PMC:6194691 / 17677-26983 JSONTXT

{"project":"MyTest","denotations":[{"id":"30340614-7356021-30705876","span":{"begin":405,"end":407},"obj":"7356021"},{"id":"30340614-29704892-30705877","span":{"begin":583,"end":585},"obj":"29704892"},{"id":"30340614-29023798-30705878","span":{"begin":984,"end":986},"obj":"29023798"},{"id":"30340614-4366438-30705879","span":{"begin":988,"end":990},"obj":"4366438"},{"id":"30340614-2396537-30705879","span":{"begin":988,"end":990},"obj":"2396537"},{"id":"30340614-18208483-30705879","span":{"begin":988,"end":990},"obj":"18208483"},{"id":"30340614-27306753-30705879","span":{"begin":988,"end":990},"obj":"27306753"},{"id":"30340614-29283289-30705879","span":{"begin":988,"end":990},"obj":"29283289"},{"id":"30340614-26463008-30705880","span":{"begin":1037,"end":1039},"obj":"26463008"},{"id":"30340614-29283289-30705881","span":{"begin":1746,"end":1748},"obj":"29283289"},{"id":"30340614-29023798-30705882","span":{"begin":1856,"end":1858},"obj":"29023798"},{"id":"30340614-18923183-30705883","span":{"begin":1860,"end":1862},"obj":"18923183"},{"id":"30340614-29283289-30705884","span":{"begin":1864,"end":1866},"obj":"29283289"},{"id":"30340614-9610885-30705885","span":{"begin":1868,"end":1870},"obj":"9610885"},{"id":"30340614-23298378-30705885","span":{"begin":1868,"end":1870},"obj":"23298378"},{"id":"30340614-27836940-30705885","span":{"begin":1868,"end":1870},"obj":"27836940"},{"id":"30340614-27929105-30705885","span":{"begin":1868,"end":1870},"obj":"27929105"},{"id":"30340614-28826498-30705885","span":{"begin":1868,"end":1870},"obj":"28826498"},{"id":"30340614-28847942-30705885","span":{"begin":1868,"end":1870},"obj":"28847942"},{"id":"30340614-29023798-30705886","span":{"begin":3214,"end":3216},"obj":"29023798"},{"id":"30340614-26499397-30705887","span":{"begin":3218,"end":3220},"obj":"26499397"},{"id":"30340614-25678956-30705888","span":{"begin":3222,"end":3224},"obj":"25678956"},{"id":"30340614-26195256-30705889","span":{"begin":3226,"end":3228},"obj":"26195256"},{"id":"30340614-29283289-30705890","span":{"begin":3230,"end":3232},"obj":"29283289"},{"id":"30340614-18208483-30705891","span":{"begin":3295,"end":3297},"obj":"18208483"},{"id":"30340614-7223890-30705892","span":{"begin":3299,"end":3301},"obj":"7223890"},{"id":"30340614-6742132-30705892","span":{"begin":3299,"end":3301},"obj":"6742132"},{"id":"30340614-1713524-30705892","span":{"begin":3299,"end":3301},"obj":"1713524"},{"id":"30340614-19794399-30705892","span":{"begin":3299,"end":3301},"obj":"19794399"},{"id":"30340614-22264361-30705892","span":{"begin":3299,"end":3301},"obj":"22264361"},{"id":"30340614-23818064-30705892","span":{"begin":3299,"end":3301},"obj":"23818064"},{"id":"30340614-29754206-30705892","span":{"begin":3299,"end":3301},"obj":"29754206"},{"id":"30340614-7223890-30705893","span":{"begin":3383,"end":3385},"obj":"7223890"},{"id":"30340614-28969373-30705894","span":{"begin":3435,"end":3437},"obj":"28969373"},{"id":"30340614-29023798-30705895","span":{"begin":3439,"end":3441},"obj":"29023798"},{"id":"30340614-2396537-30705896","span":{"begin":3447,"end":3449},"obj":"2396537"},{"id":"30340614-27306753-30705897","span":{"begin":3451,"end":3453},"obj":"27306753"},{"id":"30340614-28826498-30705898","span":{"begin":3455,"end":3457},"obj":"28826498"},{"id":"30340614-1713524-30705899","span":{"begin":3459,"end":3461},"obj":"1713524"},{"id":"30340614-29754206-30705900","span":{"begin":3463,"end":3465},"obj":"29754206"},{"id":"30340614-24002448-30705900","span":{"begin":3463,"end":3465},"obj":"24002448"},{"id":"30340614-25492117-30705900","span":{"begin":3463,"end":3465},"obj":"25492117"},{"id":"30340614-28323163-30705900","span":{"begin":3463,"end":3465},"obj":"28323163"},{"id":"30340614-28526764-30705900","span":{"begin":3463,"end":3465},"obj":"28526764"},{"id":"30340614-13760238-30705901","span":{"begin":3540,"end":3542},"obj":"13760238"},{"id":"30340614-29023798-30705902","span":{"begin":3564,"end":3566},"obj":"29023798"},{"id":"30340614-2396537-30705903","span":{"begin":3584,"end":3586},"obj":"2396537"},{"id":"30340614-1713524-30705904","span":{"begin":3588,"end":3590},"obj":"1713524"},{"id":"30340614-26077718-30705905","span":{"begin":3592,"end":3594},"obj":"26077718"},{"id":"30340614-28826498-30705906","span":{"begin":3675,"end":3677},"obj":"28826498"},{"id":"30340614-25678956-30705907","span":{"begin":3777,"end":3779},"obj":"25678956"},{"id":"30340614-27929105-30705908","span":{"begin":3781,"end":3783},"obj":"27929105"},{"id":"30340614-26975356-30705909","span":{"begin":3785,"end":3787},"obj":"26975356"},{"id":"30340614-29754206-30705910","span":{"begin":3855,"end":3857},"obj":"29754206"},{"id":"30340614-26975356-30705911","span":{"begin":3859,"end":3861},"obj":"26975356"},{"id":"30340614-29023798-30705912","span":{"begin":4220,"end":4222},"obj":"29023798"},{"id":"30340614-27306753-30705913","span":{"begin":4291,"end":4293},"obj":"27306753"},{"id":"30340614-27929105-30705914","span":{"begin":4295,"end":4297},"obj":"27929105"},{"id":"30340614-28826498-30705915","span":{"begin":4299,"end":4301},"obj":"28826498"},{"id":"30340614-6742132-30705916","span":{"begin":4307,"end":4309},"obj":"6742132"},{"id":"30340614-1713524-30705916","span":{"begin":4307,"end":4309},"obj":"1713524"},{"id":"30340614-19794399-30705916","span":{"begin":4307,"end":4309},"obj":"19794399"},{"id":