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Cited by 21Metabolism and Genetic DisordersLysosomal Storage Disorders ResearchMultiple Sclerosis Research Studies

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Neurocognitive benchmarks following transplant for emerging cerebral adrenoleukodystrophy

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Pierpont, Elizabeth I., Nascene, David R., Shanley, Ryan, Kenney-Jung, Daniel L., Ziegler, Richard S., Miller, Weston P., Gupta, Ashish O., Lund, Troy C., Orchard, Paul J., Eisengart, Julie B.·2020·Neurology
DOI 10.1212/wnl.0000000000009929PMC PMC7455349
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Abstract

OBJECTIVE: To quantify benchmark treatment outcomes that may be enabled by newborn screening surveillance for X-linked adrenoleukodystrophy (ALD), we report neurocognitive, neuropsychiatric, and MRI change for boys who underwent hematopoietic stem cell transplant (HSCT) at initial stages of demyelination, prior to neurocognitive signs of disease. METHODS: Retrospective chart review identified 36 patients whose cerebral ALD was detected and treated early, with lesion severity less than 5 on the ALD-specific MRI scoring system. Median age at transplant was 7.3 years (range, 4.0-16.1). Progression of radiologic disease on MRI in the 2 years following HSCT was examined relative to the severity of the initial lesion for 33 patients, and longitudinal neurocognitive and neuropsychiatric outcomes were studied for 30 patients. RESULTS: Patients whose pretransplant lesion extended beyond the splenium of the corpus callosum and adjacent periventricular white matter (MRI severity score >2) demonstrated lower posttransplant neurocognitive scores, more neuropsychiatric symptoms, and more disease progression on MRI than patients with a less severe lesion. Changes from baseline neurocognitive functioning were greater at 2 years posttransplant as compared to 1 year. There was greater variance and risk of lesion progression as pretransplant MRI severity increased. CONCLUSION: To realize the full benefits of newborn screening, clinicians must detect very small demyelinating lesions during surveillance and intervene quickly. Novel interventions that reduce risks inherent in allogeneic transplantation are needed. Trial endpoints should include direct neurocognitive assessment and extend at least 2 years posttreatment to provide the greatest sensitivity to detect neurocognitive morbidity.

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Figure 1 Details of patient population and study inclusion for neuropsychological and MRI endpoints Of the 149 patients who underwent allogeneic hematopoietic stem cell transplantation (HSCT), 36 had a pretransplant MRI severity score <5. In this group, 33 patients survived and achieved acceptable engraftment after a single HSCT. All 33 had follow-up MRIs for analysis; 30 had neurocognitive follow-up. cALD = cerebral adrenoleukodystrophy.
Figure 1 Details of patient population and study inclusion for neuropsychological and MRI endpoints Of the 149 patients who underwent allogeneic hematopoietic stem cell transplantation (HSCT), 36 had a pretransplant MRI severity score <5. In this group, 33 patients survived and achieved acceptable engraftment after a single HSCT. All 33 had follow-up MRIs for analysis; 30 had neurocognitive follow-up. cALD = cerebral adrenoleukodystrophy.CC BY-NC-ND · PubMed Central
Figure 2 Progression of white matter disease in cerebral adrenoleukodystrophy Representative T2 fluid-attenuated inversion recovery axial images demonstrate the differences in white matter involvement among MRI severity scores. In increasing order of lesion severity, images A–D depict MRI severity scores of 1, 2, 3, and 4.5 respectively, as demyelination progresses further into the parietal white matter.
Figure 2 Progression of white matter disease in cerebral adrenoleukodystrophy Representative T2 fluid-attenuated inversion recovery axial images demonstrate the differences in white matter involvement among MRI severity scores. In increasing order of lesion severity, images A–D depict MRI severity scores of 1, 2, 3, and 4.5 respectively, as demyelination progresses further into the parietal white matter.CC BY-NC-ND · PubMed Central
Figure 3 MRI progression by initial lesion severity 2 years following transplantation for cerebral adrenoleukodystrophy (A) Scatterplot of pretransplant MRI severity vs 2-year MRI outcomes shows greater radiographic disease progression associated with higher pretransplant MRI score. The red line represents the regression line fitted to the data that were obtained. A black comparison line depicts the slope had there been no change in patient MRI scores from baseline to 2-years posttransplant. (B) Boxplots compare the change in MRI severity score from pretransplant to 2 years post-transplant in the very low severity (VLS) group (pretransplant MRI severity 0.5–2) and the low severity (LS) group (pretransplant MRI severity 2.5–4.5). The lower and upper box boundaries correspond to the first and third quartiles (the 25th and 75th percentiles), with a black line at the median. For the VLS group, median change in MRI severity was 0 points; for the LS group, median change was 3.5 points. Vertical lines extend to the largest value no more than 1.5 times the interquartile range from the box boundary.
Figure 3 MRI progression by initial lesion severity 2 years following transplantation for cerebral adrenoleukodystrophy (A) Scatterplot of pretransplant MRI severity vs 2-year MRI outcomes shows greater radiographic disease progression associated with higher pretransplant MRI score. The red line represents the regression line fitted to the data that were obtained. A black comparison line depicts the slope had there been no change in patient MRI scores from baseline to 2-years posttransplant. (B) Boxplots compare the change in MRI severity score from pretransplant to 2 years post-transplant in the very low severity (VLS) group (pretransplant MRI severity 0.5–2) and the low severity (LS) group (pretransplant MRI severity 2.5–4.5). The lower and upper box boundaries correspond to the first and third quartiles (the 25th and 75th percentiles), with a black line at the median. For the VLS group, median change in MRI severity was 0 points; for the LS group, median change was 3.5 points. Vertical lines extend to the largest value no more than 1.5 times the interquartile range from the box boundary.CC BY-NC-ND · PubMed Central
Figure 4 Two-year neurocognitive outcomes following hematopoietic stem cell transplantation at a stage of relatively low MRI severity (A–F) The relationship of pretransplant MRI severity score plotted with 2-year transplant outcomes revealed that neurocognitive skill areas were differentially impacted. While domains such as processing speed and fine motor dexterity showed greater susceptibility to poor outcomes when the MRI severity was higher, verbal reasoning skills and working memory generally remained intact across this low severity spectrum. The resilience of verbal reasoning skills in particular can inflate the perception of a child's functioning, as a child with intact communication and motor coordination generally appears unaffected by disease, but these perceptions of intact functioning likely obscure cerebral adrenoleukodystrophy–related neurocognitive changes that can occur and were quantified in this study. HSCT = hematopoietic stem cell transplantation.
Figure 4 Two-year neurocognitive outcomes following hematopoietic stem cell transplantation at a stage of relatively low MRI severity (A–F) The relationship of pretransplant MRI severity score plotted with 2-year transplant outcomes revealed that neurocognitive skill areas were differentially impacted. While domains such as processing speed and fine motor dexterity showed greater susceptibility to poor outcomes when the MRI severity was higher, verbal reasoning skills and working memory generally remained intact across this low severity spectrum. The resilience of verbal reasoning skills in particular can inflate the perception of a child's functioning, as a child with intact communication and motor coordination generally appears unaffected by disease, but these perceptions of intact functioning likely obscure cerebral adrenoleukodystrophy–related neurocognitive changes that can occur and were quantified in this study. HSCT = hematopoietic stem cell transplantation.CC BY-NC-ND · PubMed Central

