JPND European Spinocerebellar Ataxia Type 3/Machado-Joseph Disease Initiative

Spinocerebellar ataxia type 3/Machado-Joseph disease (SCA3) is worldwide the most common autosomal dominantly inherited ataxia disorder. It is caused by expansion of polyglutamine encoding CAG repeats in the ATXN3 gene. Currently, there is no treatment for SCA3. However, as there is an advanced understanding of the molecular mechanisms underlying SCA3, new therapeutic approaches are being developed, and the SCA3 field is entering a phase of intense trial activity. To enable interventional trials, availability of large cohorts that consist of preclinical mutation carriers and mildly affected patients is mandatory. For this purpose, the European Spinocerebellar Ataxia Type 3/Machado-Joseph Disease Initiative (ESMI) will set up a trial ready cohort by bringing together 7 European cohorts and 1 US cohort, which together comprise more than 800 subjects. We will integrate the existing data in a common database and apply standardized and quality-controlled clinical assessment, MRI and biobanking protocols. A major part of our initiative will be the development and validation of innovative assessment instruments and disease markers, including a new highly sensitive motor test battery, ambulatory sensor-based activity measurement, automated MRI volumetric evaluation, diffusion tensor imaging (DTI), and blood as well as CSF markers based on transcript profiling and disease protein (ataxin-3) measurement. In addition, we will assess the impact of lifestyle on disease evolution by appropriate questionnaires. By exploiting the data obtained in this cohort, we will develop a revised model of SCA3 disease evolution that conceives the preclinical (pre-ataxia) stage and the ataxia stage as the graded manifestation of one disease process, and that will take lifestyle factors into account. Our research directly impacts not only on feasibility and design of interventional trials, but also on routine health care because the new instruments, such as automated activity measurement and MRI analysis, can be used in diagnosis and routine management of ataxia patients. The European and national ataxia patient organizations are directly involved in the planning and management of this project.

Imaging (P. Giunti, UCL) Our EUROSCA data suggest that brainstem, cerebellar and basal ganglia volumes measured by MRI are more sensitive markers of disease progression than clinical scales [Reetz et al. 2013]. To validate this, we will apply an automated brain segmentation pipeline, Learning Embeddings for Atlas Propagation (LEAP), developed by IXICO (London, UK) [Wolz et al. 2010]. LEAP is currently used for hippocampus segmentation where it performs robustly across different imaging platforms and MRI field strengths as well as across morphological variations found in healthy subjects and patients. The method is integrated into the regulatory approved medical device Assessa to provide automated segmentation of brain structures and was used as an exemplar method for the qualification of low hippocampal volume as enrichment biomarker in clinical trials in Alzheimer's disease with the European Medicines Agency. LEAP has been successfully applied to segmenting the brain into 134 structures including the ones relevant for SCA3. To adapt the method for the specific needs of SCA3 research, we will subcontract IXICO. In a first step, existing MRI data will be used to further optimize the automated segmentation technique. In a second step, the optimized method will be applied to the prospectively collected MRIs. Findings will be compared to matched controls of the Assessa database.
Recent diffusion tensor imaging (DTI) studies detected widespread microstructural white matter pathology in the cerebellum, brainstem, and additional brain regions suggesting that DTI can be used as a highly sensitive MRI biomarker [Guimaraes et al. 2013]. We will therefore include DTI in our MRI protocol. Data will be analysed with tract-based spatial statistics (TBSS). We will put particular emphasis on studying whether white matter abnormalities can be detected in preclinical mutation carriers. We will collect also biomaterial for the establishment of biomarkers (Human Biol. sample section)

The research will have direct impact on health care, as novel instruments, such as automated activity measurements and brain morphometric analysis, can be used in routine management of ataxia patients.