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

Lead Research Organisation: University College London
Department Name: Institute of Neurology

Abstract

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.

Technical Summary

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)

Planned Impact

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.

Publications

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Title ESMI MRI atlas 
Description Complete database propagation based on a cerebellar atlas has been achieved and quality control database propagations have been carried out. A working instance of the segmentation algorithm (WB LEAP) is capable of providing whole brain segmentation including cerebellum sub-divisions. Retrospective MRI data has been segmented with the modified WB LEAP for optimization reference. As next steps, the WB LEAP pipeline will be optimized for cerebellar segmentations, and the resulting optimized pipeline will be applied to analyse the retrospective imaging data within ESMI. 
Type Of Material Model of mechanisms or symptoms - human 
Year Produced 2018 
Provided To Others? No  
Impact Segmentation and analysis of MRI from patients with cerebellar ataxia. 
 
Title ESMI blood and CSF biomarkers 
Description Neurofilament Light Chain (NfL) has recently been suggested as a promising diagnostic, progression and therapeutic efficacy biomarker in several neurodegenerative diseases (Zetterberg H. Neuron, 91(1):1-3; 2016). As part of WP4, NfL levels will be quantified in plasma and serum samples from ESMI patients and controls by two different assays using the SIMOA technology in order to investigate its potential as biomarker for SCA3. Additionally, other proteins implicated in neurodegeneration will also be quantified: Tau, GFAP and UCHL-1 in plasma samples, and pNfH in serum samples. Levels of these proteins will be correlated with clinical data and imaging. 
Type Of Material Biological samples 
Year Produced 2018 
Provided To Others? No  
Impact Describing new blood and CSF biomarkers which can track the evolution of SCA 3. 
 
Title MRI analysis 
Description ESMI MRI scans have been carried out at all sites participating in the prospective MRI study within ESMI (Bonn, London and Nijmegen; associated partners Aachen, Essen and Groningen). In addition Heidelberg will participate in the prospective MRI study as associated partner. Quality assurance scans have already been performed in Aachen and collection of in vivo data will start soon. Overall, 96 MRI scans have been obtained within the ESMI project by the end of 2018. 78 of these are from SCA3 subjects and 18 from control subjects. Quality assurance has demonstrated excellent data quality, allowing for cross-site analyses on various parameters. 
Type Of Material Physiological assessment or outcome measure 
Year Produced 2019 
Provided To Others? No  
Impact Characterisation of novel biomarkers in SCA3 
 
Title Neurology 4-PLEX A kit 
Description Commercial kit that have been tested in the samples from this study 
Type Of Material Technology assay or reagent 
Year Produced 2018 
Provided To Others? Yes  
Impact Potential to characterise blood and CSF biomarker 
 
Title ESMI database 
Description Development of the ESMI database has been completed successfully and the database has been in full operational use since the end of April 2017. Integration of data from existing databases with the new ESMI database was enabled in November 2017. Thus, for all ESMI subjects who previously participated in other studies, data collected within the framework of ESMI gets linked with existing data from previous studies. 
Type Of Material Database/Collection of data 
Year Produced 2017 
Provided To Others? No  
Impact This database will allow to include patients with different types of cerebellar ataxia in a common research database. 
 
Description ESMI collaborations 2018 
Organisation Eberhard Karls University of Tubingen
Country Germany 
Sector Academic/University 
PI Contribution The ESMI consortium held its annual meeting on 22/23 May 2017 in Coimbra, Portugal. We provided an update of the project stage in our site.
Collaborator Contribution In between face-to-face meetings the ESMI Executive Board has held monthly conference calls to discuss project progress, content-related aspects and administrative issues. The next face-to-face consortium meeting is planned for May 2018.
Impact -New biochemical disease markers.
Start Year 2016
 
Description ESMI collaborations 2018 
Organisation German Centre for Neurodegenerative Diseases
Country Germany 
Sector Public 
PI Contribution The ESMI consortium held its annual meeting on 22/23 May 2017 in Coimbra, Portugal. We provided an update of the project stage in our site.
Collaborator Contribution In between face-to-face meetings the ESMI Executive Board has held monthly conference calls to discuss project progress, content-related aspects and administrative issues. The next face-to-face consortium meeting is planned for May 2018.
Impact -New biochemical disease markers.
Start Year 2016
 
Description ESMI collaborations 2018 
Organisation Radboud University Nijmegen
Country Netherlands 
Sector Academic/University 
PI Contribution The ESMI consortium held its annual meeting on 22/23 May 2017 in Coimbra, Portugal. We provided an update of the project stage in our site.
Collaborator Contribution In between face-to-face meetings the ESMI Executive Board has held monthly conference calls to discuss project progress, content-related aspects and administrative issues. The next face-to-face consortium meeting is planned for May 2018.
Impact -New biochemical disease markers.
Start Year 2016
 
Description ESMI collaborations 2018 
Organisation University of Azores
Country Portugal 
Sector Academic/University 
PI Contribution The ESMI consortium held its annual meeting on 22/23 May 2017 in Coimbra, Portugal. We provided an update of the project stage in our site.
Collaborator Contribution In between face-to-face meetings the ESMI Executive Board has held monthly conference calls to discuss project progress, content-related aspects and administrative issues. The next face-to-face consortium meeting is planned for May 2018.
Impact -New biochemical disease markers.
Start Year 2016
 
Description ESMI collaborations 2018 
Organisation University of Coimbra
Country Portugal 
Sector Academic/University 
PI Contribution The ESMI consortium held its annual meeting on 22/23 May 2017 in Coimbra, Portugal. We provided an update of the project stage in our site.
Collaborator Contribution In between face-to-face meetings the ESMI Executive Board has held monthly conference calls to discuss project progress, content-related aspects and administrative issues. The next face-to-face consortium meeting is planned for May 2018.
Impact -New biochemical disease markers.
Start Year 2016
 
Description Ataxia UK presented the ESMI project at their Ataxia UK patient conference in October 2018 and published an article about the ESMI consortium meeting in the autumn edition of their Ataxia Magazine. 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Patients, carers and/or patient groups
Results and Impact Some participants contacted the research team after this activity
Year(s) Of Engagement Activity 2018