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Impairment of paravascular clearance pathways in the aging brain
Open accessAbstract
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‐β 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
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“In AD, reactive astrogliosis is upregulated corresponds to the severity of astroglial activation and high levels of proinflammatory cytokines and the hypertrophic processes make aberrant contacts with nearby cerebral vessels and neurons, leading to neurovascular uncoupling.[ 42 ]”
From Multifunctional Nanostructure RAP‐RL Rescues Alzheimer's Cognitive Deficits through Remodeling the Neurovascular Unit (2021) · cites this paper as [42]
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“Impaired glymphatic function has been suggested to be instrumental in a range of brain diseases; this has been illustrated most in Alzheimer's dementia (7, 19, 20) but has also been shown to be relevant in posttraumatic encephalopathy (21), ageing (22), sleep (23, 24), depression (20), and exercise (25).”
From Brain-wide glymphatic enhancement and clearance in humans assessed with MRI. (2018) · cites this paper as [22]
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In the citing paper
“and paravascular clearance has been shown to be impaired with ageing (22).”
From Brain-wide glymphatic enhancement and clearance in humans assessed with MRI. (2018) · cites this paper as [22]
In the citing paper
“Yet the glymphatic system degrades with age, suggesting a causal relationship between sleep disturbance and symptomatic progression in the neurodegenerative dementias.”
From Glymphatic failure as a final common pathway to dementia (2020) · cites this paper as [52]
In the citing paper
“Aging is also associated with a steep fall in glymphatic flow in the brains of both rodents and humans.”
From Glymphatic failure as a final common pathway to dementia (2020) · cites this paper as [52]
In the citing paper
“CSF inflow of larger tracers are reduced by up to 85% in aged wild-type mice”
From Glymphatic failure as a final common pathway to dementia (2020) · cites this paper as [52]
In the citing paper
“The decrease in glymphatic flow in old mice is in part mediated by mislocation of AQP4 water channels away from the vascular wall (52) and possible by atrophy of meningeal lymphatic vessel (42).”
From Glymphatic failure as a final common pathway to dementia (2020) · cites this paper as [52]
In the citing paper
“while contrast clearance in human brain tissue was inversely correlated to age in all subjects studied (50, 52–54).”
From Glymphatic failure as a final common pathway to dementia (2020) · cites this paper as [52]
In the citing paper
“As individuals age, there is a decline in the efficiency of these transport mechanisms in eliminating waste products such as Aβ.156,157”
From Antiageing strategy for neurodegenerative diseases: from mechanisms to clinical advances (2025) · cites this paper as [157]
In the citing paper
“both the brain glymphatic and meningeal lymphatic systems deteriorate with age”
From Living on the Edge of the CNS: Meninges Cell Diversity in Health and Disease (2021) · cites this paper as Kress et al., 2014
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Iliff, J. J., Wang, M., Liao, Y., Plogg, B. A., Peng, W., Gundersen, G. A., Benveniste, H., Vates, G. E., Deane, R., Goldman, S. A., et al. (2012) · Science Translational Medicine · doi:10.1126/scitranslmed.3003748 · Cited by 5,824 · cited 10×
“nel and measuring the thresholded area as a percentage of the overall region area, as described previously.(4) The fluorescence area”
BackgroundMethodInfluentialSelf-citationSleep Drives Metabolite Clearance from the Adult Brain
Xie, L., Kang, H., Xu, Q., Chen, M. J., Liao, Y., Thiyagarajan, M., O’Donnell, J., Christensen, D. J., Nicholson, C., Iliff, J. J., et al. (2013) · Science · doi:10.1126/science.1241224 · Cited by 5,411 · cited 10×
“In a prior study, we observed that dynamic changes in the brain extracellular volume fraction are key regulators of glymphatic pathway function during the sleep– wake cycle, greater extracellular volume fraction during sleep facilitating the exchange of paravascular CSF with ISF.(6) The decline in glymphatic pathway a…”
BackgroundMethodInfluentialSelf-citationProtein aggregation and neurodegenerative disease
Ross, C. A., & Poirier, M. A. (2004) · Nature Medicine · doi:10.1038/nm1066 · Cited by 3,454 · cited 1×
“A central histopathological hallmark of each of these diseases is the presence of misaggregated proteins, including senile plaques comprised of amyloid-b (Ab) in AD, neurofibrillary tangles comprised of hyperphosphorylated tau in AD and CTE, Pick bodies comprised of hyperphosphorylated tau in frontotemporal dementia,…”
BackgroundJUNCTIONS BETWEEN INTIMATELY APPOSED CELL MEMBRANES IN THE VERTEBRATE BRAIN
Brightman, M., & Reese, T. S. (1969) · The Journal of Cell Biology · doi:10.1083/jcb.40.3.648 · Cited by 2,457
Decreased Clearance of CNS β-Amyloid in Alzheimer’s Disease
Mawuenyega, K. G., Sigurdson, W., Ovod, V., Munsell, L., Kasten, T., Morris, J. C., Yarasheski, K. E., & Bateman, R. J. (2010) · Science · doi:10.1126/science.1197623 · Cited by 2,078
Diffusion in Brain Extracellular Space
Syková, E., & Nicholson, C. (2008) · Physiological Reviews · doi:10.1152/physrev.00027.2007 · Cited by 1,481
Nielsen, S. M., Nagelhus, E. A., Amiry-Moghaddam, M. R., Bourque, C. W., Agre, P. C., & Ottersen, O. P. (1997) · Journal of Neuroscience · doi:10.1523/jneurosci.17-01-00171.1997 · Cited by 1,440 · cited 1×
“Perivascular AQP4 Polarization Is Impaired in the Aging Brain AQP4, an astroglial water channel, is localized in a highly polarized manner to endfoot processes surrounding the cerebral vasculature in addition to the glial limitans externa, which abuts the pia mater and bounds the subarachnoid CSF compartment.(19,20) T…”
BackgroundShibata, M., Yamada, S., Kumar, S. R., Calero, M., Bading, J., Frangione, B., Holtzman, D. M., Miller, C. A., Strickland, D. K., Ghiso, J., et al. (2000) · Journal of Clinical Investigation · doi:10.1172/jci10498 · Cited by 1,413 · cited 1×
“In addition to paravascular pathways of Ab clearance, the clearance of Ab by BBB transporters such as low-density lipoprotein receptor–related protein 1 are major contributors to Ab efflux from the brain.(15) We surmise that these are likely overlapping processes.”