"30340614-23818064-30705917","span":{"begin":4314,"end":4316},"obj":"23818064"},{"id":"30340614-28526764-30705918","span":{"begin":4318,"end":4320},"obj":"28526764"},{"id":"30340614-26993512-30705919","span":{"begin":4322,"end":4324},"obj":"26993512"},{"id":"30340614-26195256-30705920","span":{"begin":4552,"end":4554},"obj":"26195256"},{"id":"30340614-18208483-30705921","span":{"begin":4556,"end":4558},"obj":"18208483"},{"id":"30340614-29283289-30705922","span":{"begin":4560,"end":4562},"obj":"29283289"},{"id":"30340614-29754206-30705923","span":{"begin":4564,"end":4566},"obj":"29754206"},{"id":"30340614-24252464-30705924","span":{"begin":4568,"end":4570},"obj":"24252464"},{"id":"30340614-29368214-30705924","span":{"begin":4568,"end":4570},"obj":"29368214"},{"id":"30340614-26463008-30705925","span":{"begin":4949,"end":4951},"obj":"26463008"},{"id":"30340614-28883786-30705926","span":{"begin":4953,"end":4956},"obj":"28883786"},{"id":"30340614-28883786-30705927","span":{"begin":5083,"end":5086},"obj":"28883786"},{"id":"30340614-29023798-30705928","span":{"begin":5146,"end":5148},"obj":"29023798"},{"id":"30340614-29754206-30705929","span":{"begin":5537,"end":5539},"obj":"29754206"},{"id":"30340614-26975356-30705930","span":{"begin":5541,"end":5543},"obj":"26975356"},{"id":"30340614-29023798-30705931","span":{"begin":5687,"end":5689},"obj":"29023798"},{"id":"30340614-18208483-30705932","span":{"begin":5691,"end":5693},"obj":"18208483"},{"id":"30340614-13760238-30705933","span":{"begin":5695,"end":5697},"obj":"13760238"},{"id":"30340614-23489283-30705934","span":{"begin":5699,"end":5702},"obj":"23489283"},{"id":"30340614-18208483-30705935","span":{"begin":5885,"end":5887},"obj":"18208483"},{"id":"30340614-29754206-30705936","span":{"begin":5889,"end":5891},"obj":"29754206"},{"id":"30340614-26975356-30705937","span":{"begin":5893,"end":5895},"obj":"26975356"},{"id":"30340614-23818064-30705938","span":{"begin":6096,"end":6098},"obj":"23818064"},{"id":"30340614-28552391-30705939","span":{"begin":6662,"end":6663},"obj":"28552391"},{"id":"30340614-29023798-30705940","span":{"begin":6665,"end":6667},"obj":"29023798"},{"id":"30340614-27306753-30705941","span":{"begin":6677,"end":6679},"obj":"27306753"},{"id":"30340614-29283289-30705942","span":{"begin":6681,"end":6683},"obj":"29283289"},{"id":"30340614-2254158-30705943","span":{"begin":6689,"end":6692},"obj":"2254158"},{"id":"30340614-1373020-30705943","span":{"begin":6689,"end":6692},"obj":"1373020"},{"id":"30340614-19002474-30705943","span":{"begin":6689,"end":6692},"obj":"19002474"},{"id":"30340614-24145049-30705943","span":{"begin":6689,"end":6692},"obj":"24145049"},{"id":"30340614-27522506-30705943","span":{"begin":6689,"end":6692},"obj":"27522506"},{"id":"30340614-29039724-30705943","span":{"begin":6689,"end":6692},"obj":"29039724"},{"id":"30340614-28862640-30705943","span":{"begin":6689,"end":6692},"obj":"28862640"},{"id":"30340614-19794399-30705944","span":{"begin":6931,"end":6933},"obj":"19794399"},{"id":"30340614-26077718-30705945","span":{"begin":6954,"end":6956},"obj":"26077718"},{"id":"30340614-27522506-30705946","span":{"begin":6958,"end":6961},"obj":"27522506"},{"id":"30340614-28862640-30705947","span":{"begin":6963,"end":6966},"obj":"28862640"},{"id":"30340614-26030524-30705947","span":{"begin":6963,"end":6966},"obj":"26030524"},{"id":"30340614-29127332-30705947","span":{"begin":6963,"end":6966},"obj":"29127332"},{"id":"30340614-29141865-30705947","span":{"begin":6963,"end":6966},"obj":"29141865"},{"id":"30340614-28971799-30705947","span":{"begin":6963,"end":6966},"obj":"28971799"},{"id":"30340614-29740121-30705947","span":{"begin":6963,"end":6966},"obj":"29740121"},{"id":"30340614-25678956-30705948","span":{"begin":7131,"end":7133},"obj":"25678956"},{"id":"30340614-29023798-30705949","span":{"begin":7303,"end":7305},"obj":"29023798"},{"id":"30340614-26499397-30705950","span":{"begin":7307,"end":7309},"obj":"26499397"},{"id":"30340614-26195256-30705951","span":{"begin":7311,"end":7313},"obj":"26195256"},{"id":"30340614-7223890-30705952","span":{"begin":7315,"end":7317},"obj":"7223890"},{"id":"30340614-6742132-30705953","span":{"begin":7319,"end":7321},"obj":"6742132"},{"id":"30340614-26077718-30705954","span":{"begin":7323,"end":7325},"obj":"26077718"},{"id":"30340614-26993512-30705955","span":{"begin":7327,"end":7329},"obj":"26993512"},{"id":"30340614-19002474-30705956","span":{"begin":7331,"end":7334},"obj":"19002474"},{"id":"30340614-27522506-30705957","span":{"begin":7336,"end":7339},"obj":"27522506"},{"id":"30340614-29127332-30705958","span":{"begin":7341,"end":7344},"obj":"29127332"},{"id":"30340614-29740121-30705959","span":{"begin":7346,"end":7349},"obj":"29740121"},{"id":"30340614-6155466-30705959","span":{"begin":7346,"end":7349},"obj":"6155466"},{"id":"30340614-7510047-30705959","span":{"begin":7346,"end":7349},"obj":"7510047"},{"id":"30340614-20565964-30705959","span":{"begin":7346,"end":7349},"obj":"20565964"},{"id":"30340614-7223890-30705960","span":{"begin":8201,"end":8203},"obj":"7223890"},{"id":"30340614-6742132-30705961","span":{"begin":8205,"end":8207},"obj":"6742132"},{"id":"30340614-6411905-30705962","span":{"begin":8209,"end":8212},"obj":"6411905"},{"id":"30340614-2254158-30705963","span":{"begin":8278,"end":8281},"obj":"2254158"},{"id":"30340614-20565964-30705964","span":{"begin":8530,"end