One of the most prevalent manifestations of progressive neurodegenerative disorders in Western societies is dementia. The most common form is Alzheimer’s disease (AD), with progressive cerebral accumulation of the extracellular amyloid beta (Aß) protein. Therapeutic options for AD are virtually absent, in part because most dementias can only be diagnosed with certainty at autopsy.
Cerebral Amyloid Angiopathy
Apart from the parenchymal accumulation of amyloid beta, this same peptide also frequently aggregated in the walls of small brain arterioles, named cerebral amyloid angiopathy (CAA). CAA causes vascular dysfunction which independently contributes to cognitive decline. The vessel wall weakens due to the amyloid accumulation, resulting in microbleeds and clinical strokes, which are often fatal. At LUMC, we are particularly focusing on this vascular amyloid accumulation because CAA is not just a disease of old age, but also occurs in a severe hereditary form. This disease, hereditary cerebral amyloid angiopathy – Dutch type (HCHWA-D), commonly known as Katwijk Disease is geographically and historically linked to LUMC and forms a particular research focus of our lab.
Our research program consists of two parts:
- Development of in vivo imaging techniques to detect amyloid aggregates in disease models and ultimately in humans. We use multi-photon fluorescence microscopy to detect amyloid directly. Secondly, we develop techniques to image the pathological and functional consequences of amyloid accumulation. Of particular interest are MRI techniques to detect iron and myelin changes associated with dementia using susceptibility-weighted imaging (SWI) or quantitative susceptibility mapping (QSM), which allow quantification of iron and myelin in the brain. We have a unique combination of pre-clinical models, tissue collections and high-field MRI systems that allow us to explore these imaging techniques in depth. Secondly, we also pioneer techniques to image the impaired vascular function in these diseases, assessing brain perfusion, vascular reactivity and blood-brain-barrier integrity at the level of the entire brain with MRI, or individual vessels with multi-photon imaging.
- Development of potential therapies for CAA (and AD). We are focusing on finding new drug targets associated with the development of the disease for which drugs are already available, such as inflammatory pathways. Secondly, Dr. van Roon is developing antisense oligonucleotides (AON) to inhibit amyloid beta formation.
Lastly, we have many collaborations with other research groups interested in using our in vivo imaging techniques.
A. Detection of iron accumulation and myelin structural alterations with high field MRI in human tissue
B. In vivo multi-photon microscopy of the brain cortex, showing a single arteriole with amyloid in the vessel wall (blue)
C. Whole brain perfusion and arterial transit times using time-encoded pCASL MRI
Research consortia and collaborations
We are currently collaborating in several national and EU programs. CVON-HBC (cardiovascular onderzoek Nederland) is a large consortium focusing on the relation between (cardio)vascular pathology and cognition together with AMC. PAGE-AD, a Memorabel program focussing on high field MRI and pathological differentiation between conventional and parietal lobe AD, together with VUMC and the Netherlands Brain Bank. Bioimage-NMD is an EU consortium focused on advanced diffusion imaging techniques in muscle pathology.