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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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“In the ageing brain, AQP4 migrates away from endfeet, which reduces operational capacity of the glymphatic system by ~40%.(546) Morphological atrophy of astrocytes also reduces their presence in the neuropil, which leads to an increase of extracellular diffusion channels and hence to an increase in mean diffusivity of…”
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MethodSelf-citationPerivascular spaces, glymphatic dysfunction, and small vessel disease
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“A loss in compliance would be expected to result in an increase in pulsatility, counter to the results seen in old mice(28).”
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“The glymphatic system has been suggested to be an essential component of Aβ clearance in the brain of rodents.(3,4) Glymphatic dysfunction has been found to be correlated with Aβ accumulation; however, its involvement in the pathogenesis of Alzheimer disease in humans is yet to be fully understood.”
BackgroundChanges in the composition of brain interstitial ions control the sleep-wake cycle
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MethodSelf-citationHe, X.-F., Liu, D.-X., Zhang, Q., Liang, F.-Y., Dai, G.-Y., Zeng, J.-S., Pei, Z., Xu, G.-Q., & Lan, Y. (2017) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2017.00144 · Cited by 371
“The paravascular bulk flow of the CSF and ISF is supported by the astroglial water channel AQP4 (Kress et al., 2014), which localizes to the perivascular astrocytic Frontiers in Molecular Neuroscience | www.frontiersin.org 11 May 2017 | Volume 10 | Article 144 end feet ensheathing the cerebral…”
BackgroundMethodThe glymphatic system: Current understanding and modeling
Bohr, T., Hjorth, P. G., Holst, S. C., Hrabětová, S., Kiviniemi, V. J., Lilius, T. O., Lundgaard, I., Mardal, K., Martens, E. A., Mori, Y., et al. (2022) · iScience · doi:10.1016/j.isci.2022.104987 · Cited by 401
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“As there may be regional differences in tracer penetration throughout the brain (Kress et al., 2014), we measured fractional tracer penetration in serial coronal sections made at 100 mm intervals through the brain.”
MethodImpaired meningeal lymphatic drainage in patients with idiopathic Parkinson’s disease
Ding, X., Wang, X., Xia, D., Liu, H., Tian, H., Fu, Y., Chen, Y., Qin, C., Wang, J.-Q., Zhang, Z., et al. (2021) · Nature Medicine · doi:10.1038/s41591-020-01198-1 · Cited by 375
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“These values remain unaffected by increasing age, despite that fact that ageing results in profound morphological changes of the cells of the grey matter (Kress et al. 2014).”
BackgroundInfluentialMultisensory gamma stimulation promotes glymphatic clearance of amyloid
Murdock, M. H., Yang, C.-Y., Sun, N., Pao, P.-C., Blanco-Duque, C., Kahn, M. C., Kim, T., Lavoie, N. S., Victor, M. B., Islam, M. R., et al. (2024) · Nature · doi:10.1038/s41586-024-07132-6 · Cited by 379
“We used established methods to quantify AQP4 polarization 12,21 .”
BackgroundMethodNorepinephrine-mediated slow vasomotion drives glymphatic clearance during sleep
Hauglund, N. L., Andersen, M., Tokarska, K., Radovanovic, T., Kjaerby, C., Sørensen, F. L., Bojarowska, Z., Untiet, V., Ballestero, S. B., Kolmos, M. G., et al. (2025) · Cell · doi:10.1016/j.cell.2024.11.027 · Cited by 349
Self-citationLymphatic Vessel Network Structure and Physiology
Breslin, J. W., Yang, Y., Scallan, J. P., Sweat, R. S., Adderley, S., & Murfee, W. L. (2018) · Comprehensive physiology · doi:10.1002/cphy.c180015 · Cited by 420
Alves de Lima, K., Rustenhoven, J., & Kipnis, J. (2020) · Annual Review of Immunology · doi:10.1146/annurev-immunol-102319-103410 · Cited by 348
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“However, perivascular AQP4 localization was also markedly reduced in the aging brain and was significantly associated with slowing of perivascular CSF influx into and through the brain parenchyma [6].”