":8533},"obj":"20565964"},{"id":"30340614-20565964-30705965","span":{"begin":8673,"end":8676},"obj":"20565964"},{"id":"30340614-16281912-30705965","span":{"begin":8673,"end":8676},"obj":"16281912"},{"id":"30340614-16793937-30705965","span":{"begin":8673,"end":8676},"obj":"16793937"},{"id":"30340614-29023798-30705966","span":{"begin":8756,"end":8758},"obj":"29023798"},{"id":"30340614-19002474-30705967","span":{"begin":8764,"end":8767},"obj":"19002474"},{"id":"30340614-29127332-30705968","span":{"begin":8769,"end":8772},"obj":"29127332"},{"id":"30340614-20565964-30705969","span":{"begin":8774,"end":8777},"obj":"20565964"},{"id":"30340614-16174293-30705970","span":{"begin":8779,"end":8782},"obj":"16174293"},{"id":"30340614-19076439-30705970","span":{"begin":8779,"end":8782},"obj":"19076439"},{"id":"30340614-27166428-30705970","span":{"begin":8779,"end":8782},"obj":"27166428"},{"id":"30340614-7510047-30705971","span":{"begin":8981,"end":8984},"obj":"7510047"},{"id":"30340614-16793937-30705972","span":{"begin":8986,"end":8989},"obj":"16793937"},{"id":"30340614-6411905-30705973","span":{"begin":8991,"end":8994},"obj":"6411905"},{"id":"30340614-6411905-30705974","span":{"begin":9226,"end":9229},"obj":"6411905"},{"id":"30340614-29127332-30705975","span":{"begin":9300,"end":9303},"obj":"29127332"}],"namespaces":[{"prefix":"_base","uri":"https://www.uniprot.org/uniprot/testbase"},{"prefix":"UniProtKB","uri":"https://www.uniprot.org/uniprot/"},{"prefix":"uniprot","uri":"https://www.uniprot.org/uniprotkb/"}],"text":"Routes of perivascular efflux\nSome of the possible routes for perivascular movements of solutes are indicated in Fig. 5. Whether or not actual fluid filled spaces exist around the blood vessels, it is believed that substances can move along preferential routes parallel to the blood vessels. (The description that follows is primarily for grey matter. As suggested originally by Rosenberg et al. in 1980 [65] there are likely to be preferential routes for fluid movement parallel to axons in white matter. It should also be noted that there may be regional variations, see e.g. [66, 67]). The idea that the basement membranes of microvessels can provide a preferential route stems from observations that when horseradish peroxidase is introduced into CSF with consequential influx along arteries the peroxidase is found to be localized in the basement membranes around microvessels. The idea has subsequently been supported by similar observations for other macromolecules (see e.g. [16, 68–72]). However, calculations by Asgari et al. [73] imply that unless the matrix of the microvascular basement membranes has a resistance substantially less than a sleeve of ®Matrigel with the same dimensions, they will not provide a preferential route for fluid flow parallel to the microvessels. A preferential route for movement along the vessels does not conflict with the movements of solutes outward by diffusion into the surrounding interstitial fluid. Regardless of whether or not the microvessel basement membranes provide a route with relatively low resistance, the distance from anywhere in the parenchyma to the nearest larger vessel is still likely to be relatively small, e.g. 100–200 µm. (Striking images of the vascular tree can be seen in [72]). For distances this short, diffusion is expected to be the dominant mechanism of extracellular movement [16, 24, 72, 74–81].\nFig. 5 Diagram indicating putative perivascular routes for substances to move into, out of and through the brain parenchyma. The lumens of arteries, arterioles, venules and veins are surrounded by a layer of endothelial cells with a basement membrane, then a layer of vessel wall including smooth muscle, and outside that there may be a further perivascular space with fluid and connective tissue bounded by basement membranes of the smooth muscle, pial and glial cells. Close to the surfaces of the brain these further spaces are often called Virchow-Robin spaces. Movements parallel to the large vessels may be intramural, through the extracellular space of the vessel wall, or extramural either in the outermost basement membranes or, in the opinion of some workers, in a fluid filled space. In this review both intramural and extramural pathways are called perivascular routes. Parallel to microvessels movement may be preferentially within the basement membrane separating the endothelial cells from the glial endfeet or it may be more diffuse through the interstitial spaces between the parenchymal cells\nMarkers for perivascular transport clearly have perivascular pathways for entry and exit from the parenchyma, but there is controversy as to whether efflux, influx or both occur along arteries and/or veins (for discussion see [16, 39, 41, 52, 72]). Efflux along arteries has been seen in many studies (e.g. [70, 82–88]) with substances even reaching the large arteries near the circle of Willis [82], and influx has also been seen in many studies [15, 16, 25, 69, 71, 79, 84, 88–92]. Evidence of influx along some vessels was obtained as early as 1960 [93]. Perivenous influx [16] and efflux [25, 69, 84, 94] have been reported. Efflux along unspecified blood vessels has also been seen [79]. The available evidence suggests that both influx and efflux occur along both arteries and veins [41, 78, 95] either via common pathways or separately along parallel pathways [88, 95] (see Proposal 2 below). In Fig. 5 movements are shown as occurring in both directions along both.