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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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“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…”
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“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.”
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“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…”
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Self-citationThe Role of Basement Membranes in Cerebral Amyloid Angiopathy
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“Additionally, Kress et al. (2014) identified reduced para-arterial CSF influx in aged wild-type animals, as well as reduced ISF efflux and Aβ1−40 clearance.”
BackgroundNeurobiological Links between Stress, Brain Injury, and Disease
Guo, H., Zheng, L., Xu, H., Pang, Q., Ren, Z., Gao, Y. Z., & Wang, T. (2022) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2022/8111022 · Cited by 56
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“The important function of CSF in clearing beta-amyloid and tau protein, whose toxic aggregation defines AD, has been widely documented (Kress et al., 2014; Ueno et al., 2014; Xin et al., 2018; Carare et al., 2020).”
BackgroundNoninvasive ultrasonic induction of cerebrospinal fluid flow enhances intrathecal drug delivery
Aryal, M., Azadian, M. M., Hart, A. R., Macedo, N., Zhou, Q., Rosenthal, E. L., & Airan, R. D. (2022) · Journal of Controlled Release · doi:10.1016/j.jconrel.2022.06.067 · Cited by 54
Continuous positive airway pressure increases CSF flow and glymphatic transport
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“Future clinical and experimental studies should further investigate the potential benefits of CPAP to sustain brain waste clearance in neurodegenerative states, such as aging, which is associated with impaired glymphatic transport (42), sluggish CSF flow, and decreased CSF opening pressure (67).”
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The Glymphatic System in Diabetes-Induced Dementia
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“Moreover, impaired glymphatic transport results in a 40% decrease in the clearance of Aβ in the brain of mice (54).”
BackgroundPhysiological and Pathological Factors Affecting Drug Delivery to the Brain by Nanoparticles
Islam, Y., Leach, A. G., Smith, J. A., Pluchino, S., Coxon, C. R., Sivakumaran, M., Downing, J. R., Fatokun, A. A., Teixidò, M., & Ehtezazi, T. (2021) · Advanced Science · doi:10.1002/advs.202002085 · Cited by 52
Ependymal cells-CSF flow regulates stress-induced depression
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“Reduced cerebrovascular reactivity has been associated with higher MVPVS burden (Blair et al., 2020; Kapoor et al., 2022) which has also been substantiated in rodents (Hadaczek et al., 2006; Kress et al., 2014).”
BackgroundParavascular spaces: entry to or exit from the brain?
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Novel Players in the Aging Synapse: Impact on Cognition
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Cerebrospinal fluid β-amyloid42 and neurofilament light relate to white matter hyperintensities
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Glymphatic system function in patients with newly diagnosed focal epilepsy
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“Cerebral vascular pulsatility was evaluated by in vivo 2-photon microscopy as described previously.(12,38) Animals were anesthetized, and their body temperature was maintained at physiological parameters by placing them on a heating pad (37 C).”
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“ISF flow is a complex process related to many factors, such as age, brain activity, and structural characteristics within the ECS [1, 4, 5].”
BackgroundLongitudinal MRI-visible perivascular space (PVS) changes with long-duration spaceflight
Hupfeld, K. E., Richmond, S. B., McGregor, H. R., Schwartz, D. L., Luther, M. N., Beltran, N. E., Kofman, I. S., Dios, Y. E. D., Riascos, R., Wood, S. J., et al. (2022) · Scientific Reports · doi:10.1038/s41598-022-11593-y · Cited by 51
Self-citationNormal glymphatic system function in patients with migraine: A pilot study
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“The term “glymphatic” was coined based on two-photon imaging research [6, 222, 229], which emphasized the reliance on glial cells and functional similarity with the peripheral lymphatic sys-tem that helps to clear waste materials from the interstitial spaces between cells [222, 227].”
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“162,163 Combining such approaches with 4D CSF flow could provide further insights into how the driving mechanisms (e.g., cardiac, respiratory) of CSF motion change during aging and dementia.”
BackgroundMicroglial dynamics and neuroinflammation in prodromal and early Parkinson’s disease
Mogensen, F. L., Seibler, P., Grünewald, A., & Michelucci, A. (2025) · Journal of Neuroinflammation · doi:10.1186/s12974-025-03462-y · Cited by 60
“Interestingly, the activity of the glymphatic system decreases with aging, and the clearance of beta-amyloid is impaired by 40% in old mice [73].”