BackgroundCerebral Arterial Pulsation Drives Paravascular CSF–Interstitial Fluid Exchange in the Murine Brain
Iliff, J. J., Wang, M., Zeppenfeld, D. M., Venkataraman, A., Plog, B. A., Liao, Y., Deane, R., & Nedergaard, M. (2013) · The Journal of Neuroscience · doi:10.1523/jneurosci.1592-13.2013 · Cited by 1,319 · cited 4×
“Impairment of glymphatic pathway function was accompanied by a 27% reduction in cerebral arterial wall pulsatility, which is an important contributor to paravascular flux along the glymphatic pathway.(7,17,26) In addition, we show that impairment of paravascular CSF–ISF exchange is similarly associated with loss of pe…”
BackgroundMethodResultInfluentialSelf-citationLindsay, J. (2002) · American Journal of Epidemiology · doi:10.1093/aje/kwf074 · Cited by 1,261 · cited 1×
“In the case of AD, incidence increases from approximately 12% in the 70s to >50% in the 80s.(1) A central histopathological hallmark of each of these diseases is the presence of misaggregated proteins, including senile plaques comprised of amyloid-b (Ab) in AD, neurofibrillary tangles comprised of hyperphosphorylated…”
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Jiang, Q. (2019) · Stroke and Vascular Neurology · doi:10.1136/svn-2018-000197 · Cited by 38
“CSF tracer clearance was gradually reduced from middle-aged (12–13 months) to old (18 months) brain compared with young (2–3 months) brain.(11) In mouse Alzheimer’s disease model, Peng et al found reduced clearance of β-amyloid and glymphatic influx which worsened with advanced age.”
BackgroundMagnetic Resonance Imaging and Modeling of the Glymphatic System
Kaur, J., Davoodi‐Bojd, E., Fahmy, L. M., Zhang, L., Ding, G., Hu, J., Zhang, Z., Chopp, M., & Jiang, Q. (2020) · Diagnostics · doi:10.3390/diagnostics10060344 · Cited by 40
Light sheet fluorescence microscopy of optically cleared brains for studying the glymphatic system
Bèchet, N. B., Kylkilahti, T. M., Mattsson, B., Petrášová, M., Shanbhag, N. C., & Lundgaard, I. (2020) · Journal of Cerebral Blood Flow & Metabolism · doi:10.1177/0271678x20924954 · Cited by 41
“Brain slice analysis has been confined to five to six coronal slices as processing entire brains using this method would be extremely laborious and time consuming.(17,36) Our main aim with this study was to establish whether light sheet microscopy of optically cleared brains could be used to study glymphatic function…”
MethodResidual Disease in Glioma Recurrence: A Dangerous Liaison with Senescence
Putavet, D. A., & de Keizer, P. L. J. (2021) · Cancers · doi:10.3390/cancers13071560 · Cited by 41
Uchida, K. (2022) · Cells · doi:10.3390/cells11050919 · Cited by 41
“Aging is partly associated with the loss of perivascular aquaporin-4 polarization, resulting in the impairment of CSF–ISF exchange [37].”
BackgroundMethodGlymphatic System Dysfunction in Central Nervous System Diseases and Mood Disorders
Zhang, D., Li, X., & Li, B. (2022) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2022.873697 · Cited by 40
Sensitivity analysis on a network model of glymphatic flow
Stevens, K. A., Tithof, J., Cook, D. D., Thomas, J. H., & Kelley, D. H. (2022) · Journal of The Royal Society Interface · doi:10.1098/rsif.2022.0257 · Cited by 39
Kim, Y., Pérez‐González, R., Miller, C., Kurz, M., D’Acunzo, P., Goulbourne, C. N., & Levy, E. (2022) · Neurochemical Research · doi:10.1007/s11064-022-03701-1 · Cited by 42
“1 3 brain, leading to cognitive decline among the elderly [39].”
Assessment of factors influencing glymphatic activity and implications for clinical medicine
Gędek, A., Koziorowski, D., & Szlufik, S. (2023) · Frontiers in Neurology · doi:10.3389/fneur.2023.1232304 · Cited by 47
“Such an arrangement of channels (polarization), enables real communication between the CSF and the parenchyma of the brain (16), and the mixing of fluids (CSF and ISF–interstitial fluid).”
Anti‐seizure medication response and the glymphatic system in patients with focal epilepsy
Kim, S. T., Kim, S. E., Lee, D. A., Lee, H., & Park, K. M. (2023) · European Journal of Neurology · doi:10.1111/ene.16097 · Cited by 39
“Reductions in glymphatic system function are mediated by mislocation of aquaporin 4 water channels away from the vascular wall and possibly by atrophy of meningeal lymphatic vessels with aging [44, 45].”
