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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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In the citing paper
“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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Citations
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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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“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…”
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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.”
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…”
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“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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Items 701–800 of 998
Xiong, X., Hu, T., Yin, Z., Zhang, Y., Chen, F., & Lei, P. (2022) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2022.944283 · Cited by 26
“This finding was also observed in patients with fatal familial insomnia (Kress et al., 2014).”
BackgroundResultGlymphatic pathway in sporadic cerebral small vessel diseases: From bench to bedside
Xu, J., Su, Y., Fu, J., Shen, Y., Dong, Q., & Cheng, X. (2023) · Ageing Research Reviews · doi:10.1016/j.arr.2023.101885 · Cited by 24
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“Accumulated evidence suggests that AQP4 is necessary not only for water homeostasis but also to clear small molecules and metabolites, including A β and Tau proteins, from interstitial space (Iliff et al. (2012, 2014) [223,224]; Kress et al. (2014) [225]).”
BackgroundRemote ischemic conditioning: A treatment for vascular cognitive impairment
Hess, D., Khan, M., Morgan, J. C., & Hoda, M. N. (2015) · Brain Circulation · doi:10.4103/2394-8108.172885 · Cited by 22
“(23) Moreover, the loss of arterial pulsatility with aging and the inflammation and gliosis often found in aging brain impair this glymphatic pathway and clearance of amyloid-beta.(24)Defects in this glymphatic clearance system from ischemia and infarcts may be related to deposition of amyloid-beta and tau and may pro…”
BackgroundCerebrospinal fluid biomarkers of infantile congenital hydrocephalus
Limbrick, D. D., Baksh, B. S., Morgan, C. D., Habiyaremye, G., McAllister, J. P., Inder, T. E., Mercer, D., Holtzman, D. M., Strahle, J. M., Wallendorf, M., et al. (2017) · PLoS ONE · doi:10.1371/journal.pone.0172353 · Cited by 24
“While this mechanism of CSF absorption has not been well-studied in immature brains, aged rats with amyloid-beta injected into cortical parenchyma show diminished glymphatic/paravascular clearance[71].”
BackgroundDesigning in vitro Blood-Brain Barrier Models Reproducing Alterations in Brain Aging
Osipova, E. D., Komleva, Y. K., Morgun, A. V., Lopatina, O. L., Panina, Y. A., Olovyannikova, R. Y., Vais, E. F., Salmin, V. V., & Salmina, A. B. (2018) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2018.00234 · Cited by 25
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Glymphatic system of the brain: structure and practical significance
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Lymphatics in Eye Fluid Homeostasis: Minor Contributors or Significant Actors?
Subileau, M., & Vittet, D. (2021) · Biology · doi:10.3390/biology10070582 · Cited by 22
“Consistent with this statement, glymphatic activity is described to decrease with aging [111,112], which coincides with the appearance of eye neurodegenerative diseases in the elderly persons.”
BackgroundHidaka, Y., Hashimoto, M., Suehiro, T., Fukuhara, R., Ishikawa, T., Tsunoda, N., Koyama, A., Honda, K., Miyagawa, Y., Yoshiura, K., et al. (2022) · Fluids and Barriers of the CNS · doi:10.1186/s12987-022-00381-5 · Cited by 22
“Aged mice reportedly have a disruption in meningeal lymphatic function [5], and advancing age was associated with a decline in the efficiency of CSF-interstitial fluid exchange in rodents [36].”
BackgroundAltered dynamics of glymphatic flow in a mature-onset Tet-off APP mouse model of amyloidosis
Ben-Nejma, I. R. H., Keliris, A., Vanreusel, V., Ponsaerts, P., der Linden, A. V., & Keliris, G. A. (2023) · Alzheimer s Research & Therapy · doi:10.1186/s13195-023-01175-z · Cited by 24
“Moreover, ageing was associated with reduced and more fragmented slow-wave sleep, particularly in AD [33, 34], but also with a decreased CSF flow coinciding with a massive depolarisation of astrocytic AQP4 [22].”