\nThere has also been disagreement over which of the structural components of the arteries provide the principal routes for periarterial transport with some favouring an extramural, fluid filled perivascular space, possibly containing connective tissue fibres [16], between the vessel walls and the astrocyte endfeet, see e.g. [25, 71, 78, 79, 81, 83–85, 87, 92, 96]5 while others favour the view that “perivascular spaces” are not fluid filled, free spaces but rather perivascular pathways via basement membranes either within the smooth muscle layer or on the outside surface of the artery [52, 70, 72, 88, 97–99] (see Fig. 5).\nFree spaces may be highly compressible, allowing modest changes in pressure to change their dimensions as envisaged in the proposal that variations in the blood pressure within the vessels somehow drive perivascular movements. By contrast basement membranes are likely to be much less compressible and are likely to offer much greater resistance to flow (see [73, 100, 101]), thus precluding blood pressure variations as the driving force for perivascular flow (see next section). Diem et al. [100] have proposed vasomotion as an alternative. Pizzo et al. [16] have suggested that both basement membrane routes and other, extramural routes exist with their relative importance depending on the size of vessel and the size of the solute. Another proposed variation is a hybrid with an extramural basement membrane route mediating fluxes into the brain and an intramural basement membrane route between smooth muscle cells mediating fluxes outwards [88, 95].\nIt is quite evident that solutes even as large as amyloid-β have access to the basement membranes between the smooth muscle cells (see e.g. [16, 70, 93, 102]), but it is not known whether the solutes reach these locations via an intramural route with movement along basement membranes as favoured by Carare, Weller, Hawkes and colleagues [70, 88, 95] or via extramural pathways with subsequent penetration from these into the basement membranes within the vessel wall (see Figure 21 in Sect. 5.7.1.2) or some mixture of the two. Arbel-Ornath et al. [87] used two-photon imaging to investigate the position of a 3 kDa fluorescent dextran during efflux following injection into the parenchyma. Shortly after injection they saw fluorescence within the parenchyma, in perivascular spaces surrounding small arteries and, at lower concentration, between the smooth muscle cells.\nThere has been controversy about the nature of the connections between the perivascular spaces adjacent to larger blood vessels within the parenchyma, the CSF and the perivascular spaces of the vessels passing through the subarachnoid spaces [1, 16, 25, 54, 71, 72, 81, 103–109]. However, whatever the exact perivascular pathway used, solutes exiting from the parenchyma along perivascular routes appear to be effluxed partly to CSF in the basal cisterns or subarachnoid spaces and partly to the outer meninges [85] and/or lymphatics [94, 107, 109–115]. Movement of small solutes and water does take place between fluid in the subarachnoid space and fluid within the perivascular spaces (see Section 4.1.1.1 of [41]). However a substantial proportion of perivascular efflux of large solutes appears to pass to lymph without first appearing in CSF in the cisterna magna6 (see Fig. 6) [16, 39, 52, 82, 83, 94, 96, 105, 107, 111, 115–119].\nFig. 6 Schematic diagram indicating possible routes for efflux of large solutes from the parenchyma along perivascular routes. a Large solutes emerging from the parenchyma via intramural or extramural routes along arteries (and possibly veins) may either mix with CSF or continue along the walls of blood vessels. The blood vessels span the subarachnoid space (see Figs. 1 and 6) before leaving the brain to reach the rest of the body. The fluid that continues along these vessels may enter either blood or lymph, but solutes as large as serum albumin will enter only lymph. b Large solutes that have reached CSF will be taken to sites of CSF outflow including the arachnoid villi, where the solutes will enter venous blood, and the cribriform plate, where they will enter lymph. (Based primarily on data for radio-iodinated serum albumin RISA [82, 83, 125] and on the location of the pia surrounding arteries taken from [103]). The anatomical relations of the pathways or spaces remain controversial\nThose solutes that do reach CSF from the parenchyma can be taken out of the cranium via CSF outflow. Routes for CSF outflow were reviewed comprehensively by Pollay in 2010 [119] This outflow is partly via arachnoid villi, partly via perineural routes including those across the cribriform plate to the nasal mucosa [119–121] and possibly also via extra-parenchymal perivascular routes (see Fig. 6) [16, 81, 105, 111, 119, 122–124]. Outflow via arachnoid villi leads directly to venous blood while outflow via the cribriform plate may deliver solutes directly to lymphatics or to the extracellular fluid in the nasal mucosa [118, 121, 125]. Small solutes (e.g. lactate) and solutes even as large as inulin may leave the nasal mucosa by entering blood across peripheral capillary walls but larger solutes (e.g. albumin) will leave via lymph flow to cervical lymph nodes [125]. Outflow via other routes leads at least in part to lymph (see e.g. [111])."}