BackgroundYue, Y., Zhang, X., Lv, W., Lai, H., & Shen, T. (2023) · Neural Regeneration Research · doi:10.4103/1673-5374.390970 · Cited by 38
“Previous studies have revealed that glymphatic clearance dysfunction can occur in aged brains (Kress et al., 2014) and neurodegeneration diseases (Ringstad et al., 2017).”
BackgroundMicrostructural Bias in the Assessment of Periventricular Flow as Revealed in Postmortem Brains
Li, S., Chen, R., Cao, Z., Zhu, Q., Ma, Y., Zhu, K., Lin, Z., Wu, D., & Initiative, A. D. N. (2025) · Radiology · doi:10.1148/radiol.250753 · Cited by 39
Howe, M. D., Atadja, L. A., Furr, J. W., Maniskas, M. E., Zhu, L., McCullough, L. D., & Urayama, A. (2018) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2018.07.019 · Cited by 36
“Previous work has shown that aging impairs glymphatic flow (Kress et al., 2014), and that multiple microinfarctions disrupt CSF flow in middle-aged mice (12 months-old)(Venkat et al., 2017; Wang et al., 2017).”
BackgroundCombined effects of aquaporin-4 and hypoxia produce age-related hydrocephalus
Trillo-Contreras, J. L., Ramírez‐Lorca, R., Hiraldo-González, L., Sánchez-Gomar, I., Galán‐Cobo, A., Suárez‐Luna, N., Pedro, E. S. D. R.-D., Toledo‐Aral, J. J., Villadiego, J., & Echevarrı́a, M. (2018) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2018.08.006 · Cited by 41
Higher physiological vulnerability to hypoxic exposure with advancing age in the human brain
Vestergaard, M. B., Jensen, M. L., Arngrim, N., Lindberg, U., & Larsson, H. B. W. (2018) · Journal of Cerebral Blood Flow & Metabolism · doi:10.1177/0271678x18818291 · Cited by 38
“Inhibited clearance of waste products in the brain has been discussed as a major contributor to declining brain health and the development of neurodegenerative diseases.(22,48) Thus, cerebral lactate concentration could be used as a marker of brain clearance function.”
BackgroundCircadian Rhythm Disruption and Alzheimer's Disease: The Dynamics of a Vicious Cycle
Sharma, A., Sethi, G., Tambuwala, M. M., Aljabali, A. A. A., Chellappan, D. K., Dua, K., & Goyal, R. (2020) · Current Neuropharmacology · doi:10.2174/1570159x18666200429013041 · Cited by 50
Back, D. B., Choi, B., Han, J., Kwon, K. J., Choi, D., Shin, C. Y., Lee, J., & Kim, H. Y. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21186929 · Cited by 38
“Change in the AQP4 distribution from a perivascular to a parenchymal pattern, also known as the depolarization of AQP4, has been reported in various animal [8,12,17,32] and human studies [33,34] of various neurodegenerative diseases.”
ResultIseki, C., Takahashi, Y., Adachi, M., Igari, R., Sato, H., Koyama, S., Ishizawa, K., Ohta, Y., & Kato, T. (2022) · Acta Neurologica Scandinavica · doi:10.1111/ane.13710 · Cited by 37
Alghanimy, A., Martin, C., Gallagher, L., & Holmes, W. M. (2023) · PLoS ONE · doi:10.1371/journal.pone.0282955 · Cited by 39
“the brain of aged mice, possibly due to reduced arterial pulsatility, along with changes in AQP4 expression [37].”
BackgroundSun, M., Zhang, M., Di, F., Bai, W., Sun, J., Zhang, M., Sun, J., Li, M., & Liang, X. (2024) · Ecotoxicology and Environmental Safety · doi:10.1016/j.ecoenv.2024.116874 · Cited by 41
Lian, X., Liu, Z., Gan, Z., Yan, Q., Tong, L., Qiu, L., Liu, Y., Chen, J., & Li, Z. (2025) · Neural Regeneration Research · doi:10.4103/nrr.nrr-d-24-00764 · Cited by 40
“This decline is likely due to diminished arteriole vessel-wall pulsatility and extensive depolarization of AQP4 (Kress et al., 2014).”
InfluentialCan insulin signaling pathways be targeted to transport Aβ out of the brain?
Vandal, M., Bourassa, P., & Calon, F. (2015) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2015.00114 · Cited by 37
“Experiments with intraparenchymal radiotracer injections show that significant amount of Aβ is effluxed through paravascular glymphatic system from the interstitial space to the CSF (Kress et al., 2014).”
Experimental alcoholism primes structural and functional impairment of the glymphatic pathway
Liu, Q., Yan, L., Huang, M., Zeng, H., Satyanarayanan, S. K., Shi, Z., Chen, D., Lu, J., Pei, Z., Yao, X., et al. (2019) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2019.06.029 · Cited by 38
Defining novel functions for cerebrospinal fluid in ALS pathophysiology
Kwong, K. C. N. K., Mehta, A. R., Nedergaard, M., & Chandran, S. (2020) · Acta Neuropathologica Communications · doi:10.1186/s40478-020-01018-0 · Cited by 41
Self-citationMarkovic, S. J., Fitzgerald, M., Peiffer, J. J., Scott, B. R., Rainey‐Smith, S. R., Sohrabi, H. R., & Brown, B. M. (2021) · Ageing Research Reviews · doi:10.1016/j.arr.2021.101322 · Cited by 37
Chen, J., Wang, L., Xu, H., Wang, Y., & Liang, Q. (2021) · Journal of Leukocyte Biology · doi:10.1002/jlb.5mr0321-632r · Cited by 38
Zhou, X., Li, Y., Lenahan, C., Ou, Y., Wang, M., & He, Y. (2021) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2021.698036 · Cited by 39
Self-citationDynamic infrared imaging of cerebrospinal fluid tracer influx into the brain
Keil, S. A., Braun, M., O’Boyle, R. P., Sevao, M., Pedersen, T. J., Agarwal, S., Jansson, D., & Iliff, J. J. (2022) · Neurophotonics · doi:10.1117/1.nph.9.3.031915 · Cited by 36
Self-citationWijesinghe, P., Whitmore, C. A., Campbell, M., Li, C. H., Tsuyuki, M., To, E. C., Haynes, J. R., Pham, W. N., & Matsubara, J. A. (2023) · Frontiers in Neuroscience · doi:10.3389/fnins.2023.1107436 · Cited by 37
“Several studies have reported AQP4 depolarization with AD pathology (Yang et al., 2011; Kress et al., 2014), notably in human postmortem frontal cortex tissue (Zeppenfeld et al.”