BackgroundInfluentialGlymphatic dysfunction in the pathogenesis of neurodegenerative diseases and pathological aging
Shirolapov, I. V., Zakharov, A. V., Bulgakova, S. V., Khivintseva, E., Sergeeva, M. S., Romanchuk, N., Pavlova, O. N., & Kazantsev, V. (2023) · Genes and Cells · doi:10.23868/gc546022 · Cited by 22
Fine Particulate Matter Exposure and Cerebrospinal Fluid Markers of Vascular Injury
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“Exploratory analyses considered potential interaction effects of age [40, 41] and diabetes e [16, 18, 42–44]; however, because of small sample size in the diabetes subgroup, we were unable to perform the latter analysis and therefore considered effect modification of age only.”
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Glymphatic pathway dysfunction in severe obstructive sleep apnea: A meta-analysis
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“Thenegativecorrelationofglymphaticfunctionwithageinboth groupsisconsistentwiththeavailableliterature 3,47 – 49 .”
Association between arterial stiffness and the presence of cerebral small vessel disease markers
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“Increased arterial pulsatility can drive glymphatic influx to the brain parenchyma and blood–brain barrier break down, which causes greater extravasation of fluid into the perivascular space (Kress et al., 2014; Mestre et al., 2017).”
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“Neuroinflammation and reactive astrogliosis are the main features of craniocerebral trauma, in which the glymphatic function of interstitial Aβ clearance is obviously impaired [7, 15].”
BackgroundNassir, C. M. N. C. M., Damodaran, T. K., Yusof, S. R., Norazit, A., Chilla, G. S. V. N., Huen, I., Nagaraja, B. P. K., Ibrahim, N. M., & Mustapha, M. (2021) · Pharmaceutics · doi:10.3390/pharmaceutics13081207 · Cited by 22
The meningeal lymphatic vasculature in neuroinflammation
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“One recent study (Kress et al., 2014) shows reduced CSF flow in aged mice, which might be explained in part by arterial stiffening, though other mechanisms are likely to play a role as well.”
BackgroundSelf-citationLiu, X. L., Ouyang, F., Hu, L. T., Sun, P., Yang, J., Sun, Y. J., Liao, M., Lan, L., Pei, Z., & Fan, Y. (2022) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2022.883503 · Cited by 21
“The paravascular material exchange, mainly through cerebrospinal fluid (CSF) and interstitial fluid (ISF), is supported by the astrocytes involving AQP4 (Kress et al., 2014), which normally localizes to the perivascular astrocytic end feet.”
BackgroundLiu, Y., Wang, Z., Cao, C., Xu, Z., Lü, J., Shen, H., Li, X., Li, H., Wu, J., & Chen, G. (2022) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2022/8808677 · Cited by 21
“CD31 images were used to identify the astrocytes around the blood vessels [32].”
RetractedZhang, Y., Pang, Y., Feng, W., Jin, Y., Chen, S., Ding, S., Wang, Z., Zou, Y., Li, Y., Wang, T., et al. (2022) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-022-04533-6 · Cited by 22
“The image was uniformly thresholded at a pixel intensity of 50 (out of 255), and then the mean gray value (AU) was measured [31].”
MethodNovel therapeutic strategies targeting mitochondria as a gateway in neurodegeneration
Trigo, D., Vitória, J., & Silva, O. A. B. D. C. E. (2022) · Neural Regeneration Research · doi:10.4103/1673-5374.355750 · Cited by 22
“Glymphatic dysfunction has been hypothesized to particularly contribute to aging-associated brain dysfunction due to increased Aβ accumulation (Kress et al., 2014), and impaired glymphatic clearance has in fact been described in AD animal models, associated with Aβ deposition (Peng et al., 2016);…”
BackgroundProgress on Brain and Ocular Lymphatic System
Xu, Y., Cheng, L., Lu, Y., Yi, Q., Xiao, L., & Chen, H. (2022) · BioMed Research International · doi:10.1155/2022/6413553 · Cited by 21
“More interestingly, comparing the results of rats of different ages, it was found that the clearance rate of β-amyloid protein was decreased in aged mice and the normal distribution of AQP4 in the perivascular space in the brain was lost [34].”
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“Several studies have also demonstrated the associations between RHIs and vascular pathology, which likely contributes to long-term detrimental effects on cerebrovascular functions (38, 39) and ISF-CSF exchange (40).”
