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@ARTICLE{Baumeister:284029,
author = {Baumeister, Hannah and Wegner, Philipp and Ferreira,
Mónica and Schaprian, Tamara and França, Marcondes C and
Rezende, Thiago Junqueira Ribeiro and Muro Martinez, Alberto
Rolim and Jiang, Hong and Chen, Zhao and Weihua, Liao and
Grobe-Einsler, Marcus and Koyak, Berkan and Önder, Demet
and van de Warrenburg, Bart and van Gaalen, Judith and Durr,
Alexandra and Coarelli, Giulia and Synofzik, Matthis and
Schöls, Ludger and Giunti, Paola and Garcia-Moreno, Hector
and Öz, Gülin and Joers, James and Timmann, Dagmar and
Thieme, Andreas G and Jacobi, Heike and de Vries, Jeroen and
Barker, Peter and Onyike, Chiadikaobi and Ratai, Eva-Maria
and Schmahmann, Jeremy D and Reetz, Kathrin and Infante, Jon
and Huebener-Schmid, Jeannette and Kuegler, David and
Klockgether, Thomas and Berron, David and Faber, Jennifer},
collaboration = {DELCODE/DANCER and Groups, ESMI MRI Study},
othercontributors = {Lüsebrink-Rindsland, Jann Falk Silvester and
HetzerBernsen, StefanSarah and Ewers, Michael and
Hellmann-Regen, Julian David Nicolai and Spruth, Eike Jakob
and Janowitz, Daniel and Kilimann, Ingo and Kronmüller,
Marie Theres and Spottke, Annika and Peters, Oliver and
Priller, Josef and Bürger, Katharina and Teipel, Stefan and
Jessen, Frank and Düzel, Emrah and Gamez, Anna and
Asperger, Hannah and Kimmich, Okka and Petzold, Gabor C and
Pracht, Eberhard and Stöcker, Tony},
title = {{B}rain atrophy staging in spinocerebellar ataxia type 3
for clinical prognosis and trial enrichment.},
journal = {EBioMedicine},
volume = {123},
issn = {2352-3964},
address = {Amsterdam [u.a.]},
publisher = {Elsevier},
reportid = {DZNE-2026-00072},
pages = {106090},
year = {2026},
abstract = {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.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.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.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.National Ataxia Foundation (NAF).},
keywords = {Humans / Atrophy / Machado-Joseph Disease: pathology /
Machado-Joseph Disease: diagnosis / Machado-Joseph Disease:
genetics / Machado-Joseph Disease: diagnostic imaging /
Prognosis / Male / Magnetic Resonance Imaging / Brain:
pathology / Brain: diagnostic imaging / Female / Middle Aged
/ Adult / Disease Progression / Severity of Illness Index /
Aged / Ataxia (Other) / Disease progression modelling
(Other) / Imaging biomarker (Other) / Machine learning
(Other) / Movement disorders (Other)},
cin = {Clinical Research (Bonn) / AG Berron / Clinical Research
Platform (CRP) / AG Radbruch / AG Spottke / AG Gasser / AG
Schöls / AG Reuter / Patient Studies (Bonn)},
ddc = {610},
cid = {I:(DE-2719)1011001 / I:(DE-2719)5000070 /
I:(DE-2719)1011401 / I:(DE-2719)5000075 / I:(DE-2719)1011103
/ I:(DE-2719)1210000 / I:(DE-2719)5000005 /
I:(DE-2719)1040310 / I:(DE-2719)1011101},
pnm = {353 - Clinical and Health Care Research (POF4-353) / 354 -
Disease Prevention and Healthy Aging (POF4-354)},
pid = {G:(DE-HGF)POF4-353 / G:(DE-HGF)POF4-354},
experiment = {EXP:(DE-2719)DELCODE-20140101 /
EXP:(DE-2719)DANCER-20150101 / EXP:(DE-2719)ESMI-20140101},
typ = {PUB:(DE-HGF)16},
pubmed = {pmid:41443080},
pmc = {pmc:PMC12800623},
doi = {10.1016/j.ebiom.2025.106090},
url = {https://pub.dzne.de/record/284029},
}