{"project":"2_test","denotations":[{"id":"30340614-7356021-30705876","span":{"begin":405,"end":407},"obj":"7356021"},{"id":"30340614-29704892-30705877","span":{"begin":583,"end":585},"obj":"29704892"},{"id":"30340614-29023798-30705878","span":{"begin":984,"end":986},"obj":"29023798"},{"id":"30340614-4366438-30705879","span":{"begin":988,"end":990},"obj":"4366438"},{"id":"30340614-2396537-30705879","span":{"begin":988,"end":990},"obj":"2396537"},{"id":"30340614-18208483-30705879","span":{"begin":988,"end":990},"obj":"18208483"},{"id":"30340614-27306753-30705879","span":{"begin":988,"end":990},"obj":"27306753"},{"id":"30340614-29283289-30705879","span":{"begin":988,"end":990},"obj":"29283289"},{"id":"30340614-26463008-30705880","span":{"begin":1037,"end":1039},"obj":"26463008"},{"id":"30340614-29283289-30705881","span":{"begin":1746,"end":1748},"obj":"29283289"},{"id":"30340614-29023798-30705882","span":{"begin":1856,"end":1858},"obj":"29023798"},{"id":"30340614-18923183-30705883","span":{"begin":1860,"end":1862},"obj":"18923183"},{"id":"30340614-29283289-30705884","span":{"begin":1864,"end":1866},"obj":"29283289"},{"id":"30340614-9610885-30705885","span":{"begin":1868,"end":1870},"obj":"9610885"},{"id":"30340614-23298378-30705885","span":{"begin":1868,"end":1870},"obj":"23298378"},{"id":"30340614-27836940-30705885","span":{"begin":1868,"end":1870},"obj":"27836940"},{"id":"30340614-27929105-30705885","span":{"begin":1868,"end":1870},"obj":"27929105"},{"id":"30340614-28826498-30705885","span":{"begin":1868,"end":1870},"obj":"28826498"},{"id":"30340614-28847942-30705885","span":{"begin":1868,"end":1870},"obj":"28847942"},{"id":"30340614-29023798-30705886","span":{"begin":3214,"end":3216},"obj":"29023798"},{"id":"30340614-26499397-30705887","span":{"begin":3218,"end":3220},"obj":"26499397"},{"id":"30340614-25678956-30705888","span":{"begin":3222,"end":3224},"obj":"25678956"},{"id":"30340614-26195256-30705889","span":{"begin":3226,"end":3228},"obj":"26195256"},{"id":"30340614-29283289-30705890","span":{"begin":3230,"end":3232},"obj":"29283289"},{"id":"30340614-18208483-30705891","span":{"begin":3295,"end":3297},"obj":"18208483"},{"id":"30340614-7223890-30705892","span":{"begin":3299,"end":3301},"obj":"7223890"},{"id":"30340614-6742132-30705892","span":{"begin":3299,"end":3301},"obj":"6742132"},{"id":"30340614-1713524-30705892","span":{"begin":3299,"end":3301},"obj":"1713524"},{"id":"30340614-19794399-30705892","span":{"begin":3299,"end":3301},"obj":"19794399"},{"id":"30340614-22264361-30705892","span":{"begin":3299,"end":3301},"obj":"22264361"},{"id":"30340614-23818064-30705892","span":{"begin":3299,"end":3301},"obj":"23818064"},{"id":"30340614-29754206-30705892","span":{"begin":3299,"end":3301},"obj":"29754206"},{"id":"30340614-7223890-30705893","span":{"begin":3383,"end":3385},"obj":"7223890"},{"id":"30340614-28969373-30705894","span":{"begin":3435,"end":3437},"obj":"28969373"},{"id":"30340614-29023798-30705895","span":{"begin":3439,"end":3441},"obj":"29023798"},{"id":"30340614-2396537-30705896","span":{"begin":3447,"end":3449},"obj":"2396537"},{"id":"30340614-27306753-30705897","span":{"begin":3451,"end":3453},"obj":"27306753"},{"id":"30340614-28826498-30705898","span":{"begin":3455,"end":3457},"obj":"28826498"},{"id":"30340614-1713524-30705899","span":{"begin":3459,"end":3461},"obj":"1713524"},{"id":"30340614-29754206-30705900","span":{"begin":3463,"end":3465},"obj":"29754206"},{"id":"30340614-24002448-30705900","span":{"begin":3463,"end":3465},"obj":"24002448"},{"id":"30340614-25492117-30705900","span":{"begin":3463,"end":3465},"obj":"25492117"},{"id":"30340614-28323163-30705900","span":{"begin":3463,"end":3465},"obj":"28323163"},{"id":"30340614-28526764-30705900","span":{"begin":3463,"end":3465},"obj":"28526764"},{"id":"30340614-13760238-30705901","span":{"begin":3540,"end":3542},"obj":"13760238"},{"id":"30340614-29023798-30705902","span":{"begin":3564,"end":3566},"obj":"29023798"},{"id":"30340614-2396537-30705903","span":{"begin":3584,"end":3586},"obj":"2396537"},{"id":"30340614-1713524-30705904","span":{"begin":3588,"end":3590},"obj":"1713524"},{"id":"30340614-26077718-30705905","span":{"begin":3592,"end":3594},"obj":"26077718"},{"id":"30340614-28826498-30705906","span":{"begin":3675,"end":3677},"obj":"28826498"},{"id":"30340614-25678956-30705907","span":{"begin":3777,"end":3779},"obj":"25678956"},{"id":"30340614-27929105-30705908","span":{"begin":3781,"end":3783},"obj":"27929105"},{"id":"30340614-26975356-30705909","span":{"begin":3785,"end":3787},"obj":"26975356"},{"id":"30340614-29754206-30705910","span":{"begin":3855,"end":3857},"obj":"29754206"},{"id":"30340614-26975356-30705911","span":{"begin":3859,"end":3861},"obj":"26975356"},{"id":"30340614-29023798-30705912","span":{"begin":4220,"end":4222},"obj":"29023798"},{"id":"30340614-27306753-30705913","span":{"begin":4291,"end":4293},"obj":"27306753"},{"id":"30340614-27929105-30705914","span":{"begin":4295,"end":4297},"obj":"27929105"},{"id":"30340614-28826498-30705915","span":{"begin":4299,"end":4301},"obj":"28826498"},{"id":"30340614-6742132-30705916","span":{"begin":4307,"end":4309},"obj":"6742132"},{"id":"30340614-1713524-30705916","span":{"begin":4307,"end":4309},"obj":"1713524"},{"id