BackgroundSelf-citationUnderstanding the role of the perivascular space in cerebral small vessel disease
Brown, R., Benveniste, H., Black, S. E., Charpak, S., Dichgans, M., Joutel, A., Nedergaard, M., Smith, K. J., Zloković, B. V., & Wardlaw, J. M. (2018) · Cardiovascular Research · doi:10.1093/cvr/cvy113 · Cited by 346
Self-citationCerebrospinal fluid dynamics and intracranial pressure elevation in neurological diseases
Bothwell, S. W., Janigro, D., & Patabendige, A. (2019) · Fluids and Barriers of the CNS · doi:10.1186/s12987-019-0129-6 · Cited by 348
Tissue mechanics regulate brain development, homeostasis and disease
Barnes, J. M., Przybyla, L., & Weaver, V. M. (2017) · Journal of Cell Science · doi:10.1242/jcs.191742 · Cited by 344
“Slowing of CSF flux through the brain is also associated with increasing age (Kress et al., 2014), which might affect cell functions that are dependent on sensing shear flow.”
BackgroundImpairment of the Glymphatic Pathway and Putative Meningeal Lymphatic Vessels in the Aging Human
Zhou, Y., Cai, J., Zhang, W., Gong, X., Yan, S., Zhang, K., Luo, Z., Sun, J., Jiang, Q., & Lou, M. (2020) · Annals of Neurology · doi:10.1002/ana.25670 · Cited by 305
“Our finding that the glymphatic pathway was impaired in the aging human brain is in agreement with multiple previous studies.(8,9) Aging has been considered as an essential factor in the regulation of the brain”
ResultSleep Disturbance, Cognitive Decline, and Dementia: A Review
Wu, M. N., Rosenberg, P. B., Spira, A. P., & Wennberg, A. M. V. (2017) · Seminars in Neurology · doi:10.1055/s-0037-1604351 · Cited by 325
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Emerging roles for dynamic aquaporin-4 subcellular relocalization in CNS water homeostasis
Salman, M. M., Kitchen, P., Halsey, A., Wang, M. X., Törnroth-Horsefield, S., Conner, A. C., Badaut, J., Iliff, J. J., & Bill, R. M. (2022) · Brain · doi:10.1093/brain/awab311 · Cited by 303
“In each case, impairment of perivascular exchange was associated with a reduction in the cell-level localization of AQP4 to perivascular processes.(57,61,62) When this perivascular localization of AQP4 is disrupted by deletion of the Snta1 gene, glymphatic function is similarly impaired.”
BackgroundSelf-citationHealthy aging and the blood–brain barrier
Banks, W. A., Reed, M. J., Logsdon, A. F., Rhea, E. M., & Erickson, M. A. (2021) · Nature Aging · doi:10.1038/s43587-021-00043-5 · Cited by 319
Impaired Glymphatic Transport in Spontaneously Hypertensive Rats
Mortensen, K. N., Sanggaard, S., Mestre, H., Lee, H., Kostrikov, S., Xavier, A. L. R., Gjedde, A., Benveniste, H., & Nedergaard, M. (2019) · The Journal of Neuroscience · doi:10.1523/jneurosci.1974-18.2019 · Cited by 266
“Whereas previous studies have used amount of brain tracer uptake and area coverage as markers of glymphatic influx (Iliff et al., 2012, 2013a; Kress et al., 2014; Plog et al., 2015; Peng et al., 2016), the present study shows that brain tracer concentrations after CM tracer infusion depend on the efficacy of the glymp…”
BackgroundMethodResultInfluentialSelf-citationGlymphatic system clears extracellular tau and protects from tau aggregation and neurodegeneration
Ishida, K., Yamada, K., Nishiyama, R., Hashimoto, T., Nishida, I., Abe, Y., Yasui, M., & Iwatsubo, T. (2022) · Journal of Experimental Medicine · doi:10.1084/jem.20211275 · Cited by 298
“impaired in aged brain (Kress et al., 2014) and also associated with”
Cerebral small vessel disease: Capillary pathways to stroke and cognitive decline
Østergaard, L., Engedal, T. S., Moreton, F. C., Hansen, M. B., Wardlaw, J. M., Dalkara, T., Markus, H. S., & Muir, K. W. (2015) · Journal of Cerebral Blood Flow & Metabolism · doi:10.1177/0271678x15606723 · Cited by 290
“Indeed, impaired glymphatic clearance has recently emerged as a potential therapeutic target.(58) Located in the layers of capillary basement membrane, pericytes are therefore exposed to amyloid during its perivascular removal and clearance across the BBB.”
