To what extent does the subarachnoid cerebrospinal fluid (CSF) compartment communicate directly with the extravascular compartment of human brain tissue? Interconnection between the subarachnoid CSF compartment and brain perivascular spaces is reported in some animal studies, but with controversy, and in vivo CSF tracer studies in humans are lacking. In the present work, we examined the distribution of a CSF tracer in the human brain by MRI over a prolonged time span. For this, we included a reference cohort, representing close to healthy individuals, and a cohort of patients with dementia and anticipated compromise of CSF circulation (idiopathic normal pressure hydrocephalus). The MRI contrast agent gadobutrol, which is confined to the extravascular brain compartment by the intact blood-brain barrier, was used as a CSF tracer. Standardized T1-weighted MRI scans were performed before and after intrathecal gadobutrol at defined time points, including at 24 hours, 48 hours, and 4 weeks. All MRI scans were aligned and brain regions were segmented using FreeSurfer, and changes in normalized T1 signals over time were quantified as percentage change from baseline. The study provides in vivo evidence of access to all human brain subregions of a substance administered intrathecally. Clearance of the tracer substance was delayed in the dementia cohort. These observations translate previous findings in animal studies into humans and open new prospects concerning intrathecal treatment regimens, extravascular contrast-enhanced MRI, and assessment of brain clearance function.

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The brain lacks lymph vessels and must rely on other mechanisms for clearance of waste products, including amyloid β that may form pathological aggregates if not effectively cleared. It has been proposed that flow of interstitial fluid through the brain's interstitial space provides a mechanism for waste clearance. Here we compute the permeability and simulate pressure-mediated bulk flow through 3D electron microscope (EM) reconstructions of interstitial space. The space was divided into sheets (i.e., space between two parallel membranes) and tunnels (where three or more membranes meet). Simulation results indicate that even for larger extracellular volume fractions than what is reported for sleep and for geometries with a high tunnel volume fraction, the permeability was too low to allow for any substantial bulk flow at physiological hydrostatic pressure gradients. For two different geometries with the same extracellular volume fraction the geometry with the most tunnel volume had 36% higher permeability, but the bulk flow was still insignificant. These simulation results suggest that even large molecule solutes would be more easily cleared from the brain interstitium by diffusion than by bulk flow. Thus, diffusion within the interstitial space combined with advection along vessels is likely to substitute for the lymphatic drainage system in other organs.T ransport of nutrients and waste within the brain's parenchyma is paramount to healthy brain function. Although lymphatic vessels occur within the meninges (1, 2), they are absent from the brain's parenchyma. This raises the question of how waste products are cleared from the brain (3-8). There is an urgent need to resolve this question, given the fact that several neurological disorders are associated with accumulation of toxic debris and molecules in the brain interstitium (9). Most notably, insufficient clearance may contribute to the development of Alzheimer's disease and multiple sclerosis (9, 10).Recently the "glymphatic" hypothesis (10) was launched. This hypothesis holds that the brain is endowed with a waste clearance system driven by bulk flow of fluid through the interstitium, from paraarterial to paravenous spaces, facilitated by astrocytic aquaporin-4 (AQP4). Further, it was proposed that cerebral arterial pulsation (11) and respiration (12) drive paravascular fluid movement and cerebrospinal fluid (CSF)-interstitial fluid (ISF) exchange. Here, bulk flow is defined as the movement of fluid down the pressure gradient, advection is the transport of a substance by bulk flow, and convection is transport by a combination of advection and diffusion.There is strong evidence for paravascular advection (8, 13-15), although the details of influx and efflux pathways and the underlying driving forces are debated (10, 15-17). There are, however, controversies regarding the relative importance of advective versus diffusive transport within the interstitial space (3,5,7,8), and the idea that a hydrostatic pressure gradient can cause an advective flow within the ...