Cerebrospinal fluid turnover as a driver of brain clearance DOI Creative Commons
Nina G. Smets, Gustav J. Strijkers, Vegard Vinje

et al.

NMR in Biomedicine, Journal Year: 2023, Volume and Issue: 37(7)

Published: Sept. 2, 2023

Cerebrospinal fluid (CSF) has historically been considered to function as a sink for brain-derived waste disposal. Recent work suggested that CSF interacts even more intensely with brain tissue than previously recognized, through perivascular spaces penetrate the brain. Cardiac pulsations, vasomotion, and respiration have drive flow in these spaces, thereby enhancing clearance. However, intrinsic role of production relation its distribution volume (turnover) is not an explicit component recent concepts on Here, we review turnover volume, focusing preclinical evidence. Herein, highlight use MRI establishing CSF-related parameters. We describe impact sleep, effect anesthesia, aging, hypertension turnover, how this relates Evaluation available evidence suggests major determinant In addition, propose several putative drivers clearance, but also conditions associated impaired such may actually relate altered turnover.

Language: Английский

Fluid transport in the brain DOI
Martin Kaag Rasmussen, Humberto Mestre, Maiken Nedergaard

et al.

Physiological Reviews, Journal Year: 2021, Volume and Issue: 102(2), P. 1025 - 1151

Published: May 5, 2021

The brain harbors a unique ability to, figuratively speaking, shift its gears. During wakefulness, the is geared fully toward processing information and behaving, while homeostatic functions predominate during sleep. blood-brain barrier establishes stable environment that optimal for neuronal function, yet imposes physiological problem; transcapillary filtration forms extracellular fluid in other organs reduced to minimum brain. Consequently, depends on special [the cerebrospinal (CSF)] flushed into along perivascular spaces created by astrocytic vascular endfeet. We describe this pathway, coined term glymphatic system, based dependency endfeet their adluminal expression of aquaporin-4 water channels facing CSF-filled spaces. Glymphatic clearance potentially harmful metabolic or protein waste products, such as amyloid-β, primarily active sleep, when drivers, cardiac cycle, respiration, slow vasomotion, together efficiently propel CSF inflow periarterial brain's space contains an abundance proteoglycans hyaluronan, which provide low-resistance hydraulic conduit rapidly can expand shrink sleep-wake cycle. system brain, meets requisites maintain homeostasis similar peripheral organs, considering blood-brain-barrier paths formation egress CSF.

Language: Английский

Citations

340
The glymphatic system: Current understanding and modeling DOI Creative Commons
Tomas Bohr, Poul G. Hjorth, Sebastian C. Holst

et al.

iScience, Journal Year: 2022, Volume and Issue: 25(9), P. 104987 - 104987

Published: Aug. 20, 2022

We review theoretical and numerical models of the glymphatic system, which circulates cerebrospinal fluid interstitial around brain, facilitating solute transport. Models enable hypothesis development predictions transport, with clinical applications including drug delivery, stroke, cardiac arrest, neurodegenerative disorders like Alzheimer's disease. sort existing into broad categories by anatomical function: Perivascular flow, transport in brain parenchyma, interfaces to perivascular spaces, efflux routes, links neuronal activity. Needs opportunities for future work are highlighted wherever possible; new models, expanded novel experiments inform could all have tremendous value advancing field.

Language: Английский

Citations

177
The glymphatic hypothesis: the theory and the evidence DOI Creative Commons
Stephen B. Hladky,

Margery A. Barrand

Fluids and Barriers of the CNS, Journal Year: 2022, Volume and Issue: 19(1)

Published: Feb. 3, 2022

Abstract The glymphatic hypothesis proposes a mechanism for extravascular transport into and out of the brain hydrophilic solutes unable to cross blood–brain barrier. It suggests that there is circulation fluid carrying inwards via periarterial routes, through interstitium outwards perivenous routes. This review critically analyses evidence surrounding mechanisms involved in each these stages. There good both influx efflux occur along routes but no principal route outflow perivenous. Furthermore, inflow unlikely be adequate provide would needed account solute efflux. A tenet flow sweeps parenchyma. However, velocity any possible circulatory within too small compared diffusion effective movement. By comparison earlier classical describing proposed entry parenchyma across barrier, movements by diffusion, partly near surfaces carried “preferred routes” including perivascular spaces, white matter tracts subependymal spaces. did not suggest Evidence still incomplete concerning fate leaving brain. large proportion eliminated from go lymph nodes before reaching blood proportions delivered directly or indirectly CSF which then enters are as yet unclear. In addition, understood why how absence AQP4 normally highly expressed on glial endfeet lining reduces rates elimination delivery it remote sites injection. Neither nor adequately explain move into, Features more complete description discussed. All aspects require further study.

Language: Английский

Citations

164
The glymphatic system: implications for drugs for central nervous system diseases DOI
Terhi J. Lohela, Tuomas O. Lilius, Maiken Nedergaard

et al.

Nature Reviews Drug Discovery, Journal Year: 2022, Volume and Issue: 21(10), P. 763 - 779

Published: Aug. 10, 2022

Language: Английский

Citations

128
Cerebrospinal fluid can exit into the skull bone marrow and instruct cranial hematopoiesis in mice with bacterial meningitis DOI
Fadi E. Pulous,

Jean C. Cruz-Hernández,

Chongbo Yang

et al.

