported to be potentially useful as a quantitative biomarker of disease progression in Krabbe disease.7,9 Our findings suggest that RD may be a more sensitive biomarker than FA to quantitatively evaluate the degree and temporal evolution of Krabbe disease. MD ratios are smaller than RD ratios. This may be explained by the mathematical definition of MD: MD ¼ (AD þ 2RD)/3. Indeed, almost all AD ratios are close to 0. This means that there is no or only minimal difference in AD values between patients and controls, particularly in patient 2. This may reflect the relative axonal preservation at least in the early stages of Krabbe disease. In patient 1, the AD values in the centrum semiovale and corpus callosum were higher compared to controls. This may reflect diffuse fibrillary gliosis

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throughout the most affected white matter with proliferation of astrocytes. There are a number of limitations in our study: The small sample size, the different protocols that have been used to acquire the DTI data between the patients, and the ROI-based analysis which is observer dependent. Finally, the biological interpretation of the relationship between DTI values and changes and the underlying histopathological components remains speculative.

5.

10.

11. 12. 13.

Conclusion 14.

DTI allows a quantitative evaluation of white matter damage in Krabbe disease. RD seems to be the most sensitive DTI parameter in agreement with the histopathological findings in Krabbe disease, a primary myelin disorder. This may be important in the early identification of the onset of demyelination. The role of RD as a sensitive biomarker of disease progression in Krabbe disease has to be further evaluated in a larger cohort of patients.

Conflicts of interest The authors report no conflicts of interest. The authors are responsible for the content and writing of the article.

15. 16. 17.

18. 19.

20.

references 21. 1. Suzuki K. Globoid cell leukodystrophy (Krabbe’s disease): update. J Child Neurol 2003;18:595e603. 2. Sakai N. Pathogenesis of leukodystrophy for Krabbe disease: molecular mechanism and clinical treatment. Brain Dev 2009;31:485e7. 3. Duffner PK, Barczykowski A, Jalal K, et al. Early infantile Krabbe disease: results of the world-wide Krabbe registry. Pediatr Neurol 2011;45:141e8. 4. Feldman HM, Yeatman JD, Lee ES, et al. Diffusion tensor imaging: a review for pediatric researchers and clinicians. J Dev Behav Pediatr 2010;31:346e56. 5. Isaacson J, Provenzale JM. Diffusion tensor imaging for evaluation of the childhood brain and pediatric white matter disorders. Neuroimaging Clin N Am 2011;21:179e89. 6. Guo AC, Petrella JR, Kurtzberg J, et al. Evaluation of white matter anisotropy in Krabbe disease with diffusion tensor MR imaging: initial experience. Radiology 2001;218:809e15. 7. McGraw P, Llang L, Escolar ML, et al. Krabbe disease treated with hematopoietic stem cell transplantation: serial assessment of anisotropy measurements-initial experience. Radiology 2005;236:221e30. 8. Provenzale JM, Escolar M, Kurtzberg J. Quantitative analysis of diffusion tensor imaging data in serial assessment of Krabbe disease. Ann N Y Acad Sci 2005;1064:220e9. 9. Escolar ML, Poe MD, Smith JK, et al. Diffusion tensor imaging detects abnormalities in the corticospinal tracts of neonates

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Novel diffusion tensor imaging findings in Krabbe disease.

Krabbe disease is a lysosomal disorder that primarily affects myelin. Diffusion tensor imaging (DTI) provides quantitative information about the white...
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