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Krabbe Disease Treated with Hematopoietic Stem Cell Transplantation: Serial Assessment of Anisotropy Measurements—Initial Experience¹

¹ From the Department of Radiology (P.M., L.L., S.M., J.M.P.) and Department of Pediatrics, Division of Pediatric Blood and Marrow Transplantation (J.K.), Duke University Medical Center, Erwin Rd, Box 3808, Durham, NC 27710; and Center for the Study of Development and Learning, University of North Carolina at Chapel Hill, School of Medicine, Chapel Hill, NC (M.E.). Received April 20, 2004; revision requested June 29; revision received August 5; accepted August 20. Address correspondence to J.M.P. (e-mail: prove001{at}mc.duke.edu).

	ABSTRACT

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION References

 
PURPOSE: To prospectively compare diffusion-tensor magnetic resonance (MR) imaging anisotropy measurements of white matter (WM) regions in early and late treatment groups of Krabbe disease patients treated with stem cell transplantation.

MATERIALS AND METHODS: The study was approved by the Institutional Review Board and was compliant with Health Insurance Portability and Accountability Act; informed consent was obtained from the families of all patients. Patients with early-onset Krabbe disease (four girls and three boys) underwent diffusion-tensor MR imaging before and after stem cell transplantation. Fractional anisotropy (FA) values from serial studies were compared in patients who underwent transplantation at less than 1 month (early group, two girls and one boy) and those who underwent transplantation at 5–8 months (late group, two girls and two boys). FA values were measured in the genu and splenium of the corpus callosum, the frontal WM, and the internal capsule; were compared with those of five age-matched children in the comparison group (normal MR images and no proved neurologic disease); and were expressed as a ratio. Images obtained after transplantation were evaluated at approximately 1 (n = 7), 2 (n = 6), 3 (n = 1), and 4 (n = 1) years.

RESULTS: Before transplantation, mean FA ratios in the early group for all four WM regions ranged between 97% and 117%. At 1 year, mean FA ratios at all locations were either 92% or 93%. At 2 years after transplantation, mean FA ratios were between 83% and 92%. In one patient imaged at 3 years, the mean FA ratio was 97%; in another patient imaged at 4 years, the mean FA ratio was 77%. Before transplantation, mean FA ratios in the late group ranged between 55% and 74%. Mean FA ratios were between 37% and 50% at 1 year after transplantation and between 36% and 39% at 2 years.

CONCLUSION: All patients had decreases in FA ratios over time. The early group had higher initial FA ratios and lower subsequent decreases, which may indicate amelioration of the dysmyelinating process.

© RSNA, 2005

	INTRODUCTION

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION References

 
Krabbe disease, also known as globoid cell leukodystrophy, is an autosomal recessive white matter (WM) disease that results from accumulation of two substances that are normally degraded by ß-galactocerebrosidase, an enzyme that is deficient in Krabbe disease (1). One substance, ß-galactocerebroside, accumulates within macrophages to form characteristic globoid cells. Another substance, galactosylsphigosine, is toxic to oligodendroglia responsible for myelin formation, which results in loss of myelin. Two major forms of Krabbe disease are recognized: early onset (infantile) and late onset; both forms are marked by loss of myelin in the central and peripheral nervous systems (2). The early-onset form occurs in infants and young children and usually follows a progressive course of neurologic deterioration characterized by a vegetative state and death within the first 2–4 years of life.

In the past, no curative treatment options have existed. However, hematopoietic stem cell transplantation is a promising therapy based on the fact that donor leukocytes can provide the deficient enzyme to cells in the peripheral and central nervous systems. Authors of one study (3) of five children with Krabbe disease treated with hematopoietic stem cell transplantation reported reversal or lack of progression of clinical and radiologic findings, with resumption of leukocyte ß-galactocerebrosidase activity. This type of treatment and others that may follow increase the importance of a sensitive means of radiologic assessment of disease progression and treatment response.

The maturation of brain WM is dependent in large part on myelination and is critical for the development of the central nervous system. This process begins in the second trimester of gestation and continues into early adulthood (4). The critical period at which myelination occurs is from the third trimester of gestation through the 2nd year of life. In the past few decades, the patterns of myelination have been well documented at conventional magnetic resonance (MR) imaging (4). The development of diffusion-tensor MR imaging offers the promise of a more sensitive means to assess myelination patterns compared with routine spin-echo MR imaging. With diffusion-tensor MR imaging, the MR signal is sensitized to microscopic movement of water molecules. Water motion in WM myelination is anisotropic (ie, has a tendency to diffuse along one direction rather than in all directions), a feature that can be quantitatively and reproducibly measured with anisotropy maps. On such maps, anisotropy is shown to be higher in more compact WM structures (eg, the corpus callosum) than in less compact WM structures and gray matter (5). Anisotropy measurements of WM structures have been shown to increase with age to correspond to the degree of maturation and myelination of the central nervous system. It appears reasonable that diffusion-tensor MR imaging could serve as a sensitive means for following changes in WM in diseases in which primarily the WM is affected.

We hypothesized that infants with Krabbe disease would have decreased anisotropy measurements at baseline compared with age-matched subjects. This hypothesis was based on the fact that subtle neurologic deficits can be seen in neonates with Krabbe disease and that subtle demyelinating lesions have been reported in an affected fetus (6). We also hypothesized that infants treated with hematopoietic stem cell transplantation at a very early age would have a greater increase of anisotropy values (presumed to represent myelination and further growth of axons) following therapy than infants who were treated at a later age. Thus, the purpose of our study was to prospectively compare anisotropy measurements obtained at diffusion-tensor MR imaging of WM regions in Krabbe disease patients treated with stem cell transplantation at an early age with measurements in those treated at a later age.

	MATERIALS AND METHODS

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION References

 
Patients
We prospectively studied a patient population that consisted of four girls and three boys in whom early infantile-onset Krabbe disease was diagnosed either on a clinical basis (ie, neurologic impairment in the 1st year of life, two girls and two boys) or in the neonatal period because of an affected sibling with Krabbe disease and very low or absent levels of serum ß-galactocerebrosidase (two girls and one boy). All patients were treated with allogeneic hematopoietic stem cell transplantation at Duke University Medical Center between August 1999 and January 2002. The Institutional Review Board at our medical center approved the study, and informed consent was obtained from the families of all patients. Our study was compliant with the Health Insurance Portability and Accountability Act. In six patients, transplantation was performed with unrelated, banked, and partially HLA-mismatched umbilical cord blood from unrelated donors, and one patient received HLA-matched bone marrow from a carrier sibling. Entry criteria included an established diagnosis of Krabbe disease, treatment with stem cell transplantation, and more than one diffusion-tensor MR imaging examination performed at least 10 months after transplantation. The study population consisted of seven consecutive patients meeting those criteria.

Age-matched Comparison Group
Children in the comparison group were chosen from a database that included names of children who underwent clinical imaging, including diffusion-tensor MR imaging, had normal MR findings, and never had a subsequent diagnosis of neurologic disease. Ethnicity of the comparison group was not taken into account. The age of children in the comparison group was always within 1 month of the age of the Krabbe disease patients when the Krabbe disease patients were imaged before 1 year of age and was generally within 2 months of the age of Krabbe disease patients when these patients were subsequently imaged at or beyond 1 year of age. The Institutional Review Board at our medical center approved this retrospective component of our study and granted a waiver of informed consent for the children in the comparison group. The most common reasons for MR imaging in the comparison group were growth delay, developmental delay, and correlation with abnormalities suspected at computed tomography (CT).