BackgroundDeciphering the astrocyte reaction in Alzheimer's disease
Perez-Nievas, B. G., & Serrano-Pozo, A. (2018) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2018.00114 · Cited by 282
“This common mechanism could explain the finding of calcium overload (Kuchibhotla et al., 2008) and hyperactive neurons (Busche et al., 2008, 2012) found in the proximity of plaques using multiphoton calcium imaging in live APP/PS1 mice, although the latter finding was attributed to a decreased…”
BackgroundGlymphatic system impairment in multiple sclerosis: relation with brain damage and disability
Carotenuto, A., Cacciaguerra, L., Pagani, E., Preziosa, P., Filippi, M., & Rocca, M. A. (2021) · Brain · doi:10.1093/brain/awab454 · Cited by 288
Clearance of cerebral Aβ in Alzheimer’s disease: reassessing the role of microglia and monocytes
Zuroff, L. R., Daley, D. A., Black, K. L., & Koronyo‐Hamaoui, M. (2017) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-017-2463-7 · Cited by 292
“Advanced age also reduced glymphatic clearance rates in murine models, perhaps due to an age-dependent loss of AQP4 polarization [294].”
BackgroundSimon, M. J., Wang, M. X., Ismail, O., Braun, M., Schindler, A. G., Reemmer, J., Wang, Z., Haveliwala, M. A., O’Boyle, R. P., Han, W., et al. (2022) · Alzheimer s Research & Therapy · doi:10.1186/s13195-022-00999-5 · Cited by 293
“We next sought to replicate and extend findings from our prior study [13] to define whether similar changes in AQP4 localization are observed in the aging rodent brain as are observed in aging and AD human subjects ([20], Fig.”
BackgroundMethodResultInfluentialSelf-citationPhysical Exercise Inhibits Inflammation and Microglial Activation
Mee-inta, O., Zhao, Z., & Kuo, Y. (2019) · Cells · doi:10.3390/cells8070691 · Cited by 285
“Impaired glymphatic function is evident in aging and neurodegenerative diseases [118,119].”
BackgroundBanerjee, G., Kim, H. J., Fox, Z. V., Jäger, H. R., Wilson, D., Charidimou, A., Na, H. K., Na, D. L., Seo, S. W., & Werring, D. J. (2017) · Brain · doi:10.1093/brain/awx003 · Cited by 260
“Alternatively CAA may disrupt perivascular drainage via perturbations in normal arteriolar pulsation (Hawkes et al., 2014; Kress et al., 2014).”
BackgroundLymphatic drainage system of the brain: A novel target for intervention of neurological diseases
Sun, B., Wang, L.-H., Yang, T., Sun, J., Mao, L., Yang, M., Yuan, H., Colvin, R. A., & Yang, X. (2017) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2017.08.007 · Cited by 264
Achariyar, T. M., Li, B., Peng, W., Verghese, P. B., Shi, Y., McConnell, E., Benraiss, A., Kasper, T., Song, W., Takano, T., et al. (2016) · Molecular Neurodegeneration · doi:10.1186/s13024-016-0138-8 · Cited by 256
“the wake state [27], aging [42] and in brain injury and trauma [46, 73], could reduce the delivery and distribution of apoE to brain, which may lead to apoE related disorder in the long-term.”
