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Peer-reviewedCC BY 4.0Communications Medicine

Brain aging in Type II GM1 gangliosidosis

  • Connor J. Lewis1,2
  • Selby I. Chipman1,2
  • Precilla D’Souza1,2
  • Jean M. Johnston1,2
  • Muhammad H. Yousef3
  • William A. Gahl2
  • Cynthia J. Tifft1,2
  • Maria T. Acosta1,2
  1. 1Office of the Clinical Director, National Human Genome Research Institute, Bethesda, MD USA
  2. 2Medical Genetics Branch, National Human Genome Research Institute, Bethesda, MD USA
  3. 3Department of Perioperative Medicine, National Institutes of Health Clinical Center, Bethesda, MD USA
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Abstract

Background: GM1 gangliosidosis is an inherited, progressive, and fatal neurodegenerative lysosomal storage disorder with no approved treatment. In this study, we present the first use of MRI-based predicted brain age in GM1 gangliosidosis aimed at assessing the neuronal degeneration in this cohort.

Methods: We calculated a predicted brain age and Brain Structures Age Gap Estimation (BSAGE) for 81 MRI scans from 41 Type II (26 juvenile and 15 late-infantile) GM1 gangliosidosis patients and 897 MRI scans from 556 neurotypical controls (NC) utilizing BrainStructuresAges, a machine learning MRI analysis pipeline.

Results: NC shows whole-brain aging at a rate of 0.83 per chronological year compared with 1.57 in juvenile GM1 patients and 12.25 in late-infantile GM1 patients. Accelerated and distinct brain aging is observed throughout midbrain structures, including the thalamus and caudate nucleus, hindbrain structures, including the cerebellum and brainstem, and the ventricles in juvenile and late-infantile GM1 patients compared to NC, reflecting neurodegeneration from disease progression. Cross-sectional evaluations of BSAGE for the whole brain show an average BSAGE = 35.50 years in the late-infantile cohort, 21.19 years in the juvenile cohort, and 0.03 years in NC. Predicted brain age and BSAGE both correlate with cross-sectional and longitudinal clinical outcome assessments.

Conclusions: Predicted brain age accurately reflects the neurodegenerative clinical trajectories of the Type II GM1 disease subtypes. Correlations with clinical outcome assessments indicate evaluations of predicted brain aging may be an important candidate neuroimaging outcome measure for clinical trials in GM1 gangliosidosis.

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Cite

BibTeXRIS
BibTeX
@article{lewis2026brain,
  title = {{Brain aging in Type II GM1 gangliosidosis}},
  author = {Connor J. Lewis and Selby I. Chipman and Precilla D’Souza and Jean M. Johnston and Muhammad H. Yousef and William A. Gahl and Cynthia J. Tifft and Maria T. Acosta},
  journal = {Communications Medicine},
  year = {2026},
  month = jul,
  doi = {10.1038/s43856-026-01745-w},
  url = {https://doi.org/10.1038/s43856-026-01745-w},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - Brain aging in Type II GM1 gangliosidosis
AU  - Connor J. Lewis
AU  - Selby I. Chipman
AU  - Precilla D’Souza
AU  - Jean M. Johnston
AU  - Muhammad H. Yousef
AU  - William A. Gahl
AU  - Cynthia J. Tifft
AU  - Maria T. Acosta
PY  - 2026
DA  - 2026/07/06
JO  - Communications Medicine
DO  - 10.1038/s43856-026-01745-w
UR  - https://doi.org/10.1038/s43856-026-01745-w
AB  - Background: GM1 gangliosidosis is an inherited, progressive, and fatal neurodegenerative lysosomal storage disorder with no approved treatment. In this study, we present the first use of MRI-based predicted brain age in GM1 gangliosidosis aimed at assessing the neuronal degeneration in this cohort.  Methods: We calculated a predicted brain age and Brain Structures Age Gap Estimation (BSAGE) for 81 MRI scans from 41 Type II (26 juvenile and 15 late-infantile) GM1 gangliosidosis patients and 897 MRI scans from 556 neurotypical controls (NC) utilizing BrainStructuresAges, a machine learning MRI analysis pipeline.  Results: NC shows whole-brain aging at a rate of 0.83 per chronological year compared with 1.57 in juvenile GM1 patients and 12.25 in late-infantile GM1 patients. Accelerated and distinct brain aging is observed throughout midbrain structures, including the thalamus and caudate nucleus, hindbrain structures, including the cerebellum and brainstem, and the ventricles in juvenile and late-infantile GM1 patients compared to NC, reflecting neurodegeneration from disease progression. Cross-sectional evaluations of BSAGE for the whole brain show an average BSAGE = 35.50 years in the late-infantile cohort, 21.19 years in the juvenile cohort, and 0.03 years in NC. Predicted brain age and BSAGE both correlate with cross-sectional and longitudinal clinical outcome assessments.  Conclusions: Predicted brain age accurately reflects the neurodegenerative clinical trajectories of the Type II GM1 disease subtypes. Correlations with clinical outcome assessments indicate evaluations of predicted brain aging may be an important candidate neuroimaging outcome measure for clinical trials in GM1 gangliosidosis.
SN  - 2730-664X
ER  -