BackgroundZhao, H., Sun, M., Zhang, Y., Kong, W., Fan, L., Wang, K., Xu, Q., Chen, B., Dong, J., Shi, Y., et al. (2023) · Aging and Disease · doi:10.14336/ad.2023.0516 · Cited by 22
“As an important component of the glymphatic system, the perivascular spaces may be deeply involved in fluid drainage and metabolic waste removal in the brain [39-41].”
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“It is reported that glym-phatic system dysfunction could cause the accumulation of extracellular Aβ before the onset of dementia and Alzheimer’s disease (AD) [9, 10].”
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“, 2013) and that its function becomes impaired with increasing age (Kress et al., 2014).”
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“Glymphatic function is impaired in rodent models of aging (Kress et al., 2014), cerebrovascular injury (Wang et al.”
BackgroundSelf-citationRhythms in barriers and fluids: Circadian clock regulation in the aging neurovascular unit
Skapetze, L., Owino, S., Lo, E. H., Arai, K., Merrow, M. W., & Harrington, M. E. (2023) · Neurobiology of Disease · doi:10.1016/j.nbd.2023.106120 · Cited by 20
“Studies in mice demonstrate that the glymphatic function is impaired already by middle age, with further loss as mice continue to age (Kress et al., 2014).”
BackgroundHagiwara, A., Tomizawa, Y., Hoshino, Y., Yokoyama, K., Kamagata, K., Sekine, T., Takabayashi, K., Nakaya, M., Maekawa, T., Akashi, T., et al. (2023) · American Journal of Neuroradiology · doi:10.3174/ajnr.a8066 · Cited by 20
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Astrocyte aquaporin mediates a tonic water efflux maintaining brain homeostasisPreprint
Pham, C., Komaki, Y., Deàs-Just, A., Gac, B. L., Mouffle, C., Franco, C., Chaperon, A., Vialou, V., Tsurugizawa, T., Cauli, B., et al. (2024) · eLife · doi:10.7554/elife.95873 · Cited by 23
“AQP4 has been proposed to maintain the circulation of cerebrospinal fluid (CSF), underlying the clearance efficacy of glymphatic system (Hablitz et al., 2020; Kress et al., 2014; Mestre et al., 2018a; Smith et al., 2017).”
BackgroundZhang, Q., Song, Q., Gu, X., Zheng, M., Wang, A., Jiang, G., Huang, M., Chen, H., Qiu, Y., Bo, B., et al. (2021) · Advanced Science · doi:10.1002/advs.202001918 · Cited by 19
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“” To better quantify this “ polarization, ” using AQP4 + CD31 images as examples, our measurement methodology was consistent with previous studies (Kress et al., 2014).”
BackgroundResultBlood-brain barrier water permeability across the adult lifespan: A multi-echo ASL study
Padrela, B. E., Slivka, M., Sneve, M. H., Garrido, P. F., Dijsselhof, M. B. J., Hageman, T., Geier, O. M., Grydeland, H., Mahroo, A., Kuijer, J. P. A., et al. (2025) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2024.12.012 · Cited by 19
“…given to the role of astrocytes and alterations in aquaporin-4 (AQP4) expressions, and both have been related to the accumulation of amyloid-β in the brain in animal models (W. Yang et al., 2012; J. Yang et al., 2011; Kress et al., 2014) and humans (Hoshi et al., 2012; Zep-penfeld et al., 2017).”
Mi, L., Yuan, J., Jiang, Y., Hu, Y., Lv, C., Xu, Y., Liu, M., Liu, T., Liu, X., Huang, J., et al. (2025) · Drug Delivery · doi:10.1080/10717544.2025.2486840 · Cited by 20
“…excessively or when the distance for transporting aβ to the BBB is too far, aβ needs to be cleared by the glymphatic system via the isF pathway (Kress et al. 2014). thus, Gs and BBB complement each other in clearing interstitial solutes, and glym-phatic system also promotes BBB transport…”
The Glymphatic System and Its Role in Neurovascular Diseases
Krings, T., Takemoto, Y., Mori, K., & Kee, T. P. (2025) · Journal of Neuroendovascular Therapy · doi:10.5797/jnet.ra.2025-0020 · Cited by 19
“57) In addition to medium and large vessel atherosclerotic steno-occlusive disease, cerebral small vessel disease (CSVD) leading to leukoencephalopathy will also have a profound effect on the GS and has recently been implicated in cognitive deterioration.”