Age at Time of Transplantation
For the purpose of this study, patients were divided into two groups based on their age at transplantation: An early transplantation group consisted of patients who received transplants within 1 month of birth (n = 3, two girls and one boy), and a late transplantation group consisted of patients who received transplants later in the 1st year of life (n = 4, two girls and two boys). Patients in the early transplantation group were asymptomatic and were identified on the basis of a sibling who had a previous diagnosis of the disease. The average age at the time of pretreatment imaging was 13 days. For each patient, we chose MR images obtained after transplantation that were the closest match to those obtained at yearly intervals following transplantation. Images that were obtained at a time not close to a yearly interval were not analyzed.

Diagnosis in the four patients in the late transplantation group was made on the basis of typical neurologic symptoms and signs of Krabbe disease, such as irritability, increased muscle tone, abnormal reflexes, developmental delay, and very low or absent levels of serum ß-galactocerebrosidase. These patients underwent transplantation at ages ranging from 5 to 8 months (mean, 6.5 months). The average age at the time of pretreatment MR imaging was 5.5 months. Three of these patients are still alive. One patient died at age 34 months (28 months after transplantation) of unexplained causes.

Clinical Neurodevelopmental Scoring
All patients underwent periodic neurodevelopmental evaluations after transplantation. Findings of solely the last available neurologic evaluation were assessed for the following developmental parameters relative to the age-matched children in the comparison group: expressive language, receptive language, gross motor skills, fine motor skills, and cognitive ability (7). Standard scores (ie, scores relative to the general population) were provided for each parameter, with a score of 100 representing the average score for the general population. We then assigned patients to one of five categories, depending on their standard score, and we assigned a numeric score for each category. Patients with a score of greater than 100 were assigned a category score of 5, those with a score of 71–100 were assigned a category score of 4, those with a score of 41–70 were assigned a category score of 3, those with a score of 11–40 were assigned a category score of 2, and those with a score 10 or smaller were assigned a category score of 1. Because five parameters were assessed, the maximal functional score was 25 and the minimal functional score was 5.

Imaging Techniques
For each MR examination, unenhanced transverse T1-weighted, intermediate-weighted, and T2-weighted images and transverse and coronal contrast material–enhanced T1-weighted images were obtained. All imaging examinations were performed with a 1.5-T clinical MR imager (Signa; GE Healthcare, Milwaukee, Wis) by using a standard head coil. The diffusion-tensor imaging protocol consisted of a single-shot spin-echo echo-planar sequence with a repetition time of 12 000 msec, echo time of 101 msec, field of view of 22 cm², 128 x 64 matrix, and 6-mm contiguous section through the entire brain. At diffusion-tensor imaging, four signals were acquired (by using a pulse sequence that was designed to optimize signal-to-noise ratio but had twice the diffusion-tensor imaging time of that used for routine clinical imaging) for Krabbe disease patients and two signals were acquired for children in the comparison group. Diffusion gradients were encoded in six directions with a b value of 1000 sec/mm², and an additional image was acquired with no diffusion gradient (b = 0 sec/mm²). Imaging was performed through the entire brain. A single neuroradiologist (L.L., with 3 years of pediatric MR imaging experience) assessed the diffusion-tensor and T2-weighted images for closeness of fit to one another. In all cases, the images were similar to one another in terms of the imaging plane and section level. Therefore, coregistration of the images was not necessary.

Patients and their families often had to travel great distances for imaging at our institution, which precluded imaging at prescribed intervals. Instead, imaging was performed at irregular intervals on a clinical basis as requested by the transplantation program of the Division of Pediatric Hematology-Oncology.

Evaluation of Conventional and Diffusion-Tensor MR Images
Conventional MR images from all examinations in all patients were viewed by using a picture archiving and communication system workstation that allowed adjustments to window and level settings. The MR images were reviewed for the presence of abnormal hyperintense signal intensity (SI) on T1- and T2-weighted images in a consensus by two fellowship-trained neuroradiologists (S.M. with 6 years of pediatric brain MR imaging experience and J.M.P. with 16 years of experience) blinded to the results of fractional anisotropy (FA) measurements by using well-established standards for normal development (4). A third fellowship-trained neuroradiologist (L.L.) placed the regions of interest (ROIs) on FA maps in the peripheral frontal lobe WM, the genu of the corpus callosum, the splenium of the corpus callosum, and the posterior limb of the internal capsule (hereafter, the internal capsule). A uniform ROI was placed on each side of the midline (ie, two ROIs per structure) in the following regions of WM: the peripheral frontal lobe WM, the genu of the corpus callosum, the splenium of the corpus callosum, and the internal capsule. Each ROI was drawn semiautomatically by using Functool software (GE Medical Systems). An oval shape was chosen for ROIs because it best conformed to the morphology of the structures being measured. This neuroradiologist measured FA values for all diffusion-tensor studies with standard-size ROIs that measured 44 mm² ± 4 (equivalent to 4–5 pixels) by recording the highest FA value in a structure and not attempting to measure the values in areas of abnormal SI. Mean values obtained from the two ROIs within each structure were calculated.

ROIs were placed on FA maps by using a workstation (Advantage Windows; GE Medical Systems) operating Functool software. The six independent elements of the diffusion tensor—D_xx, D_yy, D_zz, D_xy, D_xz, and D_yz—were statistically calculated for each voxel by using a previously described method (8). FA values range from 0 to 1, where 0 represents isotropic diffusion and 1 represents highly anisotropic diffusion. FA is a ratio of diffusion coefficients, and therefore it is unitless. All measurements were made on a color-coded anisotropy map.

All measurements were performed on FA maps that were oriented in the transverse plane. ROIs for the internal capsule and the genu and splenium of the corpus callosum were drawn within the midportion of these structures, which were readily identified on diffusion-tensor MR images. Anatomic landmarks were chosen to ensure that ROI placement was consistent for anisotropy measurements of the other WM regions that were evaluated. The frontal WM ROIs were all drawn on the image one or two sections superior to the roof of the lateral ventricle in WM of the superior frontal gyri, within the most peripheral portion of the WM that could still accommodate a standard-sized ROI. The ROI was manually manipulated after visual inspection of the FA map to ensure documentation of the highest anisotropy value within each structure. Therefore, ROI placement differed from study to study within the same patient. Abnormal hyperintense regions on T2-weighted images did not usually coincide with regions in which the FA values were measured, because regions of abnormal SI typically have lower FA values than does normal-appearing WM. However, in some of the patients in the late transplantation group, no normal WM was seen on T2-weighted images in the region in which ROIs were to be placed. In those cases, the ROI showing the highest anisotropy value was placed, by necessity, in the abnormal-appearing WM. FA maps and T2-weighted images were not coregistered because the different section thickness and interspace gap for the two sequences prevented it.

Comparison of Anisotropy Values in Krabbe Disease Patients and Age-matched Children
Data obtained from the examination of each Krabbe disease patient were compared with data obtained for five children of the same age in the comparison group. Thus, for example, for each patient, an MR image obtained within the 1st month of life was compared with images obtained in the five children with normal studies who were imaged within the 1st month of life; the same procedure was used for all images obtained at a later time for all seven patients with Krabbe disease. Mean anisotropy values at each site in Krabbe disease patients were then expressed as a percentage of the mean values seen in the age-matched comparison group.

