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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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BackgroundReactive astrocytes: The nexus of pathological and clinical hallmarks of Alzheimer’s disease
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“In vivo microdialysis studies have shown that levels of Aβ rise in the ISF of the CNS during wakefulness and decline during sleep (Kang et al., 2009).”
BackgroundInfluentialCircadian and sleep dysfunction in Alzheimer’s disease
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“This, in turn, may help fully characterise impairment of CSF-mediated clearance pathways with age (Kress et al., 2014), as well as the contribution to Ab accumulation in AD.”
BackgroundInteraction between blood-brain barrier and glymphatic system in solute clearance
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“The movement of subarachnoid CSF containing Aβ inward along peri-arterial spaces may promote deposition of Aβ in the vascular wall when the downstream pathways of CSF-ISF exchange are impaired(10, 76), particularly in the setting of aging and vascular injury when vascular smooth muscle uptake of Aβ may be impaired(42).”
BackgroundSelf-citationIt's complicated: The relationship between sleep and Alzheimer's disease in humans
Lucey, B. P. (2020) · Neurobiology of Disease · doi:10.1016/j.nbd.2020.105031 · Cited by 172
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“This clearance system becomes progressively impaired with normal aging in mouse models.(38) Ab42 and t-tau levels could therefore correlate in normal aging because they reflect the agerelated changes in the clearance system through this common paravascular pathway.”
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“It is likely that the glymphatic pathway also contributes to the distribution of other growth factors, neuromodulators, carrier proteins, and nutrients (Kress et al., 2014).”
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“At the same time, dysfunction of perivascular clearance may limit effective waste removal from the brain [4, 53, 69], including Aβ [39] and tau [32], which might further accelerate vascular Aβ accumulation and thus dysfunction of perivascular clearance in a vicious cycle.”
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“It has also been demonstrated that perivascular clearance dysfunction—essentially secondary to age-related changes in the vascular wall or BBB breakdown—leads to a vicious feed-forward cycle, further driving PVS dysfunction and β-amyloid accumulation both in the vascular wall and in the brain [66].”
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Self-citationCells of the Blood–Brain Barrier: An Overview of the Neurovascular Unit in Health and Disease
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“in vivo and ex vivo fluorescence microscopy, in a separate study investigators studied interstitial solute clearance after Aβ injection into the brain parenchyma of mice (Kress et al., 2014).”
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“During natural sleep, there is a marked increase of the brain’s interstitial space as compared with wakefulness, possibly resulting from the shrinkage of astroglial cells (Mendelsohn and Larrick, 2013; Xie et al., 2013; Kress et al., 2014; O’Donnell et al., 2015).”
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“Expression of aquaporin 4, forming water channels, was similarly decreased in old astrocytes, which may contribute to agedependent deficits in the glymphatic system responsible for the protein waste clearance [40].”
BackgroundPerivascular spaces and their role in neuroinflammation
Ineichen, B. V., Okar, S. V., Proulx, S. T., Engelhardt, B., Lassmann, H., & Reich, D. S. (2022) · Neuron · doi:10.1016/j.neuron.2022.10.024 · Cited by 151
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BackgroundSleep Disturbance as Potential Risk and Progression Factor for Parkinson’s Disease
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BackgroundPDGF-B Is Required for Development of the Glymphatic System
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“…perivascular influx in multiple brain regions, including dorsal cortex and thalamus, was first robustly developed at P14, at which point the pattern of tracer distribution resembled the pattern of tracer penetration in adult mice (Figures 1D, 1G, and 1J) (Iliff et al., 2012; Kress et al., 2014).”
BackgroundMethodInfluentialSelf-citationHippocampal vascular reserve associated with cognitive performance and hippocampal volume
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The Alarmin HMGB1 Mediates Age-Induced Neuroinflammatory Priming
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“…clearance pathways are impaired in the aged brain, indicating that pathological accumulation of inflammatory mol- ecules, including HMGB1, may also occur (Kress et al., 2014); (2) aged animals may have increases in cell death, which would also cause HMGB1 release (Jackson et al., 2009).”
BackgroundVoluntary running enhances glymphatic influx in awake behaving, young mice
von Holstein-Rathlou, S., Petersen, N. C., & Nedergaard, M. (2018) · Neuroscience Letters · doi:10.1016/j.neulet.2017.10.035 · Cited by 147
“The two KX anesthetized groups displayed a strong enhancement of CSF tracer intensity along the lateral cortex, consistent with previous reports [20].”
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Goulay, R., Romo, L. M., Hol, E. M., & Dijkhuizen, R. M. (2019) · Translational Stroke Research · doi:10.1007/s12975-019-00755-2 · Cited by 144
“7%/h of Aβ production for control subjects and AD patients) [14, 46, 47], although different forms of APP and Aβ overproduction can be the primary cause of Aβ accumulation in certain genetic forms of AD [48].”
