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Brain atrophy staging in spinocerebellar ataxia type 3 for clinical prognosis and trial enrichment

Background - Spinocerebellar ataxia type 3 (SCA3) is characterised by progressive brain atrophy, with regional volume loss detectable via MRI prior to clinical manifestation. We aimed to identify the previously unknown sequence of brain atrophy in SCA3 and evaluate whether this sequence can be trans...

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Main Authors: Baumeister, Hannah (Author) , Wegner, Philipp (Author) , Ferreira, Mónica (Author) , Schaprian, Tamara (Author) , França, Marcondes C. (Author) , Rezende, Thiago Junqueira Ribeiro (Author) , Muro Martinez, Alberto Rolim (Author) , Jiang, Hong (Author) , Chen, Zhao (Author) , Weihua, Liao (Author) , Grobe-Einsler, Marcus (Author) , Koyak, Berkan (Author) , Önder, Demet (Author) , van de Warrenburg, Bart (Author) , van Gaalen, Judith (Author) , Durr, Alexandra (Author) , Coarelli, Giulia (Author) , Synofzik, Matthis (Author) , Schöls, Ludger (Author) , Giunti, Paola (Author) , Garcia-Moreno, Hector (Author) , Öz, Gülin (Author) , Joers, James (Author) , Timmann, Dagmar (Author) , Thieme, Andreas G. (Author) , Jacobi, Heike (Author) , de Vries, Jeroen (Author) , Barker, Peter (Author) , Onyike, Chiadikaobi (Author) , Ratai, Eva-Maria (Author) , Schmahmann, Jeremy D. (Author) , Reetz, Kathrin (Author) , Infante, Jon (Author) , Huebener-Schmid, Jeannette (Author) , Kuegler, David (Author) , Klockgether, Thomas (Author) , Berron, David (Author) , Faber, Jennifer (Author) , Lüsebrink, Falk (Author) , Hetzer, Stefan (Author) , Ewers, Michael (Author) , Hellmann-Regen, Julian (Author) , Spruth, Eike (Author) , Janowitz, Daniel (Author) , Kilimann, Ingo (Author) , Kronmüller, Marie T. (Author) , Spottke, Annika (Author) , Peters, Oliver (Author) , Priller, Josef (Author) , Buerger, Katharina (Author) , Teipel, Stefan (Author) , Jessen, Frank (Author) , Düzel, Emrah (Author) , Gamez, Anna (Author) , Asperger, Hannah (Author) , Kimmich, Okka (Author) , Petzold, Gabor C. (Author) , Teichmann, Kennet (Author) , Bernsen, Sarah (Author) , Hill, Katharina (Author) , Willemse, Ilse (Author) , van Prooije, Teije (Author) , Erdlenbruch, Friedrich (Author) , Ernst, Thomas (Author) , Bender, Benjamin (Author) , Jende, Johann E. (Author) , Bushara, Khalaf (Author) , Manrique, Leire (Author) , Lallemant-Dudek, Pauline (Author) , Romanzetti, Sandro (Author) , Lange, Alexander (Author) , Shrestha, Maya (Author) , Ludwig, Anton (Author) , Rosenow, Alena (Author) , Elter, Tim (Author) , Santana, Magda M. (Author) , Pracht, Eberhard (Author) , Stoecker, Tony (Author)
Format: Article (Journal)
Language:English
Published: 23 December 2025
In: EBioMedicine
Year: 2026, Volume: 123, Pages: 1-13
ISSN:2352-3964
DOI:10.1016/j.ebiom.2025.106090
Online Access:Verlag, kostenfrei, Volltext: https://doi.org/10.1016/j.ebiom.2025.106090
Verlag, kostenfrei, Volltext: https://www.sciencedirect.com/science/article/pii/S2352396425005407
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Author Notes:Hannah Baumeister, Philipp Wegner, Mónica Ferreira, Tamara Schaprian, Marcondes C. França, Thiago Junqueira Ribeiro Rezende, Alberto Rolim Muro Martinez, Hong Jiang, Zhao Chen, Liao Weihua, Marcus Grobe-Einsler, Berkan Koyak, Demet Önder, Bart van de Warrenburg, Judith van Gaalen, Alexandra Durr, Giulia Coarelli, Matthis Synofzik, Ludger Schöls, Paola Giunti, Hector Garcia-Moreno, Gülin Öz, James Joers, Dagmar Timmann, Andreas G. Thieme, Heike Jacobi, Jeroen de Vries, Peter Barker, Chiadikaobi Onyike, Eva-Maria Ratai, Jeremy D. Schmahmann, Kathrin Reetz, Jon Infante, Jeannette Huebener-Schmid, David Kuegler, Thomas Klockgether, David Berron, and Jennifer Faber, on behalf of the DELCODE/DANCER, and ESMI MRI Study Groups
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Summary:Background - Spinocerebellar ataxia type 3 (SCA3) is characterised by progressive brain atrophy, with regional volume loss detectable via MRI prior to clinical manifestation. We aimed to identify the previously unknown sequence of brain atrophy in SCA3 and evaluate whether this sequence can be translated into an atrophy staging framework to enable accurate clinical prognosis and trial enrichment. - Methods - We included data from 322 SCA3 mutation carriers, enrolled in observational studies conducted across Europe, the Americas, and Asia. Participants underwent follow-up assessments up to five years after baseline. The Subtype and Stage Inference machine learning algorithm was applied to estimate the most likely atrophy sequence(s) from baseline anatomical MRI. The Scale for the Assessment and Rating of Ataxia (SARA) was used to capture ataxia severity. Atrophy stages were analysed in relation to SARA and time from disease onset. Interventional trials were simulated to estimate required sample sizes under different atrophy stage eligibility criteria. - Findings - We identified a uniform sequence of brain atrophy in SCA3, characterised by earliest volumetric decline in the caudal brainstem and substantial involvement of the white matter. Atrophy stage was associated with both SARA and time from disease onset. Atrophy staging outperformed single-region volumetrics in predicting SARA over time. Applying atrophy stage cut-offs substantially reduced the sample sizes needed to adequately power hypothetical clinical trials. - Interpretation - These findings yield mechanistic insights into the progression of neurodegeneration in SCA3 and possess immediate translational relevance, facilitating patient stratification and sample enrichment for interventional trials. - Funding - National Ataxia Foundation (NAF).
Item Description:Gesehen am 07.04.2026
Physical Description:Online Resource
ISSN:2352-3964
DOI:10.1016/j.ebiom.2025.106090

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