Perivascular spaces in the brain: anatomy, physiology and pathology

Wardlaw, Joanna M.; Benveniste, Helene; Zloković, Berislav V.; Mestre, Humberto; Lee, Hedok; Doubal, Fergus; Brown, Rosalind; Ramirez, Joel; MacIntosh, Bradley J.; Tannenbaum, Allen; Ballerini, Lucia; Rungta, Ravi L.; Boido, Davide; Sweeney, Melanie D.; Montagne, Axel; Charpak, Serge; Joutel, Anne; Smith, Kenneth J.; Black, Sandra E.

doi:10.1038/s41582-020-0312-z

Cited by 501 publications

(598 citation statements)

References 127 publications

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“…Of the 15 relevant papers that addressed any aspect of rodent-human MRI, seven were narrative reviews [42][43][44][45][46][47][48], one was an editorial [49] and seven were original research [22,[50][51][52][53][54][55] (Table 1). Of these, six focused on AD (four reviews [42][43][44][45], one editorial [49] and one original paper [52]), one review [47] on stroke, two original papers on Huntington's disease [51,54], one original paper each on ageing [50] and hypertension [55], two original papers [22,53] and one review on SVD [48] and one review briefly summarised functional MRI (fMRI) applications in several diseases [46], including stroke and neurodegeneration.…”

Section: Resultsmentioning

confidence: 99%

“…Novel MRI Methods in Rodents and Scope for Rodent-Human Translation PVS are small conduits that envelop penetrating cerebral arterioles/venules where CSF can exchange with interstitial fluid (ISF) [48]. As part of the glymphatic system, PVS are thought to clear brain fluid and waste, facilitated by aquaporin-4 (AQP4) water channel-mediated CSF-ISF exchange at the peri-capillary space before clearance to lymphatic vessels [34,130,131].…”

Section: Mr Spectroscopy To Assess Metabolitesmentioning

confidence: 99%

“…While aspects of the physiology are controversial [132,133], CSF-ISF exchange studies provide opportunities to understand PVS in vascular and neurodegenerative diseases. PVS become enlarged and more visible in SVD and are associated with inflammation, impaired CVR, increased BBB permeability and vascular pulsatility [48]. Their small size makes them difficult to assess in humans.…”

Section: Mr Spectroscopy To Assess Metabolitesmentioning

confidence: 99%

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A Review of Translational Magnetic Resonance Imaging in Human and Rodent Experimental Models of Small Vessel Disease

Stringer

Lee

Huuskonen

et al. 2020

Transl. Stroke Res.

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Cerebral small vessel disease (SVD) is a major health burden, yet the pathophysiology remains poorly understood with no effective treatment. Since much of SVD develops silently and insidiously, non-invasive neuroimaging such as MRI is fundamental to detecting and understanding SVD in humans. Several relevant SVD rodent models are established for which MRI can monitor in vivo changes over time prior to histological examination. Here, we critically review the MRI methods pertaining to salient rodent models and evaluate synergies with human SVD MRI methods. We found few relevant publications, but argue there is considerable scope for greater use of MRI in rodent models, and opportunities for harmonisation of the rodent-human methods to increase the translational potential of models to understand SVD in humans. We summarise current MR techniques used in SVD research, provide recommendations and examples and highlight practicalities for use of MRI SVD imaging protocols in pre-selected, relevant rodent models.

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Section: Resultsmentioning

confidence: 99%

Section: Mr Spectroscopy To Assess Metabolitesmentioning

confidence: 99%

Section: Mr Spectroscopy To Assess Metabolitesmentioning

confidence: 99%

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A Review of Translational Magnetic Resonance Imaging in Human and Rodent Experimental Models of Small Vessel Disease

Stringer

Lee

Huuskonen

et al. 2020

Transl. Stroke Res.

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“…PVS fluid movement is proposed to be highly driven by arterial pulsations [ 171 , 172 , 173 , 174 ]. Unfortunately, an exact anatomical description for the PVS remains contested and the reader is referred to other publications for further details [ 160 , 166 , 175 , 176 , 177 ]. Due to this uncertainty, the specific route CSF follows to enter the PVS is also unclear.…”

Section: Targeting the Choroid Plexuses For Brain Delivery: Futilementioning

confidence: 99%

“…However, the intraparenchymal bulk flow incorporated within the glymphatic hypothesis directly conflicts with data indicating diffusion as the singular driver of fluid and solute movement through most of the brain extracellular space. The ongoing debate on fluid movement between and within the parenchyma and the PVS is not a topic for the current work and the reader is referred to a trove of information in numerous reviews [ 160 , 166 , 175 , 176 , 179 , 180 , 181 , 182 , 183 , 184 , 185 ]. Additionally, differential movement of fluid in white and gray matter [ 179 ] plus intraparenchymal drainage sites (e.g., extrachoroidal CSF sources, ventricular mixing, etc.)…”

