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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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“Interestingly, many of these factors are prominent in other diseases 10 and could represent important therapeutic targets to restore paravascular CSF-ISF exchange.”
InfluentialKaur, J., Fahmy, L. M., Davoodi‐Bojd, E., Zhang, L., Ding, G., Hu, J., Zhang, Z., Chopp, M., & Jiang, Q. (2021) · Frontiers in Neuroanatomy · doi:10.3389/fnana.2021.665803 · Cited by 108
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“While the role of the glymphatic pathway both in the clearance (21, 28, 29, 38, 41, 42) and delivery (21, 39, 43–48) of solutes has been established by multiple groups, prior studies using fluorescent, radiolabeled, and gadolinium-based tracers also suggest that convective flow through this pathway might be exploited…”
InfluentialSelf-citationHuman and mouse cortical astrocytes differ in aquaporin-4 polarization toward microvessels
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“Aging reduces glymphatic clearance, which is associated with the accumulation of beta amyloid protein and other proteins associated with Alzheimer’s disease, which is also marked by severe sleep-wake and circadian dysregulation (71, 93).”
BackgroundThe glymphatic system and meningeal lymphatics of the brain: new understanding of brain clearance
Yankova, G., Bogomyakova, O. B., & Тулупов, А. А. (2021) · Reviews in the Neurosciences · doi:10.1515/revneuro-2020-0106 · Cited by 110
Astroglial Calcium Signaling in Aging and Alzheimer's Disease
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“Aging was found to decrease the density of astroglial aquaporin 4 and hence impair glymphatic clearance (Kress et al. 2014), which may exacerbate retention of toxic misfolded proteins (such as, for example, amyloidβ) in the senescent brain.”
BackgroundHydraulic resistance of periarterial spaces in the brain
Tithof, J., Kelley, D. H., Mestre, H., Nedergaard, M., & Thomas, J. H. (2019) · Fluids and Barriers of the CNS · doi:10.1186/s12987-019-0140-y · Cited by 101
Self-citationA clinical primer for the glymphatic system
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The Blood–Brain Barrier and Its Intercellular Junctions in Age-Related Brain Disorders
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“Nevertheless, the aquaporin 4 in astrocytic endfeet is indispensable to BBB function as its knockout results in altered brain microvasculature and decreased water exchange through the BBB [17], furthermore its subcellular distribution shows an age dependent depolarization accompanied by decreased protein clearance [18…”
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“More fluid and metabolites remain in dilated PVS and obstruct the perivascular pathways.(24,26,40,41,102) Aging also dysregulates glymphatic function because AQP4 mislocalizes during astrogliosis (Figure 5).”
BackgroundAstrocytes in the regulation of cerebrovascular functions
Cohen‐Salmon, M., Slaoui, L., Mazaré, N., Gilbert, A., Oudart, M., Alvear‐Perez, R., Elorza‐Vidal, X., Chever, O., & Boulay, A. (2021) · Glia · doi:10.1002/glia.23924 · Cited by 93
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Aquaporins in Brain Edema and Neuropathological Conditions
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“It was discovered that amyloid-β was cleared along the glymphatic pathway, and AQP4-null mice showed a reduction in CSF flux of 65%, and a reduction in amyloid-β clearance of 55%, suggesting a role of AQP4 in neurodegenerative diseases such as Alzheimer’s [97,98].”
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“CSF-ISF exchange decreases with 27% reduction of intracortical arterioles and loss of polarized expression of AQP4 along the penetrating arteries (Kress et al., 2014).”
BackgroundThe blood–brain barrier: a help and a hindrance
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Immune dynamics in the CNS and its barriers during homeostasis and disease*
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“The astrocytic water channel AQP4 has a clear role in glymphatic pathway function, including perivascular CSF-interstitial fluid (ISF) exchange and Aβ and tau clearance from the brain [6, 7, 31].”
Self-citationGlymphatic Dysfunction Induced Oxidative Stress and Neuro-Inflammation in Major Depression Disorders
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“Since the regulation of AQP4 channel activity is one of the main ways through which the glymphatic system eliminates Aβ and tau aggregates [68], we decided to analyze the expression of this channel.”
