Perivascular spaces are fluid-filled spaces surrounding brain blood vessels, resembling the body’s lymphatic system in facilitating waste removal. Dysfunction of the perivascular system and subsequent failure of waste clearance may contribute to diseases like Alzheimer’s disease. However, it remains unclear how these spaces connect to each other and the body. While MRI helps visualizing perivascular spaces, high-resolution mapping poses challenges. Hence, the current project aims to overcome these challenges by creating a detailed human perivascular space atlas using advanced imaging. Understanding their anatomy provides insights into the role of these spaces in brain clearance mechanisms in brain health and disease.

Nico-lab heeft, in nauwe samenwerking met het AMC, een portfolio van verschillende software producten ontwikkeld die de aspecten van een beroerte objectief, kwantitatief en consistent kunnen analyseren. Nico-lab heeft de ambitie om wereldwijd clinical trials en behandelend artsen ondersteuning te kunnen bieden bij het diagnosticeren en behandelen van patiënten met een beroerte.

Cells release extracellular vesicles (EV), which are present in all body fluids and regulate physiological processes. Moreover, because the properties of EV change during disease, EV are potential biomarkers for diseases as cancer, cardiovascular disease, and preeclampsia. Consequently, EV research is thriving as reflected by an exponentially growing number of publications and the 2013 Nobel Prize in Medicine. Nevertheless, an EV-based biomarker has still not been realized because existing technologies lack either sensitivity or speed. The technical challenge is to identify disease-specific EV between a multitude of other EV and non-EV particles with a diameter as small as 30 nm. To address this challenge, novel technology is urgently needed. In EV-Radar (RApid Detection And Recognition of EV), I will combine the sensitivity of dark-field microscopy with the speed of flow cytometry to achieve the first nanoparticle analyser capable of characterising single EV ≥30 nm at a clinically useful rate of 10,000 EV/s. The characterisation of 10,000 EV/s enables a significant count of disease-specific EV within minutes, which is a prerequisite to establish an EV-based biomarker. EV-Radar will consist of a disposable optofluidic chip and one camera to measure 1 scatter signal and 3 fluorescence signals per EV. To identify disease-specific EV, I will implement new analysis strategies based on combined fluorescence antibody detection, particle sizing, and refractive index determination. To demonstrate the clinical applicability of EV-Radar, I will identify tumour-derived EV in blood plasma of patients with prostate cancer. Once validated, EV-Radar will become the gold standard for single EV analysis in hospital laboratories. Outside the clinic, EV-Radar may become an important tool in microbiology (bacteria, viruses), materials science (synthetic nanoparticles), and oceanography (plankton, nanoplastics), as well as other fields where rapid identification of single nanoparticles is of critical importance.

-

Brain homeostasis depends on delivery of nutrients and oxygen, as well as removal of waste products. In recent years, a spike in interest for brain clearance pathways emerged with a strong focus on sleep, since brain clearance seems enhanced during deep sleep. This has resulted in studies on the role of sleep that gained much attention in the field and from the public. Yet, the interpretation of these studies is heavily debated, since the exact mechanisms remain obscure. Similarly, the role of impaired brain clearance in vascular and neurological pathologies is unclear. Within the current debate on the mechanisms of brain clearance, perivascular spaces and movement of cerebrospinal fluid (CSF) within these, play a central role. However, important factors remain unknown, such as the processes determining the efficiency of brain clearance, including the driving forces. Moreover, a major limitation is that at the moment almost all knowledge arises from rodent models with very limited translation to human studies. This limitation also holds for the role of sleep in brain clearance. Brain clearance involves diffusion (along a concentration gradient), flow (along a pressure gradient), and mixing. Mixing, as a result of vital oscillations, can greatly enhance solute clearance when net flow is absent or limited, such as in perivascular spaces along penetrating arteries. Three important natural forces might generate such oscillations, acting at different frequencies: the cardiac (≈1 Hz), the respiratory (≈0.2 Hz) and the vasomotor forces (≈0.1 Hz). In the current project, we aim to quantify the contribution of these physiological processes to brain clearance with regard to mixing as well as net flow and to assess if and how this changes during sleep. The current team of researchers provides a great opportunity to address the project in a truly translational manner: it will combine the expertise of the UMC (Amsterdam) on mechanistic studies of brain clearance in rodents with the LUMC’s (Leiden) newly-developed non-invasive MRI approach in humans, exploiting the improved resolution capabilities of ultra-high field MRI (7 Tesla). This will enables us to: 1) image the relevant anatomical substructures with high resolution techniques in rodents (perivascular spaces around penetrating arteries and veins); 2) obtain a 3D reconstruction of perivascular spaces in humans in vivo; 3) perform experimental manipulation of cardiac, respiratory, and vasomotor forces in rodents; 4) study the role of sleep in brain clearance in rodents; and 5) apply human MRI to capture whole brain CSF dynamics, including perivascular spaces of penetrating arteries in awake and during sleep. A better understanding of the process of brain clearance is crucial for new treatment strategies in neurodegenerative diseases as well as a clearer insight into the impact of e.g. aging, hypertension and sleep on brain clearance.