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“This is consistent with the observation that the polarization of AQP4 in the perivascular spaces is impaired in old animals [64], leading to failure of waste clearance and accumulation of A in the brain.”
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“Clear-ance rates appear to be reduced in old mice [69], whereas sleep, ketamine/xylazine anesthesia or balanced anesthetics with dexmedetomidine may improve clearance [87, 89].”
BackgroundInfluentialSelf-citationWu, C., Liao, W., Chu, Y., Hsiao, M., Kung, Y., Wang, J., & Chen, W. (2024) · Advanced Science · doi:10.1002/advs.202401039 · Cited by 50
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“Additionally, the clearance rate of intracortically injected A β in aged mice is 40 % lower than in young mice(Kress et al., 2014).”
Resolving the mysteries of brain clearance and immune surveillance
Kipnis, J., Benveniste, H., Eichmann, A., Thomas, J., Reich, D. S., Lewis, L. D., Tsai, L., Drieu, A., Bakker, E. N. T. P., Kelley, D. H., et al. (2025) · Neuron · doi:10.1016/j.neuron.2025.10.036 · Cited by 56
“119 This expansion reduces resistance to fluid flow, thereby facilitating enhanced glymphatic clearance during sleep.”
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“(Iliff, Wang et al. 2013; Rangroo Thrane, Thrane et al. 2013; Yang, Kress et al. 2013; Kress, Iliff et al. 2014).”
BackgroundRen, X., Liu, S., Lian, C., Li, H., Li, K., Li, L., & Zhao, G. (2021) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2021.659457 · Cited by 47
“This cardiac pulsation along the entire vascular bed is believed to be the most critical physical mechanism for glymphatic propulsion, facilitating CSF movement in the glymphatic system (Kyrtsos and Baras, 2015; Kiviniemi et al., 2016; Hablitz et al., 2020).”
BackgroundCognitive Impairment in Idiopathic Normal Pressure Hydrocephalus
Xiao, H., Hu, F., Ding, J., & Ye, Z. (2022) · Neuroscience Bulletin · doi:10.1007/s12264-022-00873-2 · Cited by 46
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“AQP4 perivascular polarization was measured as previously described [27, 41].”
BackgroundMethodZhang, Y., Peng, B., Chen, S., Liang, Q., Zhang, Y., Lin, S., Xu, Z., Zhang, J., Hou, G., & Qiu, Y. (2024) · Journal of Affective Disorders · doi:10.1016/j.jad.2024.03.023 · Cited by 48
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“Linear regression analysis shows that the decrease in perivascular AQP4 polarization distribution was significantly associated with the reduction in paravascular CSF influx (Kress et al., 2014).”
Hasan‐Olive, M. M., Enger, R., Hansson, H., Nagelhus, E. A., & Eide, P. K. (2019) · Fluids and Barriers of the CNS · doi:10.1186/s12987-019-0160-7 · Cited by 47
Meningeal Lymphatics: A Review and Future Directions From a Clinical Perspective
Hershenhouse, K. S., Shauly, O., Gould, D. J., & Patel, K. M. (2019) · Neuroscience Insights · doi:10.1177/1179069519889027 · Cited by 47
Abe, Y., Ikegawa, N., Yoshida, K., Muramatsu, K., Hattori, S., Kawai, K., Murakami, M., Tanaka, T., Goda, W., Goto, M., et al. (2020) · Acta Neuropathologica Communications · doi:10.1186/s40478-020-00936-3 · Cited by 45
Updated Understanding of the Glial-Vascular Unit in Central Nervous System Disorders
Yao, D., Zhang, R., Xie, M., Ding, F., Wang, M., & Wang, W. (2022) · Neuroscience Bulletin · doi:10.1007/s12264-022-00977-9 · Cited by 47
“Sleep disturbance and ageing are reported to affect the directional movement of CSF in the PVS [126, 127].”
