The Glymphatic System and Waste Clearance with Brain Aging: A Review

Abstract

The glymphatic system is a glial-dependent waste clearance pathway in the brain, in place of lymphatic vessels, dedicated to drain away soluble waste proteins and metabolic products. Specifically, the glymphatic network serves as a "front end" for waste clearance, and is connected downstream to an authentic lymphatic network, associated with dura covering the brain as well as cranial nerves and large vessels at the skull exits. The anatomical and functional interconnections between these two networks are not completely understood. Several key physiological processes have been identified that control glymphatic transport function and waste clearance from brain. In this review, we aim to provide an overview and discussion of the concept behind the glymphatic system, current evidence, and controversies, while specifically focusing on the consequences of aging and evidence of its existence in human brain. Discovering novel strategies for optimizing and maintaining efficient brain waste clearance across the lifespan may in the future prove to be important for preventing cognitive decline and sustaining healthy aging.

Keywords: AQP4; Aging; Cerebrospinal fluid transport; Glymphatic; Human brain; Perivascular space; Pulsatility; Sleep; Waste solutes.

Fig 1. Glymphatic transport and waste drainage concept

Original concept of the glymphatic transport [1], highlighting the periarterial and the perivenous space, and the astrocytic endfeet with aquaporin 4 (AQP4) water channels and forming a sheath around the blood vessels. Cerebrospinal fluid is driven by convection through the periarterial space and is propelled across the astroglia end-feet to mix with interstitial fluid and waste products. From there the waste and excess fluids are driven towards the peri-venous space, to ultimately be directed towards the lymphatic vessels and general circulation for breakdown and clearance. The black particles represent ‘waste’ particles in the interstitial fluid (e.g. amyloid-beta). SubA = subarachnoid space; Oli = oligodendrocyte; AQP4 = aquaporin 4 water channels.

Fig. 2. Glymphatic transport measured by contrast enhanced MRI

The population averaged (N=5) concentration maps from rat brain presented in three orthogonal planes (A–C), 1 hr after administration of the macrocyclic MR contrast agent gadoterate meglumine (DOTAREM, MW 558.64 Da) into the cisterna magna (based on [24]). The color coded DOTAREM maps are overlaid on the corresponding anatomical brain template and tissue uptake is evident into the cerebellum (CB), hippocampus (Hip), hypothalamus and pons, in a concentration range of ~0.1–0.2mM. Data based on Lee et al. 2017 [24]. CB=cerebellum; Hip=hippocampus. Color bar represents the DOTAREM concentration. D shows the corresponding whole brain and CSF DOTAREM concentrations as a function of time and it can be observed that the maximal retention of the contrast molecule in whole brain and CSF is ~0.045mM and 1.2 mM, respectively.

Fig. 3. Conceptual medical illustration of brain waste clearance along cranial nerves

The front-end of the glymphatic system is shown including peri-arterial, interstitial space and peri-arterial transport of CSF (green arrow). A cranial nerve is illustrated and waste solutes (in black) are shown to drain along the cranial nerve. Another possibility is that waste solutes with fluid enters the nerve and waste solutes are draining along fascicles and/or axons. It is currently not known if interstitial waste solutes travel along the cranial nerves or within the nerve itself (i.e. penetrating epineurium and draining along or inside fascicles). It is also unknown if perineural drainage of waste solutes serves as major clearance routes after intraparenchymal administration and more systematic studies are needed.

Fig. 4. Medical illustration of lymphatic vessels associated with larger vessels of the dura

Medical illustration of the topography of the lymphatic vessel network imbedded in the dura (dura not shown) overlying the rodent brain based on work from several investigators [38,73,84]. A: Lateral view showing the dural sinuses including the superior sagittal sinus (SSS) and transverse sinus (TS). The lymphatic vessels are shown in green are running alongside the venous sinuses. Lymphatic vessels are also running alongside the middle meningeal artery (MMA), a larger dural artery originating from the external carotid artery. The lymphatic vessels (LV) drain into cervical lymph nodes including the deep cervical lymph nodes (DCLN). B: Top view of rat brain showing the topology of the lymphatic network associated with the dural sinuses and superficial veins. OFS = Olfactory sinus; SS=Sigmoid sinus.

Fig. 5. Vessels, cranial nerves and lymph vessels at the site of the jugular foramen

Fig. 5 is an illustration of how lymphatic vessels in the dura might drain to the deep cervical lymph nodes (DCLN). A: The ventral aspect of the rat skull is shown; the right side shows the brain in situ (modified from: [85]). The jugular foramen is highlighted and shows the exit of the vagal nerve (X), internal jugular vein (IJV) and internal carotid artery (ICA). B: High magnification of the area of the jugular foramen with the proposed exiting vessels and vagal nerve. Lymphatic vessels (LV) associated with dura lining the ventral surface of the skull might exit at this site into the DCLNs. This drawing is a proposed illustration of the connection between dural LVs and DCLNs.