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Journal Article•DOI•

Evaluating glymphatic pathway function utilizing clinically relevant intrathecal infusion of CSF tracer

Lijun Yang1, Lijun Yang2, Benjamin T. Kress2, Harris J Weber2, Meenakshisundaram Thiyagarajan2, Baozhi Wang1, Rashid Deane2, Helene Benveniste3, Jeffrey J. Iliff4, Jeffrey J. Iliff2 •
Hebei Medical University1, University of Rochester Medical Center2, Stony Brook University3, Oregon Health & Science University4
01 May 2013-Journal of Translational Medicine (BioMed Central)-Vol. 11, Iss: 1, pp 107-107
TL;DR: Lumbar intrathecal contrast delivery is a clinically useful approach that could be used in conjunction with dynamic contrast enhanced MRI nuclear imaging to assess glymphatic pathway function in humans.
Abstract: Neurodegenerative diseases such as Alzheimer’s are associated with the aggregation of endogenous peptides and proteins that contribute to neuronal dysfunction and loss. The glymphatic system, a brain-wide perivascular pathway along which cerebrospinal fluid (CSF) and interstitial fluid (ISF) rapidly exchange, has recently been identified as a key contributor to the clearance of interstitial solutes from the brain, including amyloid β. These findings suggest that measuring changes in glymphatic pathway function may be an important prognostic for evaluating neurodegenerative disease susceptibility or progression. However, no clinically acceptable approach to evaluate glymphatic pathway function in humans has yet been developed. Time-sequenced ex vivo fluorescence imaging of coronal rat and mouse brain slices was performed at 30–180 min following intrathecal infusion of CSF tracer (Texas Red- dextran-3, MW 3 kD; FITC- dextran-500, MW 500 kD) into the cisterna magna or lumbar spine. Tracer influx into different brain regions (cortex, white matter, subcortical structures, and hippocampus) in rat was quantified to map the movement of CSF tracer following infusion along both routes, and to determine whether glymphatic pathway function could be evaluated after lumbar intrathecal infusion. Following lumbar intrathecal infusions, small molecular weight TR-d3 entered the brain along perivascular pathways and exchanged broadly with the brain ISF, consistent with the initial characterization of the glymphatic pathway in mice. Large molecular weight FITC-d500 remained confined to the perivascular spaces. Lumbar intrathecal infusions exhibited a reduced and delayed peak parenchymal fluorescence intensity compared to intracisternal infusions. Lumbar intrathecal contrast delivery is a clinically useful approach that could be used in conjunction with dynamic contrast enhanced MRI nuclear imaging to assess glymphatic pathway function in humans.

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Citations
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Journal Article•DOI•
Structural and functional features of central nervous system lymphatic vessels

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Antoine Louveau1, Igor Smirnov1, Timothy J. Keyes1, Jacob D. Eccles1, Sherin J. Rouhani1, J. David Peske1, Noël C. Derecki1, David Castle1, James Mandell1, Kevin S. Lee1, Tajie H. Harris1, Jonathan Kipnis1 •
University of Virginia1
16 Jul 2015-Nature
TL;DR: In searching for T-cell gateways into and out of the meninges, functional lymphatic vessels lining the dural sinuses are discovered, which may call for a reassessment of basic assumptions in neuroimmunology and sheds new light on the aetiology of neuroinflammatory and neurodegenerative diseases associated with immune system dysfunction.
Abstract: One of the characteristics of the central nervous system is the lack of a classical lymphatic drainage system. Although it is now accepted that the central nervous system undergoes constant immune surveillance that takes place within the meningeal compartment, the mechanisms governing the entrance and exit of immune cells from the central nervous system remain poorly understood. In searching for T-cell gateways into and out of the meninges, we discovered functional lymphatic vessels lining the dural sinuses. These structures express all of the molecular hallmarks of lymphatic endothelial cells, are able to carry both fluid and immune cells from the cerebrospinal fluid, and are connected to the deep cervical lymph nodes. The unique location of these vessels may have impeded their discovery to date, thereby contributing to the long-held concept of the absence of lymphatic vasculature in the central nervous system. The discovery of the central nervous system lymphatic system may call for a reassessment of basic assumptions in neuroimmunology and sheds new light on the aetiology of neuroinflammatory and neurodegenerative diseases associated with immune system dysfunction.

