Secondary failure of Lentiviral Vector Gene Therapy in a Cerebral Adrenoleukodystrophy Patient with an ABCD1 Whole-Gene Deletion.

A nine-year boy with adrenoleukodystrophy due to an ABCD1 whole gene deletion was diagnosed with the active cerebral adrenoleukodystrophy characterized by demyelination and gadolinium enhancement on brain MRI. He underwent hemopoietic cell transplant (HCT) with autologous CD34+ cells transduced with an ABCD1-expressing lentiviral vector (eli-cel, elivaldogene autotemcel) as part of the ALD-104 clinical trial. Fifty days after HCT, the patient's MRI showed gadolinium resolution; whole blood vector copy number (VCN) was 0.666 copies/mL. Six months following HCT, an MRI showed re-emergence of gadolinium enhancement; VCN had decreased to 0.029 copies/mL. Polyclonal antibodies to the ABCD1 gene product were detectable 9 months after transplant showing reactivity to peroxisomes, suggesting an immune response, however, no antibody binding to human CD34+ cells could be shown. The patient underwent a successful allogeneic HCT 12 months after gene therapy with resultant gadolinium resolution, cerebral disease stabilization, and the disappearance of antibodies. The coincident VCN loss and appearance of antibody to the ABCD1 gene product is of interest, and we postulate that it is related to the patient's whole ABCD1 gene deletion. We suggest close monitoring of loss of gene therapy efficacy due to immune response in patients with full deletions who are considering gene therapy.

Targeting VEGF-mediated blood-brain barrier disruption in advanced cerebral leukodystrophy.

The earliest clinical manifestation of cerebral adrenoleukodystrophy (CALD) is adrenal insufficiency (AI) characterized by elevations in ACTH and loss of cortisol. We showed high (though physiologically achievable) levels of ACTH increases endothelial permeability, increases anisotropy, and increases VEGF secretion. An ACBD1 knockout endothelial cell line had increased sensitivity to ACTH and VEGF. Inhibition of VEGF via application of anti-VEGF (bevacizumab) improved permeability. Six boys with advanced CALD were treated with bevacizumab combined with dexamethasone and ruxolitinib as immune suppressants. Most boys had decreases in gadolinium enhancement on MRI indicating improvement in endothelial function, though all boys continued to progress symptomatically.

Natural history of craniovertebral abnormalities in a single-center study in 54 patients with Hurler syndrome.

OBJECTIVE: Craniovertebral junction (CVJ) abnormalities are common and well documented in mucopolysaccharidosis type I-Hurler syndrome (MPS IH), often causing severe spinal canal narrowing. However, the requirement for surgical decompression and/or fusion is uncommon. Although hematopoietic cell transplant (HCT) has been shown to prolong the lives of patients with MPS IH, its effect in halting or reversing musculoskeletal abnormalities is less clear. Unfortunately, there are currently no universal guidelines for imaging or indication for surgical interventions in these patients. The goal of this study was to track the progression of the CVJ anatomy in patients with MPS IH following HCT, and to examine radiographic features in patients who needed surgical intervention. METHODS: Patients with MPS IH treated at the University of Minnesota with allogeneic HCT between 2008 and 2020 were retrospectively reviewed. Patients who underwent CVJ surgery were identified with chart review. All MPS IH cervical scans were examined, and the odontoid retroflexion angle, clivoaxial angle (CXA), canal width, and Grabb-Oakes distance (pB-C2) were measured yearly for up to 7 years after HCT. Longitudinal models based on the measurements were made. An intraclass correlation coefficient was used to measure interrater reliability. Nine children without MPS IH were examined for control CVJ measurements. RESULTS: A total of 253 cervical spine MRI scans were reviewed in 54 patients with MPS IH. Only 4 (7.4%) patients in the study cohort required surgery. Three of them had posterior fossa and C1 decompression, and 1 had a C1-2 fusion. There was no statistically significant difference in the spinal parameters that were examined between surgery and nonsurgery groups. Among the measurements, canal width and CXA varied drastically in patients with different neck positions. Odontoid retroflexion angle and CXA tended to decrease with age. Canal width and pB-C2 tended to increase with age. CONCLUSIONS: Based on the data, the authors observed an increase in canal width and pB-C2, whereas the CXA and odontoid retroflexion angle became more acute as the patients aged after HCT. The longitudinal models derived from these data mirrored the development in children without MPS IH. Spinal measurements obtained on MR images alone are not sufficient in identifying patients who require surgical intervention. Symptom monitoring and clinical examination, as well as pathological spinal cord changes on MRI, are more crucial in assessing the need for surgery than is obtaining serial imaging.

