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)
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.
Organisations
- University College London (Lead Research Organisation)
- Eberhard Karls University of Tübingen (Collaboration)
- University of Coimbra (Collaboration)
- Mayo Clinic (Collaboration)
- Radboud University Nijmegen (Collaboration)
- German Centre for Neurodegenerative Diseases (Collaboration)
- University of Azores (Collaboration)
People |
ORCID iD |
Paola Giunti (Principal Investigator) |
Publications
Afonso Ribeiro J
(2021)
Lower urinary tract and bowel dysfunction in spinocerebellar ataxias.
in Annals of clinical and translational neurology
Brown AF
(2021)
Friedreich's Ataxia Frequency in a Large Cohort of Genetically Undetermined Ataxia Patients.
in Frontiers in neurology
Faber J
(2021)
Regional Brain and Spinal Cord Volume Loss in Spinocerebellar Ataxia Type 3.
in Movement disorders : official journal of the Movement Disorder Society
Faber J
(2024)
Stage-Dependent Biomarker Changes in Spinocerebellar Ataxia Type 3.
in Annals of neurology
Garcia-Moreno H
(2022)
Tau and neurofilament light-chain as fluid biomarkers in spinocerebellar ataxia type 3.
in European journal of neurology
Garcia-Moreno H
(2023)
Neurological disease in xeroderma pigmentosum: prospective cohort study of its features and progression.
in Brain : a journal of neurology
Hengel H
(2022)
Characterization of Lifestyle in Spinocerebellar Ataxia Type 3 and Association with Disease Severity.
in Movement disorders : official journal of the Movement Disorder Society
Hengel H
(2024)
Correction to: The frequency of non-motor symptoms in SCA3 and their association with disease severity and lifestyle factors.
in Journal of neurology
Hübener-Schmid J
(2021)
Polyglutamine-Expanded Ataxin-3: A Target Engagement Marker for Spinocerebellar Ataxia Type 3 in Peripheral Blood.
in Movement disorders : official journal of the Movement Disorder Society
Morris S
(2023)
Impact of specialist ataxia centres on health service resource utilisation and costs across Europe: cross-sectional survey
in Orphanet Journal of Rare Diseases
Motamed-Gorji N
(2024)
Elevated Bile Acid 3ß,5a,6ß-Trihydroxycholanoyl Glycine in a Subset of Adult Ataxias Including Niemann-Pick Type C
in Antioxidants
Nethisinghe S
(2021)
Hsp90 Inhibition: A Promising Therapeutic Approach for ARSACS.
in International journal of molecular sciences
Nethisinghe S
(2021)
Interruptions of the FXN GAA Repeat Tract Delay the Age at Onset of Friedreich's Ataxia in a Location Dependent Manner.
in International journal of molecular sciences
Pellerin D
(2024)
Intronic FGF14 GAA repeat expansions are a common cause of ataxia syndromes with neuropathy and bilateral vestibulopathy
in Journal of Neurology, Neurosurgery & Psychiatry
Prudencio M
(2020)
Toward allele-specific targeting therapy and pharmacodynamic marker for spinocerebellar ataxia type 3.
in Science translational medicine
Santana M
(2023)
A standardised protocol for blood and cerebrospinal fluid collection and processing for biomarker research in ataxia
in Neuropathology and Applied Neurobiology
Thomas-Black G
(2022)
The attitude of patients with progressive ataxias towards clinical trials.
in Orphanet journal of rare diseases
Vallortigara J
(2023)
Patient pathways for rare diseases in Europe: ataxia as an example
in Orphanet Journal of Rare Diseases
Wilke C
(2020)
Neurofilaments in spinocerebellar ataxia type 3: blood biomarkers at the preataxic and ataxic stage in humans and mice.
in EMBO molecular medicine
Yau WY
(2020)
The repeat variant in MSH3 is not a genetic modifier for spinocerebellar ataxia type 3 and Friedreich's ataxia.
in Brain : a journal of neurology
Zeitlberger A
(2018)
Advances in the understanding of hereditary ataxia - implications for future patients
in Expert Opinion on Orphan Drugs
Zeitlberger AM
(2018)
Plasma Markers of Neurodegeneration Are Raised in Friedreich's Ataxia.
in Frontiers in cellular neuroscience
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 | MSD-ECL assay |
Description | MSD-ECL Ataxin-3 assay to measure ataxin-3 levels in plasma and CSF |
Type Of Material | Technology assay or reagent |
Year Produced | 2020 |
Provided To Others? | Yes |
Impact | Potential use of ataxin-3 as target engagement biomarker in future clinical trials. |
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 Tübingen |
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 | MSD-ECL Ataxin-3 assay development |
Organisation | Mayo Clinic |
Department | Department of Neuroscience |
Country | United States |
Sector | Hospitals |
PI Contribution | -Plasma and CSF samples from human subjects. -Data analysis. -Review of manuscript. |
Collaborator Contribution | -Development of Ataxia-3 assay. -Plasma and CSF samples from human subjects. -Data analysis. -Drafting of the manuscript. |
Impact | -MSD-ECL Ataxin-3 assay. -Article in Science Translational Medicine. |
Start Year | 2019 |
Title | MSD-ECL Ataxin-3 |
Description | The MSD-ECL Ataxin-3 assay allows the quantification of ataxin-3 levels in plasma and CSF. |
Type | Support Tool - For Fundamental Research |
Current Stage Of Development | Early clinical assessment |
Year Development Stage Completed | 2020 |
Development Status | Under active development/distribution |
Impact | Potential use of ataxin-3 as a target engagement biomarker in future clinical trials. |
Title | Neurology 4-Plex A |
Description | The Neurology 4-Plex A assay allows the simultaneous quantification of tau, neurofilament light-chain, glial fibrillary acidic protein and ubiquitin carboxy-terminal hydrolase L1 in biological fluids. So far, tau and neurofilament light-chain seem promising biomarkers. |
Type | Support Tool - For Fundamental Research |
Current Stage Of Development | Early clinical assessment |
Year Development Stage Completed | 2020 |
Development Status | Under active development/distribution |
Impact | Potential development of progression biomarkers in SCA3. |
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 |
Description | Press release Ataxia-3 |
Form Of Engagement Activity | A press release, press conference or response to a media enquiry/interview |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Public/other audiences |
Results and Impact | Press release regarding the publication of the results from the MSD-ECL Ataxia-3 assay in the journal Science Translational Medicine. The article was published through UCL and Ataxia UK websites and disseminated to other researchers and patients. |
Year(s) Of Engagement Activity | 2020 |
Description | SCA3 biomarkers |
Form Of Engagement Activity | A magazine, newsletter or online publication |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Patients, carers and/or patient groups |
Results and Impact | https://www.ucl.ac.uk/ion/news/2022/jun/identification-sca3-biomarkers-interview-dr-hector-garcia-moreno |
Year(s) Of Engagement Activity | 2022 |