Section: Targeting the Choroid Plexuses For Brain Delivery: Futilementioning

confidence: 99%

Targeting the Choroid Plexuses for Protein Drug Delivery

et al. 2020

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Delivery of therapeutic agents to the central nervous system is challenged by the barriers in place to regulate brain homeostasis. This is especially true for protein therapeutics. Targeting the barrier formed by the choroid plexuses at the interfaces of the systemic circulation and ventricular system may be a surrogate brain delivery strategy to circumvent the blood-brain barrier. Heterogenous cell populations located at the choroid plexuses provide diverse functions in regulating the exchange of material within the ventricular space. Receptor-mediated transcytosis may be a promising mechanism to deliver protein therapeutics across the tight junctions formed by choroid plexus epithelial cells. However, cerebrospinal fluid flow and other barriers formed by ependymal cells and perivascular spaces should also be considered for evaluation of protein therapeutic disposition. Various preclinical methods have been applied to delineate protein transport across the choroid plexuses, including imaging strategies, ventriculocisternal perfusions, and primary choroid plexus epithelial cell models. When used in combination with simultaneous measures of cerebrospinal fluid dynamics, they can yield important insight into pharmacokinetic properties within the brain. This review aims to provide an overview of the choroid plexuses and ventricular system to address their function as a barrier to pharmaceutical interventions and relevance for central nervous system drug delivery of protein therapeutics. Protein therapeutics targeting the ventricular system may provide new approaches in treating central nervous system diseases.

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Enlarged Perivascular Spaces in Infancy and Autism Diagnosis, Cerebrospinal Fluid Volume, and Later Sleep Problems

Garic,

McKinstry,

Rutsohn

et al. 2023

JAMA Netw Open

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ImportancePerivascular spaces (PVS) and cerebrospinal fluid (CSF) are essential components of the glymphatic system, regulating brain homeostasis and clearing neural waste throughout the lifespan. Enlarged PVS have been implicated in neurological disorders and sleep problems in adults, and excessive CSF volume has been reported in infants who develop autism. Enlarged PVS have not been sufficiently studied longitudinally in infancy or in relation to autism outcomes or CSF volume.ObjectiveTo examine whether enlarged PVS are more prevalent in infants who develop autism compared with controls and whether they are associated with trajectories of extra-axial CSF volume (EA-CSF) and sleep problems in later childhood.Design, Setting, and ParticipantsThis prospective, longitudinal cohort study used data from the Infant Brain Imaging Study. Magnetic resonance images were acquired at ages 6, 12, and 24 months (2007-2017), with sleep questionnaires performed between ages 7 and 12 years (starting in 2018). Data were collected at 4 sites in North Carolina, Missouri, Pennsylvania, and Washington. Data were analyzed from March 2021 through August 2022.ExposurePVS (ie, fluid-filled channels that surround blood vessels in the brain) that are enlarged (ie, visible on magnetic resonance imaging).Main Outcomes and MeasuresOutcomes of interest were enlarged PVS and EA-CSF volume from 6 to 24 months, autism diagnosis at 24 months, sleep problems between ages 7 and 12 years.ResultsA total of 311 infants (197 [63.3%] male) were included: 47 infants at high familial likelihood for autism (ie, having an older sibling with autism) who were diagnosed with autism at age 24 months, 180 high likelihood infants not diagnosed with autism, and 84 low likelihood control infants not diagnosed with autism. Sleep measures at school-age were available for 109 participants. Of infants who developed autism, 21 (44.7%) had enlarged PVS at 24 months compared with 48 infants (26.7%) in the high likelihood but no autism diagnosis group (P = .02) and 22 infants in the control group (26.2%) (P = .03). Across all groups, enlarged PVS at 24 months was associated with greater EA-CSF volume from ages 6 to 24 months (β = 4.64; 95% CI, 0.58-8.72; P = .002) and more frequent night wakings at school-age (F = 7.76; η2 = 0.08; P = .006).Conclusions and RelevanceThese findings suggest that enlarged PVS emerged between ages 12 and 24 months in infants who developed autism. These results add to a growing body of evidence that, along with excessive CSF volume and sleep dysfunction, the glymphatic system could be dysregulated in infants who develop autism.

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Perivascular spaces in the brain: anatomy, physiology and pathology

Cited by 501 publications

References 127 publications

A Review of Translational Magnetic Resonance Imaging in Human and Rodent Experimental Models of Small Vessel Disease

A Review of Translational Magnetic Resonance Imaging in Human and Rodent Experimental Models of Small Vessel Disease

Targeting the Choroid Plexuses for Protein Drug Delivery

Enlarged Perivascular Spaces in Infancy and Autism Diagnosis, Cerebrospinal Fluid Volume, and Later Sleep Problems

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