Quantitative brain morphometry identifies cerebellar, cortical, and subcortical gray and white matter atrophy in late-onset Tay-Sachs disease.

Cerebellar atrophy is a characteristic sign of late-onset Tay-Sachs disease (LOTS). Other structural neuroimaging abnormalities are inconsistently reported. Our study aimed to perform a detailed whole-brain analysis and quantitatively characterize morphometric changes in LOTS patients. Fourteen patients (8 M/6F) with LOTS from three centers were included in this retrospective study. For morphometric brain analyses, we used deformation-based morphometry, voxel-based morphometry, surface-based morphometry, and spatially unbiased cerebellar atlas template. The quantitative whole-brain morphometric analysis confirmed the finding of profound pontocerebellar atrophy with most affected cerebellar lobules V and VI in LOTS patients. Additionally, the atrophy of structures mainly involved in motor control, including bilateral ventral and lateral thalamic nuclei, primary motor and sensory cortex, supplementary motor area, and white matter regions containing corticospinal tract, was present. The atrophy of the right amygdala, hippocampus, and regions of occipital, parietal and temporal white matter was also observed in LOTS patients in contrast with controls (p < 0.05, FWE corrected). Patients with dysarthria and those initially presenting with ataxia had more severe cerebellar atrophy. Our results show predominant impairment of cerebellar regions responsible for speech and hand motor function in LOTS patients. Widespread morphological changes of motor cortical and subcortical regions and tracts in white matter indicate abnormalities in central motor circuits likely coresponsible for impaired speech and motor function.

Diffuse CNS cortical vein malformations with chromosome 17q microduplication: Possible link to SEC14L1.

Partial trisomy of the long arm of chromosome 17 (17q) is a rare but clinically recognized syndrome that involves facial dysmorphisms, skeletal abnormalities, and global developmental delay, as well as various reports of cardiovascular, renal, and central nervous system abnormalities. This report presents a novel neuroradiologic finding of diffuse enlarged, tortuous cortical veins with physiological antegrade flow in a child with a microduplication of the distal end of 17q. To our knowledge, this finding has not been described previously. Although the exact cause for the cortical vascular anomaly is currently unknown, this duplicated region contains genes of interest for future studies that focus on normal and abnormal angiogenesis.

Venous Sinus Stenosis with Prominent Emissary Veins: A New Common Cranial MRI Finding of Mucopolysaccharidosis I.

Mucopolysaccharidosis I-Hurler (MPSIH) syndrome is the most severe form of a group of hereditary lysosomal diseases. This study aims to describe previously unreported common cranial findings of sigmoid sinus stenosis with prominent emissary veins in MPSIH. A retrospective review was conducted of 66 patients with MPSIH who were treated at our institution. A total of 12 cranial MR imaging studies from 12 different patients demonstrating the venous sinus anatomy were reviewed. All 12 patients exhibited various degrees of sigmoid or transverse sinus stenosis. Eleven had various forms of emissary veins. Of those 12 patients with imaging of the venous sinuses, 9 had a lumbar puncture within the same months as the acquisition of the venogram without any correlation between elevated opening pressure and the severity of the venous sinus stenosis. Stenotic cerebral venous sinuses with associated emissary veins, common in patients with MPSIH, may be abnormal findings due to posterior fossa horns from glycosaminoglycan depositions rather than signs of elevated intracracranial pressure or requirement of CSF diversion.

Increased pituitary volumes in patients with Sanfilippo syndrome (mucopolysaccharidosis type 3, MPS III).

