Impairment of the Glymphatic Pathway and Putative Meningeal Lymphatic Vessels in the Aging Human

Abstract

Objective Aging is a major risk factor for numerous neurological disorders, and the mechanisms underlying brain aging remain elusive. Recent animal studies demonstrated a tight relationship between impairment of the glymphatic pathway, meningeal lymphatic vessels, and aging. However, the relationship in the human brain remains uncertain. Methods In this observational cohort study, patients underwent magnetic resonance imaging before and at multiple time points after intrathecal administration of a contrast agent. Head T1‐weighted imaging was performed to assess the function of the glymphatic pathway and head high‐resolution T2–fluid attenuated inversion recovery imaging to visualize putative meningeal lymphatic vessels (pMLVs). We measured the signal unit ratio (SUR) of 6 locations in the glymphatic pathway and pMLVs, defined the percentage change in SUR from baseline to 39 hours as the clearance of the glymphatic pathway and pMLVs, and then analyzed their relationships with aging. Results In all patients (N = 35), the SUR of the glymphatic pathway and pMLVs changed significantly after intrathecal injection of the contrast agent. The clearance of both the glymphatic pathway and pMLVs was related to aging (all p < 0.05). The clearance of pMLVs was significantly related to the clearance of the glymphatic pathway (all p < 0.05), and the clearance of the glymphatic pathway was significantly faster in patients with early filling of pMLVs than those with late filling (all p < 0.05). Interpretation We revealed that both the glymphatic pathway and pMLVs might be impaired in the aging human brain through the novel, clinically available method to simultaneously visualize their clearance. Our findings also support that in humans, pMLVs are the downstream of the glymphatic pathway. Ann Neurol 2020;87:357–369

Aging Is Positively Associated with Peri-Sinus Lymphatic Space Volume: Assessment Using 3T Black-Blood MRI

“…Recent animal and human studies have shown that intrathecal gadolinium injections lead to peri-sinus contrast enhancement in dural lymphatics visible on MRI at 50–200 min after intrathecal gadolinium injection; this finding supports the assertion that there is a link between the glymphatic system and MR-visible dural lymphatics [ 10 , 31 , 32 ]. Therefore, the direct assessment of the dural lymphatics via MRI may offer an in vivo evaluation of the glymphatic system and further study is required to explore MRI-visible dural lymphatics and their relationships with the glymphatic system.…”

Neurofluid Dynamics and the Glymphatic System: A Neuroimaging Perspective

“…Measurements of signals at locations including the ventricles and brain parenchyma, predefined as the “glymphatic pathway” showed that the delayed clearance of the “glymphatic pathway” was related to aging. The study also examined heavily T2-weighted fluid-attenuated inversion recovery images to visualize putative meningeal lymphatic vessels; the delayed visualization of meningeal lymphatics compared to that of the “glymphatic pathway” indicated that meningeal lymphatics are downstream of the “glymphatic pathway” ( 28 ). Practically, the intrathecal injection of GBCAs has not been approved by U.S. Food and Drug Administration (FDA), making its clinical application impossible.…”

Magnetic Resonance Imaging and Modeling of the Glymphatic System

“…MRI has provided the evidence of presence of meningeal lymphatic vessels in human and non-human primates for CNS waste clearance [66]. A very recent study on humans utilizing MRI provided a clinical methodology to simultaneously visualize the glymphatic system clearance, deep cervical lymph nodes, and putative meningeal lymphatic vessels [30]-this MRI study also reported decreased glymphatic system and meningeal lymphatic CSF tracer clearance with increased age [30].…”

“…Normal physiology (such as blood pressure [21], sleep [14], anesthesia [22], body posture [23], and aging [19,21,[24][25][26][27][28][29][30]) affects the glymphatic system. It was demonstrated that a 10 bpm decrease in heart rate (bradycardia) reduces waste clearance and results in a nearly 20% additional accumulation of beta-amyloid in the brain parenchyma, whereas a 30 bpm increase in heart rate (tachycardia) showed a nearly 30% reduction in beta-amyloid levels in the brain parenchyma [21].…”