Research Program

Aims of the CAVIA project

The overall aim of this project is to further develop and validate biochemical and neuroimaging methods to provide effective diagnostic tools that will allow detection of CAA during life, to establish the contribution of CAA to cognitive decline and dementia and to facilitate potential future personalized therapy. Target populations comprise patients with memory complaints of uncertain cause but also more advanced cases where identification of the cause of disease may direct therapeutic interventions.

Workpackage 1. Body fluid biomarkers of CAA.

The aims of this work-package are:
1.    Identification of a signature profile of Aβ peptides in CSF that reflects the pathological development of CAA.
a.    Unbiased identification of Aβ peptides specifically associated with CAA
b.    Targeted analysis of Aβ peptides with known specificity for CAA

2.    Identification of novel, non-Aβ, protein biomarkers in body fluids (especially CSF) related to vascular activation and functional disturbances of the blood-brain barrier function in CAA.
3.    Identify which CSF biomarkers can be translated into blood biomarkers of CAA / failing Aβ clearance.

Workpackage II. Functional neuroimaging biomarkers

The aims of this work-package are:
1.    Development of a global, minimally invasive stimulus to detect CAA-related impairment of microvascular functioning
2.    Complete hemodynamic characterization of vascular responses in CAA to provide a sensitive and specific marker
3.    Study the added value of a comprehensive imaging protocol
4.    Correlation of microvascular function biomarkers with the fluid markers as developed in WP1

Patient cohorts in the Discovery / validation phases (WP I and II):

1- (Pre-)symptomatic patients with HCHWA-D with a genetic-based diagnosis (n=10, LUMC) and 10 age- and gender-matched controls (RUMC). Data available: CSF, blood, (functional) MRI, clinical follow-up.
2- Patients with probable CAA (sporadic CAA patients with a diagnosis established according to the modified Boston criteria (Knudsen 2001, Smith 2003)), from the Radboudumc / Boston populations (n=15-30; data available: CSF, serum, (functional) MRI, clinical follow-up), with high level of certainty of CAA (biopsy-based confirmation of the diagnosis).
3- Patients with early-onset, familial, AD
4- Patients with late-onset AD, with either a high or low likelihood of having CAA (based on the modified Boston criteria, T2* and other MRI) Radboudumc, J. Bosch Ziekenhuis)

Mouse and human tissues with CAA (WP I and II):

Tg-SwDI mice, Tg-5xFAD mice (Stony Brook, USA); data available: CSF, blood, histology, behavior. Human brain tissue CAA collection with all clinical information (VUmc).

Workpackage III: Biomarker application

The aims of this work-package are:
1.    Determine the correlations between blood biomarkers of CAA and available neuroimaging manifestations of preclinical CAA (lobar microbleeds on brain MRI) in population-based cohorts of community-dwelling subjects and in subjects with SVD.
2.    Define occurrence of, and grade of severity of, CAA based on body fluid biomarkers and study the correlation with parameters of cognitive (dys)function.
3.    Application of novel MRI-based biomarkers, resulting from WP II, to the population-based cohorts (pilot).

Population-based cohorts in the application phase (WP III):

1.    The Rotterdam Study. This is a population-based prospective cohort study in middle aged and elderly subjects. The study was started in 1990, and currently includes almost 15,000 individuals who are examined at 3-4 year time intervals. Extensive information is collected on each individuals by means of interview, physical examination, laboratory tests and more detailed examinations which include cognitive testing and neuroimaging. Available data from approximately 2300 community dwelling individuals include: multiple plasma samples, brain MRI (including sequences for detection of microbleeds and other markers of small vessel disease), extensive cognitive evaluations (at multiple time points), follow-up for occurrence of dementia and clinical stroke.
2.    RUNDMC study cohort, includes patients in whom the clinical dilemma as outlined above is reflected and investigates the risk factors and clinical consequences of cerebral small vessel disease (n=503 non-demented elderly). Small vessel disease was defined as the presence of lacunar infarcts and/or white matter lesions on neuroimaging. Symptoms of small vessel disease include acute symptoms, such as transient ischemic attacks or lacunar syndromes, or subacute manifestations, such as cognitive, motor (gait) disturbances and/or depressive symptoms. Available data: extensive clinical phenotyping, baseline serum and plasma, routine cerebral MRI, diffusion tensor imaging and resting state fMRI.

 

 

 

Results of the project

At this page, novel results that will be obtained during this project, will be presented here.