BackgroundSelf-citationNaeser, M. A., Martin, P. I., Ho, M. D., Krengel, M., Bogdanova, Y., Knight, J., Hamblin, M. R., Fedoruk, A., Poole, L. G., Cheng, C.-H., et al. (2022) · Journal of Alzheimer s Disease Reports · doi:10.3233/adr-220022 · Cited by 46
Jin, Y., Zhang, W., Yu, M., Li, J., Du, Y., Wang, W., Chen, G., Ding, X., & Ding, J. (2024) · Sleep Medicine · doi:10.1016/j.sleep.2024.01.028 · Cited by 46
Pseudotumor Cerebri and Glymphatic Dysfunction
Bezerra, M. L. D. S., Ferreira, A. C. A. D. F., & de Oliveira‐Souza, R. (2018) · Frontiers in Neurology · doi:10.3389/fneur.2017.00734 · Cited by 46
“(34) observed a reduction of 40% of β-amyloid (Aβ) clearance in the brain of aged in comparison with young mice.”
BackgroundWu, T., Su, F., Feng, Y., Liu, B., Li, M., Liang, F., Li, G., Li, X., Zhang, Y., Cai, Z.-Q., et al. (2019) · Stem Cells · doi:10.1002/stem.3103 · Cited by 46
“The loss of perivascular polarization or genetic deletion of AQP-4 impairs glymphatic function.(14,15) However, it is not clear whether glymphatic system is impaired and ASO distribution is disrupted in HD.”
BackgroundOhene, Y., Harrison, I. F., Evans, P., Thomas, D. L., Lythgoe, M. F., & Wells, J. A. (2020) · Magnetic Resonance in Medicine · doi:10.1002/mrm.28496 · Cited by 45
The emerging importance of lymphatics in health and disease: an NIH workshop report
Mehrara, B. J., Radtke, A. J., Randolph, G. J., Wachter, B. T., Greenwel, P., Rovira, I. I., Galis, Z. S., & Muratoglu, S. C. (2023) · Journal of Clinical Investigation · doi:10.1172/jci171582 · Cited by 48
“The glymphatic system is influenced by aging, sleep cycles, and genetic factors (58, 60–62).”
Deák, F., Freeman, W. M., Ungvari, Z. I., Csiszár, A., & Sonntag, W. E. (2015) · The Journals of Gerontology Series A · doi:10.1093/gerona/glv206 · Cited by 45
Brain drains: new insights into brain clearance pathways from lymphatic biology
Bower, N. I., & Hogan, B. M. (2018) · Journal of Molecular Medicine · doi:10.1007/s00109-018-1634-9 · Cited by 43
“Interestingly, the glymphatic system functions most efficiently during sleep when there is a 60% increase in interstitial space due to a reduction in the size of cells within the brain [13] and the efficiency of this clearance mechanism is also reduced in the aging brain, suggesting potentially important roles in age-…”
BackgroundDrainage of senescent astrocytes from brain via meningeal lymphatic routes
Li, Q., Chen, Y., Feng, W., Cai, J., Gao, J., Ge, F., Zhou, T., Wang, Z., Ding, F., Marshall, C., et al. (2022) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2022.04.005 · Cited by 43
Self-citationLiu, E., Peng, X., Ma, H., Zhang, Y., Yang, X., Zhang, Y., Sun, L., & Yan, J. (2021) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2020.611494 · Cited by 43
Dysfunction of the Blood-brain Barrier in Cerebral Microbleeds: from Bedside to Bench
Wang, H., Zhang, C., Qiu, Y., Chen, A., Li, Y., & Hu, B. (2021) · Aging and Disease · doi:10.14336/ad.2021.0514 · Cited by 47
“The CAA pathology in the elderly might be related to the reduction of Aβ clearance, and may be aggravated by aging, as a result of the thickening of vessel walls, loss of vasoactivity, and alteration of basement membrane proteins [38, 73-75].”
