The fine anatomy of the perivascular compartment in the human brain: relevance to dilated perivascular spaces in cerebral amyloid angiopathy

Sharp, Matthew MacGregor; Bulters, Diederik; Brandner, Sebastian; Holton, Janice L.; Verma, Ajay; Werring, David J.; Carare, Roxana O.

doi:10.1111/nan.12480

Cited by 23 publications

(16 citation statements)

References 9 publications

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“…Basement membranes and cell components surrounding cortical arteries are compacted so that there is no perivascular “space” for transport of tracers [ 23 , 37 ]; transport appears to be along basement membranes as shown in the present study. This contradicts the statement in the glymphatic literature that there is transport of tracers into the brain along perivascular “spaces” [ 17 ].…”

Section: Discussionmentioning

confidence: 78%

“…Tracers injected into the CSF pass into the brain and spinal cord tissue along the outer aspects of arteries and this system has been variously named as convective tracer influx and the glymphatic system [ 17 , 30 ]. Electron microscope studies have shown that there are no perivascular spaces around arteries in the cerebral cortex [ 23 , 37 , 40 ] although dilated perivascular spaces do develop in other parts of the brain such as cerebral white matter and the basal ganglia [ 32 ]. Perivascular spaces in the basal ganglia have been demonstrated by electron microscopy [ 28 ].…”

Section: Introductionmentioning

confidence: 99%

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Convective influx/glymphatic system: tracers injected into the CSF enter and leave the brain along separate periarterial basement membrane pathways

et al. 2018

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Tracers injected into CSF pass into the brain alongside arteries and out again. This has been recently termed the “glymphatic system” that proposes tracers enter the brain along periarterial “spaces” and leave the brain along the walls of veins. The object of the present study is to test the hypothesis that: (1) tracers from the CSF enter the cerebral cortex along pial-glial basement membranes as there are no perivascular “spaces” around cortical arteries, (2) tracers leave the brain along smooth muscle cell basement membranes that form the Intramural Peri-Arterial Drainage (IPAD) pathways for the elimination of interstitial fluid and solutes from the brain. 2 μL of 100 μM soluble, fluorescent fixable amyloid β (Aβ) were injected into the CSF of the cisterna magna of 6–10 and 24–30 month-old male mice and their brains were examined 5 and 30 min later. At 5 min, immunocytochemistry and confocal microscopy revealed Aβ on the outer aspects of cortical arteries colocalized with α-2 laminin in the pial-glial basement membranes. At 30 min, Aβ was colocalised with collagen IV in smooth muscle cell basement membranes in the walls of cortical arteries corresponding to the IPAD pathways. No evidence for drainage along the walls of veins was found. Measurements of the depth of penetration of tracer were taken from 11 regions of the brain. Maximum depths of penetration of tracer into the brain were achieved in the pons and caudoputamen. Conclusions drawn from the present study are that tracers injected into the CSF enter and leave the brain along separate periarterial basement membrane pathways. The exit route is along IPAD pathways in which Aβ accumulates in cerebral amyloid angiopathy (CAA) in Alzheimer’s disease. Results from this study suggest that CSF may be a suitable route for delivery of therapies for neurological diseases, including CAA.Electronic supplementary materialThe online version of this article (10.1007/s00401-018-1862-7) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 78%

Section: Introductionmentioning

confidence: 99%

Convective influx/glymphatic system: tracers injected into the CSF enter and leave the brain along separate periarterial basement membrane pathways

et al. 2018

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“…Here we define this as the space between the vessel and the astrocytic endfoot domain, a space supported by structural study [6, 34]. However, other groups have defined the perivascular compartment using ultra-stuctural studies to be between the leptomeningeal layer adjacent to the side of tunica media facing side the parenchyma and the leptomeningeal layer adjacent to the glia limitans (astrocyte end feet) [35]. It will be important to follow up this work with additional tissue staining to elucidate the microstructural anatomy of these dilated spaces.…”