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Authors
Pierpont, E. I., Nascene, D. R., Shanley, R., Kenney-Jung, D. L., Ziegler, R. S., Miller, W. P., Gupta, A. O., Lund, T. C., Orchard, P. J., & Eisengart, J. B.
Affiliations
  • University of Minnesota (US)
  • From the Departments of Pediatrics (E.I.P., R.S.Z., W.P.M., A.O.G., T.C.L., P.J.O., J.B.E.), Radiology (D.R.N.), Bioinformatics and Biostatistics Core (R.S.), and Neurology (D.L.K.-J.), University of Minnesota, Minneapolis; and Sangamo Therapeutics (W.P.M.), Richmond, CA.
Corresponding author
Pierpont, Elizabeth I.
ORCID
Venue
Neurology
Publisher
Ovid Technologies (Wolters Kluwer Health)
Published
2020-08-04
Volume
95
Issue
5
Pages
e591-e600
ISSN
  • 0028-3878 (ISSN-L)
  • 1526-632X
DOI
10.1212/wnl.0000000000009929
PMC
PMC7455349
OpenAlex
W3039456116
Cited by
21
References
22
Citations by year
2026: 2 · 2025: 3 · 2024: 5 · 2023: 2 · 2022: 4 · 2021: 4 · 2020: 1
FWCI
1.82
Type
journal article
Language
en
Open access
Licence
cc-by-nc-nd
Locations
  • Neurology (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
Funders
  • National Institutes of Health (UL1TR002494, KL2TR002492)
  • National Center for Advancing Translational Sciences
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Metabolism and Genetic Disorders
  • Health Sciences › Medicine › Genetics (clinical) › Lysosomal Storage Disorders Research
  • Health Sciences › Medicine › Clinical Neurology › Multiple Sclerosis Research Studies
Keywords
cerebral adrenoleukodystrophy, X-linked adrenoleukodystrophy, hematopoietic stem cell transplantation, newborn screening, neuropsychological outcomes, neuropsychiatric symptoms, demyelination, splenium of corpus callosum, periventricular white matter, disease progression, clinical trial endpoints
MeSH terms
Adolescent, Adrenoleukodystrophy, Child, Child, Preschool, Humans, Infant, Newborn, Magnetic Resonance Imaging, Male, Neonatal Screening, Treatment Outcome, Hematopoietic Stem Cell Transplantation, Benchmarking, Early Diagnosis

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