":"30340614-19794399-30705916","span":{"begin":4307,"end":4309},"obj":"19794399"},{"id":"30340614-23818064-30705917","span":{"begin":4314,"end":4316},"obj":"23818064"},{"id":"30340614-28526764-30705918","span":{"begin":4318,"end":4320},"obj":"28526764"},{"id":"30340614-26993512-30705919","span":{"begin":4322,"end":4324},"obj":"26993512"},{"id":"30340614-26195256-30705920","span":{"begin":4552,"end":4554},"obj":"26195256"},{"id":"30340614-18208483-30705921","span":{"begin":4556,"end":4558},"obj":"18208483"},{"id":"30340614-29283289-30705922","span":{"begin":4560,"end":4562},"obj":"29283289"},{"id":"30340614-29754206-30705923","span":{"begin":4564,"end":4566},"obj":"29754206"},{"id":"30340614-24252464-30705924","span":{"begin":4568,"end":4570},"obj":"24252464"},{"id":"30340614-29368214-30705924","span":{"begin":4568,"end":4570},"obj":"29368214"},{"id":"30340614-26463008-30705925","span":{"begin":4949,"end":4951},"obj":"26463008"},{"id":"30340614-28883786-30705926","span":{"begin":4953,"end":4956},"obj":"28883786"},{"id":"30340614-28883786-30705927","span":{"begin":5083,"end":5086},"obj":"28883786"},{"id":"30340614-29023798-30705928","span":{"begin":5146,"end":5148},"obj":"29023798"},{"id":"30340614-29754206-30705929","span":{"begin":5537,"end":5539},"obj":"29754206"},{"id":"30340614-26975356-30705930","span":{"begin":5541,"end":5543},"obj":"26975356"},{"id":"30340614-29023798-30705931","span":{"begin":5687,"end":5689},"obj":"29023798"},{"id":"30340614-18208483-30705932","span":{"begin":5691,"end":5693},"obj":"18208483"},{"id":"30340614-13760238-30705933","span":{"begin":5695,"end":5697},"obj":"13760238"},{"id":"30340614-23489283-30705934","span":{"begin":5699,"end":5702},"obj":"23489283"},{"id":"30340614-18208483-30705935","span":{"begin":5885,"end":5887},"obj":"18208483"},{"id":"30340614-29754206-30705936","span":{"begin":5889,"end":5891},"obj":"29754206"},{"id":"30340614-26975356-30705937","span":{"begin":5893,"end":5895},"obj":"26975356"},{"id":"30340614-23818064-30705938","span":{"begin":6096,"end":6098},"obj":"23818064"},{"id":"30340614-28552391-30705939","span":{"begin":6662,"end":6663},"obj":"28552391"},{"id":"30340614-29023798-30705940","span":{"begin":6665,"end":6667},"obj":"29023798"},{"id":"30340614-27306753-30705941","span":{"begin":6677,"end":6679},"obj":"27306753"},{"id":"30340614-29283289-30705942","span":{"begin":6681,"end":6683},"obj":"29283289"},{"id":"30340614-2254158-30705943","span":{"begin":6689,"end":6692},"obj":"2254158"},{"id":"30340614-1373020-30705943","span":{"begin":6689,"end":6692},"obj":"1373020"},{"id":"30340614-19002474-30705943","span":{"begin":6689,"end":6692},"obj":"19002474"},{"id":"30340614-24145049-30705943","span":{"begin":6689,"end":6692},"obj":"24145049"},{"id":"30340614-27522506-30705943","span":{"begin":6689,"end":6692},"obj":"27522506"},{"id":"30340614-29039724-30705943","span":{"begin":6689,"end":6692},"obj":"29039724"},{"id":"30340614-28862640-30705943","span":{"begin":6689,"end":6692},"obj":"28862640"},{"id":"30340614-19794399-30705944","span":{"begin":6931,"end":6933},"obj":"19794399"},{"id":"30340614-26077718-30705945","span":{"begin":6954,"end":6956},"obj":"26077718"},{"id":"30340614-27522506-30705946","span":{"begin":6958,"end":6961},"obj":"27522506"},{"id":"30340614-28862640-30705947","span":{"begin":6963,"end":6966},"obj":"28862640"},{"id":"30340614-26030524-30705947","span":{"begin":6963,"end":6966},"obj":"26030524"},{"id":"30340614-29127332-30705947","span":{"begin":6963,"end":6966},"obj":"29127332"},{"id":"30340614-29141865-30705947","span":{"begin":6963,"end":6966},"obj":"29141865"},{"id":"30340614-28971799-30705947","span":{"begin":6963,"end":6966},"obj":"28971799"},{"id":"30340614-29740121-30705947","span":{"begin":6963,"end":6966},"obj":"29740121"},{"id":"30340614-25678956-30705948","span":{"begin":7131,"end":7133},"obj":"25678956"},{"id":"30340614-29023798-30705949","span":{"begin":7303,"end":7305},"obj":"29023798"},{"id":"30340614-26499397-30705950","span":{"begin":7307,"end":7309},"obj":"26499397"},{"id":"30340614-26195256-30705951","span":{"begin":7311,"end":7313},"obj":"26195256"},{"id":"30340614-7223890-30705952","span":{"begin":7315,"end":7317},"obj":"7223890"},{"id":"30340614-6742132-30705953","span":{"begin":7319,"end":7321},"obj":"6742132"},{"id":"30340614-26077718-30705954","span":{"begin":7323,"end":7325},"obj":"26077718"},{"id":"30340614-26993512-30705955","span":{"begin":7327,"end":7329},"obj":"26993512"},{"id":"30340614-19002474-30705956","span":{"begin":7331,"end":7334},"obj":"19002474"},{"id":"30340614-27522506-30705957","span":{"begin":7336,"end":7339},"obj":"27522506"},{"id":"30340614-29127332-30705958","span":{"begin":7341,"end":7344},"obj":"29127332"},{"id":"30340614-29740121-30705959","span":{"begin":7346,"end":7349},"obj":"29740121"},{"id":"30340614-6155466-30705959","span":{"begin":7346,"end":7349},"obj":"6155466"},{"id":"30340614-7510047-30705959","span":{"begin":7346,"end":7349},"obj":"7510047"},{"id":"30340614-20565964-30705959","span":{"begin":7346,"end":7349},"obj":"20565964"},{"id":"30340614-7223890-30705960","span":{"begin":8201,"end":8203},"obj":"7223890"},{"id":"30340614-6742132-30705961","span":{"begin":8205,"end":8207},"obj":"6742132"},{"id":"30340614-6411905-30705962","span":{"begin":8209,"end":8212},"obj":"6411905"},{"id":"30340614-2254158-30705963","span":{"begin":8278