280023 20260309111155.0 10.1016/j.lanepe.2025.101339 doi pmid:40678042 pmid pmc:PMC12270660 pmc altmetric:178874846 altmetric DZNE-2025-00867 English 610 Berger, Moritz 0 Progression of biological markers in spinocerebellar ataxia type 3: longitudinal analysis of prospective data from the ESMI cohort. [Amsterdam] 2025 Elsevier article DRIVER Output Types/Journal article DataCite Journal Article journal journal PUB:(DE-HGF)16 1755681458_25773 PUB:(DE-HGF) ARTICLE BibTeX JOURNAL_ARTICLE ORCID Journal Article 0 EndNote Spinocerebellar ataxia type 3 (SCA3) is an autosomal dominantly inherited adult-onset disease. We aimed to describe longitudinal changes in clinical and biological findings and to identify predictors for clinical progression.We used data from participants enrolled in the ESMI cohort collected between Nov 09, 2016 and July 18, 2023. The data freeze included data from 14 sites in five European countries and the United States. We assessed ataxia with the Scale for the Assessment and Rating of Ataxia (SARA). We measured disease-specific mutant ataxin-3 protein (ATXN3) and neurofilament light chain (NfL) in plasma and performed MRIs. Data were analysed by regression modelling on a timescale defined by onset. The onset of abnormality of a marker was defined as the time at which its value, as determined by modelling, exceeded the mean ± 2 SD of healthy controls. To study responsiveness of markers, we determined the sensitivity to change ratios (SCSs).Data from 291 SCA3 mutation carriers before and after clinical onset and 121 healthy controls were included. NfL levels became abnormal in SCA3 mutation carriers more than 20 years (-21.5 years [95% CI n.d.-9.5]) before onset. The earliest MRI abnormality was volume loss of medulla oblongata (-4.7 years [95% CI n.d.-3.3]). The responsiveness of markers depended on the disease stage. Across all stages, pons volume had the highest responsiveness with an SCS of 1.35 [95% CI 1.11-1.78] exceeding that of SARA (0.99 [95% CI 0.88-1.11]). In SCA3, lower age (p = 0.0459 [95% CI of slope change -0.0018 to 0.0000]) and lower medulla oblongata volume (p < 0.0001 [95% CI of slope change -0.0298 to -0.0115]) were predictors of SARA progression.Our study provides quantitative information on the progression of biological markers in SCA3 mutation carriers before and after onset of ataxia, and allowed the identification of predictors for clinical progression. Our data could prove useful for the design of future clinical trials.HEU Joint Programme - Neurodegenerative Disease Research (JPND) (Federal Ministry of Education and Research, Germany; The Netherlands Organisation for Health Research and Development; Foundation for Science and Technology, Portugal; Medical Research Council, Regional Fund for Science and Technology, Azores), and Servier. At the US sites this work was in part supported by the National Ataxia Foundation and the National Institute of Neurological Disorders and Stroke (NINDS) grant R01NS080816. 353 - Clinical and Health Care Research (POF4-353) G:(DE-HGF)POF4-353 POF4-353 POF IV 0 Dataset connected to CrossRef, PubMed, , Journals: pub.dzne.de ATXN3 Other Biomarker Other Disease modelling Other MRI Other NfL Other Spinocerebellar ataxia Other Staging model Other Garcia-Moreno, Hector 1 Ferreira, Mónica P:(DE-2719)9003289 2 dzne Hubener-Schmid, Jeannette 3 Schaprian, Tamara P:(DE-2719)2812594 4 dzne Wegner, Philipp P:(DE-2719)9002349 5 dzne Elter, Tim-Lukas P:(DE-2719)9001258 6 dzne Teichmann, Kennet M P:(DE-2719)9002253 7 dzne Santana, Magda M 8 Grobe-Einsler, Marcus P:(DE-2719)9001510 9 dzne Oender, Demet P:(DE-2719)9000685 10 dzne Koyak, Berkan S C P:(DE-2719)9001550 11 dzne Bernsen, Sarah P:(DE-2719)9000485 12 dzne Pereira de Almeida, Luís 13 Silva, Patrick 14 Ribeiro, Joana Afonso 15 Cunha, Inês 16 Gonzalez-Robles, Cristina 17 Khan, Shamsher 18 Heslegrave, Amanda 19 Zetterberg, Henrik 20 Lima, Manuela 21 Raposo, Mafalda 22 Ferreira, Ana F 23 Vasconcelos, João 24 van de Warrenburg, Bart P 25 van Gaalen, Judith 26 van Prooije, Teije H 27 de Vries, Jeroen 28 Schols, Ludger P:(DE-2719)2810795 29 dzne Riess, Olaf 30 Synofzik, Matthis P:(DE-2719)2811275 31 dzne Timmann, Dagmar 32 Thieme, Andreas 33 Erdlenbruch, Friedrich 34 Infante, Jon 35 Pelayo-Negro, Ana L 36 Manrique, Leire 37 Reetz, Kathrin 38 Dogan, Imis 39 Oz, Gulin 40 Joers, James M 41 Bushara, Khalafalla 42 Onyike, Chiadikaobi 43 Povazan, Michal 44 Jacobi, Heike 45 Schmahmann, Jeremy D 46 Ratai, Eva-Maria 47 Schmid, Matthias P:(DE-2719)2811245 48 dzne Giunti, Paola 49 Klockgether, Thomas P:(DE-2719)2810314 50 dzne Faber, Jennifer P:(DE-2719)2811327 51 Last author dzne 10.1016/j.lanepe.2025.101339 Vol. 55, p. 101339 - PERI:(DE-600)3055963-7 101339 The lancet / Regional health. 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