BackgroundMethodSelf-citationCerebrospinal fluid regulates skull bone marrow niches via direct access through dural channels
Mazzitelli, J. A., Smyth, L. C. D., Cross, K. A., Dykstra, T., Sun, J., Du, S., Mamuladze, T., Smirnov, I., Rustenhoven, J., & Kipnis, J. (2022) · Nature Neuroscience · doi:10.1038/s41593-022-01029-1 · Cited by 261
Schain, A. J., Melo‐Carrillo, A., Strassman, A. M., & Burstein, R. (2017) · Journal of Neuroscience · doi:10.1523/jneurosci.3390-16.2017 · Cited by 264
Cerebrospinal Fluid Clearance in Alzheimer Disease Measured with Dynamic PET
de Leon, M. J., Li, Y., Okamura, N., Tsui, W. H., Saint-Louis, L. A., Glodzik, L., Osorio, R. S., Fortea, J., Butler, T., Pirraglia, E., et al. (2017) · Journal of Nuclear Medicine · doi:10.2967/jnumed.116.187211 · Cited by 246
“Suggesting CSF clearance abnormalities in AD, impaired glymphatic CSF clearance was recently observed in aged wild-type mice (5) and in an AD mouse model (6).”
BackgroundSelf-citationThe glymphatic hypothesis: the theory and the evidence
Hladky, S. B., & Barrand, M. A. (2022) · Fluids and Barriers of the CNS · doi:10.1186/s12987-021-00282-z · Cited by 283
“These factors include: knockout of AQP4 [11]; sleep [37]; anaesthesia (especially that incorporating the α2 adrenoceptor agonists xylazine or medetomidine) [37, 201]; traumatic brain injury [15]; age [177]; posture [202]; ablation of meningeal lymphatics [203]; small vessel disease [19]; idi‐ opathic normal pressure h…”
BackgroundThe glymphatic system: implications for drugs for central nervous system diseases
Lohela, T. J., Lilius, T. O., & Nedergaard, M. (2022) · Nature Reviews Drug Discovery · doi:10.1038/s41573-022-00500-9 · Cited by 254
Self-citationAstrocyte Endfeet in Brain Function and Pathology: Open Questions
Díaz-Castro, B., Robel, S., & Mishra, A. (2023) · Annual Review of Neuroscience · doi:10.1146/annurev-neuro-091922-031205 · Cited by 238
Glymphatic influx and clearance are accelerated by neurovascular coupling
Holstein-Rønsbo, S., Gan, Y., Giannetto, M. J., Rasmussen, M. K., Sigurdsson, B., Beinlich, F. R. M., Rose, L., Untiet, V., Hablitz, L. M., Kelley, D. H., et al. (2023) · Nature Neuroscience · doi:10.1038/s41593-023-01327-2 · Cited by 248
Self-citationBenveniste, H., Lee, H., Ding, F., Sun, Q., Al-Bizri, E., Makaryus, R., Probst, S., Nedergaard, M., Stein, E. A., & Lu, H. (2017) · Anesthesiology · doi:10.1097/aln.0000000000001888 · Cited by 236
Self-citationXiong, Y., Mahmood, A., & Chopp, M. (2018) · Chinese Journal of Traumatology · doi:10.1016/j.cjtee.2018.02.003 · Cited by 253
Eide, P. K., & Ringstad, G. A. (2018) · Journal of Cerebral Blood Flow & Metabolism · doi:10.1177/0271678x18760974 · Cited by 239
“Experimental data provide evidence that glymphatic function becomes impaired with increasing age.(41) Therefore, we cannot exclude that some of the differences in tracer clearance observed between iNPH and REF individuals may be attributed to age.”
BackgroundNeurodegenerative Diseases: Regenerative Mechanisms and Novel Therapeutic Approaches
Hussain, R., Zubair, H., Sarah, P., & Shahab, M. (2018) · Brain Sciences · doi:10.3390/brainsci8090177 · Cited by 244
COVID-19 and chronic fatigue syndrome: Is the worst yet to come?
Wostyn, P. (2021) · Medical Hypotheses · doi:10.1016/j.mehy.2020.110469 · Cited by 236
“The subsequent transport of CSF into the dense and complex brain parenchyma is facilitated by aquaporin-4 (AQP4) water channels which are expressed in a highly polarized manner in astrocytic endfeet ensheathing the cerebral vasculature [7].”
