Regional Brain Loss in NMR as a biomarker of SCA3-type dominant ataxia

26 de July de 2021

Researchers from the hereditary ataxias and paraplegias CSUR os the University Hospital Marques de Valdecilla and IDIVAL´s neurodegenerative diseases group led by Dr. Jon Infante, participate in a European multicenter study designed to identify preclinical and progression biomarkers in the most common form of autosomal dominant cerebellar ataxia, SCA3. The identification of precise, reliable and easily accessible biomarkers is one of the necessary requirements for the development of clinical trials with the best guarantees of success. This study published in the journal Movement Disorders.

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. 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. On this study, it was 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.

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. In 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.

For more than two decades, the hereditary ataxias and paraplegias CSUR os the University Hospital Marques de Valdecilla and IDIVAL´s neurodegenerative diseases group have been part of a European consortium that seeks to define the natural history of autosomal dominant cerebellar ataxias, as well as to build cohorts prepared for spawning. ongoing clinical trials. Within the framework of this consortium, various European projects (EUROSCA, RISCA, ESMI) have been financed, with the participation of HUMV-IDIVAL. The current project is part of the ESMI study (European Spinocerebellar ataxia type3 / Machado-Joseph disease initiativa), EU Joint Program – Neurodegenerative Disease Research (JPND).

Referencia: Faber J, Schaprian T, Berkan K, Reetz K, França MC Jr, de Rezende TJR, Hong J, Liao W, van de Warrenburg B, van Gaalen J, Durr A, Mochel F, Giunti P, Garcia-Moreno H, Schoels L, Hengel H, Synofzik M, Bender B, Oz G, Joers J, de Vries JJ, Kang JS, Timmann-Braun D, Jacobi H, Infante J, Joules R, Romanzetti S, Diedrichsen J, Schmid M, Wolz R, Klockgether T. Regional Brain and Spinal Cord Volume Loss in Spinocerebellar Ataxia Type 3. Mov Disord. 2021 May 5. doi: 10.1002/mds.28610. Epub ahead of print. PMID: 33951232.