PURPOSE: To evaluate apparent pituitary gland enlargement in patients with Sanfilippo syndrome observed at our institution. METHODS: Twelve patients with Sanfilippo syndrome with brain MRI were studied. Anterior, posterior, and whole pituitary volumes were estimated using the prolate ellipsoid volume calculation method (π/6 × L × W × H). Convexity along the upper pituitary margin (Elster's grade) was also measured. These values were compared to two age- and sex-matched groups (normal controls and patients with Hurler syndrome) using one-way ANOVA followed by Tukey's post hoc analysis for multiple comparisons. RESULTS: In the Sanfilippo cohort, the mean whole pituitary volume was 529.9 mm, the mean anterior pituitary volume was 333.4 mm, and the mean posterior pituitary volume was 59.1 mm with Elster's grade of 4.2. In the control cohort, the mean whole pituitary volume was 217.4 mm, the mean anterior pituitary volume was 154.8 mm, and the mean posterior pituitary volume was 28.4 mm with Elster's grade of 2.5. In the Hurler syndrome cohort, the mean whole pituitary volume was 310.0 mm, the mean anterior pituitary volume was 178.2 mm, and the mean posterior pituitary volume was 35.4 mm with Elster's grade of 3.5. CONCLUSION: In our cohort of patients with Sanfilippo syndrome, whole, anterior, and posterior pituitary volumes and degree of convexity along the upper pituitary border were all significantly greater than controls. The cause of these morphological changes is unclear, as is clinical correlation of the findings.

A case series of adrenoleukodystrophy in children conceived through in vitro fertilization with an egg donor.

Objective: To report 3 cases of adrenoleukodystrophy (ALD) in children conceived by in vitro fertilization (IVF) and egg donation. Design: A case report. Patients: Patients aged 4-5 years old, evaluated by the University of Minnesota Leukodystrophy Center, who were diagnosed with ALD after being conceived by IVF with oocytes provided by the same donor. Interventions: One patient received a hematopoietic stem cell transplant from a human leukocyte antigen-matched donor, and 1 patient received autologous lentiviral corrected hematopoietic cells. The disease state in 1 patient was unfortunately too advanced for effective treatment to be administered. Main Outcome Measures: Progression of disease after diagnosis or treatment was observed by cerebral magnetic resonance imaging and monitoring the development or advancement of any cognitive, adaptive, and motor deficits. Results: Patients who received a transplant for ALD successfully experienced little to no disease progression at least 6 months to 1 year after treatment. Conclusions: These 3 cases of transmission of ALD through oocyte donation and IVF highlight the potential need to implement more comprehensive genetic screening of gamete donors to prevent the transfer of rare but severe genetic diseases through IVF. Further, these cases highlight limitations in carrier screening guidelines that limit reportable variants to pathogenic and likely pathogenic variants.

Contrast enhancement in cerebral adrenoleukodystrophy: a comparison of T1 TSE and MPRAGE sequences.

PURPOSE: To compare conventional T1 TSE with MPRAGE for enhancement detection in cerebral adrenoleukodystrophy (CALD). MATERIALS AND METHODS: Contrast-enhanced T1 TSE and MPRAGE sequences of 34 CALD patients demonstrating enhancement were evaluated. Contrast ratios were calculated by drawing ROIs to the most enhancing part of demyelination and normal-appearing deep white matter on both T1 TSE and MPRAGE. A comparison was performed between ratios using paired T test. RESULTS: Mean age of 34 included male children was 8 (5-11 years). There was no statistically significant difference between T1 TSE and MPRAGE ratios. However, in 4 out of 34 examinations, minimal contrast enhancement was noted only in T1 TSE sequence. CONCLUSION: Our data indicate that both T1 TSE and MPRAGE sequences are valuable in determining contrast enhancement in CALD. Although there is not a statistically significant difference between the two techniques, T1 TSE sequence appears to be more sensitive for low degree of enhancement.

Glycoprotein nonmetastatic melanoma protein B (GNMPB) as a novel biomarker for cerebral adrenoleukodystrophy.

