Brain clearance

Perivascular spaces are unique to the brain and contribute to waste clearance and fluid homeostasis. Impaired clearance may lead to accumulation of toxic proteins in various types of dementia, such as Alzheimer’s disease and cerebral amyloid angiopathy (CAA). We study the anatomy of the perivascular system, its driving forces (e.g. cardiac contraction, respiration, vasomotion) and how sleep, aging, and cardiovascular pathologies such as hypertension and blood-brain barrier dysfunction affect brain clearance.

Focus

The role of sleep in brain clearance

Investigator: Nina Smets

Support: NWO

In this project we study the anatomy of perivascular spaces, the driving forces for perivascular flow, and how these parameters are affected by sleep and hypertension. We use 2-photon imaging and immunohistochemistry to address our research questions.

Team: Erik N.T.P. Bakker, Gustav J. Strijkers, Bram F. Coolen, (Thijs) M.J.P. van Osch (LUMC), Lydiane Hirschler (LUMC), Balázs ÖRZSIK (LUMC), Judith de Vos.

The impact of blood-brain barrier dysfunction on brain clearance

Investigator: Shakira van der Panne

Support: Zon MW, Alzheimer Nederland

In this project we study the impact of blood-brain barrier (BBB) dysfunction on brain clearance via perivascular spaces. BBB dysfunction is a common denominator of several cerebrovascular and neurodegenerative diseases. Breakdown of the BBB leads to leakage of blood proteins into the perivascular space. We will use MRI, ultrasound, immunohistochemistry and confocal imaging to study how BBB disruption affects physiological waste clearance and fluid homeostasis.

Team: Gustav J. Strijkers, Elga H.E. de Vries, Louise van der Weerd (LUMC), Erik N.T.P. Bakker.

A Translational Approach Towards Understanding Brain Waste Clearance in Cerebral Amyloid Angiopathy

Investigator: Ellen Vermeersch

Support: Leducq Foundation

Many neurodegenerative diseases are thought to be caused or accelerated by impaired brain clearance. One of these diseases is cerebral amyloid angiopathy (CAA) in which a toxic protein, called amyloid-β, accumulates in the vessel wall, leading to hemorrhagic stroke and dementia. We aim to elucidate fundamental unanswered questions related to brain clearance by focusing on both healthy brains and brains affected by CAA. This is done in a translational (from rodent to man), multimodal (from electron and multi-photon microscopy to MRI), and multidisciplinary (from mechanistic modeling to clinical) fashion.

Team: Matthias J.P. van Osch, Erik N.T.P. Bakker. Consortium members: Susanne J. van Veluw,  Helene Benveniste, Jeffrey J. Iliff, Andy Y. Shih, Roxana O. Carare, Sylvie Lorthois, William E. Van Nostrand, Gabor C. Petzold, Steven M. Greenberg.

Beating brain dysfunction: elucidating the role of arterial pulsations in glymphatic clearance and cognitive impairment

Investigator: Daphne Naessens

Support: Dutch Heart Foundation, DCVA Heart-Brain Connection crossroads (HBCx)

Hypertension has emerged as an important risk factor for cognitive impairment and dementia, including Alzheimer’s disease. We obtained cerebrospinal fluid from spontaneously hypertensive rats (SHR) that were either left untreated or treated with two different antihypertensive medications from a relatively young age onwards. One group of SHR was treated with amlodipine, a calcium channel blocker, while another group received atenolol, a β-blocker. In this project we study the impact of antihypertensive treatment on CSF composition, to determine which type of medication is most beneficial for the brain. We will use proteomics and immunohistochemistry in this project.

Team: Nina G. Smets, Erik N.T.P. Bakker.

The role of sleep in brain clearance and prevention of Alzheimer’s disease

Investigator: Daphne Naessens

Support: Alzheimer Nederland

Sleep is essential for normal brain function, but it remains unclear through which mechanisms this occurs. Animal studies suggested that sleep facilitates clearance of waste products from the brain, and that this becomes less efficient with aging and several pathological conditions. Subsequent work in both humans and animals showed that sleep improves removal of the Alzheimer’s disease protein, amyloid-β, and that sleep deprivation increased parenchymal amyloid-β burden. Although the role of sleep in brain clearance seems evident, the exact mechanisms are still not fully understood. In this project, we will investigate whether sleep enhances clearance of waste products. We will use MRI in this project on awake and sleeping/sedated animals.

Team: Erik N.T.P. Bakker, Gustav J. Strijkers, Bram F. Coolen.

Lasering Psoriasis away

Investigator: Meagan Doppegieter

Support: Health Holland, TKI-PPP grant

In this project we test the hypothesis that pulsed dye laser treatment reduces the symptoms of psoriasis by destruction of the perivascular nerve endings via heating of the blood vessels. By gaining insight in the mechanism of action of laser treatment, we aim to develop a model to predict laser settings for individualized optimal treatment.

Team: Ton A.G.J.M. van Leeuwen, Maurice C.G. Aalders, Leah S. Wilk, Nick van der Beek, Erik N.T.P. Bakker

Output

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Internships

We have internships available for bachelor and master students who are interested in the vascular contribution to dementia. We perform preclinical studies, focused on brain clearance via perivascular spaces (glymphatics). We study how disruption of the blood-brain barrier, hypertension, and sleep affect driving forces and waste clearance from the brain. Techniques involve MRI, intravital microscopy, immunohistochemistry, electron microscopy, and ex-vivo vascular functional analyses.   

For more information, contact Erik Bakker at n.t.bakker@amsterdamumc.nl