A Translational Approach Towards Understanding Brain Waste Clearance in Cerebral Amyloid Angiopathy | 2023

• Matthias VAN OSCH, Leiden University Medical Center (Netherlands)
• Susanne VAN VELUW, Massachusetts General Hospital (USA)

The brain produces myriads of metabolic waste products that need to be removed through brain clearance for normal brain function. However, our knowledge on the drainage of these waste products is still limited and highly debated, although recent discoveries describe a clearance pathway along the walls of blood vessels (termed perivascular spaces). This limited understanding of brain clearance is especially troubling, since 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. CAA is a highly prevalent and currently untreatable condition, affecting the brains of >50% of individuals over 80 and ~80-100% of patients with Alzheimer’s disease. This consortium brings together internationally recognized leaders in the fields of CAA and brain clearance, who sometimes have opposing views on the underlying physiological principles of brain clearance, with experts using innovative imaging techniques to measure and manipulate brain clearance in animal models and humans. Together 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. The specific goals of our consortium are to 1) establish a data-driven, integrated multi-scale understanding of perivascular brain clearance in health and CAA, 2) translate experimental findings from rodent models to the human brain, and 3) identify relevant driving forces to be tested in future clinical trials to enhance brain clearance.