Abstract
BACKGROUND: Given that new therapeutic options for spinocerebellar ataxias are on the horizon, there is a need for markers that reflect disease-related alterations, in particular, in the preataxic stage, in which clinical scales are lacking sensitivity.
OBJECTIVE: The objective of this study was to quantify regional brain volumes and upper cervical spinal cord areas in spinocerebellar ataxia type 3 in vivo across the entire time course of the disease.
METHODS: We applied a brain segmentation approach that included a lobular subsegmentation of the cerebellum to magnetic resonance images of 210 ataxic and 48 preataxic spinocerebellar ataxia type 3 mutation carriers and 63 healthy controls. In addition, cervical cord cross-sectional areas were determined at 2 levels.
RESULTS: The metrics of cervical spinal cord segments C3 and C2, medulla oblongata, pons, and pallidum, and the cerebellar anterior lobe were reduced in preataxic mutation carriers compared with controls. Those of cervical spinal cord segments C2 and C3, medulla oblongata, pons, midbrain, cerebellar lobules crus II and X, cerebellar white matter, and pallidum were reduced in ataxic compared with nonataxic carriers. Of all metrics studied, pontine volume showed the steepest decline across the disease course. It covaried with ataxia severity, CAG repeat length, and age. The multivariate model derived from this analysis explained 46.33% of the variance of pontine volume.
CONCLUSION: Regional brain and spinal cord tissue loss in spinocerebellar ataxia type 3 starts before ataxia onset. Pontine volume appears to be the most promising imaging biomarker candidate for interventional trials that aim at slowing the progression of spinocerebellar ataxia type 3. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 2273-2281 |
| Number of pages | 9 |
| Journal | Movement Disorders |
| Volume | 36 |
| Issue number | 10 |
| Early online date | May 5 2021 |
| DOIs | |
| State | Published - Oct 2021 |
Bibliographical note
Funding Information:K.R.: received grants from the German Federal Ministry of Education and Research (BMBF 01GQ1402, 01DN18022), the German Research Foundation (IRTG 2150), and Alzheimer Forschung Initiative e.V. (NL‐18002CB) and honoraria for presentations or advisory boards from Biogen and Roche.
Funding Information:
D.T.‐B.: received funding from the Deutsche Forschungsgemeinschaft (DFG), DHAG, and Bernd Fink Foundation.
Funding Information:
.C.F. was supported by grants from Brazilian governmental agencies (CNPq and FAPESP). B.v.W. received funding from ZonMW, EU Joint Programme — Neurodegenerative Disease Research (JPND) project, was supported under the aegis of JPND through funding from the Netherlands Organisation for Health Research and Development. A.D. received BIOSCA NCT01470729 sponsorship from Assistance Publique — Hôpitaux de Paris. P.G. received support from the EU Joint Programme — Neurodegenerative Disease Research (JPND) project and was supported under the aegis of JPND through funding from the Medical Research Council. H.G.‐M. received a JPND grant rom the Medical Research Council and support from CureSCA3 and Fathers Foundation. L.S. received support from the EU Joint Programme ‐ Neurodegenerative Disease Research (JPND) project and support under the aegis of JPND through the Federal Ministry of Education and Research (BMBF; funding codes 01ED1602A/B). G.O. — the study was in part funded by the National Ataxia Foundation. The Center for Magnetic Resonance Research is supported by the National Institute of Biomedical Imaging and Bioengineering (NIBIB) grant P41 EB027061 and the Institutional Center Cores for Advanced Neuroimaging award P30 NS076408. R.J. is a paid employee of IXICO Plc, contracted to undertake this work. The involvement of R.W. was funded by IXICO. T.K. received support from the EU Joint Programme — Neurodegenerative Disease Research (JPND) project and under the aegis of JPND through the Federal Ministry of Education and Research (BMBF; funding codes 01ED1602A/B). Relevant conflicts of interest/financial disclosures: M
Funding Information:
M.C.F. Jr: received research grants from PTC and Pfizer; took part in advisory boards for Biogen, Avexis and PTC.
Funding Information:
J.F.: received funding from the National Ataxia Foundation and as a fellow of the Hertie Academy for Clinical Neuroscience.
Funding Information:
A.D.: receiving grants from the National Institut of Health (RO1), French National Hospital Clinical Research Program (PHRC), Agence National de Recherche (ANR), Triplet Therapeutics, Biogen, Minoryx Therapeutics, Roche, and Verum; serves on the advisory boards of Triplet Therapeutics and Minoryx Therapeutics.