Pan, J., Fu, Y., Yang, P., Li, W., Luo, Z., Zhang, A., Du, J., Mei, F., Liu, F., Qi, S., et al. (2025) · Cellular and Molecular Neurobiology · doi:10.1007/s10571-025-01598-2 · Cited by 20
“Aging is also accompanied by structural and functional changes in cerebral arterioles, including decreased pulsatility of small intracortical arterioles (Kress et al. 2014) and increased vessel tortuosity, both of which increase the resistance to CSF flow within the PVS (Bennett et al. 2024).”
Barlattani, T., Luca, D. D., Giambartolomei, S., Bologna, A., Innocenzi, A., Bruno, F., Socci, V., Malavolta, M., Rossi, A., Berardis, D. D., et al. (2025) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2025.1653144 · Cited by 20
Astrocytes, HIV and the Glymphatic System: A Disease of Disrupted Waste Management?
Tice, C. M., McDevitt, J. K., & Langford, D. (2020) · Frontiers in Cellular and Infection Microbiology · doi:10.3389/fcimb.2020.523379 · Cited by 23
Liu, S., Hou, B., You, H., Zhang, Y., Zhu, Y., Ma, C., Zuo, Z., & Feng, F. (2021) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2021.599724 · Cited by 19
“The results revealed that BG-PVS are associated with numerous cardiovascular risk factors (such as age, sex, and hypertensive arteriopathy), consistent with previous studies (Zhu et al., 2010; Kress et al., 2014; Kyrtsos and Baras, 2015; Ramirez et al., 2016).”
BackgroundResultLi, A. M., Chen, L., Liu, H., Li, Y., Duan, W., & Xu, J. (2021) · Magnetic Resonance in Medicine · doi:10.1002/mrm.29137 · Cited by 17
Molecular Mechanisms and Risk Factors for the Pathogenesis of Hydrocephalus
Li, J., Zhang, X., GUO, J. X., Chen, Y., & Yang, J. (2022) · Frontiers in Genetics · doi:10.3389/fgene.2021.777926 · Cited by 21
Nguchu, B. A., Zhao, J., Wang, Y., Uwisengeyimana, J. D. D., Wang, X., Qiu, B., & Li, H. (2022) · Frontiers in Neurology · doi:10.3389/fneur.2022.819594 · Cited by 19
“In a variety of research tests, impaired glymphatic clearance has been associated with cognitive dysfunction, with aged individuals being at higher risk due to age-related alterations such as weakening of arterial pulsatility and AQP4 polarization dysfunctions, and stiffness or flexibility of large elastic arteries (1…”
BackgroundSleep: The Tip of the Iceberg in the Bidirectional Link Between Alzheimer's Disease and Epilepsy
Szabo, A. B., Cretin, B., Gérard, F., Curot, J., Barbeau, E. J., Pariente, J., Dahan, L., & Valton, L. (2022) · Frontiers in Neurology · doi:10.3389/fneur.2022.836292 · Cited by 21
“First, these channels show an age-dependent decline even in wild-type mice (83), leading to a decrease by 40% of intraparenchymally injected Aβ-clearance efficiency.”
BackgroundThe glymphatic system and subarachnoid hemorrhage: disruption and recovery
Quintin, S. S., Barpujari, A., Mehkri, Y., Hernandez, J. S., & Lucke-Wold, B. P. (2022) · Exploration of Neuroprotective Therapy · doi:10.37349/ent.2022.00023 · Cited by 19
“CSF from the subarachnoid space flows into the brain via PVSs of the leptomeningeal arteries [17, 18].”
BackgroundTekieh, T., Robinson, P. A., & Postnova, S. (2022) · Scientific Reports · doi:10.1038/s41598-022-15109-6 · Cited by 23
Spitz, S., Ko, E. C., Ertl, P., & Kamm, R. D. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24032171 · Cited by 19
“Furthermore, both age-associated alterations in circadian rhythms and a decrease in CSF turnover rate might contribute to an abated clearance efficiency in the aging cerebrum [10,13,14].”
