Branding/Logomark minus Citation Combined Shape Icon/Bookmark-empty Icon/Copy Icon/Collection Icon/Close Copy 7 no author result Created with Sketch. Icon/Back Created with Sketch. Match!

Brain-wide pathway for waste clearance captured by contrast-enhanced MRI

Published on Mar 1, 2013in Journal of Clinical Investigation 12.28
· DOI :10.1172/JCI67677
Jeffrey J. Iliff24
Estimated H-index: 24
(UR: University of Rochester),
Hedok Lee14
Estimated H-index: 14
(SBU: Stony Brook University)
+ 3 AuthorsHelene Benveniste37
Estimated H-index: 37
(SBU: Stony Brook University)
Cite
Abstract
The glymphatic system is a recently defined brain-wide paravascular pathway for cerebrospinal fluid (CSF) and interstitial fluid (ISF) exchange that facilitates efficient clearance of solutes and waste from the brain. CSF enters the brain along para-arterial channels to exchange with ISF, which is in turn cleared from the brain along para-venous pathways. Because soluble amyloid β clearance depends on glymphatic pathway function, we proposed that failure of this clearance system contributes to amyloid plaque deposition and Alzheimer’s disease progression. Here we provide proof of concept that glymphatic pathway function can be measured using a clinically relevant imaging technique. Dynamic contrast-enhanced MRI was used to visualize CSF-ISF exchange across the rat brain following intrathecal paramagnetic contrast agent administration. Key features of glymphatic pathway function were confirmed, including visualization of para-arterial CSF influx and molecular size-dependent CSF-ISF exchange. Whole-brain imaging allowed the identification of two key influx nodes at the pituitary and pineal gland recesses, while dynamic MRI permitted the definition of simple kinetic parameters to characterize glymphatic CSF-ISF exchange and solute clearance from the brain. We propose that this MRI approach may provide the basis for a wholly new strategy to evaluate Alzheimer’s disease susceptibility and progression in the live human brain.
  • References (16)
  • Citations (282)
Cite
References16
Newest
Published on Aug 15, 2012in Science Translational Medicine 17.16
Jeffrey J. Iliff24
Estimated H-index: 24
(URMC: University of Rochester Medical Center),
Minghuan Wang6
Estimated H-index: 6
(URMC: University of Rochester Medical Center)
+ 8 AuthorsSteven A. Goldman88
Estimated H-index: 88
(URMC: University of Rochester Medical Center)
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...
Published on Aug 1, 2011in British Journal of Radiology 1.94
Bilal Battal11
Estimated H-index: 11
,
Murat Kocaoglu21
Estimated H-index: 21
+ 3 AuthorsCem Tayfun14
Estimated H-index: 14
Cerebrospinal fluid (CSF) spaces include ventricles and cerebral and spinal subarachnoid spaces. CSF motion is a combined effect of CSF production rate and superimposed cardiac pulsations. Knowledge of CSF dynamics has benefited considerably from the development of phase-contrast (PC) MRI. There are several disorders such as communicating and non-communicating hydrocephalus, Chiari malformation, syringomyelic cyst and arachnoid cyst that can change the CSF dynamics. The aims of this pictorial re...
Published on Mar 29, 2010in Glia 5.83
Thomas Misje Mathiisen4
Estimated H-index: 4
(University of Oslo),
Knut P. Lehre24
Estimated H-index: 24
(University of Oslo)
+ 1 AuthorsOle Petter Ottersen84
Estimated H-index: 84
(University of Oslo)
The unravelling of the polarized distribution of AQP4 in perivascular astrocytic endfeet has revitalized the interest in the role of astrocytes in controlling water and ion exchange at the brain–blood interface. The importance of the endfeet is based on the premise that they constitute a complete coverage of the vessel wall. Despite a number of studies based on different microscopic techniques this question has yet to be resolved. We have made an electron microscopic 3D reconstruction of perivas...
Published on Feb 1, 2010in Minimally Invasive Neurosurgery
U. Schick1
Estimated H-index: 1
,
C. Musahl1
Estimated H-index: 1
,
K. Papke1
Estimated H-index: 1
OBJECTIVE: Intracranial hypotension is a frequently misdiagnosed syndrome which is caused by reduced intracranial cerebrospinal fluid (CSF) pressure due to spontaneous spinal CSF leakage. We present our series of intracranial hypotension regarding especially the required diagnostic imaging and the treatment. METHODS: A retrospective analysis was performed on 8 patients (5 males, 3 females, mean age 49 years) with postural and non-postural headache due to spinal CSF collection. RESULTS: Cranial M...
Published on Aug 1, 2009in Journal of Neurochemistry 4.87
John Hardy149
Estimated H-index: 149
(UCL Institute of Neurology)
The amyloid hypothesis has been the basis for most work on the pathogenesis of Alzheimer’s disease. Recent clinical trials based on this hypothesis have been inconclusive. In this article I review the current status of the hypothesis and suggest that a major scientific need is to understand the normal function of amyloid-β precursor protein (APP) and think how this may relate to the cell death in the disease process.
