The parasagittal dural space of the human brain

The historical understanding of cerebrospinal fluid (CSF) production and flow comprises CSF production primarily in the choroid plexus of the 1st-3rd ventricles, flow through the aqueduct of Sylvius en route to the 4th ventricle, circulation around the subarachnoid space, and ultimately resorption into the blood circulation through arachnoid granulations. Since the discovery of a perivascular CSF clearance system in 2012 and in 2015 of lymphatic vessels localized to the dura mater of mice, there has been a growing interest in characterizing the structure and function of the tissues surrounding the dural sinuses, or the parasagittal dural (PSD) space. This work is now being pursued with increasing frequency to understand how the PSD space may relate to impaired neurofluid egress or neuroimmune function, with the intent of further informing our understanding of neurodegenerative proteinopathies and associated therapeutic avenues in disease. This review summarizes (i) our current understanding of neurofluid (comprised of CSF and interstitial fluid) circulation within the brain, as well as the (ii) anatomy and (iii) function of the PSD space in the context of neurofluid circulation and neuroimmune surveillance. With this context in place, we report on recent (iv) abilities to quantify the PSD volume and function in humans, (v) large-scale studies of PSD evolution across the human lifespan, and (vi) evidence for PSD structural variation in the setting of neurodegenerative disease.