Comparison group demographics were as follows: For Krabbe disease patients imaged at 1 day of life, the comparison group included three boys and two girls with an average age of 7 days (range, 1–12 days). For patients imaged at 3 weeks, the comparison group included three boys and two girls with an average age of 21 days (range, 15–30 days). For patients imaged at 3 months, the comparison group included four girls and one boy, all 3 months old. For patients imaged at 4 months, the comparison group included three boys and two girls with an average age of 3.8 months (range, 3–5 months). For patients imaged at 5 months, the comparison group included three boys and two girls with an average age of 5 months (range, 4–6 months). For patients imaged at 6 months, the comparison group included three boys and two girls with an average age of 6.2 months (range, 5–7 months). For patients imaged at 7 months, the comparison group included all boys with an average age of 7 months (range, 6–8 months). For patients imaged at 9 months, the comparison group included four boys and one girl with an average age of 9.2 months (range, 8–10 months). For patients imaged at 10 months, the comparison group included three boys and two girls with an average age of 10 months (range, 9–11 months). For patients imaged at 12 months, the comparison group included four boys and one girl with an average age of 11.8 months (range, 10–17 months). For patients imaged at 14 months, the comparison group included four boys and one girl with an average age of 13.4 months (range, 10–18 months). For patients imaged at 15 months, the comparison group included three boys and two girls with an average age of 15 months (range, 11–18 months). For patients imaged at 16 months, the comparison group included three boys and two girls with an average age of 16.5 months (range, 11–19 months). For patients imaged at 20 months, the comparison group included three boys and two girls with an average age of 19.4 months (range, 18–22 months). For patients imaged at 25 months, the comparison group included three boys and two girls with an average age of 24.6 months (range, 23–26 months). For patients imaged at 26 months, the comparison group included three boys and two girls with an average age of 27.4 months (range, 25–29 months). For patients imaged at 31 months, the comparison group included four boys and one girl with an average age of 31.8 months (range, 29–34 months). For patients imaged at 36 months, the comparison group included three boys and two girls with an average age of 35.6 months (range, 34–36 months). Finally, for patients imaged at 49 months, the comparison group included four boys and one girl with an average age of 50.4 months (range, 47–53 months).

	RESULTS

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION References

 
Clinical Neurodevelopmental Scores
The mean scores for developmental age–adjusted parameters in the early transplantation group were as follows: expressive language, 3.33 (range, 3–4); receptive language, 3.67 (range, 3–4); gross motor skills, 2.67 (range, 1–5); fine motor skills, 3.67 (range, 3–5); and cognitive ability, 3.33 (range, 3–4). The mean cumulative score for the five developmental categories for the group was 16.6 (range, 13–22). All patients in the late transplantation group had developmental scores of 1 in every category. Therefore, the mean cumulative score for the five developmental categories for the group was 5.00. The scores for each individual are listed in the Table.

View larger version (129K): [in this window] [in a new window] [Download PPT slide]   Figure 1a. Patient 3. Serial diffusion-tensor MR images in asymptomatic boy suspected of having Krabbe disease because of a sibling with the disorder. Diagnosis was confirmed at birth. Umbilical cord blood transplantation was performed at 3 weeks of age. (a) Transverse T2-weighted image (2800/100, two signals acquired) obtained at the level of internal capsule 2 days before transplantation shows that the SI in the posterior limb of the internal capsule (arrows) was slightly higher than expected for age but no other abnormalities. T1-weighted images at this level (not shown) showed mildly increased SI. (b) Transverse T2-weighted image (2800/100) just subjacent to the cerebral vertex shows no areas of abnormal SI and normal myelination pattern for age. (c) Transverse FA map at the same level as a shows placement of ROIs in the internal capsule (ROIs 1 and 2), genu of corpus callosum (ROIs 3 and 4), and splenium of corpus callosum (ROIs 5 and 6) in sites in those structures that had the highest FA values. Mean FA ratios measured 131% of those in age-matched brains on normal MR images in the genu of corpus callosum, 116% of those in the splenium of corpus callosum, and 106% of those in the internal capsule. (d) Transverse FA map at the same level as b shows placement of ROI in frontal WM (ROIs 7 and 8). Mean FA ratio measured 113% of those in age-matched normal brain images. (e) Transverse T2-weighted image (2800/100) obtained 24 months after transplantation at the same level as a shows areas of hyperintense SI (arrows) adjacent to the trigone of lateral ventricles. The myelination pattern is otherwise normal for age. (f) Transverse T2-weighted image (2800/100) at the same level as b shows no areas of abnormal SI and normal myelination pattern for age. (g) Transverse FA map at the same level as e shows placement of ROIs in the internal capsule (ROIs 1 and 2), genu of corpus callosum (ROIs 3 and 4), and splenium of corpus callosum (ROIs 5 and 6). Mean FA ratios in the genu of corpus callosum measured 102% of those in age-matched brains on normal MR images, 88% of those in the splenium of corpus callosum, and 88% of those in the internal capsule. (h) Transverse FA map at same level as f shows placement of ROI in frontal WM (ROIs 7 and 8). Mean FA ratio measured 89% of those in age-matched brains on normal MR images.

View larger version (134K): [in this window] [in a new window] [Download PPT slide]   Figure 1b. Patient 3. Serial diffusion-tensor MR images in asymptomatic boy suspected of having Krabbe disease because of a sibling with the disorder. Diagnosis was confirmed at birth. Umbilical cord blood transplantation was performed at 3 weeks of age. (a) Transverse T2-weighted image (2800/100, two signals acquired) obtained at the level of internal capsule 2 days before transplantation shows that the SI in the posterior limb of the internal capsule (arrows) was slightly higher than expected for age but no other abnormalities. T1-weighted images at this level (not shown) showed mildly increased SI. (b) Transverse T2-weighted image (2800/100) just subjacent to the cerebral vertex shows no areas of abnormal SI and normal myelination pattern for age. (c) Transverse FA map at the same level as a shows placement of ROIs in the internal capsule (ROIs 1 and 2), genu of corpus callosum (ROIs 3 and 4), and splenium of corpus callosum (ROIs 5 and 6) in sites in those structures that had the highest FA values. Mean FA ratios measured 131% of those in age-matched brains on normal MR images in the genu of corpus callosum, 116% of those in the splenium of corpus callosum, and 106% of those in the internal capsule. (d) Transverse FA map at the same level as b shows placement of ROI in frontal WM (ROIs 7 and 8). Mean FA ratio measured 113% of those in age-matched normal brain images. (e) Transverse T2-weighted image (2800/100) obtained 24 months after transplantation at the same level as a shows areas of hyperintense SI (arrows) adjacent to the trigone of lateral ventricles. The myelination pattern is otherwise normal for age. (f) Transverse T2-weighted image (2800/100) at the same level as b shows no areas of abnormal SI and normal myelination pattern for age. (g) Transverse FA map at the same level as e shows placement of ROIs in the internal capsule (ROIs 1 and 2), genu of corpus callosum (ROIs 3 and 4), and splenium of corpus callosum (ROIs 5 and 6). Mean FA ratios in the genu of corpus callosum measured 102% of those in age-matched brains on normal MR images, 88% of those in the splenium of corpus callosum, and 88% of those in the internal capsule. (h) Transverse FA map at same level as f shows placement of ROI in frontal WM (ROIs 7 and 8). Mean FA ratio measured 89% of those in age-matched brains on normal MR images.

