Human brain clearance imaging (HBCI): a window on physiological disturbances in the prediagnostic phase of neurodegenerative diseases

The glymphatic system is a brain-wide pathway involving perivascular spaces that activates during sleep to facilitate cerebrospinal fluid-based clearance of toxic proteins and by-products from nervous tissue.

A breakdown of brain clearance is a potential root cause of protein accumulation in dementias, a process already starting years before clinical diagnosis is established. No validated biomarker of glymphatic function in humans is yet available.

This project will focus directly on this void and 1) Design and validate a set of imaging biomarkers sensitive to disturbances in brain clearance. 2) Measure the influence of sleep and sleep deprivation on the developed biomarkers. 3) Demonstrate functionality of the biomarkers in characterizing brain clearance disturbances in idiopathic normal-pressure hydrocephalus (iNPH) and early Alzheimers Disease (AD).

Our five imaging approaches are clearance of intravenous or intrathecally injected MRI contrast agent, ultrahigh field MRI at 7 Tesla to allow CSF-specific imaging of CSF mobility in perivascular spaces, analysis of different frequencies in functional MRI signals and diffusion weighted MRI. Mathematical modeling will be used to update a cerebrospinal fluid flow model incorporating the glymphatic system.

The developed biomarkers will be applied in situations of maximally activated clearance (sleep) in healthy subjects and impaired brain clearance in neurodegenerative patients (iNPH and AD), as well as in murine models.