,"end":8281},"obj":"2254158"},{"id":"30340614-20565964-30705964","span":{"begin":8530,"end":8533},"obj":"20565964"},{"id":"30340614-20565964-30705965","span":{"begin":8673,"end":8676},"obj":"20565964"},{"id":"30340614-16281912-30705965","span":{"begin":8673,"end":8676},"obj":"16281912"},{"id":"30340614-16793937-30705965","span":{"begin":8673,"end":8676},"obj":"16793937"},{"id":"30340614-29023798-30705966","span":{"begin":8756,"end":8758},"obj":"29023798"},{"id":"30340614-19002474-30705967","span":{"begin":8764,"end":8767},"obj":"19002474"},{"id":"30340614-29127332-30705968","span":{"begin":8769,"end":8772},"obj":"29127332"},{"id":"30340614-20565964-30705969","span":{"begin":8774,"end":8777},"obj":"20565964"},{"id":"30340614-16174293-30705970","span":{"begin":8779,"end":8782},"obj":"16174293"},{"id":"30340614-19076439-30705970","span":{"begin":8779,"end":8782},"obj":"19076439"},{"id":"30340614-27166428-30705970","span":{"begin":8779,"end":8782},"obj":"27166428"},{"id":"30340614-7510047-30705971","span":{"begin":8981,"end":8984},"obj":"7510047"},{"id":"30340614-16793937-30705972","span":{"begin":8986,"end":8989},"obj":"16793937"},{"id":"30340614-6411905-30705973","span":{"begin":8991,"end":8994},"obj":"6411905"},{"id":"30340614-6411905-30705974","span":{"begin":9226,"end":9229},"obj":"6411905"},{"id":"30340614-29127332-30705975","span":{"begin":9300,"end":9303},"obj":"29127332"}],"text":"Routes of perivascular efflux\nSome of the possible routes for perivascular movements of solutes are indicated in Fig. 5. Whether or not actual fluid filled spaces exist around the blood vessels, it is believed that substances can move along preferential routes parallel to the blood vessels. (The description that follows is primarily for grey matter. As suggested originally by Rosenberg et al. in 1980 [65] there are likely to be preferential routes for fluid movement parallel to axons in white matter. It should also be noted that there may be regional variations, see e.g. [66, 67]). The idea that the basement membranes of microvessels can provide a preferential route stems from observations that when horseradish peroxidase is introduced into CSF with consequential influx along arteries the peroxidase is found to be localized in the basement membranes around microvessels. The idea has subsequently been supported by similar observations for other macromolecules (see e.g. [16, 68–72]). However, calculations by Asgari et al. [73] imply that unless the matrix of the microvascular basement membranes has a resistance substantially less than a sleeve of ®Matrigel with the same dimensions, they will not provide a preferential route for fluid flow parallel to the microvessels. A preferential route for movement along the vessels does not conflict with the movements of solutes outward by diffusion into the surrounding interstitial fluid. Regardless of whether or not the microvessel basement membranes provide a route with relatively low resistance, the distance from anywhere in the parenchyma to the nearest larger vessel is still likely to be relatively small, e.g. 100–200 µm. (Striking images of the vascular tree can be seen in [72]). For distances this short, diffusion is expected to be the dominant mechanism of extracellular movement [16, 24, 72, 74–81].\nFig. 5 Diagram indicating putative perivascular routes for substances to move into, out of and through the brain parenchyma. The lumens of arteries, arterioles, venules and veins are surrounded by a layer of endothelial cells with a basement membrane, then a layer of vessel wall including smooth muscle, and outside that there may be a further perivascular space with fluid and connective tissue bounded by basement membranes of the smooth muscle, pial and glial cells. Close to the surfaces of the brain these further spaces are often called Virchow-Robin spaces. Movements parallel to the large vessels may be intramural, through the extracellular space of the vessel wall, or extramural either in the outermost basement membranes or, in the opinion of some workers, in a fluid filled space. In this review both intramural and extramural pathways are called perivascular routes. Parallel to microvessels movement may be preferentially within the basement membrane separating the endothelial cells from the glial endfeet or it may be more diffuse through the interstitial spaces between the parenchymal cells\nMarkers for perivascular transport clearly have perivascular pathways for entry and exit from the parenchyma, but there is controversy as to whether efflux, influx or both occur along arteries and/or veins (for discussion see [16, 39, 41, 52, 72]). Efflux along arteries has been seen in many studies (e.g. [70, 82–88]) with substances even reaching the large arteries near the circle of Willis [82], and influx has also been seen in many studies [15, 16, 25, 69, 71, 79, 84, 88–92]. Evidence of influx along some vessels was obtained as early as 1960 [93]. Perivenous influx [16] and efflux [25, 69, 84, 94] have been reported. Efflux along unspecified blood vessels has also been seen [79]. The available evidence suggests that both influx and efflux occur along both arteries and veins [41, 78, 95] either via common pathways or separately along parallel pathways [88, 95] (see Proposal 2 below). In Fig. 5 movements are shown as occurring in both directions along both.