BackgroundWang, T., Chen, Y., Zou, Y., Pang, Y., He, X., Chen, Y., Liu, Y., Feng, W., Zhang, Y., Li, Q., et al. (2022) · Aging and Disease · doi:10.14336/ad.2022.0219 · Cited by 45
“Among them, glymphatic dysfunction could be a main contributor to Aβ accumulation, as revealed by recent evidence from animal experiments [16-17, 19-24] as well as clinical”
BackgroundSelf-citationFournier, A. P., Gauberti, M., Quenault, A., Vivien, D., Macrez, R., & Docagne, F. (2018) · Journal of Cerebral Blood Flow & Metabolism · doi:10.1177/0271678x18754732 · Cited by 47
Hertelendy, P., Varga, D. P., Menyhárt, Á., Bari, F., & Farkas, E. (2018) · Neurochemistry International · doi:10.1016/j.neuint.2018.10.010 · Cited by 43
“more dispersed) in astrocyte end feet in old mice (Kress et al., 2014).”
BackgroundAbdelkarim, D., Zhao, Y., Turner, M. P., Sivakolundu, D. K., Lu, H., & Bart Rypma, A. (2019) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2019.09.005 · Cited by 47
Howe, M. D., Furr, J. W., Munshi, Y., Roy-O’Reilly, M. A., Maniskas, M. E., Koellhoffer, E. C., d’Aigle, J., Sansing, L. H., McCullough, L. D., & Urayama, A. (2019) · GeroScience · doi:10.1007/s11357-019-00118-7 · Cited by 43
Potential Role of Venular Amyloid in Alzheimer’s Disease Pathogenesis
Morrone, C. D., Bishay, J., & McLaurin, J. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21061985 · Cited by 43
“An alternate explanation for the presence of dextran, and potentially Aβ, along veins may be impaired glymphatic drainage with aging [38,58].”
BackgroundCaveolin-1 Regulates Perivascular Aquaporin-4 Expression After Cerebral Ischemia
Filchenko, I., Blochet, C., Buscemi, L., Price, M., Badaut, J., & Hirt, L. (2020) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2020.00371 · Cited by 45
Park, M., Kim, J. W., Ahn, S. J., Cha, Y. J., & Suh, S. H. (2020) · Journal of Clinical Medicine · doi:10.3390/jcm9103353 · Cited by 43
“is associated with impaired glymphatic/dural lymphatic clearance [6,7].”
BackgroundWan, J., Zhou, S., Mea, H. J., Guo, Y., Ku, H., & Urbina, B. (2022) · Chemical Reviews · doi:10.1021/acs.chemrev.1c00480 · Cited by 45
Brain Glymphatic/Lymphatic Imaging by MRI and PET
Lee, D. S., Suh, M., Sarker, A. K., & Choi, Y. (2020) · Nuclear Medicine and Molecular Imaging · doi:10.1007/s13139-020-00665-4 · Cited by 45
“Aging-related paravascular clearance was reported before the discovery of meningeal lymphatics [19] (Fig.”
BackgroundVascular risk factors and astrocytic marker for the glymphatic system activity
Wei, Y., Hsu, C. H., Huang, W., Lin, C., Chen, Y.-L., Chen, Y.-L., Chen, P.-Y., Shyu, Y., & Lin, C. (2023) · La radiologia medica · doi:10.1007/s11547-023-01675-w · Cited by 43
Perivascular pumping of cerebrospinal fluid in the brain with a valve mechanism
Gan, Y., Holstein-Rønsbo, S., Nedergaard, M., Boster, K. A. S., Thomas, J. H., & Kelley, D. H. (2023) · Journal of The Royal Society Interface · doi:10.1098/rsif.2023.0288 · Cited by 44
“It has been reported that a penetrating artery has pulsatility that increases from the surface to deeper brain regions [23,24].”
Self-citationLinking activity dyshomeostasis and sleep disturbances in Alzheimer disease
Slutsky, I. (2024) · Nature reviews. Neuroscience · doi:10.1038/s41583-024-00797-y · Cited by 43
“Sleep also participates in regulating Aβ elimination through the glymphatic system in wild-type mice 167 , but glymphatic transport is suppressed in fAD 168 and aged 169 mice, potentially compromising sleep-dependent Aβ clearance mechanisms in AD.”
