MRI-Based Demonstration of the Normal Glymphatic System in a Human Population: A Systematic Review

Abstract

BackgroundThe glymphatic system has been described as one that facilitates the exchange between the cerebrospinal fluid (CSF) and interstitial fluid, and many recent studies have demonstrated glymphatic flow based on magnetic resonance imaging (MRI). We aim to systematically review the studies demonstrating a normal glymphatic flow in a human population using MRI and to propose a detailed glymphatic imaging protocol.MethodsWe searched the MEDLINE and EMBASE databases to identify studies with human participants involving MRI-based demonstrations of the normal glymphatic flow. We extracted data on the imaging sequence, imaging protocol, and the targeted anatomical structures on each study.ResultsAccording to contrast-enhanced MRI studies, peak enhancement was sequentially detected first in the CSF space, followed by the brain parenchyma, the meningeal lymphatic vessel (MLV), and, finally, the cervical lymph nodes, corresponding with glymphatic flow and explaining the drainage into the MLV. Non-contrast flow-sensitive MRI studies revealed similar glymphatic inflow from the CSF space to the brain parenchyma and efflux of exchanged fluid from the brain parenchyma to the MLV.ConclusionWe may recommend T1-weighted contrast-enhanced MRI for visualizing glymphatic flow. Our result can increase understanding of the glymphatic system and may lay the groundwork for establishing central nervous system fluid dynamic theories and developing standardized imaging protocols.

Gray matter reserve determines glymphatic system function in young‐onset Alzheimer's disease: Evidenced by DTI‐ALPS and compared with age‐matched controls

“…The glymphatic system has been visualized in vivo using two‐photon imaging with a fluorescent tracer and laser‐scanning microscope 4 . In humans, direct visualization of the glymphatic flow system has been achieved using MRI tracer studies with intrathecal or intravenous injections of gadolinium‐based contrast agents 5 . However, the glymphatic system is still a hypothesis, and it involves function rather than an obvious anatomical structure.…”

Intrathecal Pseudodelivery of Drugs in the Therapy of Neurodegenerative Diseases: Rationale, Basis and Potential Applications

“…In any case, the formation of aggregates of these proteins may be the consequence of different pathogenesis, including a variable combination of increased synthesis, synthesis of structurally abnormal forms, and decreased degradation, either by intracellular (autophagy, microglia) or extracellular systems [ 13 , 14 , 15 , 16 ]. A decrease in their clearance to compartments outside the brain parenchyma has been identified as a relevant contribution to protein accumulation in the CNS fluidic systems, due to the impairment of the BBB, the CSF flow, and the glymphatic system [ 17 , 18 , 19 , 20 , 21 , 22 , 23 ]. Protein degradation involves enzymes contributing to clear target molecules, such as neprilysin or insulysin, that clear Aβ [ 24 ].…”

Toward a new nosology of neurodegenerative diseases

“…Furthermore, the formation of aggregates of these proteins may be the consequence of different pathogenesis, including a variable combination of increased synthesis, synthesis of structurally abnormal forms, and decreased degradation, either by intracellular (autophagy, microglia) or extracellular systems 16–19 . A decrease in protein clearance to compartments outside the central nervous system (CNS) parenchyma has also been implicated, which may be linked to the impairment of the blood–brain barrier (BBB), low cerebrospinal fluid (CSF) flow, and dysfunction of the glymphatic system 20–26 …”

“…A new class of biomarkers, informing etiologies, pathogenic mechanisms, and the full spectrum of hallmarks of neurodegeneration, is highly needed. Thanks to genome‐wide genetics and other “omic” techniques, and to advanced neuroimaging methods, such markers are under development 25,26,69 and hopefully will become a reality both for symptomatic and asymptomatic subjects in the next decades. In addition, data‐driven strategies using quantitative rather than categorical variables, as well as tools such as cell atlases and digital neuroanatomy atlases, will allow much more reliable quantification of contributions from pathophysiological mechanisms and their spatial–temporal evolution as well as the development of precision diagnostics 70,71 .…”

“…[16][17][18][19] A decrease in protein clearance to compartments outside the central nervous system (CNS) parenchyma has also been implicated, which may be linked to the impairment of the blood-brain barrier (BBB), low cerebrospinal fluid (CSF) flow, and dysfunction of the glymphatic system. [20][21][22][23][24][25][26] Anatomically, the different neurodegenerative processes predominantly affect vulnerable networks, leading to a wide variety of clinical pictures. The diversity and complex organization of cellular networks in the brain have hindered the systematic characterization of age-related changes in its cellular and molecular architecture, limiting our ability to understand the mechanisms underlying its functional decline during aging and disease.…”