View larger version (131K): [in this window] [in a new window] [Download PPT slide]   Figure 1c. Patient 3. Serial diffusion-tensor MR images in asymptomatic boy suspected of having Krabbe disease because of a sibling with the disorder. Diagnosis was confirmed at birth. Umbilical cord blood transplantation was performed at 3 weeks of age. (a) Transverse T2-weighted image (2800/100, two signals acquired) obtained at the level of internal capsule 2 days before transplantation shows that the SI in the posterior limb of the internal capsule (arrows) was slightly higher than expected for age but no other abnormalities. T1-weighted images at this level (not shown) showed mildly increased SI. (b) Transverse T2-weighted image (2800/100) just subjacent to the cerebral vertex shows no areas of abnormal SI and normal myelination pattern for age. (c) Transverse FA map at the same level as a shows placement of ROIs in the internal capsule (ROIs 1 and 2), genu of corpus callosum (ROIs 3 and 4), and splenium of corpus callosum (ROIs 5 and 6) in sites in those structures that had the highest FA values. Mean FA ratios measured 131% of those in age-matched brains on normal MR images in the genu of corpus callosum, 116% of those in the splenium of corpus callosum, and 106% of those in the internal capsule. (d) Transverse FA map at the same level as b shows placement of ROI in frontal WM (ROIs 7 and 8). Mean FA ratio measured 113% of those in age-matched normal brain images. (e) Transverse T2-weighted image (2800/100) obtained 24 months after transplantation at the same level as a shows areas of hyperintense SI (arrows) adjacent to the trigone of lateral ventricles. The myelination pattern is otherwise normal for age. (f) Transverse T2-weighted image (2800/100) at the same level as b shows no areas of abnormal SI and normal myelination pattern for age. (g) Transverse FA map at the same level as e shows placement of ROIs in the internal capsule (ROIs 1 and 2), genu of corpus callosum (ROIs 3 and 4), and splenium of corpus callosum (ROIs 5 and 6). Mean FA ratios in the genu of corpus callosum measured 102% of those in age-matched brains on normal MR images, 88% of those in the splenium of corpus callosum, and 88% of those in the internal capsule. (h) Transverse FA map at same level as f shows placement of ROI in frontal WM (ROIs 7 and 8). Mean FA ratio measured 89% of those in age-matched brains on normal MR images.

View larger version (131K): [in this window] [in a new window] [Download PPT slide]   Figure 1d. Patient 3. Serial diffusion-tensor MR images in asymptomatic boy suspected of having Krabbe disease because of a sibling with the disorder. Diagnosis was confirmed at birth. Umbilical cord blood transplantation was performed at 3 weeks of age. (a) Transverse T2-weighted image (2800/100, two signals acquired) obtained at the level of internal capsule 2 days before transplantation shows that the SI in the posterior limb of the internal capsule (arrows) was slightly higher than expected for age but no other abnormalities. T1-weighted images at this level (not shown) showed mildly increased SI. (b) Transverse T2-weighted image (2800/100) just subjacent to the cerebral vertex shows no areas of abnormal SI and normal myelination pattern for age. (c) Transverse FA map at the same level as a shows placement of ROIs in the internal capsule (ROIs 1 and 2), genu of corpus callosum (ROIs 3 and 4), and splenium of corpus callosum (ROIs 5 and 6) in sites in those structures that had the highest FA values. Mean FA ratios measured 131% of those in age-matched brains on normal MR images in the genu of corpus callosum, 116% of those in the splenium of corpus callosum, and 106% of those in the internal capsule. (d) Transverse FA map at the same level as b shows placement of ROI in frontal WM (ROIs 7 and 8). Mean FA ratio measured 113% of those in age-matched normal brain images. (e) Transverse T2-weighted image (2800/100) obtained 24 months after transplantation at the same level as a shows areas of hyperintense SI (arrows) adjacent to the trigone of lateral ventricles. The myelination pattern is otherwise normal for age. (f) Transverse T2-weighted image (2800/100) at the same level as b shows no areas of abnormal SI and normal myelination pattern for age. (g) Transverse FA map at the same level as e shows placement of ROIs in the internal capsule (ROIs 1 and 2), genu of corpus callosum (ROIs 3 and 4), and splenium of corpus callosum (ROIs 5 and 6). Mean FA ratios in the genu of corpus callosum measured 102% of those in age-matched brains on normal MR images, 88% of those in the splenium of corpus callosum, and 88% of those in the internal capsule. (h) Transverse FA map at same level as f shows placement of ROI in frontal WM (ROIs 7 and 8). Mean FA ratio measured 89% of those in age-matched brains on normal MR images.

View larger version (114K): [in this window] [in a new window] [Download PPT slide]   Figure 1e. Patient 3. Serial diffusion-tensor MR images in asymptomatic boy suspected of having Krabbe disease because of a sibling with the disorder. Diagnosis was confirmed at birth. Umbilical cord blood transplantation was performed at 3 weeks of age. (a) Transverse T2-weighted image (2800/100, two signals acquired) obtained at the level of internal capsule 2 days before transplantation shows that the SI in the posterior limb of the internal capsule (arrows) was slightly higher than expected for age but no other abnormalities. T1-weighted images at this level (not shown) showed mildly increased SI. (b) Transverse T2-weighted image (2800/100) just subjacent to the cerebral vertex shows no areas of abnormal SI and normal myelination pattern for age. (c) Transverse FA map at the same level as a shows placement of ROIs in the internal capsule (ROIs 1 and 2), genu of corpus callosum (ROIs 3 and 4), and splenium of corpus callosum (ROIs 5 and 6) in sites in those structures that had the highest FA values. Mean FA ratios measured 131% of those in age-matched brains on normal MR images in the genu of corpus callosum, 116% of those in the splenium of corpus callosum, and 106% of those in the internal capsule. (d) Transverse FA map at the same level as b shows placement of ROI in frontal WM (ROIs 7 and 8). Mean FA ratio measured 113% of those in age-matched normal brain images. (e) Transverse T2-weighted image (2800/100) obtained 24 months after transplantation at the same level as a shows areas of hyperintense SI (arrows) adjacent to the trigone of lateral ventricles. The myelination pattern is otherwise normal for age. (f) Transverse T2-weighted image (2800/100) at the same level as b shows no areas of abnormal SI and normal myelination pattern for age. (g) Transverse FA map at the same level as e shows placement of ROIs in the internal capsule (ROIs 1 and 2), genu of corpus callosum (ROIs 3 and 4), and splenium of corpus callosum (ROIs 5 and 6). Mean FA ratios in the genu of corpus callosum measured 102% of those in age-matched brains on normal MR images, 88% of those in the splenium of corpus callosum, and 88% of those in the internal capsule. (h) Transverse FA map at same level as f shows placement of ROI in frontal WM (ROIs 7 and 8). Mean FA ratio measured 89% of those in age-matched brains on normal MR images.

View larger version (131K): [in this window] [in a new window] [Download PPT slide]   Figure 1f. Patient 3. Serial diffusion-tensor MR images in asymptomatic boy suspected of having Krabbe disease because of a sibling with the disorder. Diagnosis was confirmed at birth. Umbilical cord blood transplantation was performed at 3 weeks of age. (a) Transverse T2-weighted image (2800/100, two signals acquired) obtained at the level of internal capsule 2 days before transplantation shows that the SI in the posterior limb of the internal capsule (arrows) was slightly higher than expected for age but no other abnormalities. T1-weighted images at this level (not shown) showed mildly increased SI. (b) Transverse T2-weighted image (2800/100) just subjacent to the cerebral vertex shows no areas of abnormal SI and normal myelination pattern for age. (c) Transverse FA map at the same level as a shows placement of ROIs in the internal capsule (ROIs 1 and 2), genu of corpus callosum (ROIs 3 and 4), and splenium of corpus callosum (ROIs 5 and 6) in sites in those structures that had the highest FA values. Mean FA ratios measured 131% of those in age-matched brains on normal MR images in the genu of corpus callosum, 116% of those in the splenium of corpus callosum, and 106% of those in the internal capsule. (d) Transverse FA map at the same level as b shows placement of ROI in frontal WM (ROIs 7 and 8). Mean FA ratio measured 113% of those in age-matched normal brain images. (e) Transverse T2-weighted image (2800/100) obtained 24 months after transplantation at the same level as a shows areas of hyperintense SI (arrows) adjacent to the trigone of lateral ventricles. The myelination pattern is otherwise normal for age. (f) Transverse T2-weighted image (2800/100) at the same level as b shows no areas of abnormal SI and normal myelination pattern for age. (g) Transverse FA map at the same level as e shows placement of ROIs in the internal capsule (ROIs 1 and 2), genu of corpus callosum (ROIs 3 and 4), and splenium of corpus callosum (ROIs 5 and 6). Mean FA ratios in the genu of corpus callosum measured 102% of those in age-matched brains on normal MR images, 88% of those in the splenium of corpus callosum, and 88% of those in the internal capsule. (h) Transverse FA map at same level as f shows placement of ROI in frontal WM (ROIs 7 and 8). Mean FA ratio measured 89% of those in age-matched brains on normal MR images.

