Stage-dependent biomarker changes in spinocerebellar ataxia type 3

• DOI: 10.1101/2023.04.21.23287817
• Publication Date: 2023-04-25T18:05:43Z
• Authors: Jennifer Faber; Moritz Berger; Wilke Carlo; Jeannette Hübener...; Tamara Schaprian; Magda M Santana; Marcus Grobe-Einsler; Dement Onder; Berkan Koyak; Paola Giunti; Hector Garcia-Moreno; Cristina Gonzalez...; Manuela Lima; Mafalda Raposo; Ana Rosa Vieira Melo; Luís Pereira de A...; Patrick Silva; Maria M Pinto; Bart P. van de Wa...; Judith van Gaalen; Jeroen Jeroen de ...; Gulin Oz; James M. Joers; Matthis Synofzik; Ludger Schöls; Olaf Riess; Jon Infante; Leire Manrique; Dagmar Timmann; Andreas Thieme; Heike Jacobi; Kathrin Reetz; Imis Dogan; Chiadikaobi Onyike; Michal Povazan; Jeremy Schmahmann; Eva-Maria Ratai; Matthias Schmid; Thomas Klockgether
• Keywords: 570; Cerebellar Ataxia; Medizin; 610; Radboudumc 3: Disorders of movement DCMN: Donders Center for Medical Neuroscience; Article; 3. Good health; All institutes and research themes of the Radboud University Medical Center; Cross-Sectional Studies; genetics [Machado-Joseph Disease]; Humans; Ataxia; ddc:610; Biomarkers

AbstractSpinocerebellar ataxia type 3/Machado–Joseph disease (SCA3) is the most common autosomal dominant ataxia. In view of the development of targeted therapies for SCA3, precise knowledge of stage-dependent fluid and MRI biomarker changes is needed.We analyzed cross-sectional data of 292 SCA3 mutation carriers including 57 pre-ataxic individuals, and 108 healthy controls from the European Spinocerebellar ataxia type 3/Machado-Joseph Disease Initiative (ESMI) cohort. Blood concentrations of mutant ATXN3 and neurofilament light (NfL) were determined, and volumes of pons, cerebellar white matter (CWM) and cerebellar grey matter (CGM) were measured on MRI.Mutant ATXN3 concentrations were high before and after ataxia onset, while NfL continuously increased and deviated from normal 11.9 years before onset. Pons and CWM volumes decreased, but the deviation from normal was only 2.0 years (pons) and 0.3 years (CWM) before ataxia onset. We propose a staging model of SCA3 that includes an initial asymptomatic carrier stage followed by the biomarker stage defined by absence of ataxia, but a significant rise of NfL. The biomarker stage leads into the ataxia stage, defined by manifest ataxia.The present analysis provides a robust framework for further studies aiming at elaboration and differentiation of the staging model of SCA3.