Adrenoleukodystrophy (ALD) is an X-linked peroxisomal disease caused by a mutation in the ABCD1 gene, producing mutations in the very long chain fatty acid transporter, ALD protein. Cerebral ALD (cALD) is a severe phenotype of ALD with neuroinflammation and neurodegeneration. Elevated levels of Glycoprotein Nonmetastatic Melanoma Protein B (GNMPB) have been recently documented in neurodegenerative diseases such as Alzheimer's disease, Multiple Sclerosis and Amyotrophic Lateral Sclerosis. Our objective was to measure the levels cerebral spinal fluid (CSF) GNMPB in cALD patients to determine if GNMPB could be a potential biomarker in tracking cALD disease progression. CSF GNMPB levels were significantly higher in cALD patients versus controls (2407 ± 1672 pg/mL vs. 639.5 ± 404 pg/mL, p = 0.0009). We found a positive correlation between CSF GNMPB and MRI disease severity score levels (R2 = 0.3225, p < 0.0001) as well as the gadolinium intensity score (p = 0.0204). Boys with more severe neurologic deficits also had higher levels of CSF GNMPB (p < 0.0001). A positive correlation was shown between CSF GNMPB and another biomarker, chitotriosidase (R2 = 0.2512, p = 0.0244). These data show that GNMPB could be a potential biomarker of cALD disease state and further studies should evaluate it as a predictor of the disease progression.

Torcular pseudomass in newborns and its association with delivery: follow up or leave it alone?

PURPOSE: The cranial epidural space (ES) is a potential space and is not generally recognized unless there is underlying pathology. With MRI in newborns, we have frequently observed T2 hyperintense thickening of the ES posterior to the confluence of sinuses, also referred to as "torcular pseudomass" (TP). We aim to identify the frequency of TP and possible associations with delivery. METHODS: Retrospectively, brain MRIs of 194 neonates obtained within the first 2 weeks of life were evaluated. If TP was present, imaging characteristics and thickness were assessed by two observers, using fat-suppressed T2WI/FLAIR, T1WI, and SWI. Exclusion criteria were motion artifact, lack of sagittal T2WI, and lack of clinical data. Medical records were evaluated for demographic and clinical data. Follow-up exams were evaluated if available. Patients with TP and without were compared using Student t and chi-square tests. RESULTS: TP was present in 64/158 (40%). No difference was found between the groups regarding sex, gestational age, birth weight, delivery type, fetal presentation during delivery, birth difficulty, and neurological sequelae (p > 0.05). Eight patients with TP underwent follow-up imaging, and in 6/8, TP completely resolved. Two patients showed persistent TP, improving from 3.2 to 1 mm in one child and from 3.2 to 2.8 mm in the other within a week. CONCLUSION: TP frequently occurs in early newborns. TP does not appear to be associated with factors related to delivery, shows complete resolution in most cases with a follow-up, and is likely of no clinical importance.

Stability of serial platelet and urine protein measurements in patients receiving nusinersen for spinal muscular atrophy.

INTRODUCTION/AIMS: Patients undergoing nusinersen treatment for spinal muscular atrophy are subject to measurements of platelet count and urine protein before each injection due to concern for platelet depletion and renal dysfunction according to the prescribing information. These tests may be uncomfortable or inconvenient and may cause delays in treatment. However, it is still unclear whether these values have been significantly affected by nusinersen treatment. Our aim in this study was to determine whether these measurements ever reached critical values that necessitated withholding treatment at our center. METHODS: Records from 57 patients treated with nusinersen at our institution between 2017 and 2020 were retrospectively analyzed. Laboratory values for platelet count, random urine protein, and total urine protein:creatinine ratio were collected from all patients before each procedure. RESULTS: Mean patient age was 28.9 years (range, 2-76 years). Mean platelet count was 307 × 109 /L (range, 96-755 × 109 /L; normal lab limits, 150-450 × 109 /L), mean random urine protein was 0.164 g/L (range, <0.05-0.73 g/L), and mean total urine protein:creatinine ratio was 0.885 g per gram creatinine (range, 0.12-9.71 g per gram creatinine). No laboratory values precluded continuing treatment for any patient. DISCUSSION: Although further study on a larger cohort is warranted for more definitive conclusions, it may not be necessary to measure platelet count and urine protein before each nusinersen treatment, particularly in the maintenance phase.

