Cerebrospinal fluid (CSF) plays essential roles in development, physiology, and pathology of the brain. Beyond the protection of the brain from trauma, CSF transports and regulates molecules that are essential for neuronal metabolism[1]. On one hand, CSF and blood-CSF barrier control the entry of iron, metabolites, electrolytes, and proteins into the brain[2]. On the other hand, CSF also serves as a drainage pathway of metabolic waste[3, 4]. The CSF flowing through the perivascular spaces may remove amyloid-beta and other toxic molecules by actively exchanging with the interstitial fluid[5–7]. Recent studies further suggested that dysfunction of brain clearance mechanisms could be responsible for the accumulation of amyloid-beta and tau protein in Alzheimer’s Disease (AD)[8–11].
CSF is mainly secreted by the choroid plexus, most of which is attached to the walls of the lateral ventricles. The anterior choroidal artery originating from the internal cerebral artery and the posterior choroidal artery originating from the posterior cerebral artery provide blood supply to the choroid plexus in the lateral ventricle. Distinct from the blood-brain barrier, capillaries of the choroid plexus are fenestrated and water exchanges freely between the choroid plexus stroma and the blood. The boundary between the choroid plexus and the CSF is composed of a monolayer of choroidal epithelial cells that have tight junctions between each other and form the blood-CSF barrier. Because of this unique vascular structure, the perfusion of the choroid plexus may show special characteristics compared to other regions of the brain. In addition, early studies showed that the choroid plexus blood flow was associated with CSF production [12, 13]. Therefore, the characteristics of choroid plexus perfusion would be of great interest.
However, studies of the choroid plexus perfusion were rarely performed, which were partly obstructed by the shortage of safe methods. A small number of early studies were performed with radioactive tracers and animal models. Townsend et al. [14], Faraci et al.[15–17] and Williams et al. [18] injected radioactive microspheres and measured radiation doses of the choroid plexus on sacrificed animals. After years of medical imaging developments, only a few studies reported choroid plexus perfusion or permeability in human subjects using contrast-enhanced MRI with Gadolinium-based contrast agents (GBCA) [19, 20]. However, these studies didn’t provide absolute blood flow, which is challenging with GBCA because of the nonlinear dependence of signal on concentration and tissue distribution. More rapid outflow in the highly vascular choroid plexus may limit its accuracy. Concerns about the deposition of Gadolinium in tissue may also limit the use of the technique, especially in research studies with little individual benefit to subjects[21, 22]. Therefore, it would be highly desirable to develop a clinically feasible and totally non-invasive method for measurement of choroid plexus perfusion.
Arterial spin labeling (ASL) perfusion MRI is an appealing non-invasive and quantitative option for the measurement of choroid plexus blood flow. In an ASL scan, the endogenous arterial blood water is labeled by radiofrequency pulses. When the labeled blood flows into the brain tissue, it results in reduced signal compared to a control scan with non-labeled blood. Through the measurement of the signal change between the control and label scans, ASL is able to quantify the blood flow using the endogenous arterial blood water signal. Therefore, ASL provides a safe technique without contrast agent administration and a clinically feasible option for characterizing choroid plexus perfusion.
Clearly visible choroid plexus signal has been observable in brain ASL imaging studies for many years, such as the Fig. 10 of Dai et al.[23], the Fig. 1 of Mutsaerts et al.[24], and the Fig. 9 of Amukotuwa et al.[25]. The ASL signal of the choroid plexus has been also observed in patients with Alzheimer’s Disease[26]. In a recent resting-state functional study with ASL, our results further indicated that the ASL signal of the choroid plexus didn’t participate in flow fluctuations present in brain networks[27]. However, sources of high ASL signal in the choroid plexus were not discussed in the above work.
Recently, we reported the feasibility to detect choroid plexus perfusion using ASL in abstract form [28, 29], but the blood flow quantification methods were not fully developed. Johnson et al.[30] implemented this method to evaluate perfusion changes after angiogenesis, but they used a single delay ASL experiment which couldn’t provide the dynamic characteristics of choroid plexus perfusion.
In this work, we sought to establish ASL as a tool to quantify the dynamic characteristics of choroid plexus perfusion. The perfusion characterization can serve as a preliminary reference for studies of physiological and pathological modulation of choroid plexus function.