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author Faber, Jennifer
Berger, Moritz
Carlo, Wilke
Hübener-Schmid, Jeannette
Schaprian, Tamara
Santana, Magda M
Grobe-Einsler, Marcus
Onder, Dement
Koyak, Berkan
Giunti, Paola
Garcia-Moreno, Hector
Gonzalez-Robles, Cristina
Lima, Manuela
Raposo, Mafalda
Melo, Ana Rosa Vieira
de Almeida, Luis Pereira
Silva, Patrick
Pinto, Maria M
van de Warrenburg, Bart P.
van Gaalen, Judith
de Vries, Jeroen
Jeroen,
Oz, Gulin
Joers, James M.
Synofzik, Matthis
Schöls, Ludger
Riess, Olaf
Infante, Jon
Manrique, Leire
Timmann, Dagmar
Thieme, Andreas
Jacobi, Heike
Reetz, Kathrin
Dogan, Imis
Onyike, Chiadikaobi
Povazan, Michal
Schmahmann, Jeremy
Ratai, Eva-Maria
Schmid, Matthias
Klockgether, Thomas
author_facet Faber, Jennifer
Berger, Moritz
Carlo, Wilke
Hübener-Schmid, Jeannette
Schaprian, Tamara
Santana, Magda M
Grobe-Einsler, Marcus
Onder, Dement
Koyak, Berkan
Giunti, Paola
Garcia-Moreno, Hector
Gonzalez-Robles, Cristina
Lima, Manuela
Raposo, Mafalda
Melo, Ana Rosa Vieira
de Almeida, Luis Pereira
Silva, Patrick
Pinto, Maria M
van de Warrenburg, Bart P.
van Gaalen, Judith
de Vries, Jeroen
Jeroen,
Oz, Gulin
Joers, James M.
Synofzik, Matthis
Schöls, Ludger
Riess, Olaf
Infante, Jon
Manrique, Leire
Timmann, Dagmar
Thieme, Andreas
Jacobi, Heike
Reetz, Kathrin
Dogan, Imis
Onyike, Chiadikaobi
Povazan, Michal
Schmahmann, Jeremy
Ratai, Eva-Maria
Schmid, Matthias
Klockgether, Thomas
author_sort Faber, Jennifer
collection PubMed
description Spinocerebellar 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.
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spelling pubmed-101685032023-05-10 Stage-dependent biomarker changes in spinocerebellar ataxia type 3 Faber, Jennifer Berger, Moritz Carlo, Wilke Hübener-Schmid, Jeannette Schaprian, Tamara Santana, Magda M Grobe-Einsler, Marcus Onder, Dement Koyak, Berkan Giunti, Paola Garcia-Moreno, Hector Gonzalez-Robles, Cristina Lima, Manuela Raposo, Mafalda Melo, Ana Rosa Vieira de Almeida, Luis Pereira Silva, Patrick Pinto, Maria M van de Warrenburg, Bart P. van Gaalen, Judith de Vries, Jeroen Jeroen, Oz, Gulin Joers, James M. Synofzik, Matthis Schöls, Ludger Riess, Olaf Infante, Jon Manrique, Leire Timmann, Dagmar Thieme, Andreas Jacobi, Heike Reetz, Kathrin Dogan, Imis Onyike, Chiadikaobi Povazan, Michal Schmahmann, Jeremy Ratai, Eva-Maria Schmid, Matthias Klockgether, Thomas medRxiv Article Spinocerebellar 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. Cold Spring Harbor Laboratory 2023-04-25 /pmc/articles/PMC10168503/ /pubmed/37163081 http://dx.doi.org/10.1101/2023.04.21.23287817 Text en https://creativecommons.org/licenses/by-nc-nd/4.0/This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (https://creativecommons.org/licenses/by-nc-nd/4.0/) , which allows reusers to copy and distribute the material in any medium or format in unadapted form only, for noncommercial purposes only, and only so long as attribution is given to the creator.
spellingShingle Article
Faber, Jennifer
Berger, Moritz
Carlo, Wilke
Hübener-Schmid, Jeannette
Schaprian, Tamara
Santana, Magda M
Grobe-Einsler, Marcus
Onder, Dement
Koyak, Berkan
Giunti, Paola
Garcia-Moreno, Hector
Gonzalez-Robles, Cristina
Lima, Manuela
Raposo, Mafalda
Melo, Ana Rosa Vieira
de Almeida, Luis Pereira
Silva, Patrick
Pinto, Maria M
van de Warrenburg, Bart P.
van Gaalen, Judith
de Vries, Jeroen
Jeroen,
Oz, Gulin
Joers, James M.
Synofzik, Matthis
Schöls, Ludger
Riess, Olaf
Infante, Jon
Manrique, Leire
Timmann, Dagmar
Thieme, Andreas
Jacobi, Heike
Reetz, Kathrin
Dogan, Imis
Onyike, Chiadikaobi
Povazan, Michal
Schmahmann, Jeremy
Ratai, Eva-Maria
Schmid, Matthias
Klockgether, Thomas
Stage-dependent biomarker changes in spinocerebellar ataxia type 3
title Stage-dependent biomarker changes in spinocerebellar ataxia type 3
title_full Stage-dependent biomarker changes in spinocerebellar ataxia type 3
title_fullStr Stage-dependent biomarker changes in spinocerebellar ataxia type 3
title_full_unstemmed Stage-dependent biomarker changes in spinocerebellar ataxia type 3
title_short Stage-dependent biomarker changes in spinocerebellar ataxia type 3
title_sort stage-dependent biomarker changes in spinocerebellar ataxia type 3
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10168503/
https://www.ncbi.nlm.nih.gov/pubmed/37163081
http://dx.doi.org/10.1101/2023.04.21.23287817
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