Evaluation of Neurofilament Light Chain as a Biomarker of Neurodegeneration in X-Linked Childhood Cerebral Adrenoleukodystrophy.

Cerebral adrenoleukodystrophy (CALD) is a devastating, demyelinating neuroinflammatory manifestation found in up to 40% of young males with an inherited mutation in ABCD1, the causative gene in adrenoleukodystrophy. The search for biomarkers which correlate to CALD disease burden and respond to intervention has long been sought after. We used the Olink Proximity Extension Assay (Uppsala, Sweden) to explore the cerebral spinal fluid (CSF) of young males with CALD followed by correlative analysis with plasma. Using the Target 96 Neuro Exploratory panel, we found that, of the five proteins significantly increased in CSF, only neurofilament light chain (NfL) showed a significant correlation between CSF and plasma levels. Young males with CALD had a 11.3-fold increase in plasma NfL compared with controls. Importantly, 9 of 11 young males with CALD who underwent HCT showed a mean decrease in plasma NfL of 50% at 1 year after HCT compared with pre-HCT levels. In conclusion, plasma NfL could be a great value in determining outcomes in CALD and should be scrutinized in future studies in patients prior to CALD development and after therapeutic intervention.

A common yet undescribed MRI finding in newborns: posterior epidural space edema of the cervical and upper thoracic spine.

PURPOSE: Posterior spinal epidural space (PSES) is a fat-containing space. We noted numerous spinal MRIs demonstrating T2-hyperintense thickening of the cervical/thoracic PSES in early newborns, resembling epidural edema. Our aim is to describe the appearance/frequency of this finding and explore any associations with delivery. METHODS: Retrospectively, 202 spinal/cranial MRIs, belonging to newborns within the first 2 weeks of life, were evaluated using sagittal fat-suppressed T2, T1-FLAIR, and STIR. Exclusion criteria were motion, incomplete spine imaging, lack of sagittal T2/STIR, and inadequate clinical data. Ninety-three patients were included in the final analysis. We reviewed all cases for T2 hyperintense thickened PSES and, if present, accompanying abnormal T1 signal. The spinal canal and PSES thickness were measured. Clinical and demographic data were collected. Follow-up exams were evaluated, if available. Cases with thickened PSES and without were compared. RESULTS: T2-hyperintense thickened PSES was present in 60/93 (64.5%). Mean PSES thickness was 2.3 mm (0.7-4.6). The mean PSES thickness/spinal canal diameter ratio was 0.2 (0.1-0.5). No cord compression was identified. One had a hyperintense T1 PSES signal, compatible with epidural hemorrhage. No difference was found between those with thickened PSES and without, regarding sex, gestational age, birth weight, birth method, difficult delivery, fetal position, or neurologic status (p>0.05). Follow-up imaging was available in 10, with complete resolution of T2 hyperintense PSES thickening. CONCLUSION: T2 hyperintense PSES thickening is common in imaged newborns and reversible at follow-up. No significant neurologic outcomes were found related to its presence; thus, follow-up does not appear necessary.

Dentate nucleus signal intensity changes on T1-weighted MRI after repeated administrations of linear and macrocyclic gadolinium-based contrast agents: a pediatric intraindividual case-control study.