Published on Oct 1, 2008in Physiological Reviews 24.25
Eva Syková10
Estimated H-index: 10
,
Charles Nicholson12
Estimated H-index: 12
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 molecules in the brain. Deviations from the equation reveal loss of molecules across the blood-brain barrier, through cellular uptake, binding, or other mechanisms. Early diffusion measurements used radiolabeled sucrose and other tracers. Presently, the real-time iontophoresis (RTI) method is employed for smal...
Published on Mar 1, 2008in Neurosurgery 4.61
Kubilay Aydin17
Estimated H-index: 17
(Istanbul University),
Ege Terzibasioglu5
Estimated H-index: 5
(Istanbul University)
+ 5 AuthorsM. Inan Turantan4
Estimated H-index: 4
(Istanbul University)
OBJECTIVE: Intrathecal gadolinium (Gd)-enhanced magnetic resonance (MR) cisternography is a newly introduced imaging method. Two main objectives of this study were to investigate the sensitivity of Gd-enhanced MR cisternography for presurgical localization of cerebrospinal fluid (CSF) leaks in patients with CSF rhinorrhea and to study the potential long-term adverse effects of intrathecal Gd application. METHODS: Fifty-one patients (19 women; mean age, 36.2 yr) with CSF rhinorrhea were included ...
Published on Jul 1, 2007in Journal of Cerebral Blood Flow and Metabolism 6.04
Dennis R. Groothuis36
Estimated H-index: 36
(NU: Northwestern University),
Michael W. Vavra3
Estimated H-index: 3
(NU: Northwestern University)
+ 5 AuthorsHoward L. Lipton39
Estimated H-index: 39
(NU: Northwestern University)
We examined the roles of diffusion, convection and capillary transporters in solute removal from extracellular space (ECS) of the brain. Radiolabeled solutes (eight with passive distribution and four with capillary or cell transporters) were injected into the brains of rats (n = 497) and multiple-time point experiments measured the amount remaining in brain as a function of time. For passively distributed compounds, there was a relationship between lipid:water solubility and total brain efflux:d...
Published on Mar 2, 2007in Pflügers Archiv: European Journal of Physiology 3.38
Jeppe Praetorius32
Estimated H-index: 32
(AU: Aarhus University)
The cerebrospinal fluid (CSF) provides mechanical and chemical protection of the brain and spinal cord. This review focusses on the contribution of the choroid plexus epithelium to the water and salt homeostasis of the CSF, i.e. the secretory processes involved in CSF formation. The choroid plexus epithelium is situated in the ventricular system and is believed to be the major site of CSF production. Numerous studies have identified transport processes involved in this secretion, and recently, t...
Published on Mar 1, 2005in Morphologie
R.O. Weller1
Estimated H-index: 1
(Southampton General Hospital)
Summary The meninges comprise the dura mater and the leptomeninges (arachnoid and pia mater). Dura forms an outer endosteal layer related to the bones of the skull and spine and an inner layer closely applied to the arachnoid mater. Leptomeninges have multiple functions and anatomical relationships. The outer parietal layer of arachnoid is impermeable to CSF due to tight intercellular junctions; elsewhere leptomeningeal cells form demosomes and gap junctions. Trabeculae of leptomeninges compartm...
Cited By282
Newest
Published on May 8, 2019in Acta neuropathologica communications
Alex J. Smith18
Estimated H-index: 18
(UCSF: University of California, San Francisco),
Tianjiao Duan (UCSF: University of California, San Francisco), A. S. Verkman125
Estimated H-index: 125
(UCSF: University of California, San Francisco)
Redistribution of the water channel aquaporin-4 (AQP4) away from astrocyte endfeet and into parenchymal processes is a striking histological feature in mouse models of Alzheimer’s disease (AD) and other neurological conditions with prominent astrogliosis. AQP4 redistribution has been proposed to impair bulk Aβ clearance in AD, resulting in increased amyloid deposition in the brain; however, this finding is controversial. Here, we provide evidence in support of a different and novel role of AQP4 ...
Published in Scientific Reports 4.01
Kulam Najmudeen Magdoom2
Estimated H-index: 2
(UF: University of Florida),
Alec C. Brown (UF: University of Florida)+ -3 AuthorsMalisa Sarntinoranont19
Estimated H-index: 19
(UF: University of Florida)
Investigating the mechanisms by which metabolic wastes are cleared from nervous tissue is important for understanding natural function and the pathophysiology of several neurological disorders including Alzheimer’s disease. Recent evidence suggests clearance may be the function of annular spaces around cerebral blood vessels, called perivascular spaces (PVS), through which cerebrospinal fluid (CSF) is transported from the subarachnoid space into brain parenchyma to exchange with interstitial flu...