Section: Discussionmentioning

confidence: 99%

Targeted Assessment of Enlargement of the Perivascular Space in Alzheimer’s Disease and Vascular Dementia Subtypes Implicates Astroglial Involvement Specific to Alzheimer’s Disease

Boespflug

Simon

Leonard

et al. 2018

JAD

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Waste clearance from the brain parenchyma occurs along perivascular pathways. Enlargement of the perivascular space (ePVS) is associated with pathologic features of Alzheimer’s disease (AD), although the mechanisms and implications of this dilation are unclear. Fluid exchange along the cerebral vasculature is dependent on the perivascular astrocytic water channel aquaporin-4 (AQP4) and loss of perivascular AQP4 localization is found in AD. We directly measured ePVS in postmortem samples of pathologically characterized tissue from participants who were cognitively intact or had AD or mixed dementia (vascular lesions with AD). We found that both AD and mixed dementia groups had significantly increased ePVS compared to cognitively intact subjects. In addition, we found increased global AQP4 expression of the AD group over both control and mixed dementia groups and a qualitative reduction in perivascular localization of AQP4 in the AD group. Among these cases, increasing ePVS burden was associated with the presence of tau and amyloid-β pathology. These findings are consistent with the existing evidence of ePVS in AD and provide novel information regarding differences in AD and vascular dementia and the potential role of astroglial pathology in ePVS.

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“…Dilated perivascular spaces have not been observed in the cerebral cortex, even when there is pathology present [39] but they are common in the white matter of patients with CAA [31,40]. Considering the role of AQP4 as a water channel and that WMH and dilated perivascular spaces reflect an excess of fluid in the parenchyma, here we test the hypothesis that expression of AQP4 increases in the grey matter and decreases in the white matter with onset of CAA when compared to age matched controls.…”

Section: Introductionmentioning

confidence: 93%

The Pattern of AQP4 Expression in the Ageing Human Brain and in Cerebral Amyloid Angiopathy

Owasil

O’Neill

Keable

et al. 2020

IJMS

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In the absence of lymphatics, fluid and solutes such as amyloid-β (Aβ) are eliminated from the brain along basement membranes in the walls of cerebral capillaries and arteries-the Intramural Peri-Arterial Drainage (IPAD) pathway. IPAD fails with age and insoluble Aβ is deposited as plaques in the brain and in IPAD pathways as cerebral amyloid angiopathy (CAA); fluid accumulates in the white matter as reflected by hyperintensities (WMH) on MRI. Within the brain, fluid uptake by astrocytes is regulated by aquaporin 4 (AQP4). We test the hypothesis that expression of astrocytic AQP4 increases in grey matter and decreases in white matter with onset of CAA. AQP4 expression was quantitated by immunocytochemistry and confocal microscopy in post-mortem occipital grey and white matter from young and old non-demented human brains, in CAA and in WMH. Results: AQP4 expression tended to increase with normal ageing but AQP4 expression in severe CAA was significantly reduced when compared to moderate CAA (p = 0.018). AQP4 expression tended to decline in the white matter with CAA and WMH, both of which are associated with impaired IPAD. Adjusting the level of AQP4 activity may be a valid therapeutic target for restoring homoeostasis in the brain as IPAD fails with age and CAA.

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The fine anatomy of the perivascular compartment in the human brain: relevance to dilated perivascular spaces in cerebral amyloid angiopathy

Cited by 23 publications

References 9 publications

Convective influx/glymphatic system: tracers injected into the CSF enter and leave the brain along separate periarterial basement membrane pathways

Convective influx/glymphatic system: tracers injected into the CSF enter and leave the brain along separate periarterial basement membrane pathways

Targeted Assessment of Enlargement of the Perivascular Space in Alzheimer’s Disease and Vascular Dementia Subtypes Implicates Astroglial Involvement Specific to Alzheimer’s Disease

The Pattern of AQP4 Expression in the Ageing Human Brain and in Cerebral Amyloid Angiopathy

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