BackgroundGottesman, R. F., Lutsey, P. L., Benveniste, H., Brown, D. L., Full, K. M., Lee, J., Osorio, R. S., Pase, M. P., Redeker, N. S., Redline, S. S., et al. (2024) · Stroke · doi:10.1161/str.0000000000000453 · Cited by 276
Glial Cells Shape Pathology and Repair After Spinal Cord Injury
Gaudet, A. D., & Fonken, L. K. (2018) · Neurotherapeutics · doi:10.1007/s13311-018-0630-7 · Cited by 242
Glymphatic system, AQP4, and their implications in Alzheimer’s disease
Silva, I., Silva, J., Ferreira, R., & Trigo, D. (2021) · Neurological Research and Practice · doi:10.1186/s42466-021-00102-7 · Cited by 246
Astrocyte-immune cell interactions in physiology and pathology
Han, R. T., Kim, R. D., Molofsky, A. V., & Liddelow, S. A. (2021) · Immunity · doi:10.1016/j.immuni.2021.01.013 · Cited by 223
The Neuroprotective Effects of Exercise: Maintaining a Healthy Brain Throughout Aging
Vecchio, L. M., Meng, Y., Xhima, K., Lipsman, N., Hamani, C., & Aubert, I. (2018) · Brain Plasticity · doi:10.3233/bpl-180069 · Cited by 244
Eide, P. K., & Ringstad, G. (2015) · Acta Radiologica Open · doi:10.1177/2058460115609635 · Cited by 218
“Glymphatic function has also been shown to decrease dramatically with aging (2) and in the injured brain (3).”
BackgroundDural lymphatics regulate clearance of extracellular tau from the CNS
Patel, T. K., Habimana-Griffin, L., Gao, X., Xu, B. J., Achilefu, S., Alitalo, K. K., McKee, C. A., Sheehan, P. W., Musiek, E. S., Xiong, C., et al. (2019) · Molecular Neurodegeneration · doi:10.1186/s13024-019-0312-x · Cited by 220
The Glymphatic System (En)during Inflammation
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“In neurodegenerative diseases, such as Alzheimer’s disease (AD), and to a lesser extent with normal aging, the glymphatic system is impaired, due at least in part to the dysregulated expression of AQP4 on the astrocytic endfeet [37,40,41].”
BackgroundInfluentialSelf-citationShen, T., Yue, Y., Ba, F., He, T., Tang, X., Hu, X., Pu, J., Huang, C., Lv, W., Zhang, B., et al. (2022) · npj Parkinson s Disease · doi:10.1038/s41531-022-00437-1 · Cited by 216
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Hladky, S. B., & Barrand, M. A. (2018) · Fluids and Barriers of the CNS · doi:10.1186/s12987-018-0113-6 · Cited by 206
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Deep cervical lymph node ligation aggravates AD‐like pathology of APP/PS1 mice
Wang, L., Zhang, Y., Zhao, Y., Marshall, C., Wu, T., & Xiao, M. (2019) · Brain Pathology · doi:10.1111/bpa.12656 · Cited by 199
“Recent findings suggest that the brain lymphatic system contributes to clearing the majority of extracellular Aβ from the brain (31,38,50,61,64,67).”
BackgroundSi, X., Guo, T., Wang, Z., Fang, Y., Gu, L., Cao, L., Yang, W., Gao, T., Song, Z., Tian, J., et al. (2022) · npj Parkinson s Disease · doi:10.1038/s41531-022-00316-9 · Cited by 204
Age and amyloid effects on human central nervous system amyloid‐beta kinetics
Patterson, B. W., Elbert, D. L., Mawuenyega, K. G., Kasten, T., Ovod, V., Ma, S., Xiong, C., Chott, R., Yarasheski, K., Sigurdson, W., et al. (2015) · Annals of Neurology · doi:10.1002/ana.24454 · Cited by 200
Regulation of the Blood–Brain Barrier by Circadian Rhythms and Sleep
Cuddapah, V. A., Zhang, S., & Sehgal, A. (2019) · Trends in Neurosciences · doi:10.1016/j.tins.2019.05.001 · Cited by 208
“The age-related decline is attributed to decreased arterial pulsatility and decreased localization of aquaporin-4 to perivascular endfeet [53].”
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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