PRODIA: Development of biomarkers enabling early and accurate differential diagnosis of dementia

Dementia is a threatening disease of the aging population, for which there currently is no cure available. Different forms of dementia exist, of which Alzheimer’s disease (AD) is the most prevalent, Frontotemporal dementia (FTD) is the second most prevalent in young patients (<60 years), and dementia with Lewy bodies (DLB) the second most prevalent among older patients. Currently, the clinical diagnosis of different types of dementia relies largely on documenting cognitive decline. However, early brain damage occurs already decades before the onset of clinical symptoms [1]. This opens a window of opportunity and urges for diagnosis and intervention at the earliest possible pathological stage, which is the focus of the current proposal. As the brain is inaccessible for taking a biopsy, there is a need for pathology-specific body fluid biomarkers to aid the early and differential diagnosis of various types of dementia. For example, biomarkers to correctly classify subtypes of dementia are needed to develop pathology- or disease-specific therapies. Biomarkers detecting the earliest stages of dementia will be helpful for early diagnosis, early intervention and for prediction of prognosis. This consortium has mapped changes in the proteome of ante-mortem cerebrospinal fluid (CSF) and post-mortem brain tissue of patients at different stages of Alzheimer’s and frontotemporal dementia. The unique and novel approach of PRODIA is that tissue and CSF proteomics results are integrated to select the most promising biomarker proteins for each specific dementia type. Initial data integration has yielded already four promising candidates based on these criteria. The overall aim of this project is to improve patient care by developing early CSF biomarkers for dementia subtypes with a proven relation to pathology. This aim has the following objectives: 1) Expansion and integration of the current proteomic databases for optimal candidate biomarker selection. We will expand the databases with tissue proteomics results of FTD patients. 2) Full development of immunoassays for 3 candidates in CSF. We will employ state-of-the-art and extremely sensitive technologies for a first test if the biomarkers can be measured in blood as well. 3) Clinical validation of candidate biomarkers (3 from WP2, plus 1 existing assays) in CSF of well-characterized, multi-center patient cohorts consisting of patients with different types of dementia. 4) We will establish the relation of the candidate biomarkers with the evolution progression of the specific disease pathology in-detail for each of the dementias. Therefore, we will study the expression of the validated candidate biomarkers from WPs1-3 in tissue of dementia patients and relevant controls. The consortium comprises researchers and industrial partners with strong and relevant expertise for this project, such as proven experience with brain and CSF proteomics, with full assay development for CNS biomarkers, and thorough assay and clinical validation. All patient samples are already available within strong local and (inter-)national biobanks. At the basis of PRODIA are existing tissue and CSF proteomics datasets, and their integration allows direct targeting of several dementia types and uniquely enables to generate the most specific biomarkers within one study is unprecedented. Importantly, PRODIA will generate a distinctive set of validated clinically applicable biomarkers for differential dementia diagnosis. Lastly, the outcome of this project will be unique in terms of drawing the proteomics landscape of dementia. Patients will benefit from the project by the improvement of diagnostic accuracy and increasing the chance of early treatment possibilities and therapy development, which directly improves patient care.