Funding Information:
G.O.: grants from National Institutes of Health, National Ataxia Foundation, Biogen, Inc.; consultancies for uniQure biopharma B.V., IXICO Technologies Limited.
Funding Information:
J.v.G.: supported by an Edmond J. Safra movement disorders fellowship (Michael J. Fox Foundation).
Funding Information:
H.G.‐M.: Medical Research Council (JPND grant), CureSCA3, and Fathers Foundation.
Funding Information:
J.F.: received funding from the National Ataxia Foundation and as a fellow of the Hertie Academy for Clinical Neuroscience. T.S.: none. K.B.: none. K.R.: received grants from the German Federal Ministry of Education and Research (BMBF 01GQ1402, 01DN18022), the German Research Foundation (IRTG 2150), and Alzheimer Forschung Initiative e.V. (NL-18002CB) and honoraria for presentations or advisory boards from Biogen and Roche. M.C.F. Jr: received research grants from PTC and Pfizer; took part in advisory boards for Biogen, Avexis and PTC. T.JR.R.: none. J.H.: none. W.L.: none. B.v.W.: Gossweiler Foundation, uniQure, ZonMW, Hersenstichting, Radboud University Medical Centre grants, Uniqure (consultancy). J.v.G.: supported by an Edmond J. Safra movement disorders fellowship (Michael J. Fox Foundation). A.D.: receiving grants from the National Institut of Health (RO1), French National Hospital Clinical Research Program (PHRC), Agence National de Recherche (ANR), Triplet Therapeutics, Biogen, Minoryx Therapeutics, Roche, and Verum; serves on the advisory boards of Triplet Therapeutics and Minoryx Therapeutics. F.M.: none. P.G.: none. H.G.-M.: Medical Research Council (JPND grant), CureSCA3, and Fathers Foundation. L.S.: EU — ERN-RND registry (grant 947588); E-rare/BMBF — Treat-Ion (grant 01GM1907A); E-rare/BMBF — TreatHSP (grant 01GM1905A); Innovationsfond — ZSE-DUO (grant 01NVF17031); Innovationsfond — Translate NAMSE (grant 01NVF16024). H.H.: receives support from the intramural fortüne program of the Medical Faculty of the University of Tübingen (grant 2554-0-0). M.S.: consultancy honoraria from Orphazyme Pharmaceuticals unrelated to this project. B.B.: Cofounder and shareholder of AIRAmed GmbH. G.O.: grants from National Institutes of Health, National Ataxia Foundation, Biogen, Inc.; consultancies for uniQure biopharma B.V., IXICO Technologies Limited. J.J.: none. J.J.d.V.: none. J.-S.K.: none. D.T.-B.: received funding from the Deutsche Forschungsgemeinschaft (DFG), DHAG, and Bernd Fink Foundation. H.J.: none. J.I.: honoraria as speaker from Zambon and Exeltys. R.J.: Paid employee of IXICO Plc. S.R.: none. J.D.: none. M. Schmid: none. R.W.: employee and shareholder of IXICO. RW holds IP rights and has received royalties in relation to the LEAP technology. T.K.: research support from the Deutsche Forschungsgemeinschaft (DFG), the Bundesministerium für Bildung und Forschung (BMBF), the Bundesministerium für Gesundheit (BMG), the Robert Bosch Foundation, the European Union (EU), and the National Institutes of Health (NIH); has received consulting fees from Biohaven, Roche, UBC, Uniqure, and Vico Therapeutics; has received speaker honoraria from Novartis and Bayer.
Funding Information:
This publication is an outcome of ESMI, an EU Joint Programme ‐ Neurodegenerative Disease Research (JPND) project (see www.jpnd.eu ). The project is supported under the aegis of JPND through the following funding organizations: Germany, Federal Ministry of Education and Research (BMBF; funding codes 01ED1602A/B); Netherlands, The Netherlands Organisation for Health Research and Development; Portugal, Foundation for Science and Technology and Regional Fund for Science and Technology of the Azores; United Kingdom, Medical Research Council. This project has received funding from the European Union's Horizon 2020 research and innovation program under grant agreement 643417. 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 R01 NS080816. The Center for Magnetic Resonance Research is supported by the National Institute of Biomedical Imaging and Bioengineering (NIBIB) grant P41 EB027061, and the Institutional Center Cores for Advanced Neuroimaging award P30 NS076408 and S10 OD017974 grant. Funding agencies:
Publisher Copyright:
© 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society
Keywords
- MRI
- biomarker
- spinocerebellar ataxia
- volumetry