BackgroundGlymphatic System Impairment Contributes to the Formation of Brain Edema After Ischemic Stroke
Zhu, J., Mo, J., Liu, K., Chen, Q., Li, Z., He, Y., Chang, Y., Lin, C., Yu, M., Xu, Y., et al. (2024) · Stroke · doi:10.1161/strokeaha.123.045941 · Cited by 94
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MethodCerebrospinal fluid and the early brain development of autism
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“Perivascular AQP4 is a critical component of the brain glymphatic system (57, 58).”
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Perivascular space fluid contributes to diffusion tensor imaging changes in white matter
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Glymphatic dysfunction in isolated REM sleep behavior disorder
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The pathobiology of neurovascular aging
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Glymphatic dysfunction in Alzheimer’s disease: A critical appraisal
Keil, S. A., Jansson, D., Braun, M., & Iliff, J. J. (2025) · Science · doi:10.1126/science.adv8269 · Cited by 100
Self-citationPlog, B. A., Lou, N., Pierre, C. A., Cove, A., Kenney, H. M., Hitomi, E., Kang, H., Iliff, J. J., Zeppenfeld, D. M., Nedergaard, M., et al. (2019) · Journal of neurosurgery · doi:10.3171/2019.2.jns182675 · Cited by 89
Self-citationNo Longer Underappreciated: The Emerging Concept of Astrocyte Heterogeneity in Neuroscience
Pestana, F., Edwards‐Faret, G., Belgard, T. G., Martirosyan, A., & Holt, M. G. (2020) · Brain Sciences · doi:10.3390/brainsci10030168 · Cited by 91
Volumetric distribution of perivascular space in relation to mild cognitive impairment
Sepehrband, F., Barisano, G., Sheikh‐Bahaei, N., Choupan, J., Cabeen, R. P., Lynch, K. M., Crawford, M. S., Lan, H., Mack, W. J., Chui, H. C., et al. (2020) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2020.12.010 · Cited by 86
Cai, X., Chen, Z., He, C., Zhang, P., Nie, K., Qiu, Y., Wang, L., Wang, L., Jing, P., & Zhang, Y. (2022) · CNS Neuroscience & Therapeutics · doi:10.1111/cns.13984 · Cited by 86
Andica, C., Kamagata, K., Takabayashi, K., Kikuta, J., Kaga, H., Someya, Y., Tamura, Y., Kawamori, R., Watada, H., Taoka, T., et al. (2023) · Neurobiology of Disease · doi:10.1016/j.nbd.2023.105990 · Cited by 94
Umezawa, M., Onoda, A., Korshunova, I., Jensen, A. C. Ø., Koponen, I. K., Jensen, K. A., Khodosevich, K., Vogel, U. B., & Hougaard, K. S. (2018) · Particle and Fibre Toxicology · doi:10.1186/s12989-018-0272-2 · Cited by 86
Apolipoprotein E4 and meningeal lymphatics in Alzheimer disease: a conceptual framework
Mentis, A. A., Dardiotis, E., & Chrousos, G. P. (2020) · Molecular Psychiatry · doi:10.1038/s41380-020-0731-7 · Cited by 83
Meningeal lymphatic drainage: novel insights into central nervous system disease
Zhang, Q., Niu, Y., Li, Y., Xia, C., Chen, Z., Chen, Y., & Feng, H. (2025) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-025-02177-z · Cited by 100
Matsumae, M., Sato, O., Hirayama, A., Hayashi, N., TAKIZAWA, K., Atsumi, H., & Sorimachi, T. (2016) · Neurologia medico-chirurgica · doi:10.2176/nmc.ra.2016-0020 · Cited by 84
Impaired glymphatic function in idiopathic intracranial hypertension
Eide, P. K., Pripp, A. H., Ringstad, G. A., & Valnes, L. M. (2021) · Brain Communications · doi:10.1093/braincomms/fcab043 · Cited by 85
Altered Waste Disposal System in Aging and Alzheimer’s Disease: Focus on Astrocytic Aquaporin-4
Valenza, M., Facchinetti, R., Steardo, L., & Scuderi, C. (2020) · Frontiers in Pharmacology · doi:10.3389/fphar.2019.01656 · Cited by 90
Brain perivascular space imaging across the human lifespan
Lynch, K. M., Sepehrband, F., Toga, A. W., & Choupan, J. (2023) · NeuroImage · doi:10.1016/j.neuroimage.2023.120009 · Cited by 87
“Previous studies have also shown aging is associated with reduced metabolic waste clearance, which may be attributed to age-related reduction in CSF production (41), decline in arterial pulsatility (42), increase in blood-brain barrier permeability (43) and deposition of insoluble AB aggregates (44).”