View larger version (131K): [in this window] [in a new window] [Download PPT slide]   Figure 1g. Patient 3. Serial diffusion-tensor MR images in asymptomatic boy suspected of having Krabbe disease because of a sibling with the disorder. Diagnosis was confirmed at birth. Umbilical cord blood transplantation was performed at 3 weeks of age. (a) Transverse T2-weighted image (2800/100, two signals acquired) obtained at the level of internal capsule 2 days before transplantation shows that the SI in the posterior limb of the internal capsule (arrows) was slightly higher than expected for age but no other abnormalities. T1-weighted images at this level (not shown) showed mildly increased SI. (b) Transverse T2-weighted image (2800/100) just subjacent to the cerebral vertex shows no areas of abnormal SI and normal myelination pattern for age. (c) Transverse FA map at the same level as a shows placement of ROIs in the internal capsule (ROIs 1 and 2), genu of corpus callosum (ROIs 3 and 4), and splenium of corpus callosum (ROIs 5 and 6) in sites in those structures that had the highest FA values. Mean FA ratios measured 131% of those in age-matched brains on normal MR images in the genu of corpus callosum, 116% of those in the splenium of corpus callosum, and 106% of those in the internal capsule. (d) Transverse FA map at the same level as b shows placement of ROI in frontal WM (ROIs 7 and 8). Mean FA ratio measured 113% of those in age-matched normal brain images. (e) Transverse T2-weighted image (2800/100) obtained 24 months after transplantation at the same level as a shows areas of hyperintense SI (arrows) adjacent to the trigone of lateral ventricles. The myelination pattern is otherwise normal for age. (f) Transverse T2-weighted image (2800/100) at the same level as b shows no areas of abnormal SI and normal myelination pattern for age. (g) Transverse FA map at the same level as e shows placement of ROIs in the internal capsule (ROIs 1 and 2), genu of corpus callosum (ROIs 3 and 4), and splenium of corpus callosum (ROIs 5 and 6). Mean FA ratios in the genu of corpus callosum measured 102% of those in age-matched brains on normal MR images, 88% of those in the splenium of corpus callosum, and 88% of those in the internal capsule. (h) Transverse FA map at same level as f shows placement of ROI in frontal WM (ROIs 7 and 8). Mean FA ratio measured 89% of those in age-matched brains on normal MR images.

View larger version (130K): [in this window] [in a new window] [Download PPT slide]   Figure 1h. Patient 3. Serial diffusion-tensor MR images in asymptomatic boy suspected of having Krabbe disease because of a sibling with the disorder. Diagnosis was confirmed at birth. Umbilical cord blood transplantation was performed at 3 weeks of age. (a) Transverse T2-weighted image (2800/100, two signals acquired) obtained at the level of internal capsule 2 days before transplantation shows that the SI in the posterior limb of the internal capsule (arrows) was slightly higher than expected for age but no other abnormalities. T1-weighted images at this level (not shown) showed mildly increased SI. (b) Transverse T2-weighted image (2800/100) just subjacent to the cerebral vertex shows no areas of abnormal SI and normal myelination pattern for age. (c) Transverse FA map at the same level as a shows placement of ROIs in the internal capsule (ROIs 1 and 2), genu of corpus callosum (ROIs 3 and 4), and splenium of corpus callosum (ROIs 5 and 6) in sites in those structures that had the highest FA values. Mean FA ratios measured 131% of those in age-matched brains on normal MR images in the genu of corpus callosum, 116% of those in the splenium of corpus callosum, and 106% of those in the internal capsule. (d) Transverse FA map at the same level as b shows placement of ROI in frontal WM (ROIs 7 and 8). Mean FA ratio measured 113% of those in age-matched normal brain images. (e) Transverse T2-weighted image (2800/100) obtained 24 months after transplantation at the same level as a shows areas of hyperintense SI (arrows) adjacent to the trigone of lateral ventricles. The myelination pattern is otherwise normal for age. (f) Transverse T2-weighted image (2800/100) at the same level as b shows no areas of abnormal SI and normal myelination pattern for age. (g) Transverse FA map at the same level as e shows placement of ROIs in the internal capsule (ROIs 1 and 2), genu of corpus callosum (ROIs 3 and 4), and splenium of corpus callosum (ROIs 5 and 6). Mean FA ratios in the genu of corpus callosum measured 102% of those in age-matched brains on normal MR images, 88% of those in the splenium of corpus callosum, and 88% of those in the internal capsule. (h) Transverse FA map at same level as f shows placement of ROI in frontal WM (ROIs 7 and 8). Mean FA ratio measured 89% of those in age-matched brains on normal MR images.

On conventional MR images obtained 2 years (mean, 22 months) after transplantation, no substantial changes were seen in any patient compared with the 1-year posttransplantation images. Mean FA ratios ranged between 85% and 96% in frontal WM, 86% and 102% in the genu of the corpus callosum, 83% and 88% in the splenium of the corpus callosum, and 77% and 88% in the internal capsule. Results of a single imaging study performed 3 (patient 3) or 4 years (patient 1) after transplantation are also outlined in the Table. Serial FA ratios in the four regions studied in each patient are depicted in Figures 2 –5. Although moderate decreases in FA ratios were seen over time in each region, resultant FA ratios tended to be above 80%. Over the course of the study, the lowest values were generally seen in the internal capsule.

View larger version (22K): [in this window] [in a new window] [Download PPT slide]   Figure 2. Line graph shows changes in the mean FA ratios in frontal WM in early (n = 3, solid lines) and late (n = 4, dashed lines) transplantation groups. The time to transplantation occurred at a mean of 2 weeks of life in the early transplantation group and at a mean of 6.5 months in the late transplantation group. Anisotropy ratios were higher at the time of pretransplantation imaging (time 0 on the graph), and subsequent decreases in anisotropy ratios were smaller in the early transplantation group. The symbols indicate the four patients.

View larger version (21K): [in this window] [in a new window] [Download PPT slide]   Figure 3. Line graph shows changes in the mean FA values in the genu of the corpus callosum in the early (solid lines) and late (dashed lines) transplantation groups. There are substantial differences between the two groups in anisotropy ratios at serial imaging. The symbols indicate the four patients.

View larger version (20K): [in this window] [in a new window] [Download PPT slide]   Figure 4. Line graph shows changes in the mean FA values in the splenium of the corpus callosum in the early (solid lines) and late (dashed lines) transplantation groups. There are substantial differences between the two groups in anisotropy ratios at initial and follow-up imaging. The symbols indicate the four patients.

Images obtained at approximately 1 year after transplantation generally showed a prominent increase in size of regions of abnormal SI, most notably in the corpus callosum and pons, as well as development of atrophy in various regions. Substantial decreases in FA ratios were found in all regions studied, with the biggest decreases seen in the genu of the corpus callosum. Mean FA ratios ranged between 43% and 52% in the frontal WM, 30% and 54% in the genu of the corpus callosum, 29% and 52% in the splenium of the corpus callosum, and 41% and 53% in the internal capsule.

Images obtained at approximately 2 years after transplantation generally showed enlargement of preexistent regions of abnormal SI, worsened atrophy, and abnormal SI in the thalamus. FA ratios generally continued to decrease slightly, although mild increases were seen in the internal capsule in three patients. Mean FA ratios ranged between 32% and 38% in the frontal WM, 27% and 44% in the genu of the corpus callosum, 33% and 41% in the splenium of the corpus callosum, and 44% and 49% in the internal capsule.

