Impaired peri-olfactory cerebrospinal fluid clearance mediated cognitive decline after dyssomnia

Abstract

AbstractAnimal experiments have demonstrated the dependency of CSF clearance function on age and sleep, which partially underlay the cognitive decline in the elderly. However, evidence is lacking in humans mainly due to limited method to assess CSF clearance function. We aimed to image CSF clearance pathways in human brain by dynamic MRI with intrathecal contrast agent as a CSF tracer. We performed T1-weighted and T2-fluid attenuated inversion recovery imaging with equal sequence parameters before and at multiple time points after intrathecal injection of contrast agent to visualize the putative meningeal lymphatic pathway, peri-olfactory nerve pathway and peri-optic nerve pathway. We defined the CSF clearance function as the percentage change in signal unit ratio of critical locations in these pathways from baseline to 39 hours after intrathecal injection. CSF clearance through the putative meningeal lymphatic and peri-neural pathways were clearly visualized in all 85 patients. The CSF clearance function of meningeal lymphatic and peri-neural pathways were reduced with aging (all P < 0.05). The CSF clearance function through peri-olfactory nerve pathway was positive correlated with sleep quality and cognitive function (both P < 0.05). Moreover, the CSF clearance function through peri-olfactory nerve pathway mediated the association of sleep quality with cognitive function (percent change in β [bootstrap 95% confidence interval]: 35% [−0.220, −0.003]). The study shows promise for dynamic MRI with intrathecal injection of contrast agent as a method to assess CSF clearance function through putative peri-neural pathways, and interprets the impaired clearance through putative peri-olfactory nerve pathway may explain the cognitive decline in patients with dyssomnia.