Factors Influencing Clinical Correlates of Chronic Traumatic Encephalopathy (CTE): a Review
Asken, B. M., Sullan, M. J., Snyder, A., Houck, Z. M., Bryant, V. E., Hizel, L. P., McLaren, M. E., Dede, D. E., Jaffee, M. S., DeKosky, S. T., et al. (2016) · Neuropsychology Review · doi:10.1007/s11065-016-9327-z · Cited by 90
Morrison, H. W., & Filosa, J. A. (2016) · Neuroscience · doi:10.1016/j.neuroscience.2016.09.047 · Cited by 85
“AQP4 polarity is disrupted in the days following traumatic brain injury (Kress et al., 2014; Plog et al., 2015) and transient focal ischemia (Fukuda and Badaut, 2012; Vella et al., 2015) which may contribute to brain edema after injury.”
BackgroundAchieving brain clearance and preventing neurodegenerative diseases—A glymphatic perspective
Kylkilahti, T. M., Berends, E., Ramos, M., Shanbhag, N. C., Töger, J., Bloch, K. M., & Lundgaard, I. (2021) · Journal of Cerebral Blood Flow & Metabolism · doi:10.1177/0271678x20982388 · Cited by 91
“Interestingly, the impairment of the evoked vasomotion and clearance rates in aged AD mice was linked to the loss of vascular smooth muscle cells, thus indicating that AD pathology aggravates decline of glymphatic function with age.(15) The perivascular pumping phenomenon and vasomotion thus appear to be drivers of gl…”
BackgroundThe role of glymphatic system in the cerebral edema formation after ischemic stroke
Ji, C., Yu, X., Xu, W., Lenahan, C., Tu, S., & Shao, A. (2021) · Experimental Neurology · doi:10.1016/j.expneurol.2021.113685 · Cited by 82
Functional analysis of the human perivascular subarachnoid space
Eide, P. K., & Ringstad, G. A. (2024) · Nature Communications · doi:10.1038/s41467-024-46329-1 · Cited by 85
“We also showed reduced tracer in the cerebral cortex at 2 h with increasing age, independent of diagnosis, which compares with previous experimental rodent data about impaired glymphatic function with increasing age 33 .”
ResultPistollato, F., Cano, S. S., Elío, I., Vergara, M. M., Giampieri, F., & Battino, M. A. (2016) · Advances in Nutrition · doi:10.3945/an.115.011775 · Cited by 85
Microvascular Alterations in Alzheimer's Disease
Steinman, J., Sun, H., & Feng, Z. (2021) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2020.618986 · Cited by 85
Duncombe, J., Lennen, R. J., Jansen, M. A., Marshall, I., Wardlaw, J. M., & Horsburgh, K. J. (2016) · Neuropathology and Applied Neurobiology · doi:10.1111/nan.12375 · Cited by 85
Qi, X.-M., & Ma, J. (2017) · Translational Neurodegeneration · doi:10.1186/s40035-017-0091-7 · Cited by 86
“In aging mouse brain loss of perivascular AQP4 results in impairment of perivascular CSF recirculation and Aβ clearance [77].”
BackgroundUekawa, K., Hattori, Y., Ahn, S. J., Seo, J., Casey, N., Anfray, A., Zhou, P., Luo, W., Anrather, J., Park, L., et al. (2023) · Molecular Neurodegeneration · doi:10.1186/s13024-023-00660-1 · Cited by 80
Szczygielski, J., Kopańska, M., Wysocka, A., & Oertel, J. (2021) · Frontiers in Neurology · doi:10.3389/fneur.2021.767470 · Cited by 79
“Disturbance in the cell-level distribution of AQP4, as provoked by syntrophin-1-alpha (Snta-1) gene deletion (146) or seen in brains affected by aging (147), trauma (148), or ischemic damage (149) is related to impaired function of glymphatic clearance.”
BackgroundTaoka, T., Ito, R., Nakamichi, R., Nakane, T., Sakai, M., Ichikawa, K., Kawai, H., & Naganawa, S. (2022) · Japanese Journal of Radiology · doi:10.1007/s11604-022-01275-0 · Cited by 77
“A tracer study of mice using fluorescent material and amyloid-β has been reported to show that the exchange efficiency between the subarachnoid cerebrospinal fluid (CSF) and brain parenchyma decreased dramatically with aging [2].”