	DISCUSSION

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION References

 
Hematopoietic stem cell transplantation is a relatively new treatment option for patients with Krabbe disease. Only few reports of the results of this form of treatment for Krabbe disease have been published. Authors of one initial report (3) concerning five patients concluded that central nervous system manifestations of Krabbe disease can be reversed with allogeneic hematopoietic stem cell transplantation. In a case report of a child with infantile Krabbe disease who was treated at 4 months of age after development of markedly abnormal MR imaging findings, the authors reported that the progression of neurologic deterioration was not reversed with bone marrow transplantation (9). This report has been taken as evidence indicating that transplantation performed after the first few months of life is less effective than transplantation performed earlier.

Characteristic CT findings obtained early in the disease process in infantile Krabbe disease include high attenuation within the corona radiata, the body of the caudate nucleus, and the thalamus, possibly representing fine calcifications (10,11). Later in the disease course, hypoattenuating WM lesions become prevalent. At MR imaging, hyperintense lesions are typically seen within WM on T2-weighted MR images, and to a lesser degree, in gray matter structures. In one report, 90% of early-onset Krabbe disease children had pyramidal tract involvement, 80% had cerebellar WM involvement, 70% had deep gray matter (ie, dentate nucleus, basal ganglia or thalamus) involvement, 60% had posterior corpus callosal involvement, 50% had parieto-occipital WM involvement, and 40% had cerebral atrophy (2).

In our study, notable differences were seen between findings on conventional MR images in the two groups. Pretransplantation images in the asymptomatic early transplantation group were either normal or showed only subtle abnormalities, which is consistent with previous reports (12). On the other hand, pretransplantation images in the symptomatic late transplantation group were always clearly abnormal, typically showing more widespread and larger regions of SI abnormality. Lesions were also generally seen in the WM of the parietal and occipital lobes, centrum semiovale, and corpus callosum. Because some of the locations were also later involved in the early transplantation patients, the differences on the pretransplantation images between the two groups reflect the fact that the late transplantation patients were symptomatic and further along in their disease course. Therefore, it was important to incorporate a long period of evaluation in the study to control for baseline differences between the two groups.

Posttransplantation images showed differences between the groups that were even more apparent. At conventional MR imaging, the late transplantation group much more frequently developed abnormalities in the corpus callosum, central and subcortical WM regions, cerebellar WM, and, in severe cases, the pons, which are findings similar to those reported from previous studies (2). The differences in findings in the two groups were reflected in the differences in scores of the clinical neurodevelopmental examination.

Reports about the use of diffusion-tensor MR imaging in Krabbe disease are few. In a previous study (13), diffusion-tensor MR findings in a small group of Krabbe disease patients who were treated with hematopoietic stem cell transplantation were compared with those in untreated children with Krabbe disease. Authors of that study examined the patients at a single time point after transplantation and found that FA values in WM structures in treated Krabbe disease children were intermediate between the values obtained in untreated Krabbe disease children and those obtained in the comparison group, which possibly indicates a beneficial treatment effect.

Our first hypothesis (ie, that baseline FA ratios would be decreased for Krabbe disease patients) was verified for late transplantation but not for early transplantation patients. Pretransplantation FA ratios in the early transplantation group were typically normal or slightly above normal. The above average values likely simply reflect variances caused by the small sample size. Our findings suggest that in the 1st month of life, Krabbe disease infants exhibit relatively normal myelination and axonal integrity as measured at diffusion-tensor MR imaging. Although dysmyelination and failure of myelination may be present at the time of birth, these early processes do not appear to be reflected on diffusion-tensor MR images. One report of autopsy findings in a fetus affected with Krabbe disease stated that only very subtle demyelination was present, which may explain the relatively normal findings in the early transplantation group (6). On the other hand, our first hypothesis was verified for the late transplantation group. By the time infants became symptomatic and underwent imaging, FA ratios were already moderately depressed in most regions.

In the approximately 1-year follow-up period after transplantation, there were substantial increases in anisotropy values at most sites in the early transplantation patients, which is consistent with progressive myelination and increase in axonal integrity. Decreases in FA ratios were seen at all four sites studied, but generally, FA values remained at least 85% of the values in age-matched children. The same pattern was seen at the approximately 2-year follow-up.

Changes in anisotropy values in the late transplantation patients at 1-year follow-up after transplantation were varied. In three patients, moderate increases in FA values were seen in the internal capsule, which is consistent with a mild degree of interval myelination and establishment of intact axonal pathways, but at most other sites anisotropy values failed to increase or actually decreased. All four patients had marked decreases in FA ratios in the genu of the corpus callosum. However, FA ratios increased in the internal capsule in three patients. Results obtained in the splenium of the corpus callosum and frontal WM showed more heterogeneous changes.

Our study differs from the previous diffusion-tensor MR imaging study of Krabbe disease because we used serial imaging, including pre- and posttransplantation imaging, whereas the previous study used imaging at a single time point (13). As the findings in that report suggested, our results also suggest a beneficial treatment effect of stem cell transplantation on the basis of clinical, conventional MR imaging, and diffusion-tensor MR imaging findings. We found marked differences at follow-up diffusion-tensor MR imaging in early and late transplantation patients. However, late transplantation patients often had no increase in anisotropy values or a decrease in anisotropy values and decreases in FA ratios. Therefore, our second hypothesis regarding the effects of stem cell transplantation on diffusion-tensor MR imaging studies in the two groups appears to have been verified.

Maintenance of a high level of neurologic function in the early transplantation group and stabilization of FA ratios at relatively high levels are especially notable findings. Mean scores at neurodevelopmental evaluations were substantially higher in the early transplantation group than in the late transplantation group and were associated with higher FA values in all WM regions studied. Further clinical evaluation and diffusion-tensor MR imaging will be needed to determine whether the clinical improvement and apparent amelioration of anisotropy values are maintained beyond the first few years of life. However, the early infantile form of Krabbe disease has a uniformly fatal prognosis. Therefore, even the fact that prolonged survival was seen in the late transplantation patients is worth commenting on.

A number of limitations were evident in our study. First, the small sample size allowed only a preliminary assessment of the relationship of age at transplantation to changes in anisotropy in Krabbe disease patients. Second, because untreated Krabbe disease patients typically do not undergo serial imaging, a comparison group of untreated patients was not available for comparison of FA values against those in our treated patients. Therefore, we cannot make definitive claims about the degree of treatment effect on anisotropy measurements in our two patient groups. Third, we did not assess inter- or intraobserver variability in anisotropy measurements. Fourth, because fiber tract mapping was not available to us at the time of the study, we were not able to analyze specific WM pathways that might underlay various neurologic processes in Krabbe disease. Instead, we analyzed readily identifiable WM structures that may not play an important role in this disease. Therefore, the differences we found may not reflect the differences in structures more clinically relevant to the neurologic abnormalities. Fifth, our brief comparison of SI abnormality on T2-weighted images with anisotropy is not a comparison of two quantitative measurements. Finally, we did not compare FA changes and SI abnormalities at exactly the same sites with coregistered images.

In summary, in this small study, we found that patients with Krabbe disease who underwent stem cell transplantation within the 1st month of life showed substantially smaller decreases in anisotropy ratios in four WM regions than those who were treated later in the 1st year of life. These findings correlated relatively well with global assessments of disease progression as seen at neurodevelopmental evaluations and conventional MR imaging. Diffusion-tensor MR imaging appears to offer a quantitative, reproducible method for evaluating WM abnormalities. Our results suggest that diffusion-tensor MR imaging may prove to be a fruitful method for assessing disease progression in Krabbe disease and other WM disorders. Future studies that correlate serial clinical assessments and diffusion-tensor analysis will likely prove beneficial in better understanding the role of diffusion-tensor MR imaging in disease evaluation.