BackgroundShirolapov, I. V., Zakharov, A. V., Smirnova, D. A., Lyamin, A. V., & Gayduk, A. (2023) · S S Korsakov Journal of Neurology and Psychiatry · doi:10.17116/jnevro202312309131 · Cited by 19
Perivascular spaces, plasma GFAP, and speeded executive function in neurodegenerative diseases
Andriuta, D., Ottoy, J., Ruthirakuhan, M. T., Feliciano, G. J., Dilliott, A. A., Hegele, R. A., Gao, F., McLaughlin, P. M., Rabin, J. S., Alexander, M. W., et al. (2024) · Alzheimer s & Dementia · doi:10.1002/alz.14081 · Cited by 18
Overexpression of Slit2 improves function of the paravascular pathway in the aging mouse brain
Li, G., He, X., Li, H., Wu, Y., Guan, Y., Liu, S., Jia, H., Li, Y., Wang, L., Huang, R., et al. (2018) · International Journal of Molecular Medicine · doi:10.3892/ijmm.2018.3802 · Cited by 20
“The depolarization of AQP4 in reactive astrocytes is closely associated with impairment of the paravascular pathway in the aging brain (3).”
InfluentialFu, L., Jiang, G., Weng, H., Dick, G. M., Chang, Y.-Z., & Kassab, G. S. (2019) · Brain Pathology · doi:10.1111/bpa.12759 · Cited by 20
“Soluble Aβ oligomers in the ISF flow are driven by arterial pulsation into the perivascular space located along the smooth muscle cells (SMCs) and capillary basement membrane and toward the subarachnoid space, and ultimately out of the brain (3, 14, 30, 37).”
BackgroundAstroglial Serotonin Receptors as the Central Target of Classic Antidepressants
Verkhratsky, A., Parpura, V., Scuderi, C., & Li, B. (2021) · Advances in Neurobiology · doi:10.1007/978-3-030-77375-5_13 · Cited by 19
“A uthor M anuscript A uthor M anuscript A uthor M anuscript A uthor M anuscript disease-related proteins, such as β-amyloid (Kress et al. 2014).”
BackgroundKorann, V., Panganiban, K. J., Stogios, N., Remington, G., Graff‐Guerrero, A., Chintoh, A. F., Hahn, M., & Agarwal, S. M. (2024) · The Canadian Journal of Psychiatry · doi:10.1177/07067437241290193 · Cited by 17
“33,34 Previous studies indicate that the brains of people with chronic SSDs seem to exhibit an accelerated aging process compared to their actual age, in contrast to the general population.”
Inflammation and psychomotor retardation in depression: The moderating role of glymphatic system
Liang, Q., Peng, B., Chen, S., Wei, H., Lin, S., Lin, X., Li, Y., Zhang, Y., Zhou, Z., Xu, Z., et al. (2025) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2025.03.024 · Cited by 18
Self-citationGhanizada, H., & Nedergaard, M. (2025) · Handbook of clinical neurology · doi:10.1016/b978-0-443-19104-6.00006-1 · Cited by 22
“, 2012), and loss of polarization occurs in parallel with reactive astrogliosis during pathology and aging (Kress et al., 2014; Plog et al., 2015; Gleiser et al., 2016).”
Self-citationUmlauf, A., Soontornniyomkij, B., Sundermann, E. E., Gouaux, B. D., Ellis, R. J., Levine, A. J., Moore, D. J., & Soontornniyomkij, V. (2019) · AIDS · doi:10.1097/qad.0000000000002336 · Cited by 18
“Accordingly, age-related degeneration of cerebral blood vessels may play a role in the development of cerebral Ab plaques [40,41].”
BackgroundHUCBC Treatment Improves Cognitive Outcome in Rats With Vascular Dementia
Venkat, P., Culmone, L., Chopp, M., Landschoot‐Ward, J., Wang, F., Zacharek, A., & Chen, J. (2020) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2020.00258 · Cited by 19
Cumulative Damage: Cell Death in Posthemorrhagic Hydrocephalus of Prematurity
Sevensky, R., Newville, J., Tang, H. L., Robinson, S., & Jantzie, L. L. (2021) · Cells · doi:10.3390/cells10081911 · Cited by 19
High-resolution 3D demonstration of regional heterogeneity in the glymphatic system
He, X.-Z., Li, X., Li, Z.-H., Meng, J., Mao, R.-T., Zhang, X.-K., Zhang, R., Huang, H.-L., Gui, Q., Xu, G., et al. (2022) · Journal of Cerebral Blood Flow & Metabolism · doi:10.1177/0271678x221109997 · Cited by 18
“Studies on the glymphatic system are commonly based on in vivo two-photon and ex vivo fluorescence imaging on brain slices.(2,14,22,38,39) Analysis of the local brain suggested that the glymphatic pathway represents a brain-wide anatomical system.”