BACKGROUND: An association between consecutive administrations of macrocyclic gadolinium-based contrast agent (mcGBCA) gadobutrol and linear (L)-GBCA gadopentetate dimeglumine and gadolinium retention in the pediatric brain remains incompletely understood. PURPOSE: To compare signal intensity (SI) changes in the dentate nucleus (DN) on unenhanced T1-weighted imaging (T1WI) in children who obtained mcGBCA gadobutrol with those who had previously received L-GBCA gadopentetate dimeglumine. MATERIAL AND METHODS: This retrospective study included 27 children who received L-GBCA gadopentetate dimeglumine followed by mcGBCA gadobutrol and two different control groups matched for age and sex for both periods, each involving 27 individuals with no GBCA administration from January 2010 to January 2020. DN-to-middle cerebellar peduncle (MCP) SI ratios on T1WI were determined. A repeated-measures ANOVA was performed to compare the T1WI SI ratio between children exposed to GBCA in each of the two periods and controls. Pearson correlation analysis was conducted to determine any correlation between SI ratios and confounding parameters. RESULTS: T1WI SI ratio was significantly higher in those who had only L-GBCA (1.005±0.087) or subsequent mcGBCA gadobutrol (1.002±0.104) than in control groups 1 (0.927±0.041; P<0.001) and 2 (0.930±0.041; P=0.002), respectively, but no significant difference of the T1WI SI ratio was noted between L-GBCA period and subsequent mcGBCA gadobutrol period (P=0.917). T1WI SI ratios and the L-GBCA administration number revealed a modest but significant correlation (correlation coefficient=0.034; P=0.016). CONCLUSION: Previous administration of gadopentetate dimeglumine is associated with increased T1WI SI in the DN, while subsequent administration of gadobutrol does not demonstrate any additional SI increase in the pediatric brain.

Diffusion Tensor Imaging of the Dentate Nucleus After Repeated Administration of Gadobutrol in Children.

This study aimed to investigate possible signal changes in the dentate nucleus (DN) on diffusion tensor imaging (DTI) after administration of gadobutrol in a pediatric cohort. Total of 50 pediatric patients (mean age: 6.2 ± 4.3 years) with normal renal function exposed exclusively to the macrocyclic GBCA (mcGBCA) gadobutrol and 50 age- and sex-matched control patients with nonpathological neuroimaging findings (and no GBCA administration). Mean diffusivity (MD) and fractional anisotropy (FA) values were determined in the DN. A paired t test was performed to compare FA, MD values, and DN-to-middle cerebral peduncle (MCP) T1WI SI ratios between children exposed to gadobutrol and controls. Pearson correlation analysis was conducted to determine any correlation between FA and MD values as well as T1WI SI ratios and confounding parameters. The mean FA values of DN was significantly lower in children with mcGBCA than in the control group (p < 0.001; non-GBCA group, 0.299 ± 0.03; mcGBCA group, 0.254 ± 0.05), but no significant difference of the T1WI SI ratio was noted between the mcGBCA group (0.946 ± 0.06) and the control group (0.963 ± 0.05; p = 0.336). There was also a significant MD value difference between mcGBCA group and control group (p < 0.001; non-GBCA group, 0.152 ± 0.02 × 10-3 mm2/s; mcGBCA group, 0.173 ± 0.03 × 10-3 mm2/s). A significant correlation was identified between FA/MD values and the number of mcGBCA administration (FA; correlation coefficient = - 0.355, p = 0.011 and MD; correlation coefficient = 0.334, p = 0.018). The administration of the gadobutrol was associated with higher MD and lower FA values in DN suggesting a difference in cerebellar tissue integrity between children exposed to mcGBCAs and control group.

Differential outcomes for frontal versus posterior demyelination in childhood cerebral adrenoleukodystrophy.

In the most common variant of childhood cerebral adrenoleukodystrophy (cALD), demyelinating brain lesions are distributed predominately in parieto-occipital white matter. Less frequently, lesions first develop in frontal white matter. This matched cohort study examined whether outcomes after standard treatment with hematopoietic cell transplantation (HCT) differ in patients with early stage frontal lesions as compared to parieto-occipital lesions. Retrospective chart review identified seven pediatric patients with frontal cALD lesions and MRI severity score < 10 who underwent a single HCT at our center between 1990 and 2019. Concurrent MRI, neurocognitive and psychiatric outcomes at last comprehensive follow-up (mean 1.2 years; range 0.5-2.1 years) were compared with a group of seven boys with the parieto-occipital variant matched on pre-HCT MRI severity score. Both groups showed similar rates of transplant complications and radiographic disease advancement. Neurocognitive outcomes were broadly similar, with more frequent working memory deficits among individuals with frontal lesions. Psychiatric problems (hyperactivity, aggression, and atypical behavior) were considerably more common and severe among patients with frontal lesions. Aligned with the critical role of the frontal lobes in emotional and behavioral regulation, functional disruption of self-regulation skills is widely observed among patients with frontal lesions. Comprehensive care for cALD should address needs for psychiatric care and management.