BackgroundMethod40 Hz light flickering facilitates the glymphatic flow via adenosine signaling in mice
Sun, X., Dias, L., Peng, C., Zhang, Z., Ge, H., Wang, Z., Jin, J., Jia, M., Xu, T., Guo, W. M., et al. (2024) · Cell Discovery · doi:10.1038/s41421-024-00701-z · Cited by 84
“The glymphatic clearance is mostly active during sleep 6 and its disturbance or decreased function on aging 7 , leads to the accumulation of pathogenic proteins in the brain such as tau 8,9 , β -amyloid 10 , and α - synuclein 11 .”
InfluentialUllah, R., Park, T. J., Huang, X., & Kim, M. O. (2021) · Ageing Research Reviews · doi:10.1016/j.arr.2021.101451 · Cited by 78
“Similarly, another study reported that an impaired glymphatic system reduces Aβ peptide clearance by 40 %, leading to deposition of Aβ peptides in the aging mouse brain (Kress et al., 2014).”
BackgroundMethodInfluentialKim, S. H., Ahn, J. H., Yang, H. J., Lee, P., Koh, G. Y., & Jeong, Y. (2020) · Acta Neuropathologica Communications · doi:10.1186/s40478-020-01042-0 · Cited by 79
Chen, X., Liu, X., Koundal, S., Elkin, R., Zhu, X. A., Monte, B., Xu, F., Dai, F., Pedram, M., Lee, H., et al. (2022) · Nature Aging · doi:10.1038/s43587-022-00181-4 · Cited by 80
Liang, T., Chang, F., Huang, Z., Peng, D., Zhou, X., & Liu, W. (2023) · British Journal of Radiology · doi:10.1259/bjr.20220315 · Cited by 79
Chronic cerebral hypoperfusion induces post-stroke dementia following acute ischemic stroke in rats
Back, D. B., Kwon, K. J., Choi, D.-H., Shin, C. Y., Lee, J., Han, S., & Kim, H. Y. (2017) · Journal of Neuroinflammation · doi:10.1186/s12974-017-0992-5 · Cited by 78
Simon, M. J., Wang, M. X., Murchison, C. F., Roese, N. E., Boespflug, E. L., Woltjer, R. L., & Iliff, J. J. (2018) · Scientific Reports · doi:10.1038/s41598-018-30779-x · Cited by 71
Self-citationThe glymphatic system: a new perspective on brain diseases
Ding, Z., Fan, X., Zhang, Y., Yao, M., Wang, G., Dong, Y., Liu, J., & Song, W. (2023) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2023.1179988 · Cited by 111
“The clearance rate of interstitial solutes was compared between young (2–3 months old) and old (18–20 months old) wild-type mice, and results showed that Aβ clearance was reduced by 40%, accompanied by a 27% decrease in the pulsatility of the vascular wall of the arterioles in the old mice cortex, as well as a widespr…”
BackgroundWostyn, P., Killer, H. E., & Deyn, P. P. D. (2017) · Clinical and Experimental Ophthalmology · doi:10.1111/ceo.12915 · Cited by 77
“This brain-wide pathway has been called the ’glymphatic system‘, based upon its similarity in function to the peripheral lymphatic system, and its dependence upon astroglial water transport through the water channel aquaporin-4 (AQP4), which is localized to perivascular astrocytic endfeet ensheathing the cerebral vasc…”
BackgroundOnoda, A., Takeda, K., & Umezawa, M. (2017) · Particle and Fibre Toxicology · doi:10.1186/s12989-017-0184-6 · Cited by 77
“Quantification was performed as per a previous study that detected changes in the expression level of GFAP and Aqp4 around blood vessels in the cerebral cortex [18].”
BackgroundMethodInfluentialBlood–brain barrier, bulk flow, and interstitial clearance in epilepsy
Marchi, N., Banjara, M., & Janigro, D. (2015) · Journal of Neuroscience Methods · doi:10.1016/j.jneumeth.2015.06.011 · Cited by 80
“Recent evidence support a role in amyloid β (Aβ) clearance in Alzheimer’s disease (Iliff and Nedergaard, 2013; Kress et al., 2014), as Aβ clearance requires AQ-4 expression and proper CSF–ISF exchange.”