2,897 citations

Journal Article•DOI•
The Glymphatic System: A Beginner’s Guide

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Nadia Aalling Jessen1, Anne Sofie Finmann Munk1, Iben Lundgaard1•
University of Rochester Medical Center1
07 May 2015-Neurochemical Research
TL;DR: The glymphatic system is a recently discovered macroscopic waste clearance system that utilizes a unique system of perivascular tunnels, formed by astroglial cells, to promote efficient elimination of soluble proteins and metabolites from the central nervous system.
Abstract: The glymphatic system is a recently discovered macroscopic waste clearance system that utilizes a unique system of perivascular tunnels, formed by astroglial cells, to promote efficient elimination of soluble proteins and metabolites from the central nervous system. Besides waste elimination, the glymphatic system also facilitates brain-wide distribution of several compounds, including glucose, lipids, amino acids, growth factors, and neuromodulators. Intriguingly, the glymphatic system function mainly during sleep and is largely disengaged during wakefulness. The biological need for sleep across all species may therefore reflect that the brain must enter a state of activity that enables elimination of potentially neurotoxic waste products, including β-amyloid. Since the concept of the glymphatic system is relatively new, we will here review its basic structural elements, organization, regulation, and functions. We will also discuss recent studies indicating that glymphatic function is suppressed in various diseases and that failure of glymphatic function in turn might contribute to pathology in neurodegenerative disorders, traumatic brain injury and stroke.

1,144 citations

Cites background from "Evaluating glymphatic pathway funct..."

  • ...It is in this regard important to note that subsequent analysis showed that intrathecal lumbar injections, which are routinely used in clinical myelographic studies, provide a viable alternative route to assess the basic parameters of glymphatic function [135]....

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Journal Article•DOI•
Clearance systems in the brain—implications for Alzheimer disease

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Jenna M. Tarasoff-Conway1, Roxana O. Carare2, Ricardo S. Osorio1, Lidia Glodzik1, Tracy Butler1, Els Fieremans1, Leon Axel1, Henry Rusinek1, Charles Nicholson1, Berislav V. Zlokovic3, Blas Frangione1, Kaj Blennow4, Joël Ménard5, Henrik Zetterberg4, Thomas Wisniewski1, Mony J. de Leon1 •
New York University1, Southampton General Hospital2, University of Southern California3, University of Gothenburg4, Paris Descartes University5
01 Aug 2015-Nature Reviews Neurology
TL;DR: The clearance systems of the brain as they relate to proteins implicated in AD pathology are described, with the main focus on Aβ.
Abstract: Accumulation of toxic protein aggregates-amyloid-β (Aβ) plaques and hyperphosphorylated tau tangles-is the pathological hallmark of Alzheimer disease (AD). Aβ accumulation has been hypothesized to result from an imbalance between Aβ production and clearance; indeed, Aβ clearance seems to be impaired in both early and late forms of AD. To develop efficient strategies to slow down or halt AD, it is critical to understand how Aβ is cleared from the brain. Extracellular Aβ deposits can be removed from the brain by various clearance systems, most importantly, transport across the blood-brain barrier. Findings from the past few years suggest that astroglial-mediated interstitial fluid (ISF) bulk flow, known as the glymphatic system, might contribute to a larger portion of extracellular Aβ (eAβ) clearance than previously thought. The meningeal lymphatic vessels, discovered in 2015, might provide another clearance route. Because these clearance systems act together to drive eAβ from the brain, any alteration to their function could contribute to AD. An understanding of Aβ clearance might provide strategies to reduce excess Aβ deposits and delay, or even prevent, disease onset. In this Review, we describe the clearance systems of the brain as they relate to proteins implicated in AD pathology, with the main focus on Aβ.

1,047 citations

Journal Article•DOI•
Physiology of astroglia

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Alexei Verkhratsky
01 Jan 2018-Physiological Reviews
TL;DR: Astrocytes are tightly integrated into neural networks and act within the context of neural tissue; astrocytes control homeostasis of the CNS at all levels of organization from molecular to the whole organ.
Abstract: Astrocytes are neural cells of ectodermal, neuroepithelial origin that provide for homeostasis and defense of the central nervous system (CNS). Astrocytes are highly heterogeneous in morphological appearance; they express a multitude of receptors, channels, and membrane transporters. This complement underlies their remarkable adaptive plasticity that defines the functional maintenance of the CNS in development and aging. Astrocytes are tightly integrated into neural networks and act within the context of neural tissue; astrocytes control homeostasis of the CNS at all levels of organization from molecular to the whole organ.