BackgroundGruenbaum, B. F., Zlotnik, A. A., Frenkel, A., Fleidervish, I. A., & Boyko, M. (2022) · Metabolites · doi:10.3390/metabo12050459 · Cited by 36
“In several different animal models of brain insult, including models of AD [41], aging [42], epilepsy [43] and ICH [44], AQP4 expression is lessened and its polarity becomes disrupted.”
BackgroundAquaporin 4 is differentially increased and dislocated in association with tau and amyloid-beta
Kecheliev, V., Boss, L., Maheshwari, U., Konietzko, U., Keller, A., Razansky, D., Nitsch, R. M., Klohs, J., & Ni, R. (2023) · Life Sciences · doi:10.1016/j.lfs.2023.121593 · Cited by 36
Wei, X., Huang, G., Liu, J., Ge, J., Zhang, W., & Mei, Z. (2023) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2023.114619 · Cited by 35
Regulation of microglia phagocytosis and potential involvement of exercise
Li, C., Wang, Y., Xing, Y., Han, J., Zhang, Y., Zhang, A., Hu, J., Hua, Y., & Bai, Y. (2022) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2022.953534 · Cited by 37
Barnes, A., Ballerini, L., Hernández, M. D. C. V., Chappell, F. M., Maniega, S. M., Meijboom, R., Backhouse, E. V., Stringer, M. S., Coello, R. D., Brown, R., et al. (2022) · Frontiers in Neurology · doi:10.3389/fneur.2022.889884 · Cited by 34
“The cause of PVS enlargement is not fully understood but is thought to be related to impaired fluid drainage (4), as a consequence of several pathological processes that affect the cerebral microvasculature, including blood– brain barrier dysfunction, vessel stiffening, and reduced vessel pulsatility (5, 6).”
BackgroundNeurodegeneration and inflammation crosstalk: Therapeutic targets and perspectives
Mohamed, W. M. Y., Kumar, J., Alghamdi, B. S. A., Wadan, A.-H. S., & Yamashita, T. (2022) · IBRO Neuroscience Reports · doi:10.1016/j.ibneur.2022.12.003 · Cited by 40
“It was discovered that the glymphatic system in the bodies of young, middle-aged, and old animals was susceptible to age-related alterations in function (Kress et al., 2014).”
BackgroundResultInfluentialGlymphatic system: a self-purification circulation in brain
Chen, S., Wang, H., Zhang, L., Xi, Y., Lu, Y., Yu, K., Zhu, Y., Regina, I., Bi, Y., & Tong, F. (2025) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2025.1528995 · Cited by 40
“In a model of repetitive moderate TBI, ipsilateral hemispheric CSF flow and clearance rate were impaired the day after the injury, and the glymphatic system lost 60% of its function until 28 days post-injury (Kress et al., 2014).”
Glymphatics and meningeal lymphatics unlock the brain-immune code
Kim, M. W., & Kipnis, J. (2025) · Immunity · doi:10.1016/j.immuni.2025.03.006 · Cited by 42
Dagum, P., Giovangrandi, L., Levendovszky, S. R., Winebaum, J. J., Singh, T., Cho, Y., Kaplan, R. M., Jaffee, M. S., Lim, M. M., VandeWeerd, C. L., et al. (2025) · Nature Biomedical Engineering · doi:10.1038/s41551-025-01394-9 · Cited by 48
“The resistance of the interstitial space is dynamically regulated across conditions of sleep, wake and different anaesthetic settings 2,30 .”
Self-citationAmyloid burden and sleep blood pressure in amnestic mild cognitive impairment
Tarumi, T., Harris, T. S., Hill, C., German, Z., Riley, J. R., Turner, M., Womack, K. B., Kerwin, D. R., Monson, N. L., Stowe, A. M., et al. (2015) · Neurology · doi:10.1212/wnl.0000000000002167 · Cited by 35
“Current evidence suggests that brain Ab deposition associated with age and lateonset AD are mainly attributed to a reduced clearance, which facilitates the aggregation of soluble Ab in the interstitial fluid and the formation of neurotic plaques in a concentration-dependent manner.(27,28) The patients with aMCI with e…”
BackgroundPulsed ultrasound expands the extracellular and perivascular spaces of the brain
Hersh, D. S., Nguyen, B., Dancy, J. G., Adapa, A. R., Winkles, J. A., Woodworth, G. F., Kim, A. J., & Frenkel, V. (2016) · Brain Research · doi:10.1016/j.brainres.2016.06.040 · Cited by 37
Arighi, A., Cristofori, A. D., Fenoglio, C., Borsa, S., D’Anca, M., Fumagalli, G., Locatelli, M., Carrabba, G. G., Pietroboni, A. M., Ghezzi, L., et al. (2019) · Journal of Alzheimer s Disease · doi:10.3233/jad-190119 · Cited by 37
Astrocytic connexin 43 potentiates myelin injury in ischemic white matter disease
Wang, M., Qin, C., Luo, X., Wang, J., Wang, X., Xie, M., Hu, J., Cao, J., Hu, T., Goldman, S. A., et al. (2019) · Theranostics · doi:10.7150/thno.31942 · Cited by 34
“We also analyzed the rapid pulsatile movements of the vascular wall, taking advantage of the high temporal resolution of two photon imaging in vivo [27, 36].”
