Title : Imaging brain clearance in Alzheimer’s disease
Abstract:
The circulation of cerebrospinal fluid (CSF) plays a critical role in waste clearance and immune surveillance throughout the central nervous system (CNS). Dysfunction of this system has been associated with numerous deleterious effects and is thought to play a significant role in the accumulation of pathology in Alzheimer’s disease (AD). Therefore several recent studies have examined CSF transportation and drainage in the CNS, particularly the role of the glymphatic system and meningeal lymphatic vessels, showing impaired clearance of CSF and solutes such as amyloid and tau in aging and AD. However, much of our current knowledge about CSF circulation is based on animal and post-mortem studies and it remains unclear whether reported results can be extrapolated to the living human brain. Data from human studies is limited, largely due to the lack of reliable measurement techniques. Gadolinium-based contrast agent (GBCAs) enhanced MRI has been widely used to study CSF circulation in the brain in vivo. This approach is often considered the gold standard due to its superior sensitivity compared to other available neuroimaging approaches. To date, most GBCA based CSF studies have been performed using intrathecal (IT) administration of GBCA (i.e. injection of GBCA directly into the CSF, usually via a lumbar puncture at level of the spinal cord). This approach is invasive, and not without risk. On the other hand, intravenous (IV) administration of GBCA is FDA approved for human MRI studies, considered safe and minimally invasive and has been routinely used in clinics for several decades. A growing body of evidence has shown that IV GBCAs enter CSF circulation in the human brain at multiple locations where relatively loose barriers at the interface between blood and CSF exist, such as the dural blood vessels that lack a blood-brain-barrier (BBB), the blood-CSF-barrier (BCSFB) in choroid plexus, and other locations. Therefore, IV GBCA based MRI can be used to study CSF circulation and clearance in a manner similar to intrathecal GBCA, providing a less invasive approach that is more suitable for longitudinal assessment. We have developed, significant experience optimizing, and validating an MRI technique that can detect dynamic GBCA-induced signal changes within CSF with a sub-millimeter spatial resolution, a temporal resolution of less than 10 seconds, while providing whole brain coverage. Importantly, the MRI method was designed to address several major technical challenges when using IV GBCA to study CSF circulation including optimization to measure GBCA-induced MR signal changes only from the CSF with minimal partial volume effects from blood by using a long echo time to suppress brain parenchyma and blood signals. Using these techniques, we show that IV GBCAs can enter CSF circulation in healthy human brains via several sites specifically, the choroid plexus and parasagittal dura, diffuse through CSF circulation, and drain into lymph nodes.