BackgroundInfluentialBurfeind, K. G., Murchison, C. F., Westaway, S. K., Simon, M. J., Erten‐Lyons, D., Kaye, J. A., Quinn, J. F., & Iliff, J. J. (2017) · Alzheimer's & Dementia: Translational Research & Clinical Interventions · doi:10.1016/j.trci.2017.05.001 · Cited by 136
“In the aging rodent brain, glymphatic function is impaired and interstitial Ab clearance is slowed, changes that are associated with the loss of perivascular AQP4 localization [10].”
BackgroundSelf-citationEarls, R. H., Menees, K. B., Chung, J., Barber, J., Gutekunst, C.-A., Hazim, M. G., & Lee, J.-K. (2019) · Journal of Neuroinflammation · doi:10.1186/s12974-019-1636-8 · Cited by 138
Physical Exercise Enhances Neuroplasticity and Delays Alzheimer’s Disease
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“fluid-interstitial fluid exchange and lower A 1-40 769 clearance rate than those of intact mice [210, 211].”
BackgroundNeurovascular Interactions in the Nervous System
Segarra, M., Aburto, M. R., Hefendehl, J. K., & Acker‐Palmer, A. (2019) · Annual Review of Cell and Developmental Biology · doi:10.1146/annurev-cellbio-100818-125142 · Cited by 137
Mechanobiology of the brain in ageing and Alzheimer's disease
Hall, C. M., Moeendarbary, E., & Sheridan, G. K. (2020) · European Journal of Neuroscience · doi:10.1111/ejn.14766 · Cited by 140
“Moreover, disrupted interstitial solute clearance impacts glial cell functioning and BBB integrity and exacerbates neurovascular disease (Kress et al., 2014; Simon & Iliff, 2016).”
BackgroundVascular amyloidosis impairs the gliovascular unit in a mouse model of Alzheimer’s disease
Kimbrough, I. F., Robel, S., Roberson, E. D., & Sontheimer, H. W. (2015) · Brain · doi:10.1093/brain/awv327 · Cited by 140
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“interstitial spinal fluid exchange (21), and that the loss of perivascular AQP4 polarization in the brain contributes to the impairment of glymphatic pathway function (36, 37).”
BackgroundYew, B., Nation, D. A., & Initiative, F. T. A. D. N. (2017) · Brain · doi:10.1093/brain/awx112 · Cited by 133
“Many models emphasize the impact of reduced cerebral blood flow (CBF) (Weller et al., 2008; Zlokovic, 2011; Kress et al., 2014), which has been associated with both normal and pathological ageing across a number of brain regions”
Joutel, A., & Chabriat, H. (2017) · Clinical Science · doi:10.1042/cs20160380 · Cited by 141
Cordone, S., Annarumma, L., Rossini, P. M., & Gennaro, L. D. (2019) · Frontiers in Pharmacology · doi:10.3389/fphar.2019.00695 · Cited by 143
“Recent reports indicate a strict relation between disrupted sleep, brain glymphatic system, and AD (O’Donnel et al., 2015; Krueger et al., 2016).”
BackgroundCleaning the sleeping brain – the potential restorative function of the glymphatic system
Hauglund, N. L., Pavan, C., & Nedergaard, M. (2020) · Current Opinion in Physiology · doi:10.1016/j.cophys.2019.10.020 · Cited by 129
Self-citationLiving on the Edge of the CNS: Meninges Cell Diversity in Health and Disease
Derk, J., Jones, H. E., Como, C., Pawlikowski, B., & Siegenthaler, J. A. (2021) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2021.703944 · Cited by 120
β-Amyloid and the Pathomechanisms of Alzheimer’s Disease: A Comprehensive View
Penke, B., Bogár, F., & Fülöp, L. (2017) · Molecules · doi:10.3390/molecules22101692 · Cited by 150
Separating vascular and neuronal effects of age on fMRI BOLD signals
Tsvetanov, K. A., Henson, R. N., & Rowe, J. B. (2020) · Philosophical Transactions of the Royal Society B Biological Sciences · doi:10.1098/rstb.2019.0631 · Cited by 136
“, 2016), together with changes in the immune response and calcium signaling, impairs byproduct clearance as the BBB efficiency breaks down (Kress et al., 2014)(Abdelkarim et al.”