BackgroundSelf-citationThe Beneficial Role of Exercise on Treating Alzheimer’s Disease by Inhibiting β-Amyloid Peptide
Tan, Z., Dong, F., Wu, L., Feng, Y.-S., & Zhang, F. (2021) · Molecular Neurobiology · doi:10.1007/s12035-021-02514-7 · Cited by 39
Glymphatic system impairment in patients with status epilepticus
Lee, D. A., Lee, J., & Park, K. M. (2022) · Neuroradiology · doi:10.1007/s00234-022-03018-4 · Cited by 36
“Glymphatic function decreases with aging, possibly because astrocytes become reactive and their AQP4 channels depolarize from the vascular endfeet to the parenchymal processes [44, 45].”
BackgroundCocaine-induced structural and functional impairments of the glymphatic pathway in mice
Chen, W., Huang, P., Zeng, H., Lin, J., Shi, Z., & Yao, X. (2020) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2020.04.057 · Cited by 35
Lights at night: does photobiomodulation improve sleep?
Valverde, A., Hamilton, C., Moro, C., Billères, M., Magistretti, P. J., & Mitrofanis, J. (2022) · Neural Regeneration Research · doi:10.4103/1673-5374.350191 · Cited by 34
“This decline in glymphatic activity with age is due largely to dysfunction of the aquaporin-4 water channels (Ahn et al., 2019), as well as an atrophy of the delicate meningeal lymphatic vessels (Kress et al., 2014).”
BackgroundNeuroendocrine pathogenesis of perimenopausal depression
Han, Y., Gu, S., Li, Y., Qian, X., Wang, F., & Huang, J. H. (2023) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2023.1162501 · Cited by 40
“The glymphatic system is dependent on the activity and polarization of aquaporin 4 (AQP4) on the terminal foot of astrocytes to mediate the exchange and flow system of cerebrospinal fluid and brain tissue fluid, and to mediate the excretion of macromolecular substances in brain tissue fluid (58).”
BackgroundSaito, Y., Kamagata, K., Andica, C., Uchida, W., Takabayashi, K., Yoshida, S., Nakaya, M., Tanaka, Y., Kamiyo, S., Sato, K., et al. (2023) · Japanese Journal of Radiology · doi:10.1007/s11604-023-01415-0 · Cited by 34
“A glymphatic system dysfunction could cause extracellular Aβ accumulation before the onset of dementia and Alzheimer’s disease (AD) [1, 2].”
BackgroundMethodThe glymphatic system and multiple sclerosis: An evolving connection
Alghanimy, A., Work, L. M., & Holmes, W. M. (2024) · Multiple Sclerosis and Related Disorders · doi:10.1016/j.msard.2024.105456 · Cited by 39
“Studies of both animals and humans have shown a strong connection between ageing and dysfunction of the glymphatic system and meningeal lymphatic vessels (Benveniste et al., 2019; Kress et al., 2014; Zhou et al., 2020).”
BackgroundAquaporin-4 and Parkinson’s Disease
Lapshina, K. V., & Ekimova, I. V. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25031672 · Cited by 34
“…the subarachnoid CSF and the brain parenchyma, which is accompanied by the impairment of clearance of labeled amyloid β from the brain parenchyma, reduction in the vessel wall pulsatility of intracortical arterioles, and loss of perivascular AQP4 polarization along the penetrating arteries [112].”
BackgroundGut–Brain Axis: Focus on Sex Differences in Neuroinflammation
Caldarelli, M., Rio, P., Marrone, A., Ocarino, F., Chiantore, M., Candelli, M., Gasbarrini, A., Gambassi, G., & Cianci, R. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25105377 · Cited by 37
Pahlavian, S. H., Bunck, A. C., Thyagaraj, S., Giese, D., Loth, F., Hedderich, D. M., Kröger, J. R., & Martin, B. A. (2016) · Annals of Biomedical Engineering · doi:10.1007/s10439-016-1602-x · Cited by 35
Wostyn, P., Groot, V. D., Dam, D. V., Audenaert, K., Killer, H. E., & Deyn, P. P. D. (2016) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-016-2348-1 · Cited by 34
“With regard to the viewpoint presented here, it is interesting to note that previous findings showed that glymphatic transport dramatically reduces with age [3], which is the primary risk factor for AMD.”