Lymphatic Vasculature: An Emerging Therapeutic Target and Drug Delivery Route
Xu, W., Harris, N. R., & Caron, K. M. (2021) · Annual Review of Medicine · doi:10.1146/annurev-med-051419-114417 · Cited by 41
Gilbert, A., Elorza‐Vidal, X., Rancillac, A., Chagnot, A., Yetim, M., Hingot, V., Deffieux, T., Boulay, A.-C., Alvear‐Perez, R., Cisternino, S., et al. (2021) · eLife · doi:10.7554/elife.71379 · Cited by 43
Fluid metabolic pathways after subarachnoid hemorrhage
Zhou, J., Guo, P., Guo, Z., Sun, X., Chen, Y., & Feng, H. (2021) · Journal of Neurochemistry · doi:10.1111/jnc.15458 · Cited by 42
“The foot process of astrocytes was swollen, and the function of AQP- 4 in regulating water was impaired (Kress et al., 2014).”
BackgroundIron Aggravates the Depressive Phenotype of Stressed Mice by Compromising the Glymphatic System
Liang, S., Lu, Y., Li, Z., Li, S., Chen, B., Zhang, M., Chen, B., Ji, M., Gong, W., Xia, M., et al. (2020) · Neuroscience Bulletin · doi:10.1007/s12264-020-00539-x · Cited by 41
Self-citationAutomated Methods for Detecting and Quantitation of Enlarged Perivascular spaces on MRI
Moses, J., Sinclair, B., Law, M., O'Brien, T. J., & Vivash, L. E. (2022) · Journal of Magnetic Resonance Imaging · doi:10.1002/jmri.28369 · Cited by 45
“They found that there was impaired drainage of the glymphatic system in aging brains.(38) Since neurodegenerative diseases develop most commonly in older populations,(39) it is possible that reduced glymphatic clearance of waste products predisposes the aging brain to the development of neurodegenerative disease.”
BackgroundEnlarged Perivascular Spaces and Age-Related Clinical Diseases
Yang, Y., Wang, M., Luan, M., Song, X., Wang, Y., Xu, L., Zhong, M., & Zheng, X. (2023) · Clinical Interventions in Aging · doi:10.2147/cia.s404908 · Cited by 41
“And in animal experiments, Kress et al found that, compared to young mice, older mice had a 27% loss in vessel pulse ability and a 40% reduction in Aβ-amyloid clearance.(18) Zenget al proposed that the microglia inflammatory process may mediate the relationship between glymphatic dysfunction and Alzheimer's Disease, a…”
ResultSelf-citationGao, M., Liu, Z., Zang, H., Wu, X. W., Yan, Y., Lin, H., Yuan, J., Liu, T., Zhou, Y., & Liu, J. (2024) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-24-0150 · Cited by 41
“Therefore, dysfunctions in the glymphatic pathway have been linked to various neurological disorders (5, 6), such as Alzheimer’s disease, in which inefficiencies in glymphatic function are associated with reduced clearance of amyloid-beta and tau proteins (7, 8).”
BackgroundNew awakenings: current understanding of sleep dysfunction and its treatment in Parkinson’s disease
Keir, L. H. M., & Breen, D. P. (2019) · Journal of Neurology · doi:10.1007/s00415-019-09651-z · Cited by 43
Modulation of lymphatic transport in the central nervous system
Li, W., Chen, D., Liu, N., Luan, Y., Zhu, S., & Wang, H. (2022) · Theranostics · doi:10.7150/thno.66026 · Cited by 42
“Both CSF production and glymphatic influx are reduced in elderly and AD mice [18, 113, 117, 118].”
BackgroundLan, Y., Wang, H., Chen, A., & Zhang, J. (2022) · Immunology · doi:10.1111/imm.13517 · Cited by 45
“According to the first GS reported study, GS has a significant role in eliminating metabolic waste substances from the ISF space and out of the brain [15].”
BackgroundInfluentialClearance Systems in the Brain, From Structure to Function
Liu, J., Guo, Y., Zhang, C., Zeng, Y., Luo, Y., & Wang, G. (2022) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2021.729706 · Cited by 46
Yoo, S., Kim, H., Kim, J., Kim, E., Kowsari, K., Reet, J. V., & Yoon, K. (2022) · Scientific Reports · doi:10.1038/s41598-022-17314-9 · Cited by 42
“3 from diameter measurement and F(4,45) = 11.”