BackgroundAlosco, M. L., Cherry, J. D., Huber, B. R., Tripodis, Y., Baucom, Z., Kowall, N. W., Saltiel, N. A., Goldstein, L. E., Katz, D. I., Dwyer, B. C., et al. (2020) · Acta Neuropathologica · doi:10.1007/s00401-020-02197-9 · Cited by 135
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New insights into coupling and uncoupling of cerebral blood flow and metabolism in the brain
Venkat, P., Chopp, M., & Chen, J. (2016) · Croatian Medical Journal · doi:10.3325/cmj.2016.57.223 · Cited by 138
Sex differences in age-related changes in the sleep-wake cycle
Carrier, J., Semba, K., Deurveilher, S., Drogos, L. L., Cyr-Cronier, J., Lord, C., & Sekerovick, Z. (2017) · Frontiers in Neuroendocrinology · doi:10.1016/j.yfrne.2017.07.004 · Cited by 139
Is Alzheimer’s Disease a Liver Disease of the Brain?
Bassendine, M. F., Taylor-Robinson, S. D., Fertleman, M., Khan, M., & Neely, D. (2020) · Journal of Alzheimer's Disease · doi:10.3233/jad-190848 · Cited by 124
“The clearance of amyloid from the brain during sleep is primarily via the glymphatic pathway [66, 67].”
BackgroundLian, C., Zhang, J., Liu, M., Zong, X., Hung, S., Lin, W., & Shen, D. G. (2018) · Medical Image Analysis · doi:10.1016/j.media.2018.02.009 · Cited by 127
Glymphatic Pathway of Gadolinium-Based Contrast Agents Through the Brain
Deike‐Hofmann, K., Reuter, J., Haase, R., Paech, D., Gnirs, R., Bickelhaupt, S., Forsting, M., Heußel, C. P., Schlemmer, H., & Radbruch, A. (2018) · Investigative Radiology · doi:10.1097/rli.0000000000000533 · Cited by 131
Venkat, P., Chopp, M., Zacharek, A., Cui, C., Zhang, L., Li, Q., Lü, M., Zhang, T., Liu, A., & Chen, J. (2016) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2016.11.002 · Cited by 128
The neurovascular unit and systemic biology in stroke — implications for translation and treatment
Tiedt, S., Buchan, A. M., Dichgans, M., Lizasoaín, I., Moro, M. Á., & Lo, E. H. (2022) · Nature Reviews Neurology · doi:10.1038/s41582-022-00703-z · Cited by 135
Direct Measurement of Cerebrospinal Fluid Production in Mice
Liu, G., Mestre, H., Sweeney, A. M., Sun, Q., Weikop, P., Du, T., & Nedergaard, M. (2020) · Cell Reports · doi:10.1016/j.celrep.2020.108524 · Cited by 131
“…A uthor M anuscript dependent decline in CSF production and the exacerbated decline in APP/PS1 mice both match prior observations of reduced glymphatic transport in aging (Kress et al., 2014), as well as findings in mice overexpressing amyloid-β (Da Mesquita et al., 2018; Peng et al., 2016).”
BackgroundSelf-citationKlostranec, J. M., Vucevic, D., Bhatia, K. D., Kortman, H. G. J., Krings, T., Murphy, K., terBrugge, K. G., & Mikulis, D. J. (2021) · Radiology · doi:10.1148/radiol.2021202043 · Cited by 130
Coles, J. A., Myburgh, E., Brewer, J. M., & McMenamin, P. G. (2017) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2017.05.002 · Cited by 123
“Since accumulation in the brain of certain catabolites and peptides is associated with neurodegenerative diseases, such as those of Alzheimer, Parkinson and Huntington (Weller et al., 2009; Klohs et al., 2014; Kress et al., 2014), their elimination is of great clinical interest.”