Nature Neuroscience, Journal Year: 2022, Volume and Issue: 25(5), P. 567 - 576

Published: May 1, 2022

Language: Английский

Citations

127
Loss of aquaporin-4 results in glymphatic system dysfunction via brain-wide interstitial fluid stagnation DOI Creative Commons
Ryszard S. Gomolka, Lauren M. Hablitz, Humberto Mestre

et al.

eLife, Journal Year: 2023, Volume and Issue: 12

Published: Feb. 9, 2023

The glymphatic system is a fluid transport network of cerebrospinal (CSF) entering the brain along arterial perivascular spaces, exchanging with interstitial (ISF), ultimately establishing directional clearance solutes. CSF facilitated by expression aquaporin-4 (AQP4) water channels on endfeet astrocytes. Mice genetic deletion AQP4 (AQP4 KO) exhibit abnormalities in structure and molecular transport. Yet, no studies have systematically examined how these correlate function. Here, we used high-resolution 3D magnetic resonance (MR) non-contrast cisternography, diffusion-weighted MR imaging (MR-DWI) intravoxel-incoherent motion (IVIM) DWI, while evaluating function using standard dynamic contrast-enhanced to better understand disrupted after AQP4. KO mice had larger spaces total volumes resulting higher content reduced space volumes, despite similar production rates vascular density compared wildtype mice. volume likely resulted increased slow but not fast diffusion measures coincided influx. This markedly altered may result from reduction clearance, leading enlargement stagnation space. Overall, useful tool evaluate serve as valuable translational biomarker study glymphatics human disease.

Language: Английский

Citations

81
Open pathways for cerebrospinal fluid outflow at the cribriform plate along the olfactory nerves DOI Creative Commons
Irene Spera, Nikola Cousin, Miriam Ries

et al.

EBioMedicine, Journal Year: 2023, Volume and Issue: 91, P. 104558 - 104558

Published: April 10, 2023

Language: Английский

Citations

62
Bulk flow of cerebrospinal fluid observed in periarterial spaces is not an artifact of injection DOI Creative Commons
Aditya Raghunandan, Antonio Ladrón-de-Guevara, Jeffrey Tithof

et al.

eLife, Journal Year: 2021, Volume and Issue: 10

Published: March 9, 2021

Cerebrospinal fluid (CSF) flowing through periarterial spaces is integral to the brain’s mechanism for clearing metabolic waste products. Experiments that track tracer particles injected into cisterna magna (CM) of mouse brains have shown evidence pulsatile CSF flow in perivascular surrounding pial arteries, with a bulk same direction as blood flow. However, driving remains elusive. Several studies suggested might be an artifact, driven by injection itself. Here, we address this hypothesis new vivo experiments where are CM using dual-syringe system, simultaneous and withdrawal equal amounts fluid. This method produces no net increase volume significant intracranial pressure. Yet, particle-tracking reveals flows consistent all respects observed earlier single-syringe injection.

Language: Английский

Citations

60
Cerebrospinal Fluid Flow DOI Creative Commons
Douglas H. Kelley, John H. Thomas

Annual Review of Fluid Mechanics, Journal Year: 2022, Volume and Issue: 55(1), P. 237 - 264

Published: Sept. 28, 2022

Circulation of cerebrospinal fluid and interstitial around the central nervous system through brain transports not only those water-like fluids but also any solutes they carry, including nutrients, drugs, metabolic wastes. Passing tissue primarily during sleep, this circulation has implications for neurodegenerative disorders Alzheimer's disease, damage stroke cardiac arrest, flow-related such as hydrocephalus syringomyelia. Recent experimental results reveal several features flow, other aspects are fully understood, its driving mechanisms. We review evidence theoretical modeling roles advection diffusion in transporting solutes. discuss both local, detailed fluid-dynamic models specific components global hydraulic overall network flow paths.

Language: Английский

Citations

58
A network model of glymphatic flow under different experimentally-motivated parametric scenarios DOI Creative Commons
Jeffrey Tithof, Kimberly A. Stevens, Peter A. R. Bork

et al.

iScience, Journal Year: 2022, Volume and Issue: 25(5), P. 104258 - 104258

Published: April 14, 2022

Flow of cerebrospinal fluid (CSF) through perivascular spaces (PVSs) in the brain delivers nutrients, clears metabolic waste, and causes edema formation. Brain-wide imaging cannot resolve PVSs, high-resolution methods access deep tissue. However, theoretical models provide valuable insight. We model CSF pathway as a network hydraulic resistances, using published parameter values. A few parameters (permeability PVSs parenchyma, dimensions astrocyte endfoot gaps) have wide uncertainties, so we focus on limits their ranges by analyzing different parametric scenarios. identify low-resistance high-resistance parenchyma only scenario that satisfies three essential criteria: flow be driven small pressure drop, exhibit good perfusion throughout cortex, substantial increase during sleep. Our results point to most important parameters, such gap dimensions, measured future experiments.

Language: Английский

Citations

52