\nThere has also been disagreement over which of the structural components of the arteries provide the principal routes for periarterial transport with some favouring an extramural, fluid filled perivascular space, possibly containing connective tissue fibres [16], between the vessel walls and the astrocyte endfeet, see e.g. [25, 71, 78, 79, 81, 83–85, 87, 92, 96]5 while others favour the view that “perivascular spaces” are not fluid filled, free spaces but rather perivascular pathways via basement membranes either within the smooth muscle layer or on the outside surface of the artery [52, 70, 72, 88, 97–99] (see Fig. 5).\nFree spaces may be highly compressible, allowing modest changes in pressure to change their dimensions as envisaged in the proposal that variations in the blood pressure within the vessels somehow drive perivascular movements. By contrast basement membranes are likely to be much less compressible and are likely to offer much greater resistance to flow (see [73, 100, 101]), thus precluding blood pressure variations as the driving force for perivascular flow (see next section). Diem et al. [100] have proposed vasomotion as an alternative. Pizzo et al. [16] have suggested that both basement membrane routes and other, extramural routes exist with their relative importance depending on the size of vessel and the size of the solute. Another proposed variation is a hybrid with an extramural basement membrane route mediating fluxes into the brain and an intramural basement membrane route between smooth muscle cells mediating fluxes outwards [88, 95].\nIt is quite evident that solutes even as large as amyloid-β have access to the basement membranes between the smooth muscle cells (see e.g. [16, 70, 93, 102]), but it is not known whether the solutes reach these locations via an intramural route with movement along basement membranes as favoured by Carare, Weller, Hawkes and colleagues [70, 88, 95] or via extramural pathways with subsequent penetration from these into the basement membranes within the vessel wall (see Figure 21 in Sect. 5.7.1.2) or some mixture of the two. Arbel-Ornath et al. [87] used two-photon imaging to investigate the position of a 3 kDa fluorescent dextran during efflux following injection into the parenchyma. Shortly after injection they saw fluorescence within the parenchyma, in perivascular spaces surrounding small arteries and, at lower concentration, between the smooth muscle cells.\nThere has been controversy about the nature of the connections between the perivascular spaces adjacent to larger blood vessels within the parenchyma, the CSF and the perivascular spaces of the vessels passing through the subarachnoid spaces [1, 16, 25, 54, 71, 72, 81, 103–109]. However, whatever the exact perivascular pathway used, solutes exiting from the parenchyma along perivascular routes appear to be effluxed partly to CSF in the basal cisterns or subarachnoid spaces and partly to the outer meninges [85] and/or lymphatics [94, 107, 109–115]. Movement of small solutes and water does take place between fluid in the subarachnoid space and fluid within the perivascular spaces (see Section 4.1.1.1 of [41]). However a substantial proportion of perivascular efflux of large solutes appears to pass to lymph without first appearing in CSF in the cisterna magna6 (see Fig. 6) [16, 39, 52, 82, 83, 94, 96, 105, 107, 111, 115–119].\nFig. 6 Schematic diagram indicating possible routes for efflux of large solutes from the parenchyma along perivascular routes. a Large solutes emerging from the parenchyma via intramural or extramural routes along arteries (and possibly veins) may either mix with CSF or continue along the walls of blood vessels. The blood vessels span the subarachnoid space (see Figs. 1 and 6) before leaving the brain to reach the rest of the body. The fluid that continues along these vessels may enter either blood or lymph, but solutes as large as serum albumin will enter only lymph. b Large solutes that have reached CSF will be taken to sites of CSF outflow including the arachnoid villi, where the solutes will enter venous blood, and the cribriform plate, where they will enter lymph. (Based primarily on data for radio-iodinated serum albumin RISA [82, 83, 125] and on the location of the pia surrounding arteries taken from [103]). The anatomical relations of the pathways or spaces remain controversial\nThose solutes that do reach CSF from the parenchyma can be taken out of the cranium via CSF outflow. Routes for CSF outflow were reviewed comprehensively by Pollay in 2010 [119] This outflow is partly via arachnoid villi, partly via perineural routes including those across the cribriform plate to the nasal mucosa [119–121] and possibly also via extra-parenchymal perivascular routes (see Fig. 6) [16, 81, 105, 111, 119, 122–124]. Outflow via arachnoid villi leads directly to venous blood while outflow via the cribriform plate may deliver solutes directly to lymphatics or to the extracellular fluid in the nasal mucosa [118, 121, 125]. Small solutes (e.g. lactate) and solutes even as large as inulin may leave the nasal mucosa by entering blood across peripheral capillary walls but larger solutes (e.g. albumin) will leave via lymph flow to cervical lymph nodes [125]. Outflow via other routes leads at least in part to lymph (see e.g. [111])."}