921 citations

Cites methods from "Evaluating glymphatic pathway funct..."

  • ...With the use of magnetic resonance imaging (MRI) in rats (760), it was shown that clinically relevant lumbar intrathecal administration of CSF tracers permits the capture of all the key components necessary to assess glymphatic function (1914)....

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Journal Article•DOI•
Impairment of paravascular clearance pathways in the aging brain

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Benjamin T. Kress1, Jeffrey J. Iliff2, Jeffrey J. Iliff1, Maosheng Xia1, Maosheng Xia3, Minghuan Wang1, Helen S. Wei1, Douglas M. Zeppenfeld2, Lulu Xie1, Hongyi Kang1, Qiwu Xu1, Jason Liew1, Benjamin A. Plog1, Fengfei Ding2, Fengfei Ding1, Rashid Deane1 •
University of Rochester1, Oregon Health & Science University2, China Medical University (PRC)3
01 Dec 2014-Annals of Neurology
TL;DR: Evaluating the efficiency of CSF–ISF exchange and interstitial solute clearance is impaired in the aging brain found that bulk flow drainage via the glymphatic system is driven by cerebrovascular pulsation, and is dependent on astroglial water channels that line paravascular CSF pathways.
Abstract: Objective: In the brain, protein waste removal is partly performed by paravascular pathways that facilitate convective exchange of water and soluble contents between cerebrospinal fluid (CSF) and interstitial fluid (ISF). Several lines of evidence suggest that bulk flow drainage via the glymphatic system is driven by cerebrovascular pulsation, and is dependent on astroglial water channels that line paravascular CSF pathways. The objective of this study was to evaluate whether the efficiency of CSF–ISF exchange and interstitial solute clearance is impaired in the aging brain. Methods: CSF–ISF exchange was evaluated by in vivo and ex vivo fluorescence microscopy and interstitial solute clearance was evaluated by radiotracer clearance assays in young (2–3 months), middle-aged (10–12 months), and old (18–20 months) wild-type mice. The relationship between age-related changes in the expression of the astrocytic water channel aquaporin-4 (AQP4) and changes in glymphatic pathway function was evaluated by immunofluorescence. Results: Advancing age was associated with a dramatic decline in the efficiency of exchange between the subarachnoid CSF and the brain parenchyma. Relative to the young, clearance of intraparenchymally injected amyloid-b was impaired by 40% in the old mice. A 27% reduction in the vessel wall pulsatility of intracortical arterioles and widespread loss of perivascular AQP4 polarization along the penetrating arteries accompanied the decline in CSF–ISF exchange. Interpretation: We propose that impaired glymphatic clearance contributes to cognitive decline among the elderly and may represent a novel therapeutic target for the treatment of neurodegenerative diseases associated with accumulation of misfolded protein aggregates. ANN NEUROL 2014;76:845–861

886 citations

Cites result from "Evaluating glymphatic pathway funct..."

  • ...Additionally, we have observed that at infusion rates that do not change ICP, paravascular CSF tracer flux follows the same patterns observed in the present study.(5,8) Because paravascular CSF recirculation occurs long after the normalization of ICP after the cessation of tracer infusion, the CSF tracer fluxes observed in the present study appear to represent the physiological movement of CSF along paravascular spaces after the tracer loading that occurs during the 5-minute infusion period....

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References
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Journal Article•DOI•
The Amyloid Hypothesis of Alzheimer's Disease: Progress and Problems on the Road to Therapeutics

[...]