Wang, F., Xu, C., Su, C., Li, J., & Lin, J. (2022) · Frontiers in Neuroscience · doi:10.3389/fnins.2022.926128 · Cited by 18
Eide, P. K. (2022) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2022.981399 · Cited by 18
“, 2013), and becoming impaired with increasing age (Kress et al., 2014).”
BackgroundVargas-Soria, M., Ramos‐Rodríguez, J. J., del Marco, À., Hierro‐Bujalance, C., Carranza-Naval, M. J., Calvo-Rodríguez, M., van Veluw, S. J., Stitt, A. W., Simó, R., Bacskai, B. J., et al. (2022) · Fluids and Barriers of the CNS · doi:10.1186/s12987-022-00380-6 · Cited by 20
“Vascular pulsation has been described as a mechanism of perivascular clearance of Aβ [49, 50] and as disease progresses; arteries show reduced vascular reactivity affecting perivascular drainage of fluids and solutes.”
BackgroundResultObenaus, A., Rodriguez‐Grande, B., Lee, J. B., Dubois, C., Fournier, M., Cador, M., Caillé, S., & Badaut, J. (2023) · Acta Neuropathologica Communications · doi:10.1186/s40478-023-01515-y · Cited by 18
“In support of this hypothesis, decreased perivascular AQP4 correlated with increased β-amyloid accumulation in humans [77] and in mice [35, 75].”
BackgroundLi, C., Pan, J., Sun, P., Wang, S., Wang, S., Feng, W., Chen, S., Chai, X., Zhao, S., & Zhu, X. (2023) · Molecular Nutrition & Food Research · doi:10.1002/mnfr.202200711 · Cited by 18
Verkhratsky, A., & Semyanov, A. V. (2023) · Sub-cellular biochemistry/Subcellular biochemistry · doi:10.1007/978-3-031-26576-1_11 · Cited by 20
Neuropsychological considerations for long-duration deep spaceflight
Faerman, A., Clark, J. B., & Sutton, J. P. (2023) · Frontiers in Physiology · doi:10.3389/fphys.2023.1146096 · Cited by 20
“Such PVS changes could lead to morphplogical changes of glymphatic pathways and impair glymphatic clearance, as seen in aging (Kress et al., 2014).”
BackgroundA meta-analysis of the relationship between sleep and β-Amyloid biomarkers in Alzheimer’s disease
Harenbrock, J., Holling, H., Reid, G., & Koychev, I. G. (2023) · Biomarkers in Neuropsychiatry · doi:10.1016/j.bionps.2023.100068 · Cited by 20
Zhu, Y., Wang, G., Kolluru, C., Gu, Y., Gao, H., Zhang, J., Wang, Y., Wilson, D. L., Zhu, X., Flask, C. A., et al. (2023) · Scientific Reports · doi:10.1038/s41598-023-40896-x · Cited by 21
“An infusion rate of 1–2 µL/min for a total volume of 1–10 µL were considered safe and would only introduce a mild and transient increase in ICP 23,26 .”
BackgroundInfluentialLi, J., Hao, Y., Wang, S., Li, W., Yue, S., Duan, X., Yang, Y., & Li, B. (2023) · Journal of Ethnopharmacology · doi:10.1016/j.jep.2023.117195 · Cited by 19
Li, J., Jia, S., Song, Y., Xu, W., & Lin, J. (2024) · Neuropharmacology · doi:10.1016/j.neuropharm.2024.109907 · Cited by 22
Functional aspects of the brain lymphatic drainage system in aging and neurodegenerative diseases
Chen, Y., He, X., Cai, J., & Li, Q. (2024) · Journal of Biomedical Research · doi:10.7555/jbr.37.20230264 · Cited by 18
Bhat, N. R. (2015) · Journal of Alzheimer s Disease · doi:10.3233/jad-150098 · Cited by 18
Why monkeys do not get multiple sclerosis (spontaneously)
Bove, R. M. (2018) · Evolution Medicine and Public Health · doi:10.1093/emph/eoy002 · Cited by 19
“This glymphatic system facilitates the flow of cerebrospinal fluid (CSF) and the clearance of interstitial solutes (including amyloid B) [83], and its efficiency is impaired in the aging brain [84].”
