Aims

Background

Proteomics studies showed differential expression of numerous proteins in dementias, but have barely 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 implementation of novel biomarkers. We hypothesize that a major hurdle is the use of different technologies for discovery (mass spectrometry) compared to the technology for large scale validation (immunoassays). This problem might be overcome by using novel immune-based platforms for both discovery and validation (=no technology-switch). In this study we investigated this alternative development pipeline with the aim to identify and validate specific cerebrospinal fluid (CSF) biomarkers for frontotemporal dementia (FTD).

Methods

Method

We analysed >600 proteins using antibody-based Olink proteomics in 394 CSF samples from controls (n=195) and FTD patients (n=199, including 34 FTLD-Tau and 54 FTLD-TDP-subtypes). Nested (generalized) linear modeling was applied to define differences and diagnostic classification models.

Results

We identified >50 CSF proteins dysregulated in FTD and one between FTLD subtypes. We detected biomarker signatures for specific diagnosis of FTD (8-9 proteins, AUC>0.85), but not to discriminate FTLD subtypes. We next developed and successfully verified custom multiplex panels for these proteins, which are currently being clinically validated in independent cohorts.

Conclusions

The discovery and verification of the novel biomarker panels to identify FTD using immunoassays shows the effectiveness of the MIRIADE strategy. The pipeline could be used for the development of other biomarkers to improve the biological diagnosis and patient care for dementias.