BackgroundWei, F., Zhang, C., Xue, R., Shan, L., Gong, S., Wang, G., Tao, J., Xu, G., Zhang, G., & Wang, L. (2017) · Life Sciences · doi:10.1016/j.lfs.2017.05.028 · Cited by 35
Ueno, M., Chiba, Y., Murakami, R., Matsumoto, K., Fujihara, R., Uemura, N., Yanase, K., & Kamada, M. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20102600 · Cited by 34
Havekes, R., Heckman, P. R. A., Wams, E. J., Stasiukonytė, N., Meerlo, P., & Eisel, U. L. M. (2019) · Cellular Signalling · doi:10.1016/j.cellsig.2019.109420 · Cited by 35
Heterogeneity of Cerebral White Matter Lesions and Clinical Correlates in Older Adults
Jung, K., Stephens, K. A., Yochim, K. M., Riphagen, J. M., Kim, C. M., Buckner, R. L., & Salat, D. H. (2021) · Stroke · doi:10.1161/strokeaha.120.031641 · Cited by 35
Vallianatou, T., Shariatgorji, M., Nilsson, A., Karlgren, M., Hulme, H., Fridjonsdottir, E., Svenningsson, P., & Andrén, P. E. (2021) · ACS Chemical Neuroscience · doi:10.1021/acschemneuro.1c00103 · Cited by 34
Liang, P.-Z., Li, L., Zhang, Y., Shen, Y. H., Zhang, L., Zhou, J., Wang, Z.-J., Wang, S., & Yang, S. (2021) · Neural Plasticity · doi:10.1155/2021/9960304 · Cited by 34
“Reactive astrogliosis is a conspicuous feature of aging and the injured brain [7, 46, 52], and reactive astrocytes lead directly to withdrawal of AQP4 from the endfeet to the soma of astroglia, thus affecting the clearance function of the glymphatic system [7].”
BackgroundInfluentialThe role of the autonomic nervous system in cerebral blood flow regulation in dementia: A review
Beishon, L., Hosford, P. S., Gurung, D., Brassard, P., Minhas, J. S., Robinson, T. G., Haunton, V. J., & Panerai, R. B. (2022) · Autonomic Neuroscience · doi:10.1016/j.autneu.2022.102985 · Cited by 34
“It has been shown that old (18 months of age) mice have fewer AQP4 expressed by end-feet when compared to young (2–3 months) mice (Kress et al., 2014).”
BackgroundHan, Y., Yi, H., Wang, Y., Li, Z., Chu, X., & Jiang, J. (2022) · ACS Nano · doi:10.1021/acsnano.2c08094 · Cited by 33
Kopeć, K., Szleszkowski, S., Koziorowski, D., & Szlufik, S. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms241210366 · Cited by 36
“Importantly the reduction in arterial pulsation is commonly seen in aging brains [17].”
BackgroundClinical magnetic resonance imaging evaluation of glymphatic function
Boyd, E., Kaur, J., Ding, G., Chopp, M., & Jiang, Q. (2024) · NMR in Biomedicine · doi:10.1002/nbm.5132 · Cited by 39
Abdolizadeh, A., Torres‐Carmona, E., Kambari, Y., Amaev, A., Song, J., Ueno, F., Koizumi, T., Nakajima, S., Agarwal, S. M., Luca, V. D., et al. (2024) · Schizophrenia Bulletin · doi:10.1093/schbul/sbae060 · Cited by 33
Han, G., Jiao, B., Zhang, Y., Wang, Z., Liang, C., Li, Y., Hsu, Y., & Bai, R. (2024) · NeuroImage · doi:10.1016/j.neuroimage.2024.120653 · Cited by 33
“Such flow may be particularly important because its speed could offer a sensitive indicator of CSF – interstitial fluid interface permeability (Gan et al., G. Han et al. 2023), which is mainly regulated by the aquaporin-4 expressed on perivascular astrocyte endfeet(Kress et al., 2014).”
Shao, X., Shou, Q., Felix, K., Ojogho, B., Jiang, X., Gold, B. T., Herting, M. M., Goldwaser, E. L., Kochunov, P., Hong, E. L., et al. (2024) · eLife · doi:10.7554/elife.96155.3 · Cited by 50
Bridging the brain and gut: neuroimmune mechanisms of neuroinflammation and therapeutic insights
Müller, L., & Benedetto, S. D. (2025) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2025.1590002 · Cited by 36
Ontogeny of Sleep and Its Functions in Infancy, Childhood, and Adolescence
Grigg-Damberger, M. M. (2016) · Springer eBooks · doi:10.1007/978-3-319-28640-2_1 · Cited by 34
“For example, chronic complaints of inadequate and/or insuffi cient sleep increase the risk and severity of Alzheimer’s disease, limiting the time the brain has to clear amyloid-beta and tau from the brain [ 33 , 130 , 131 ].”
BackgroundHead Position During Sleep: Potential Implications for Patients with Neurodegenerative Disease
Levendowski, D. J., Gamaldo, C. E., Louis, E. K. S., Ferini‐Strambi, L., Hamilton, J. M., Salat, D. H., Westbrook, P. R., & Berka, C. (2019) · Journal of Alzheimer s Disease · doi:10.3233/jad-180697 · Cited by 32
“Second, the magnitude of penetrating arterial pulsatility in the brain decreases with age [29].”
BackgroundNovel PET Biomarkers to Disentangle Molecular Pathways across Age-Related Neurodegenerative Diseases
Wilson, H., Politis, M., Rabiner, E. A., & Middleton, L. T. (2020) · Cells · doi:10.3390/cells9122581 · Cited by 34
Ding, X., & Peng, D. (2020) · Frontiers in Human Neuroscience · doi:10.3389/fnhum.2020.602496 · Cited by 32
“This distribution pattern declines with age, impairing the efficacy of the glymphatic system (Kress et al., 2014).”
BackgroundDisparate volumetric fluid shifts across cerebral tissue compartments with two different anesthetics
Ozturk, B., Monte, B., Koundal, S., Feng, D., Benveniste, H., & Lee, H. (2021) · Fluids and Barriers of the CNS · doi:10.1186/s12987-020-00236-x · Cited by 34
The Blood-Brain Barrier in Alzheimer’s Disease
Storck, S. E., Hartz, A. M. S., & Pietrzik, C. U. (2020) · Handbook of experimental pharmacology · doi:10.1007/164_2020_418 · Cited by 31
Humphreys, C. A., Smith, C., & Wardlaw, J. M. (2021) · Neuropathology and Applied Neurobiology · doi:10.1111/nan.12737 · Cited by 37
“Potential mechanisms for vascular and tissue damage include blood– brain barrier (BBB) dysfunction [17,18], para- and perivascular space abnormalities [19,20] and abnormal perfusion [21,22].”