BackgroundThe Brain's Waste-Removal System.
Benveniste, H. (2018) · Europe PMC (PubMed Central) · Cited by 18
Eisenbaum, M., Pearson, A., Ortiz, C., Koprivica, M., Cembran, A., MULLAN, M. J., Crawford, F., Ojo, J. O., & Bachmeier, C. J. (2024) · Experimental Neurology · doi:10.1016/j.expneurol.2024.114702 · Cited by 18
Tao, Y., Zhou, Y., Li, W., Ding, Y., Wu, P., Wu, Z., & Shi, H. (2025) · Sleep Medicine · doi:10.1016/j.sleep.2025.106482 · Cited by 17
Mapping the Brain’s Glymphatic System
Voumvourakis, K. I., Thomaidis, N. S., & Tsiodras, S. (2026) · Biomedicines · doi:10.3390/biomedicines14020409 · Cited by 17
“Non-invasive intrathecal MRI studies in humans corroborate this macro-scale drainage route via meningeal lymphatics, showing age-related aberrations [59,60] consistent with declining glymphatic function [61].”
Nakagawa, Y., & Yamada, S. (2019) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2019.107455 · Cited by 18
Verheggen, I. C. M., Freeze, W. M., de Jong, J. J. A., Jansen, J. F. A., Postma, A. A., van Boxtel, M. P. J., Verhey, F. R. J., & Backes, W. H. (2021) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2021.04.025 · Cited by 18
“Some publications report that CSF is exchanged with ISF due to convective flow from the para-arterial to the paravenous spaces, to clear solutes from the interstitial space (Iliff et al., 2012; Kress et al., 2014).”
Astrocytes exhibit diverse Ca2+ changes at subcellular domains during brain aging
Ding, F., Liang, S., Li, R., Yang, Z., He, Y., Yang, S., Duan, Q., Zhang, J., Lyu, J., Zhou, Z., et al. (2022) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2022.1029533 · Cited by 18
“This degenerative progression was found to produce numerous detrimental changes in astrocytes (Matias et al., 2019), including reduced glutamate uptake (Popov et al., 2021), decreased astroglial metabolic support (Verkhratsky et al., 2021), and impaired glymphatic clearance (Kress et al., 2014).”
BackgroundSelf-citationXiao, M., Hou, J., Xu, M., Li, S., & Yang, B. (2023) · Advances in experimental medicine and biology · doi:10.1007/978-981-19-7415-1_7 · Cited by 17
Liu, S., Li, H., Shen, Y., Zhu, W., Wang, Y., Wang, J., Zhang, N., Li, C., 余曙光, Lu⁃shuang, X., et al. (2023) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2023.1069155 · Cited by 16
“The loss of perivascular AQP4 in the aging mouse brain resulted in impairment of perivascular CSF recirculation and Aβ clearance (Kress et al., 2014).”
BackgroundSelf-citationDong, Y., Xu, T., Yuan, L., Wang, Y., Yu, S., Wang, Z., Chen, S., Chen, C., He, W., Stewart, T., et al. (2023) · Exploration · doi:10.1002/exp.20230029 · Cited by 17
Jukkola, J., Kaakinen, M., Singh, A., Moradi, S., Ferdinando, H., Myllylä, T., Kiviniemi, V. J., & Eklund, L. (2024) · Fluids and Barriers of the CNS · doi:10.1186/s12987-024-00509-9 · Cited by 21
“…parts of the CNS, but it also extends deeper into brain parenchyma along the perivascular spaces of penetrating arteries, mixes with brain interstitial fluid and thus may participate in the clearance of brain metabolic waste products in the absence of parenchymal lymphatic vessels [4, 5].”
BackgroundDosing, collection, and quality control issues in cerebrospinal fluid research using animal models
Barten, D. M., Cadelina, G. W., & Weed, M. R. (2017) · Handbook of clinical neurology · doi:10.1016/b978-0-12-804279-3.00004-6 · Cited by 17
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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