View larger version (19K): [in this window] [in a new window] [Download PPT slide]   Figure 5. Line graph shows changes in the mean FA values in the posterior limb of the internal capsule in the early (solid lines) and late (dashed lines) transplantation groups. There are substantial differences between the two groups. The symbols indicate the four patients.

View larger version (142K): [in this window] [in a new window] [Download PPT slide]   Figure 6a. Patient 4. Serial diffusion-tensor images in asymptomatic boy with Krabbe disease in whom diagnosis was based on a sibling with the disorder. Umbilical cord blood transplantation was performed at 5 months of age. ROIs showing the highest FA values in a region were placed in an area that had abnormal hyperintense SI on T2-weighted images because no normal-appearing WM was present in these regions. (a) Transverse T2-weighted image (2800/100) obtained at the level of the internal capsule 4 days before transplantation shows abnormal hyperintense SI. (b) Transverse T2-weighted image (2800/100) just subjacent to the cerebral vertex shows no areas of abnormal SI and normal myelination pattern for age. (c) Transverse FA map at the same level as a shows placement of ROIs in the internal capsule (ROIs 7 and 8) and genu of corpus callosum (ROIs 1 and 6). Mean FA ratios measured 91% of those in age-matched brains on normal MR images in the genu of corpus callosum and 49% of those in the internal capsule. (d) Transverse FA map shows an ROI in the splenium of corpus callosum (ROIs 4 and 5) that measured 65% of the ratios in age-matched brains on normal MR images. (e) Transverse FA map at same level as b shows placement of ROI in frontal WM (ROIs 2 and 3). Mean FA ratio measured 53% of those in age-matched normal brain images. (f) Transverse T2-weighted image (2800/100) obtained 24 months after transplantation (patient age, 26 months) shows a moderate degree of volume loss and hyperintense SI in the internal capsule, basal ganglia, and periventricular regions. (g) Transverse T2-weighted image (2800/100) at the level of the genu of corpus callosum shows abnormal hyperintense SI in the periventricular regions and corona radiata. The corpus callosum SI appears normal. (h) Transverse T2-weighted image (2800/100) near the brain vertex shows abnormal hyperintense SI in the subcortical WM. (i) Transverse FA map at the same level as f shows placement of ROIs in the internal capsule (ROIs 1 and 2) and splenium of corpus callosum (ROIs 3 and 4). Mean FA ratios measured 33% of those in the splenium of corpus callosum and 45% of those in the internal capsule. (j) Transverse FA map at the same level as g shows placement of ROIs in the genu of corpus callosum (ROIs 5 and 6), which measured 44% of this region in age-matched brains on normal MR images. (k) Transverse FA map at same level as h shows placement of ROIs in frontal WM (ROIs 8 and 9). Mean FA ratio measured 32% of those in age-matched brains on normal MR images.

View larger version (130K): [in this window] [in a new window] [Download PPT slide]   Figure 6b. Patient 4. Serial diffusion-tensor images in asymptomatic boy with Krabbe disease in whom diagnosis was based on a sibling with the disorder. Umbilical cord blood transplantation was performed at 5 months of age. ROIs showing the highest FA values in a region were placed in an area that had abnormal hyperintense SI on T2-weighted images because no normal-appearing WM was present in these regions. (a) Transverse T2-weighted image (2800/100) obtained at the level of the internal capsule 4 days before transplantation shows abnormal hyperintense SI. (b) Transverse T2-weighted image (2800/100) just subjacent to the cerebral vertex shows no areas of abnormal SI and normal myelination pattern for age. (c) Transverse FA map at the same level as a shows placement of ROIs in the internal capsule (ROIs 7 and 8) and genu of corpus callosum (ROIs 1 and 6). Mean FA ratios measured 91% of those in age-matched brains on normal MR images in the genu of corpus callosum and 49% of those in the internal capsule. (d) Transverse FA map shows an ROI in the splenium of corpus callosum (ROIs 4 and 5) that measured 65% of the ratios in age-matched brains on normal MR images. (e) Transverse FA map at same level as b shows placement of ROI in frontal WM (ROIs 2 and 3). Mean FA ratio measured 53% of those in age-matched normal brain images. (f) Transverse T2-weighted image (2800/100) obtained 24 months after transplantation (patient age, 26 months) shows a moderate degree of volume loss and hyperintense SI in the internal capsule, basal ganglia, and periventricular regions. (g) Transverse T2-weighted image (2800/100) at the level of the genu of corpus callosum shows abnormal hyperintense SI in the periventricular regions and corona radiata. The corpus callosum SI appears normal. (h) Transverse T2-weighted image (2800/100) near the brain vertex shows abnormal hyperintense SI in the subcortical WM. (i) Transverse FA map at the same level as f shows placement of ROIs in the internal capsule (ROIs 1 and 2) and splenium of corpus callosum (ROIs 3 and 4). Mean FA ratios measured 33% of those in the splenium of corpus callosum and 45% of those in the internal capsule. (j) Transverse FA map at the same level as g shows placement of ROIs in the genu of corpus callosum (ROIs 5 and 6), which measured 44% of this region in age-matched brains on normal MR images. (k) Transverse FA map at same level as h shows placement of ROIs in frontal WM (ROIs 8 and 9). Mean FA ratio measured 32% of those in age-matched brains on normal MR images.

View larger version (141K): [in this window] [in a new window] [Download PPT slide]   Figure 6c. Patient 4. Serial diffusion-tensor images in asymptomatic boy with Krabbe disease in whom diagnosis was based on a sibling with the disorder. Umbilical cord blood transplantation was performed at 5 months of age. ROIs showing the highest FA values in a region were placed in an area that had abnormal hyperintense SI on T2-weighted images because no normal-appearing WM was present in these regions. (a) Transverse T2-weighted image (2800/100) obtained at the level of the internal capsule 4 days before transplantation shows abnormal hyperintense SI. (b) Transverse T2-weighted image (2800/100) just subjacent to the cerebral vertex shows no areas of abnormal SI and normal myelination pattern for age. (c) Transverse FA map at the same level as a shows placement of ROIs in the internal capsule (ROIs 7 and 8) and genu of corpus callosum (ROIs 1 and 6). Mean FA ratios measured 91% of those in age-matched brains on normal MR images in the genu of corpus callosum and 49% of those in the internal capsule. (d) Transverse FA map shows an ROI in the splenium of corpus callosum (ROIs 4 and 5) that measured 65% of the ratios in age-matched brains on normal MR images. (e) Transverse FA map at same level as b shows placement of ROI in frontal WM (ROIs 2 and 3). Mean FA ratio measured 53% of those in age-matched normal brain images. (f) Transverse T2-weighted image (2800/100) obtained 24 months after transplantation (patient age, 26 months) shows a moderate degree of volume loss and hyperintense SI in the internal capsule, basal ganglia, and periventricular regions. (g) Transverse T2-weighted image (2800/100) at the level of the genu of corpus callosum shows abnormal hyperintense SI in the periventricular regions and corona radiata. The corpus callosum SI appears normal. (h) Transverse T2-weighted image (2800/100) near the brain vertex shows abnormal hyperintense SI in the subcortical WM. (i) Transverse FA map at the same level as f shows placement of ROIs in the internal capsule (ROIs 1 and 2) and splenium of corpus callosum (ROIs 3 and 4). Mean FA ratios measured 33% of those in the splenium of corpus callosum and 45% of those in the internal capsule. (j) Transverse FA map at the same level as g shows placement of ROIs in the genu of corpus callosum (ROIs 5 and 6), which measured 44% of this region in age-matched brains on normal MR images. (k) Transverse FA map at same level as h shows placement of ROIs in frontal WM (ROIs 8 and 9). Mean FA ratio measured 32% of those in age-matched brains on normal MR images.

