Multi-Omics Interdisciplinary Research Integration to Accelerate Dementia Biomarker Development (MIRIADE)

Abstract

Proteomics studies have shown differential expression of numerous proteins in dementias but have rarely led to novel biomarker tests for clinical use. The Marie Curie MIRIADE project is designed to experimentally evaluate development strategies to accelerate the validation and ultimate implementation of novel biomarkers in clinical practice, using proteomics-based biomarker development for main dementias as experimental case studies. We address several knowledge gaps that have been identified in the field. First, there is the technology-translation gap of different technologies for the discovery (e.g., mass spectrometry) and the large-scale validation (e.g., immunoassays) of biomarkers. In addition, there is a limited understanding of conformational states of biomarker proteins in different matrices, which affect the selection of reagents for assay development. In this review, we aim to understand the decisions taken in the initial steps of biomarker development, which is done via an interim narrative update of the work of each ESR subproject. The results describe the decision process to shortlist biomarkers from a proteomics to develop immunoassays or mass spectrometry assays for Alzheimer's disease, Lewy body dementia, and frontotemporal dementia. In addition, we explain the approach to prepare the market implementation of novel biomarkers and assays. Moreover, we describe the development of computational protein state and interaction prediction models to support biomarker development, such as the prediction of epitopes. Lastly, we reflect upon activities involved in the biomarker development process to deduce a best-practice roadmap for biomarker development.

Harmonization and standardization of biofluid‐based biomarker measurements for AT(N) classification in Alzheimer's disease

“…Even though the validation of a candidate RMP is still in progress, antibody‐free and immunoprecipitation‐based strategies have been developed to reach the required sensitivity for the detection of NfL in clinical CSF samples. This work has also been supported by the MIRIADE consortium 76 . Nonetheless, there is a strong need for the development of an MS‐based candidate RMP method to be used to assign values to potential CRMs and establish a correlation with immunoassays.…”

Bioinformatics tools and data resources for assay development of fluid protein biomarkers

“…Novel biomarker development is a long and multidisciplinary process that consists of biomarker discovery, qualification, verification and clinical validation [16,17].…”

Thimet oligopeptidase as a potential CSF biomarker for Alzheimer's disease: A cross‐platform validation study

“…Although MS identifies peptides from trypsinized proteins, antibody‐based technologies detect proteins in their native conformation, which may explain to some extent the cross‐technology translational gap often encountered in biomarker studies 8 . The emergence of antibody‐based proteomics platforms (e.g., proximity extension assays; PEA technology) together with the use of more sensitive and automated immunoassay‐based technologies may smoothen the development of optimal immunoassays for high‐throughput screening and facilitate the validation and ultimately clinical implementation of fluid biomarkers 7,8,16–19 …”

“…Unraveling novel fluid biomarkers is a long and multidisciplinary process including many phases, starting from biomarker discovery, followed by analytical (including immunoassay development) and clinical validation, and finally, by implementation in clinical settings 7–10 . To date, unbiased mass spectrometry (MS) proteomics discovery studies have uncovered numerous CSF biomarker candidates 11–13 .…”