BackgroundIntrathecal delivery and its applications in leptomeningeal disease
Khang, M., Bindra, R. S., & Saltzman, W. M. (2022) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2022.114338 · Cited by 33
Cerebral Superficial Siderosis
Weidauer, S., Neuhaus, E., & Hattingen, E. (2022) · Clinical Neuroradiology · doi:10.1007/s00062-022-01231-5 · Cited by 34
Min, J., Rouanet, J. P., Martini, A. C., Nashiro, K., Yoo, H. J., Porat, S., Cho, C., Wan, J., Cole, S. W., Head, E., et al. (2023) · Scientific Reports · doi:10.1038/s41598-023-30167-0 · Cited by 43
Mullane, K., & Williams, M. (2018) · Biochemical Pharmacology · doi:10.1016/j.bcp.2018.09.027 · Cited by 32
The Role of Sleep in Cognitive Function: The Value of a Good Night’s Rest
Gilley, R. R. (2022) · Clinical EEG and Neuroscience · doi:10.1177/15500594221090067 · Cited by 39
“During slow wave sleep, an increase of more than 60% of the extracellular volume corelated with improved interstitial solute clearance.(19) Recent research has also shown how the glymphatic system can affect amyloid beta (AB) removal.”
BackgroundPerivascular spaces as a marker of psychological trauma in depression: A 7‐Tesla MRI study
Ranti, D. L., Warburton, A. J., Rutland, J. W., Dullea, J. T., Markowitz, M., Smith, D., Kligler, S. K., Rutter, S., Langan, M. T., Arrighi‐Allisan, A. E., et al. (2022) · Brain and Behavior · doi:10.1002/brb3.2598 · Cited by 30
Zhu, B., Cao, A., Chen, C., Zhou, W., Luo, W., Gui, Y., Wang, Q., Xu, Z., & Wang, J. (2023) · International Immunopharmacology · doi:10.1016/j.intimp.2023.111215 · Cited by 32
Lowenstein, P. R., & Castro, M. G. (2017) · Clinical Immunology · doi:10.1016/j.clim.2017.07.006 · Cited by 33
“Extracellular fluid from the brain drains through well characterized perivascular channels that lead to lymphatics near the olfactory bulb, and then to the cervical lymph nodes (Carare, Hawkes, & Weller, 2014; Clapham, O'Sullivan, Weller, & Carare, 2010; Iliff et al., 2014; Iliff & Nedergaard, 2013; Iliff et al., 2012…”
Lee, W., Jung, K., Ryu, Y. J., Kim, J., Lee, S., Chu, K., Kim, M., Lee, S. K., & Roh, J. (2017) · JAMA Neurology · doi:10.1001/jamaneurol.2017.2853 · Cited by 32
“Glymphatic systemis the routewhere thecerebrospinal fluid (CSF)entersalong theperiarteriolar space into the brain parenchyma, is mixedwith the interstitial fluid, and is cleared out to the perivascular space of the venules, draining waste to perimeningeal lymphatic vessels, deep cervical lymph nodes, and finally to th…”
BackgroundHersh, D. S., Anastasiadis, P., Mohammadabadi, A., Nguyen, B., Guo, S., Winkles, J. A., Kim, A. J., Gullapalli, R. P., Keller, A., Frenkel, V., et al. (2018) · PLoS ONE · doi:10.1371/journal.pone.0192240 · Cited by 32
MRI investigation of glymphatic responses to Gd‐DTPA infusion rates
Ding, G., Chopp, M., Li, L., Zhang, L., Davoodi‐Bojd, E., Li, Q., Zhang, Z., & Jiang, Q. (2018) · Journal of Neuroscience Research · doi:10.1002/jnr.24325 · Cited by 33
Cisterna Magna Injection in Rats to Study Glymphatic Function
Ramos, M., Bèchet, N. B., Battistella, R., Pavan, C., Xavier, A. L. R., Nedergaard, M., & Lundgaard, I. (2019) · Methods in molecular biology · doi:10.1007/978-1-4939-9068-9_7 · Cited by 32
Self-citationNikolenko, V. N., Oganesyan, M. V., Vovkogon, A. D., Nikitina, A. T., Sozonova, E. A., Kudryashova, V. A., Rizaeva, N. A., Cabezas, R., Ávila-Rodriguez, M., Евгеньевна, Н. М., et al. (2019) · Current Neuropharmacology · doi:10.2174/1570159x17666191113103850 · Cited by 31
Zhang, B., Li, W., Zhuo, Y., Xiang, H., Li, W., Liu, H., Xie, L., Gao, Q., & Tan, S. (2020) · Journal of Molecular Neuroscience · doi:10.1007/s12031-020-01752-z · Cited by 33
Self-citationSpecificity of Adaptive Immune Responses in Central Nervous System Health, Aging and Diseases
Rickenbach, C., & Gericke, C. (2022) · Frontiers in Neuroscience · doi:10.3389/fnins.2021.806260 · Cited by 33
Li, L., Ding, G., Zhang, L., Davoodi‐Bojd, E., Chopp, M., Li, Q., Zhang, Z. G., & Jiang, Q. (2022) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2022.841798 · Cited by 32
Glymphatic system dysfunction in patients with cluster headache
Kim, J., Lee, D. A., Lee, H., Park, B. S., Ko, J., Park, S. H., Lee, Y. J., Kim, I. H., Park, J. H., & Park, K. M. (2022) · Brain and Behavior · doi:10.1002/brb3.2631 · Cited by 31
“The CSF formation rate and turnover in the rat brain decrease with age, which is consistent with evidence showing that glymphatic clearance decreases with age (Kress et al., 2014).”