Published on Mar 6, 2019in Fluids and Barriers of the CNS
Lori Ray (MSU: Montana State University), Jeffrey J. Iliff24
Estimated H-index: 24
(OHSU: Oregon Health & Science University)
+ 0 AuthorsJeffrey J. Heys19
Estimated H-index: 19
(MSU: Montana State University)
Background Despite advances in in vivo imaging and experimental techniques, the nature of transport mechanisms in the brain remain elusive. Mathematical modelling verified using available experimental data offers a powerful tool for investigating hypotheses regarding extracellular transport of molecules in brain tissue. Here we describe a tool developed to aid in investigation of interstitial transport mechanisms, especially the potential for convection (or bulk flow) and its relevance to inters...
Published on Mar 26, 2019in Fluids and Barriers of the CNS
Joel A. Berliner (Macquarie University), Thomas Woodcock (Macquarie University)+ 5 AuthorsMarcus A. Stoodley28
Estimated H-index: 28
(Macquarie University)
Background Fluid homeostasis in the central nervous system (CNS) is essential for normal neurological function. Cerebrospinal fluid (CSF) in the subarachnoid space and interstitial fluid circulation in the CNS parenchyma clears metabolites and neurotransmitters and removes pathogens and excess proteins. A thorough understanding of the normal physiology is required in order to understand CNS fluid disorders, including post-traumatic syringomyelia. The aim of this project was to compare fluid tran...
Published on Feb 27, 2019in Molecular Neurodegeneration 8.27
Tirth K. Patel4
Estimated H-index: 4
(WashU: Washington University in St. Louis),
LeMoyne Habimana-Griffin2
Estimated H-index: 2
(WashU: Washington University in St. Louis)
+ 9 AuthorsPatrick W. Sheehan1
Estimated H-index: 1
(WashU: Washington University in St. Louis)
Background Alzheimer’s disease is characterized by two main neuropathological hallmarks: extracellular plaques of amyloid-β (Aβ) protein and intracellular aggregates of tau protein. Although tau is normally a soluble monomer that bind microtubules, in disease it forms insoluble, hyperphosphorylated aggregates in the cell body. Aside from its role in AD, tau is also involved in several other neurodegenerative disorders collectively called tauopathies, such as progressive supranuclear palsy (PSP),...
Published in Free Radical Biology and Medicine 5.66
Yiming Cheng (NJIT: New Jersey Institute of Technology), Xinglei Liu3
Estimated H-index: 3
(NJIT: New Jersey Institute of Technology)
+ -3 AuthorsJames Haorah27
Estimated H-index: 27
(NJIT: New Jersey Institute of Technology)
Abstract The efficient clearance of the interstitial waste metabolites is essential for the normal maintenance of brain homeostasis. The brain lacks the lymphatic clearance system. Thus, the drainage of waste metabolites in the brain is dependent on a slow flow of cerebrospinal fluid (CSF) system. Glymphatic system claims the direct bulk flow transport of small size water-soluble waste metabolites into to the perivenous space by aquaporin-4 water channels of the astrocyte end-feet, but it did no...
Juan Piantino3
Estimated H-index: 3
(OHSU: Oregon Health & Science University),
Miranda M. Lim (OHSU: Oregon Health & Science University)+ -3 AuthorsJeffrey J. Iliff24
Estimated H-index: 24
(OHSU: Oregon Health & Science University)
Purpose of the Review Traumatic brain injury (TBI) is a major public health concern in the USA and worldwide. Sleep disruption and headaches are two of the most common problems reported by patients after TBI. In this manuscript, we review the current knowledge regarding the relation between post-traumatic sleep disruption and headaches. We also describe the role of the glymphatic system as a potential link between TBI, sleep, and headaches.
Published in Journal of Magnetic Resonance Imaging 3.73
Toshiaki Taoka26
Estimated H-index: 26
,
Shinji Naganawa41
Estimated H-index: 41
Published on Jun 17, 2019in The Journal of Neuroscience 6.07
Kristian Mortensen2
Estimated H-index: 2
(UCPH: University of Copenhagen),
Simon Sanggaard1
Estimated H-index: 1
(Yale University)
+ 5 AuthorsHelene Benveniste6
Estimated H-index: 6
(Yale University)
The glymphatic system is a brain-wide cerebrospinal fluid (CSF) transport system that utilizes the perivascular space for fast inflow of CSF. Arterial pulsations are a major driver of glymphatic CSF inflow, and hypertension that causes vascular pathologies, such as arterial stiffening and perivascular alterations, may impede the inflow. We used dynamic contrast-enhanced MRI (DCE-MRI) to assess the effect of hypertension on glymphatic transport kinetics in male young and adult spontaneously hyper...