Decline of intrinsic cerebrospinal fluid outflow in healthy humans with age detected by non-contrast spin-labeling MRI

BackgroundClearance of cerebrospinal fluid (CSF) is important for the removal of toxins from the brain, with implication for neurodegenerative diseases. Imaging evaluation of CSF outflow in humans has been limited, relying on injections of contrast agents. Objective of this study was to introduce a novel spin-labeling magnetic resonance imaging (MRI) technique to detect and quantify the movement of endogenously tagged CSF without administration of tracer or contrast media, and use the technique to evaluate CSF outflow in normal human subjects with varying ages. MethodsThis study was performed on a clinical 3-Tesla MRI scanner in healthy subjects (10 males and 6 females; mean age, 47.6 {+/-} 18.9 years; range, 19-71 years) with informed consent. Our non-contrast spin-labeling MRI technique applies a tag pulse on the brain hemisphere, including subarachnoid space, dura mater, brain parenchyma, and images the outflow of the tagged CSF into the superior sagittal sinus. We obtained 3-dimensional images in real time, which was analyzed to determine tagged-signal changes in different regions of the brain involved in CSF outflow or clearance. Additionally, the signal changes over time were fit to a signal curve to determine quantitative flow metrics such as relative CSF flow and volume. These were correlated against subject age to determine aging effects. ResultsWe observed the signal of the tagged CSF moving from the subarachnoid space to the dura mater and parasagittal dura, and finally draining into the superior sagittal sinus. In addition, there was strong evidence of a direct pathway by which tagged CSF flows directly from the subarachnoid space to the superior sagittal sinus, via the lateral wall of superior sagittal sinus. Furthermore, quantitative CSF outflow metrics were shown to decrease significantly with age. ConclusionsWe demonstrated a novel non-invasive MRI technique to evaluate CSF clearance in humans. In this study, we identified possible two CSF clearance pathways, and determined normative values and decline of CSF flow metrics in normal ages. Our work provides a new opportunity to better understand the relationships of these CSF clearance pathways in ages, which may be a significant factor in the age-related prevalence of neurodegenerative diseases. FundingThis study was supported by the National Institutes of Health grants: RF1AG076692 (MM) and R01HL154092 (MM); and made possible by a grant from Canon Medical Systems. Corp., Japan. Clinical trialNot applicable.