BackgroundBasal lamina changes in neurodegenerative disorders
Nguyen, B., Bix, G., & Yao, Y. (2021) · Molecular Neurodegeneration · doi:10.1186/s13024-021-00502-y · Cited by 75
“It has been reported that aged mice exhibit decreased para-vascular recirculation of CSF, diminished CSF/ISF exchange, and loss of perivascular AQP4 polarization [76, 107].”
BackgroundMunicio, C., Carrero, L., Antequera, D., & Carro, E. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24010878 · Cited by 80
Glymphatic System Pathology and Neuroinflammation as Two Risk Factors of Neurodegeneration
Szlufik, S., Kopeć, K., Szleszkowski, S., & Koziorowski, D. (2024) · Cells · doi:10.3390/cells13030286 · Cited by 84
“It was shown that owing to the weakening of glymphatic clearance efficiency, which was correlated with advancing age, the clearance of intraparenchymally injected A β was impaired by 40% [68].”
BackgroundXue, Y., Liu, N., Zhang, M., Ren, X., Tang, J., & Fu, J. (2020) · Brain Research Bulletin · doi:10.1016/j.brainresbull.2020.04.008 · Cited by 71
Liu, D., He, X., Wu, D., Zhang, Q., Yang, C., Liang, F., He, X., Dai, G., Pei, Z., Lan, Y., et al. (2017) · Neuroscience Letters · doi:10.1016/j.neulet.2017.05.064 · Cited by 78
Dysfunction of the Glymphatic System Might Be Related to Iron Deposition in the Normal Aging Brain
Zhou, W., Shen, B., Shen, W., Chen, H., Zheng, Y.-F., & Fei, J.-J. (2020) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2020.559603 · Cited by 75
“We also found a negative relationship between the function of the glymphatic system and age, which is in accordance with previous studies (Kress et al., 2014; Del C Valdés Hernández et al., 2015).”
ResultThe effect of aquaporin-4 mis-localization on Aβ deposition in mice
Pedersen, T. J., Keil, S. A., Han, W., Wang, M. X., & Iliff, J. J. (2023) · Neurobiology of Disease · doi:10.1016/j.nbd.2023.106100 · Cited by 75
“…it is noteworthy that it is the loss of perivascular AQP4 localization that was most associated with impaired glymphatic function in aging mice (Kress et al., 2014), and is associated with Aβ and tau pathology, neurocognitive decline, and dementia status in two recent human histopathological…”
BackgroundInfluentialSelf-citationChang, H., Huang, C., Hsu, S., Huang, S., Lin, K., Ho, T., Ma, M.-C., Hsiao, W.-C., & Chang, C. (2023) · Psychiatry and Clinical Neurosciences · doi:10.1111/pcn.13557 · Cited by 74
Divecha, Y. A., Rampes, S., Tromp, S., Boyanova, S., Fleckney, A. L., Fidanboylu, M., & Thomas, S. A. (2025) · Pharmacological Reviews · doi:10.1016/j.pharmr.2025.100052 · Cited by 83
“Glymphatic pathway function is dramatically impaired in the aging brain and contributes to cognitive decline among the elderly (Kress et al, 2014).”
Fluid Flow and Mass Transport in Brain Tissue
Ray, L., & Heys, J. J. (2019) · Fluids · doi:10.3390/fluids4040196 · Cited by 78
“Mestre’s meta-analysis demonstrates a clear positive correlation between AQP4 and both ISF tracer clearance and CSF influx [70,100].”
BackgroundResultSleep as a Therapeutic Target in the Aging Brain
Bah, T. M., Goodman, J. R., & Iliff, J. J. (2019) · Neurotherapeutics · doi:10.1007/s13311-019-00769-6 · Cited by 76
Self-citationAquaporin 4 deletion exacerbates brain impairments in a mouse model of chronic sleep disruption
Zhang, R., Liu, Y., Chen, Y., Li, Q., Marshall, C., Wu, T., Hu, G., & Xiao, M. (2019) · CNS Neuroscience & Therapeutics · doi:10.1111/cns.13194 · Cited by 76
Stevens, K. A., Cai, S., Ladrón-de-Guevara, A., Sun, J., Zheng, X., Du, T., Thomas, J. H., Nedergaard, M., Karniadakis, G. E., & Kelley, D. H. (2023) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2217744120 · Cited by 75
“i [(uPTV − uAIV)(2) + (vPTV − vAIV)(2)], [8]”
Self-citation
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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