John Hardy1, Dennis J. Selkoe2•
National Institutes of Health1, Brigham and Women's Hospital2
19 Jul 2002-Science
TL;DR: It has been more than 10 years since it was first proposed that the neurodegeneration in Alzheimer's disease (AD) may be caused by deposition of amyloid β-peptide in plaques in brain tissue and the rest of the disease process is proposed to result from an imbalance between Aβ production and Aβ clearance.
Abstract: It has been more than 10 years since it was first proposed that the neurodegeneration in Alzheimer9s disease (AD) may be caused by deposition of amyloid β-peptide (Aβ) in plaques in brain tissue. According to the amyloid hypothesis, accumulation of Aβ in the brain is the primary influence driving AD pathogenesis. The rest of the disease process, including formation of neurofibrillary tangles containing tau protein, is proposed to result from an imbalance between Aβ production and Aβ clearance.

12,652 citations

"Evaluating glymphatic pathway funct..." refers background in this paper

  • ...; licensee BioMed Central Lt Commons Attribution License (http://creativec reproduction in any medium, provided the or peptides and accumulation of hyperphosphorylated tau in neurofibrillary tangles are believed to contribute to the pathophysiology of AD [2-4], while analogous misfolded proteins aggregate in other neurodegenerative diseases, including Huntington’s disease and amyotrophic lateral sclerosis (ALS) [5-7]....

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Journal Article•DOI•
A paravascular pathway facilitates CSF flow through the brain parenchyma and the clearance of interstitial solutes, including amyloid β.

[...]

Jeffrey J. Iliff1, Minghuan Wang1, Minghuan Wang2, Yonghong Liao1, Benjamin A. Plogg1, Weiguo Peng1, Georg Andreas Gundersen3, Helene Benveniste4, G. Edward Vates1, Rashid Deane1, Steven A. Goldman1, Erlend A. Nagelhus3 •
University of Rochester Medical Center1, Huazhong University of Science and Technology2, University of Oslo3, Stony Brook University4
15 Aug 2012-Science Translational Medicine
TL;DR: An anatomically distinct clearing system in the brain that serves a lymphatic-like function is described and may have relevance for understanding or treating neurodegenerative diseases that involve the mis-accumulation of soluble proteins, such as amyloid β in Alzheimer's disease.
Abstract: Because it lacks a lymphatic circulation, the brain must clear extracellular proteins by an alternative mechanism. The cerebrospinal fluid (CSF) functions as a sink for brain extracellular solutes, but it is not clear how solutes from the brain interstitium move from the parenchyma to the CSF. We demonstrate that a substantial portion of subarachnoid CSF cycles through the brain interstitial space. On the basis of in vivo two-photon imaging of small fluorescent tracers, we showed that CSF enters the parenchyma along paravascular spaces that surround penetrating arteries and that brain interstitial fluid is cleared along paravenous drainage pathways. Animals lacking the water channel aquaporin-4 (AQP4) in astrocytes exhibit slowed CSF influx through this system and a ~70% reduction in interstitial solute clearance, suggesting that the bulk fluid flow between these anatomical influx and efflux routes is supported by astrocytic water transport. Fluorescent-tagged amyloid β, a peptide thought to be pathogenic in Alzheimer's disease, was transported along this route, and deletion of the Aqp4 gene suppressed the clearance of soluble amyloid β, suggesting that this pathway may remove amyloid β from the central nervous system. Clearance through paravenous flow may also regulate extracellular levels of proteins involved with neurodegenerative conditions, its impairment perhaps contributing to the mis-accumulation of soluble proteins.

3,368 citations

"Evaluating glymphatic pathway funct..." refers background or methods or result in this paper

  • ...CSF-ISF exchange along these perivascular pathways was supported by astroglial aquaporin-4 water channels and the movement of fluid through this pathway facilitated the clearance of interstitial solutes, including soluble Aβ, from the brain....

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  • ...Alternatively, this may reflect the lower levels of CSF tracer penetration into the subcortical white matter observed in our prior study [16]....

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  • ...Intracisternal CSF tracer infusions were carried out in a parallel group of animals to provide a direct comparison to the infusion route used previously [16,20]....

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  • ...The glymphatic system, a brain-wide perivascular pathway along which cerebrospinal fluid (CSF) and interstitial fluid (ISF) rapidly exchange, has recently been identified as a key contributor to the clearance of interstitial solutes from the brain, including amyloid β....

    [...]

  • ...In a recent study we reported that a large proportion of subarachnoid cerebrospinal fluid (CSF) recirculates through the brain parenchyma along perivascular spaces, exchanging with brain interstitial fluid (ISF) before being cleared via peri-venous pathways [15,16]....

