Poster #54: Shivaram Karandikar

A multi-center imaging study of neuroanatomical deviation patterns in pediatric leukodystrophies.

Shivaram Karandikar, BA, 1,2,3, Anjana Sevagamoorthy, MD, MPH, 4, Dabriel Zimmerman, BS, 1,2,3, Russell D’Aiello III, MS, 5, Lena Dorfschmidt, PhD, 1,2,3, Katherine Cyr, MS, 1,2,3, Benjamin Jung, PhD, 1,2,3, Elizabeth Levitis, PhD, 1,2,3, Laura A. Adang, MD, PhD, 4,6, Kaley Arnold, MS, 4, Mariko L. Bennett, MD, PhD, 4,6, Brittany A. Charsar, MD, PhD, 4, Carlos A. Dominguez Gonzalez, MS, 4, Francesco Gavazzi, MD, PhD, 4,6, Peter Hong, BA, 4, Jennifer L. Orthmann-Murphy, MD, PhD, 6, Sarah T. Pham, BA, 4, Kaleb Kelley, BS, 4, Miriam Lerner, BA, 4, Justine Shults, PhD, 5,7, Nivedita Thakur, MD, 8, Arastoo Vossough, MD, PhD, 9, Amy T. Waldman, MD, 4,6, Aaliyah White, BA, 4, Matthew T. Whitehead, MD, 9, Lisa Emrick, MD, 10, Jamie Fraser, MD, PhD, 11, Keith Van Haren, MD, 12,13, Stephanie Keller, MD, 14,15, Ali Fatemi, MD, 16,17, Florian Eichler, MD, 18, Joshua L. Bonkowsky, MD, PhD, 19, Jakob Seidlitz, PhD, 1,2,3,20, Aaron F. Alexander-Bloch, MD, PhD, 1,2,3 & Adeline Vanderver, MD, 4,6. 1. Department of Psychiatry, University of Pennsylvania, Philadelphia, PA 19104, USA, 2. Department of Child and Adolescent Psychiatry and Behavioral Science, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA, 3. Lifespan Brain Institute, The Children’s Hospital of Philadelphia and Penn Medicine, Philadelphia, PA 19104, USA, 4. Division of Neurology, Department of Pediatrics, Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USA, 5. Department of Biomedical and Health Informatics, Children’s Hospital of Philadelphia, Philadelphia, PA 19146, USA, 6. Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA, 7. Department of Biostatistics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA, 8. Department of Pediatrics, Division of Child and Adolescent Neurology, McGovern Medical School, UT-Houston Health Science Center, Houston, TX 77030, USA, 9. Division of Neuroradiology, Department of Radiology, Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USA, 10. Department of Neurology and Developmental Neuroscience, Baylor College of Medicine, Houston, TX 77030, USA, 11. Leukodystrophy and Myelin Disorders Program, Children's National Hospital, Washington, DC 20010, USA, 12. Department of Neurology, Stanford University, Palo Alto, CA 94304, USA, 13. Department of Neurology, Lucile Packard Children’s Hospital, Palo Alto, CA 94304, USA, 14. Department of Pediatrics, Division of Pediatric Neurology, Emory University, Atlanta, GA 30322, USA, 15. Department of Pediatric Neurology, Children’s Healthcare of Atlanta, Atlanta, GA 30329, USA, 16. Moser Center for Leukodystrophies, Kennedy Krieger Institute, Baltimore, MD 21205, USA, 17. Department of Neurology, Johns Hopkins School of Medicine, Baltimore, MD 21287, USA, 18. Department of Neurology, Massachusetts General Hospital, Boston, MA 02114, USA, 19. Division of Pediatric Neurology, Department of Pediatrics, University of Utah Health, Salt Lake City, UT 84108, USA, 20. Institute for Translational Medicine and Therapeutics, University of Pennsylvania, Philadelphia, PA 19104, USA.

Leukodystrophies are heterogeneous genetic disorders affecting brain white matter, often with overlapping clinical features. This study aimed to characterize shared and distinct neuroanatomical patterns across six genetically confirmed leukodystrophies using MRI-derived brain volumes benchmarked against normative brain growth charts. This cross-sectional, multicenter neuroimaging study used retrospective clinical MRI data from 274 patients with genetically confirmed leukodystrophies (Pelizaeus-Merzbacher disease, Metachromatic leukodystrophy, Alexander disease, Aicardi-Goutières syndrome, TUBB4A-related leukodystrophy, and POLR3-related leukodystrophy) drawn from the Myelin Disorder Biorepository Project. Healthy clinical control data from 7,205 subjects were collected from the Scans with Limited Imaging Pathology cohort at the Children’s Hospital of Philadelphia. Deep learning segmentation tools derived global and regional brain volumes, and generalized additive models for location, scale, and shape (GAMLSS) were used to construct normative brain growth charts. Centile scores quantified individual deviations from typical development and were compared to clinical measures of gross motor function, a proxy for disease severity. Distinct neuroanatomical deviation patterns were identified across leukodystrophy subtypes, with some disorders showing preferential cortical or subcortical involvement and others displaying diffuse volume loss. Centile scores differentiated disease subtypes and stratified individuals by severity. Preliminary longitudinal data suggest centile scores may track disease progression over time. The use of clinical brain growth charts provides a scalable, quantitative framework for characterizing structural brain abnormalities in pediatric leukodystrophies. This approach may facilitate the use of atrophy as an imaging biomarker of disease severity.