Idiopathic intracranial hypertension
Lenck, S., Radovanovic, I., Nicholson, P. J., Hodaie, M., Krings, T., & Pereira, V. M. (2018) · Neurology · doi:10.1212/wnl.0000000000006166 · Cited by 124
Cannula Implantation into the Cisterna Magna of Rodents
Xavier, A. L. R., Hauglund, N. L., von Holstein‐Rathlou, S., Li, Q., Sanggaard, S., Lou, N., Lundgaard, I., & Nedergaard, M. (2018) · Journal of Visualized Experiments · doi:10.3791/57378 · Cited by 127
Self-citationThe pathogenesis of cerebral small vessel disease and vascular cognitive impairment
Markus, H. S., & Joutel, A. (2025) · Physiological Reviews · doi:10.1152/physrev.00028.2024 · Cited by 140
Lundgaard, I., Wang, W., Eberhardt, A., Vinitsky, H. S., Reeves, B. C., Peng, S., Lou, N., Hussain, R., & Nedergaard, M. (2018) · Scientific Reports · doi:10.1038/s41598-018-20424-y · Cited by 136
Self-citationThe homeostatic astroglia emerges from evolutionary specialization of neural cells
Verkhratsky, A., & Nedergaard, M. (2016) · Philosophical Transactions of the Royal Society B: Biological Sciences · doi:10.1098/rstb.2015.0428 · Cited by 133
Self-citationAltered Brain Glymphatic Flow at Diffusion-Tensor MRI in Rapid Eye Movement Sleep Behavior Disorder
Bae, Y. J., Kim, J., Choi, B. S., Ryoo, N., Song, Y. S., Nam, Y., Yoon, I., Cho, S. J., & Kim, J. H. (2023) · Radiology · doi:10.1148/radiol.221848 · Cited by 121
Eide, P. K., & Hansson, H. ‐. (2018) · Neuropathology and Applied Neurobiology · doi:10.1111/nan.12420 · Cited by 119
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Self-citationShen, M. D., Nordahl, C. W., Li, D. D., Lee, A., Angkustsiri, K., Emerson, R. W., Rogers, S. J., Ozonoff, S. J., & Amaral, D. G. (2018) · The Lancet Psychiatry · doi:10.1016/s2215-0366(18)30294-3 · Cited by 115
Loss of perivascular aquaporin‐4 in idiopathic normal pressure hydrocephalus
Hasan‐Olive, M. M., Enger, R., Hansson, H., Nagelhus, E. A., & Eide, P. K. (2018) · Glia · doi:10.1002/glia.23528 · Cited by 120
“Previous studies in rodents have disclosed reduced AQP4 polarization with increasing age (Kress et al., 2014) and following traumatic brain injury (Ren et al.”
BackgroundLiu, X., Hao, J., Yao, E., Cao, J., Zheng, X., Yao, D., Zhang, C., Li, J., Pan, D., Luo, X., et al. (2020) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2020.07.022 · Cited by 121
Self-citationHe, X., Li, L., Xian, W., Li, M., Zhang, L., Xu, J., Pei, Z., Zheng, H., & Hu, X. (2021) · Journal of Neuroinflammation · doi:10.1186/s12974-021-02199-8 · Cited by 116
“efficient glymphatic clearance [10, 48], and the reactive astrocytes from DSS-fed WT mice demonstrated re-”
BackgroundChad, J. A., Pasternak, O., Salat, D. H., & Chen, J. J. (2018) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2018.07.018 · Cited by 114
“Lymphatic flow is also known to slow down with age (Kress et al., 2014) as plasma accumulates debris across the lifespan (Abd-Allah et al., 2004) so flow is unlikely to significantly contribute to the increase in free water with age.”
BackgroundInfluentialAn Integrated View on Vascular Dysfunction in Alzheimer’s Disease
Klohs, J. (2019) · Neurodegenerative Diseases · doi:10.1159/000505625 · Cited by 111
Circadian Rhythm and Alzheimer’s Disease
Homolak, J., Mudrovčić, M., Vukić, B., & Toljan, K. (2018) · Medical Sciences · doi:10.3390/medsci6030052 · Cited by 120
“Aged mice have a 40% relative decrease in glymphatic flow, which is concordant with old age being a prominent risk factor for AD [40].”
BackgroundInfluentialCui, H., Wang, W., Zheng, X., Xia, D., Liu, H., Qin, C., Tian, H., & Teng, J. (2021) · Journal of Molecular Neuroscience · doi:10.1007/s12031-021-01836-4 · Cited by 115
Demiral, Ş. B., Tomasi, D., Sarlls, J., Lee, H., Wiers, C. E., Zehra, A., Srivastava, T., Ke, K., Shokri-Kojori, E., Freeman, C. R., et al. (2019) · NeuroImage · doi:10.1016/j.neuroimage.2018.10.043 · Cited by 110
“To test these hypotheses, we conducted two separate MRI studies in 50 healthy controls in whom we measured both “fast” and “slow” apparent diffusion coefficients (ADC) (Le Bihan et al., 1988; Silva et al., 1997).”
MethodGlymphatic System as a Gateway to Connect Neurodegeneration From Periphery to CNS
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“Impairment of GS involves neurological conditions including traumatic brain injuries,(17) ischemic stroke(18) and aged brain.(19) Interestingly, brain imaging study with magnetic resonance imaging reported weakened GS perfusion following acute stroke or SAH.”
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The Role of Perioperative Sleep Disturbance in Postoperative Neurocognitive Disorders
Wang, X., Hua, D., Tang, X., Li, S., Sun, R., Xie, Z., Zhou, Z., Zhao, Y., Wang, J., Li, S., et al. (2021) · Nature and Science of Sleep · doi:10.2147/nss.s320745 · Cited by 111
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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