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Journal Article•DOI•
Protein aggregation and neurodegenerative disease.

[...]

Christopher A. Ross1, Michelle A. Poirier1•
Johns Hopkins University School of Medicine1
01 Jul 2004-Nature Medicine
TL;DR: There is increased understanding of the pathways involved in protein aggregation, and some recent clues have emerged as to the molecular mechanisms of cellular toxicity, leading to approaches toward rational therapeutics.
Abstract: Neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS) and prion diseases are increasingly being realized to have common cellular and molecular mechanisms including protein aggregation and inclusion body formation. The aggregates usually consist of fibers containing misfolded protein with a beta-sheet conformation, termed amyloid. There is partial but not perfect overlap among the cells in which abnormal proteins are deposited and the cells that degenerate. The most likely explanation is that inclusions and other visible protein aggregates represent an end stage of a molecular cascade of several steps, and that earlier steps in the cascade may be more directly tied to pathogenesis than the inclusions themselves. For several diseases, genetic variants assist in explaining the pathogenesis of the more common sporadic forms and developing mouse and other models. There is now increased understanding of the pathways involved in protein aggregation, and some recent clues have emerged as to the molecular mechanisms of cellular toxicity. These are leading to approaches toward rational therapeutics.

2,926 citations

"Evaluating glymphatic pathway funct..." refers background in this paper

  • ...Bruijn LI, Houseweart MK, Kato S, Anderson KL, Anderson SD, Ohama E, Reaume AG, Scott RW, Cleveland DW: Aggregation and motor neuron toxicity of an ALS-linked SOD1 mutant independent from wild-type SOD1....

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  • ...Extracellular depositions of amyloid β (Aβ) * Correspondence: Jeffrey_Iliff@urmc.rochester.edu; Nedergaard@urmc. rochester.edu 5Department of Anesthesiology and Peri-Operative Medicine, Oregon Health & Science University, Portland, OR 97239, USA 1Center for Translational Neuromedicine, Department of Neurosurgery, University of Rochester Medical Center, 601 Elmwood Ave., Rochester, NY 14642, USA Full list of author information is available at the end of the article © 2013 Yang et al.; licensee BioMed Central Lt Commons Attribution License (http://creativec reproduction in any medium, provided the or peptides and accumulation of hyperphosphorylated tau in neurofibrillary tangles are believed to contribute to the pathophysiology of AD [2-4], while analogous misfolded proteins aggregate in other neurodegenerative diseases, including Huntington’s disease and amyotrophic lateral sclerosis (ALS) [5-7]....

    [...]

  • ...; licensee BioMed Central Lt Commons Attribution License (http://creativec reproduction in any medium, provided the or peptides and accumulation of hyperphosphorylated tau in neurofibrillary tangles are believed to contribute to the pathophysiology of AD [2-4], while analogous misfolded proteins aggregate in other neurodegenerative diseases, including Huntington’s disease and amyotrophic lateral sclerosis (ALS) [5-7]....

    [...]

Journal Article•
Protein aggregation and neurodegenerative disease

[...]

Christopher A. Ross, Michelle A. Poirier
01 Jan 2004-Neurodegeneration
TL;DR: The most likely explanation is that inclusions and other visible protein aggregates represent an end stage of a molecular cascade of several steps, and that earlier steps in the cascade may be more directly tied to pathogenesis than the inclusions themselves as discussed by the authors.

2,416 citations

Journal Article•DOI•
Diffusion in brain extracellular space.

[...]

Eva Syková1, Charles Nicholson•
Academy of Sciences of the Czech Republic1
01 Oct 2008-Physiological Reviews
TL;DR: Experimental studies with the real-time iontophoresis method employing the cation tetramethylammonium in normal brain tissue improve the conception of ECS structure and the roles of glia and extracellular matrix in modulating the ECS microenvironment.
Abstract: Diffusion in the extracellular space (ECS) of the brain is constrained by the volume fraction and the tortuosity and a modified diffusion equation represents the transport behavior of many molecule...

1,215 citations

"Evaluating glymphatic pathway funct..." refers background in this paper

  • ...of hydration measured for both 3 kD dextrans (<20 nm) and 500 kD dextrans (>20 nm) [34]....

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