BackgroundOcular Lymphatic and Glymphatic Systems: Implications for Retinal Health and Disease
Uddin, M. N., & Rutar, M. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms231710139 · Cited by 35
“This hypothesis is based on the facts that (1) the glymphatic pathway clears metabolic waste, including amyloid beta peptide, from the CNS and AMD is associated with amyloid beta deposition [136,148], and (2) glymphatic transport of CNS waste is impaired significantly with ageing, which is a risk factor for AMD develo…”
BackgroundOlder Adults Taking AT1-Receptor Blockers Exhibit Reduced Cerebral Amyloid Retention
Nation, D. A., Ho, J. K., & Yew, B. (2016) · Journal of Alzheimer s Disease · doi:10.3233/jad-150487 · Cited by 32
Metabolite Clearance During Wakefulness and Sleep
Hladky, S. B., & Barrand, M. A. (2017) · Handbook of experimental pharmacology · doi:10.1007/164_2017_37 · Cited by 36
“Xie et al. (see also Kress et al. 2014) interpreted both the change in rate constant for inulin efflux and the dramatic change in influx seen for Texas red dextran as being consequences of a large change in the rate of glymphatic circulation (see proposal 3, Sect.”
Reiter, R. J., Sharma, R., Rosales-Corral, S., de Mange, J., Phillips, W. T., Tan, D. X., & Bitar, R. D. (2022) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2022.03.025 · Cited by 31
Vadakkan, K. I. (2015) · SpringerPlus · doi:10.1186/s40064-015-1283-1 · Cited by 31
Song, H., Ruan, Z., Gao, L., Lv, D., Sun, D., Zeng, L., Zhang, R., Zhou, X., Xu, H., & Zhang, J. (2022) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2022.974114 · Cited by 31
“The astrocyte water channel and glymphatic system disorder will lead to the accumulation of metabolic waste, which has been shown to be related to aging (Kress et al., 2014) and various neurological diseases such as Alzheimer’s disease (Sweeney and Zlokovic, 2018), idiopathic normal pressure hydrocephalus (Bae et al.”
BackgroundGlymphatic fluid transport is suppressed by the aquaporin‐4 inhibitor AER ‐271
Giannetto, M. J., Gomolka, R. S., Gahn‐Martinez, D., Newbold, E. J., Bork, P. A. R., Chang, E., Gresser, M. J., Thompson, T., Mori, Y., & Nedergaard, M. (2024) · Glia · doi:10.1002/glia.24515 · Cited by 33
“Further, loss of AQP4 polarization during aging (Kress et al., 2014; Zeppenfeld et al., 2020), in neurodegenerative disease (Harrison et al., 2020; Zeppenfeld et al., 2020), or inflammation (Pavan et al., 2021) reduces glymphatic flow.”
BackgroundSelf-citationDong, R., Han, Y., Lv, P., Jiang, L., Wang, Z., Peng, L., Liu, S., Ma, Z., Xia, T., Zhang, B., et al. (2024) · Journal of Cerebral Blood Flow & Metabolism · doi:10.1177/0271678x241237073 · Cited by 34
“13,14 Yet, there is little direct evidence that AQP4 mediated glymphatic function impairment relates to the pathophysiology of PND.”
Sighencea, M. G., Popescu, R. Ș., & Trifu, S. C. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms252212311 · Cited by 33
“…risk factor for neuropathologies associated with protein aggregation [189], in aged murine models, a pronounced decline in the cerebrospinal fluid–interstitial fluid exchange has been documented, with a notable 40% reduction in the clearance of A β injected into the brain parenchyma [171].”
Metadata
- Authors
- Kress, B. T., Iliff, J. J., Xia, M., Wang, M., Wei, H. S., Zeppenfeld, D., Xie, L., Kang, H., Xu, Q., Liew, J. A., Plog, B. A., Ding, F., Deane, R., & Nedergaard, M.
- Affiliations
- University of Rochester Medicine (US)
- Oregon Health & Science University (US)
- Corresponding author
- Iliff, Jeffrey J.
- ORCID
- Venue
- Annals of Neurology
- Publisher
- Wiley
- Published
- 2014-09-26
- Volume
- 76
- Issue
- 6
- Pages
- 845-861
- ISSN
- 0364-5134 (ISSN-L)
- 1531-8249
- PMC
- PMC4245362
- OpenAlex
- W2100314515
- Cited by
- 1,521
- References
- 42
- Citations by year
- 2026: 182 · 2025: 186 · 2024: 202 · 2023: 167 · 2022: 172 · 2021: 126 · 2020: 126 · 2019: 98 · 2018: 89 · 2017: 70 · 2016: 54 · 2015: 47 · 2014: 1
- FWCI
- 26.22
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Annals of Neurology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- American Heart Association (12SDG11820014)
- National Institutes of Health (F32 NS073373)
- Oregon Partnership for Alzheimer's Research
- Topics
- Health Sciences › Medicine › Clinical Neurology › Cerebrospinal fluid and hydrocephalus
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion Transport and Channel Regulation
- Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
- Keywords
- glymphatic system, brain aging, aquaporin-4, astrocytes, amyloid-beta clearance, cognitive decline, neurodegenerative diseases
- MeSH terms
- Aging, Animals, Brain, Cerebrovascular Circulation, Female, Male, Metabolic Clearance Rate, Mice, Inbred C57BL, Neuroglia, Microscopy, Fluorescence, Multiphoton, Mice, Aquaporin 4
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