View larger version (142K): [in this window] [in a new window] [Download PPT slide]   Figure 6d. Patient 4. Serial diffusion-tensor images in asymptomatic boy with Krabbe disease in whom diagnosis was based on a sibling with the disorder. Umbilical cord blood transplantation was performed at 5 months of age. ROIs showing the highest FA values in a region were placed in an area that had abnormal hyperintense SI on T2-weighted images because no normal-appearing WM was present in these regions. (a) Transverse T2-weighted image (2800/100) obtained at the level of the internal capsule 4 days before transplantation shows abnormal hyperintense SI. (b) Transverse T2-weighted image (2800/100) just subjacent to the cerebral vertex shows no areas of abnormal SI and normal myelination pattern for age. (c) Transverse FA map at the same level as a shows placement of ROIs in the internal capsule (ROIs 7 and 8) and genu of corpus callosum (ROIs 1 and 6). Mean FA ratios measured 91% of those in age-matched brains on normal MR images in the genu of corpus callosum and 49% of those in the internal capsule. (d) Transverse FA map shows an ROI in the splenium of corpus callosum (ROIs 4 and 5) that measured 65% of the ratios in age-matched brains on normal MR images. (e) Transverse FA map at same level as b shows placement of ROI in frontal WM (ROIs 2 and 3). Mean FA ratio measured 53% of those in age-matched normal brain images. (f) Transverse T2-weighted image (2800/100) obtained 24 months after transplantation (patient age, 26 months) shows a moderate degree of volume loss and hyperintense SI in the internal capsule, basal ganglia, and periventricular regions. (g) Transverse T2-weighted image (2800/100) at the level of the genu of corpus callosum shows abnormal hyperintense SI in the periventricular regions and corona radiata. The corpus callosum SI appears normal. (h) Transverse T2-weighted image (2800/100) near the brain vertex shows abnormal hyperintense SI in the subcortical WM. (i) Transverse FA map at the same level as f shows placement of ROIs in the internal capsule (ROIs 1 and 2) and splenium of corpus callosum (ROIs 3 and 4). Mean FA ratios measured 33% of those in the splenium of corpus callosum and 45% of those in the internal capsule. (j) Transverse FA map at the same level as g shows placement of ROIs in the genu of corpus callosum (ROIs 5 and 6), which measured 44% of this region in age-matched brains on normal MR images. (k) Transverse FA map at same level as h shows placement of ROIs in frontal WM (ROIs 8 and 9). Mean FA ratio measured 32% of those in age-matched brains on normal MR images.

View larger version (148K): [in this window] [in a new window] [Download PPT slide]   Figure 6e. Patient 4. Serial diffusion-tensor images in asymptomatic boy with Krabbe disease in whom diagnosis was based on a sibling with the disorder. Umbilical cord blood transplantation was performed at 5 months of age. ROIs showing the highest FA values in a region were placed in an area that had abnormal hyperintense SI on T2-weighted images because no normal-appearing WM was present in these regions. (a) Transverse T2-weighted image (2800/100) obtained at the level of the internal capsule 4 days before transplantation shows abnormal hyperintense SI. (b) Transverse T2-weighted image (2800/100) just subjacent to the cerebral vertex shows no areas of abnormal SI and normal myelination pattern for age. (c) Transverse FA map at the same level as a shows placement of ROIs in the internal capsule (ROIs 7 and 8) and genu of corpus callosum (ROIs 1 and 6). Mean FA ratios measured 91% of those in age-matched brains on normal MR images in the genu of corpus callosum and 49% of those in the internal capsule. (d) Transverse FA map shows an ROI in the splenium of corpus callosum (ROIs 4 and 5) that measured 65% of the ratios in age-matched brains on normal MR images. (e) Transverse FA map at same level as b shows placement of ROI in frontal WM (ROIs 2 and 3). Mean FA ratio measured 53% of those in age-matched normal brain images. (f) Transverse T2-weighted image (2800/100) obtained 24 months after transplantation (patient age, 26 months) shows a moderate degree of volume loss and hyperintense SI in the internal capsule, basal ganglia, and periventricular regions. (g) Transverse T2-weighted image (2800/100) at the level of the genu of corpus callosum shows abnormal hyperintense SI in the periventricular regions and corona radiata. The corpus callosum SI appears normal. (h) Transverse T2-weighted image (2800/100) near the brain vertex shows abnormal hyperintense SI in the subcortical WM. (i) Transverse FA map at the same level as f shows placement of ROIs in the internal capsule (ROIs 1 and 2) and splenium of corpus callosum (ROIs 3 and 4). Mean FA ratios measured 33% of those in the splenium of corpus callosum and 45% of those in the internal capsule. (j) Transverse FA map at the same level as g shows placement of ROIs in the genu of corpus callosum (ROIs 5 and 6), which measured 44% of this region in age-matched brains on normal MR images. (k) Transverse FA map at same level as h shows placement of ROIs in frontal WM (ROIs 8 and 9). Mean FA ratio measured 32% of those in age-matched brains on normal MR images.

View larger version (134K): [in this window] [in a new window] [Download PPT slide]   Figure 6f. Patient 4. Serial diffusion-tensor images in asymptomatic boy with Krabbe disease in whom diagnosis was based on a sibling with the disorder. Umbilical cord blood transplantation was performed at 5 months of age. ROIs showing the highest FA values in a region were placed in an area that had abnormal hyperintense SI on T2-weighted images because no normal-appearing WM was present in these regions. (a) Transverse T2-weighted image (2800/100) obtained at the level of the internal capsule 4 days before transplantation shows abnormal hyperintense SI. (b) Transverse T2-weighted image (2800/100) just subjacent to the cerebral vertex shows no areas of abnormal SI and normal myelination pattern for age. (c) Transverse FA map at the same level as a shows placement of ROIs in the internal capsule (ROIs 7 and 8) and genu of corpus callosum (ROIs 1 and 6). Mean FA ratios measured 91% of those in age-matched brains on normal MR images in the genu of corpus callosum and 49% of those in the internal capsule. (d) Transverse FA map shows an ROI in the splenium of corpus callosum (ROIs 4 and 5) that measured 65% of the ratios in age-matched brains on normal MR images. (e) Transverse FA map at same level as b shows placement of ROI in frontal WM (ROIs 2 and 3). Mean FA ratio measured 53% of those in age-matched normal brain images. (f) Transverse T2-weighted image (2800/100) obtained 24 months after transplantation (patient age, 26 months) shows a moderate degree of volume loss and hyperintense SI in the internal capsule, basal ganglia, and periventricular regions. (g) Transverse T2-weighted image (2800/100) at the level of the genu of corpus callosum shows abnormal hyperintense SI in the periventricular regions and corona radiata. The corpus callosum SI appears normal. (h) Transverse T2-weighted image (2800/100) near the brain vertex shows abnormal hyperintense SI in the subcortical WM. (i) Transverse FA map at the same level as f shows placement of ROIs in the internal capsule (ROIs 1 and 2) and splenium of corpus callosum (ROIs 3 and 4). Mean FA ratios measured 33% of those in the splenium of corpus callosum and 45% of those in the internal capsule. (j) Transverse FA map at the same level as g shows placement of ROIs in the genu of corpus callosum (ROIs 5 and 6), which measured 44% of this region in age-matched brains on normal MR images. (k) Transverse FA map at same level as h shows placement of ROIs in frontal WM (ROIs 8 and 9). Mean FA ratio measured 32% of those in age-matched brains on normal MR images.

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