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Perivascular spaces, glymphatic dysfunction, and small vessel disease
Open accessAbstract
Cerebral small vessel diseases (SVDs) range broadly in etiology but share remarkably overlapping pathology. Features of SVD including enlarged perivascular spaces (EPVS) and formation of abluminal protein deposits cannot be completely explained by the putative pathophysiology. The recently discovered glymphatic system provides a new perspective to potentially address these gaps. This work provides a comprehensive review of the known factors that regulate glymphatic function and the disease mechanisms underlying glymphatic impairment emphasizing the role that aquaporin-4 (AQP4)-lined perivascular spaces (PVSs), cerebrovascular pulsatility, and metabolite clearance play in normal CNS physiology. This review also discusses the implications that glymphatic impairment may have on SVD inception and progression with the aim of exploring novel therapeutic targets and highlighting the key questions that remain to be answered.
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“It is also well-establish that the quality of sleep is compromised in cardiovascular diseases (93) perhaps providing a link to impaired glymphatic clearance and subsequent protein aggregation and dementia (94).”
From Glymphatic failure as a final common pathway to dementia (2020) · cites this paper as [94]
In the citing paper
“Hypertension in particular induces hypertrophy of vascular smooth muscle cells, with a stiffening of the arterial wall that dampens arterial wall pulsatility and compliance, thus reducing convective perivascular flow (94, 100).”
From Glymphatic failure as a final common pathway to dementia (2020) · cites this paper as [94]
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“Despite having relatively distinct etiologies, EPVS are widespread and present in almost all SVD types, it is an established observation in both sporadic type 1and 2 and hereditary type 2 and 3 forms of SVD(40, 44, 45).”
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PERIVENTRICULAR WHITE MATTER LESIONS AND SLEEP ALTERATION IN OLDER PEOPLE
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The glymphatic pathway in neurological disorders.
Rasmussen, M. K., Mestre, H., & Nedergaard, M. (2018) · The Lancet Neurology · doi:10.1016/s1474-4422(18)30318-1 · Cited by 1,560
Self-citationGlymphatic failure as a final common pathway to dementia
Nedergaard, M., & Goldman, S. A. (2020) · Science · doi:10.1126/science.abb8739 · Cited by 1,145
Self-citationβ-Amyloid accumulation in the human brain after one night of sleep deprivation
Shokri-Kojori, E., Wang, G.-J., Wiers, C. E., Demiral, S. B., Guo, M., Kim, S. W., Lindgren, E., Ramirez, V., Zehra, A., Freeman, C., et al. (2018) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1721694115 · Cited by 893
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Hablitz, L. M., Vinitsky, H. S., Sun, Q., Stæger, F. F., Sigurdsson, B., Mortensen, K. N., Lilius, T. O., & Nedergaard, M. (2019) · Science Advances · doi:10.1126/sciadv.aav5447 · Cited by 629
Self-citation
Metadata
- Authors
- Mestre, H., Kostrikov, S., Mehta, R. I., & Nedergaard, M.
- Affiliations
- University of Rochester Medicine (US)
- University of Copenhagen (DK)
- Corresponding author
- Nedergaard, Maiken
- Venue
- Clinical Science
- Publisher
- Portland Press Ltd.
- Published
- 2017-08-10
- Volume
- 131
- Issue
- 17
- Pages
- 2257-2274
- ISSN
- 0143-5221 (ISSN-L)
- 1470-8736
- PMC
- PMC5567781
- OpenAlex
- W2742497781
- Cited by
- 403
- References
- 127
- Citations by year
- 2026: 54 · 2025: 58 · 2024: 66 · 2023: 52 · 2022: 53 · 2021: 40 · 2020: 32 · 2019: 32 · 2018: 14 · 2017: 2
- FWCI
- 2.70
- Type
- journal article
- Language
- en
- Open access
- Licence
- other-oa
- Locations
- Clinical Science (publishedVersion)
- PubMed (publishedVersion)
- Research at the University of Copenhagen (University of Copenhagen) (publishedVersion, other-oa)
- PubMed Central (acceptedVersion)
- Funders
- Lundbeckfonden (R155-2016–552)
- Israel Science Foundation
- Novo Nordisk Fonden (NNF13OC0004258)
- National Institute on Aging (R01AG048769)
- National Institute of Neurological Disorders and Stroke (R01NS078304, K08NS089830, R01NS100366)
- 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
- cerebral small vessel disease, enlarged perivascular spaces, glymphatic system, glymphatic dysfunction, aquaporin-4, perivascular spaces, therapeutic target
- MeSH terms
- Animals, Blood Vessels, Brain, Humans, Aquaporin 4, Cerebral Small Vessel Diseases
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