Treatment of CSF1R-Related Leukoencephalopathy: Breaking New Ground.

BACKGROUND: Colony-stimulating factor-1 receptor (CSF1R)-related leukoencephalopathy is a rapidly progressive neurodegenerative disease for which there is currently no cure. Hematopoietic stem cell transplantation (HSCT) has been proposed as a disease-modifying treatment. OBJECTIVE: The objective of this study was to determine the effect of HSCT on disease progression. METHODS: We collected all available clinical data from a cohort of 7 patients with CSF1R-related leukoencephalopathy who underwent HSCT at our institutions. Clinical data included detailed neurological examination by a board-certified neurologist, serial cognitive screens, formal neuropsychological evaluations, and serial brain magnetic resonance imaging (MRI). RESULTS: Our patients had an average disease duration of 27.6 months at the time of transplant, and we have 87 months of total posttransplant follow-up time (median, 11; range, 2-27). One patient died in the periprocedural period. The remaining patients showed a variable response to treatment, with 6 of 7 patients trending toward stabilization on motor examination, cognitive scores, and/or MRI abnormalities, especially with white matter lesion burden. CONCLUSIONS: This is the largest series of patients with CSF1R-related leukoencephalopathy receiving HSCT. We conclude that HSCT can stabilize the disease in some patients. Variability in patient responsiveness suggests that measures of disease heterogeneity and severity need to be considered when evaluating a patient's candidacy for transplant. HSCT appears to be the first disease-modifying therapy for CSF1R-related leukoencephalopathy. This milestone may serve as a foothold toward better understanding the disease's pathomechanism, thus providing new opportunities for better disease-specific therapies. © 2021 International Parkinson and Movement Disorder Society.

Dentate Nucleus Signal Intensity Changes in Children with Adrenoleukodystrophy in Comparison to Primary Brain Tumor with and without Radiotherapy after Gadobutrol Administration.

BACKGROUND AND PURPOSE: To determine whether cerebral adrenoleukodystrophy (cALD) or brain irradiation in patients with primary brain tumor affects T1-weighted imaging (T1WI) signal intensity (SI) of the dentate nucleus (DN) in a pediatric cohort who had received consecutive macrocyclic gadolinium-based contrast agent (mcGBCA) gadobutrol. METHODS: This study included 97 pediatric patients who underwent mcGBCA-enhanced MRI from 2010 to 2020 (29 children with primary brain tumors without brain radiation therapy [mcGBCA group-1], 33 children with primary brain tumors and radiation treatment [mcGBCA group-2], 35 children with cALD [mcGBCA group-3], and 97 sex-/age-matched control subjects [subgroups matched to each of the three subject groups] without GBCA administration). The DN-to-middle cerebellar peduncle (MCP) SI ratios on T1WI were then determined. A paired t-test was performed to compare SI ratios between children exposed to mcGBCA in each group and control subjects. The relationships between SI ratios and confounding variables were analyzed utilizing the Pearson correlation analysis. RESULTS: The DN-to-MCP SI ratio was significantly higher of mcGBCA group-2 (1.046±.071) or mcGBCA group-3 (.972±.038) than in the control group-2 (.983±.041, P<.001) and control group-3 (.937±.051, P = .002), respectively, but no significant difference of the SI ratio was noted between mcGBCA group-1 (.984±.032) and control-group-1 (.982±.035, P = .860). No significant correlation was noted between SI ratio values and the cumulative dose or number of mcGBCA administrations, age, or the elapsed time between the MRI examinations (all P>.05). CONCLUSIONS: Hyperintense T1WI signal in the DN may be seen in children with brain tumors undergoing brain irradiation, as well as in children with cALD.