BackgroundChen, Y. L., Wang, L.-Y., Chen, Y., Gao, J. Y., Marshall, C., Cai, Z., Hu, G., & Xiao, M. (2015) · Neuroscience · doi:10.1016/j.neuroscience.2015.12.039 · Cited by 40
“Apart from rapid transport of brain water, AQP4 has been suggested to mediate clearance of interstitial solutes, including a large proportion of soluble Aβ, from the brain parenchyma (Iliff et al., 2012; Kress et al., 2014).”
BackgroundDai, J., Lin, W., Zheng, M., Liu, Q., He, B., Luo, C., Lu, X.-L., Pei, Z., Su, H., & Yao, X. (2017) · Molecular Medicine Reports · doi:10.3892/mmr.2017.6786 · Cited by 41
“Additionally, AQP4 depolarization has been observed in the aging brain, with impaired paravascular clearance (30).”
Ma, T., Wang, F., Xu, S., & Huang, J. H. (2021) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2021.01.028 · Cited by 38
Vemuri, P., DeCarli, C. S., & Duering, M. (2022) · Stroke · doi:10.1161/strokeaha.120.032611 · Cited by 46
Hou, C., Liu, Q., Zhang, H., Wang, W., Wang, B., Cui, X., Li, J., Ren, W., & Yang, X. (2021) · Neurochemical Research · doi:10.1007/s11064-021-03478-9 · Cited by 39
“AQP4 polarization was evaluated 3 d after SAH as previously described [19].”
BackgroundMethodThe lymphatic system: a therapeutic target for central nervous system disorders
Lü, H., Cao, Y., Hu, J., Xu, J., Liu, Q., Huang, S., & Duan, C. (2022) · Neural Regeneration Research · doi:10.4103/1673-5374.355741 · Cited by 43
“In aged mice, a radiotracer clearance assay showed a reduction in CSF-ISF exchange efficiency, Aβ clearance rate, vessel wall pulsatility, and perivascular AQP4 polarization (Kress et al., 2014).”
BackgroundCognitive Impairment Is Related to Glymphatic System Dysfunction in Pediatric Multiple Sclerosis
Margoni, M., Pagani, E., Meani, A., Preziosa, P., Mistri, D., Gueye, M., Moiola, L., Filippi, M., & Rocca, M. A. (2024) · Annals of Neurology · doi:10.1002/ana.26911 · Cited by 40
“…results are also consistent with a growing body of evidence showing an association between glymphatic dysfunction and cognitive decline in adult aging 12,13 and different neurodegenerative disorders, such as Alzheimer ’ s disease, Parkinson ’ s disease, and idiopathic normal pressure hydrocephalus.”
BackgroundResultThe Ocular Glymphatic System—Current Understanding and Future Perspectives
Delle, C., Wang, X., & Nedergaard, M. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25115734 · Cited by 43
“Findings that dextran or ovalbumin tracers of 45 kDa or a smaller size are suitable for studying the retrograde ocular glymphatic transport stand in agreement with the corresponding results for the brain glymphatic system [57,59–62].”
ResultSelf-citationVascular Dementia: From Pathophysiology to Therapeutic Frontiers
Yang, H. (2025) · Journal of Clinical Medicine · doi:10.3390/jcm14186611 · Cited by 48
“The loss of vascular smooth muscle cells and pericytes in SVD causes vasomotion to decrease which worsens the perivascular pumping mechanism [71].”
Progression of Cerebral White Matter Hyperintensities and the Associated Sonographic Index
Lee, W., Jung, K., Ryu, Y. J., Lee, K., Kim, J., Lee, S., Chu, K., Kim, M., Lee, S. K., & Roh, J. (2017) · Radiology · doi:10.1148/radiol.2017162064 · Cited by 40
A critical review of brain and cognitive reserve in Huntington’s disease
Soloveva, M. V., Jamadar, S. D., Poudel, G. R., & Georgiou‐Karistianis, N. (2018) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2018.03.003 · Cited by 38
“Given that a histopathological feature of HD is the presence of intracellular inclusions of Huntingin toxic proteins, good-quality sleep may prevent these toxic proteins from building up in the brain (Kress et al., 2014; Ross and Poirier, 2004).”
Background
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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