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Samenvatting
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Het doel van het project ‘PRODIA’’ is de patientenzorg te verbeteren. Dit willen we bereiken door nieuwe, specifieke biomarkers in hersenvloeistof voor verschillende vormen van dementie te ontwikkelen. Biomarkers zijn bijvoorbeeld eiwitten die voorkomen in lichaamsvloeistoffen zoals hersenvloeistof. Deze biomarkers komen vrij in het lichaam bij het aantreden van de ziekte. Verschillende ziekten heben eigen biomarkers nodig. Aan de hand van deze biomarkers kan sneller en nauwkeuriger een diagnose worden gesteld. Hiervoor maken we gebruik van resultaten uit al uitgevoerde studies om nieuwe biomarkers te ontdekken. We combineren resultaten die in hersenweefsel gevonden zijn met die in hersenvloeistof. Zo kunnen we biomarkers vinden die relevantie hebben voor het ziekteproces terwijl die ook in hersenvloeistof gemeten kunnen worden. Deze biomarkers zullen dan verder getest worden in hersenvloeistof van patienten met verschillende vormen van dementie. Een vroege diagnose heeft directe zin, om betere behandelingen te ontwikkelen en bij de juiste dementie patient toe te passen.

Resultaten
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Het doel in het tweede jaar van PRODIA was om immunoassays te ontwikkelen om nieuwe biomarkers te valideren. Deze biomarkers hebben we geselecteerd op basis van overlap in de resultaten verkregen in de proteomics studies in zowel weefsel als hersenvloeistof van Alzheimer patienten. De validatie is afgerond voor 1 nieuwe biomarker, en bijna gereed voor 5 andere markers. Voor 2 biomarkers hebben we hiervoor de Simoa ultragevoelige technologie gebruikt. Daarnaast zijn begonnen met de validatie van de markers in weefsel voor deze nieuwe markers.

Op dit moment worden de proteomics datasets in weefsel en hersenvloeistof van patienten met Frontotemporale dementia geintegreerd. Op basis van deze integratie kunnen we de 6 top kandidaat biomarkers selecteren die we vervolgens kunnen valideren.

 

Samenvatting van de aanvraag

Samenvatting
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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.

 

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