1,720,961 research outputs found
Vascular dementia and failure of intramural periarterial drainage – the role of the dystrophin associated protein complex
No full textIntroduction: Cerebral small vessel disease (CSVD), a key aspect of vascular dementia (VaD), consists of pathological modifications to cerebral vessel walls and associated white matter lesions. Cerebral vessels have a dual function: perfusion of the brain and drainage of interstitial fluid and solutes along the walls of capillaries and arteries as Intramural Periarterial Drainage (IPAD). IPAD fails with age resulting in cerebral amyloid angiopathy (CAA), part of the spectrum of CSVD. Most animal models designed to study CAA are modified to overexpress amyloid proteins, but this is in contrast to the majority of CAA cases which occur due to a failure of clearance of soluble amyloid, rather than genetic mutations. The conduit for IPAD is the capillary and arterial basement membrane. This basement membrane is synthesised by cells of the vessel wall and its modification leads to a failure of IPAD and CAA. Polarised astrocytic extensions form end feet projections that encircle the abluminal side of the vessel wall attaching to basement membrane by the dystrophin associated protein complex (DPC), of which alpha dystrobrevin (α-DB) and aquaporin 4 (AQP4) are key components. Alterations to this complex disrupt the morphology of vessel walls, causing abnormalities to basement membranes and altering blood-brain barrier function.This thesis aims to investigate the role of the DPC in the morphology and dynamics of IPAD pathways and to ascertain if mice with altered DPC can be used to model: 1) a failure of ISF fluid clearance by IPAD and 2) the features of CSVD and VaD. The following hypothesis are tested: 1) In mice that do not express glial AQP4 the morphology of capillary IPAD pathways is altered; 2) In mice genetically modifiedfor α-DB, the morphology and dynamics of IPAD pathways and cerebral perfusion are impaired.Methods: A detailed morphological study on the capillary wall from the white and grey matter in AQP4 and α-DB deficient mice was performed using quantitative electron microscopy and immunohistochemistry for collagen IV. The pattern of IPAD in white and grey matter was imaged and quantitatively measured in α-DB deficient and wild-type control mice. Cerebral perfusion under resting state and when challenged with hypercapnia was measured in α-DB deficient mice.Results: 1) AQP4 deficient mice showed a reduction in the percentage surface area of basement membranes and an increase in the percentage surface area of intramural cells in the white matter. 2) In α-DB deficient mice, the percentage surface area occupied by basement membrane was increased in capillary walls in both grey and white matter, accompanied by an increased expression of collagen IV in the grey matter. 3) The pattern of IPAD in the grey matter of α-DB deficient mice showed fewer arterioles with fluorescent soluble Aβ in their walls compared to age matched controls. 4) Solutes from the normal white matter drain preferentially along the basement membranes of capillaries. 5) Absence of α-DB is associated with a normal perfusion but a lower capacity for adaptation to hypercapnia.Conclusions. The results highlight an important role for α-DB and the DPC in maintaining the structural integrity of basement membranes, which is reflected in the capacity for draining interstitial fluid and solutes via IPAD. The localisation of AQP4 to astrocyte endfeet by its indirect association with α-DB and the DPC is not critical for the morphology of the basement membrane in the grey matter. As the capillary walls in the grey matter appear normal and the intramural cells in the white matter are enlarged, in contrast to the findings in human disease, AQP4 deficient mice do not replicate features of CSVD and may not be a suitable model for mechanistic insights into CSVD or VaD. Since this work highlighted that IPAD occurs preferentially along the capillary walls in the normal white matter with little involvement from arteries, it is important to consider the failure of IPAD as a key mechanistic feature of white matter hyperintensities. It remains to be seen if there are changes to α-DB and the DPC in the spectrum of CSVD in human brains, as this work points to it as a suitable model for further hypothesis-based studies of CSVD
Solving an old dogma: Is it an arteriole or a venule?
No full textThere are very few reliable methods in the literature to discern with certainty between cerebral arterioles and venules. Smooth muscle cells (SMC) and pericytes are present in both arterioles and venules, so immunocytochemistry for markers specific to intramural cells (IMC) is unreliable. This study employed transmission electron microscopy (TEM) and a canine brain to produce robust criteria for the correct identification of cerebral arterioles and venules based on lumen:vessel wall area, tested against the less accurate lumen diameter:vessel wall thickness. We first used morphology of IMC to identify two distinct groups of vessels; group 1 with morphology akin to venules and group 2 with morphology akin to arterioles. We then quantitatively assessed these vessels for lumen:vessel wall area ratio and lumen diameter:wall thickness ratio. After assessing 112 vessels, we show two distinct groups of vessels that can be separated using lumen:vessel wall area (group 1, 1.89 -10.96 vs. group 2, 0.27-1.57; p < 0.001) but not using lumen diameter:vessel wall thickness where a substantial overlap in ranges between groups occurred (group 1, 1.58-22.66 vs. group 2, 1.40-11.63). We, therefore, conclude that lumen:vessel wall area is a more sensitive and preferred method for distinguishing cerebral arterioles from venules. The significance of this study is wide, as cerebral small vessel disease is a key feature of vascular dementia and understanding the pathogenesis relies on correct identification of vessels.</p
Peri-arterial pathways for clearance of α-Synuclein and tau from the brain: implications for the pathogenesis of dementias and for immunotherapy
No full textIntroduction: Accumulation of amyloid beta (Aβ), α-synuclein (αSyn), and tau in dementias indicates their age-related failure of elimination from the brain. Aβ is eliminated along basement membranes in walls of cerebral arterioles and leptomeningeal arteries (intramural peri-arterial drainage [IPAD]); IPAD is impaired with age. We test the hypothesis that αSyn and tau are also eliminated from the normal brain along IPAD pathways.Methods: Soluble αSyn or tau was injected into mouse hippocampus. Animals were perfused 5 minutes to 7 days post-injection. Blood vessels were identified by ROX-SE for light-sheet and immunolabeling for confocal microscopy. IPAD was quantified by measuring the proportion of arterioles with αSyn/tau.Results: αSyn and tau are eliminated from the brain by IPAD but with different dynamics.Discussion: Age-related failure of IPAD may play a role in the pathogenesis of synucleinopathies and tauopathies. αSyn persists within IPAD at 24 hours, which may affect immunotherapy for αSyn.</p
Arterial Pulsations cannot Drive Intramural Periarterial Drainage: Significance for Aβ Drainage
Full text linkAlzheimer's Disease (AD) is the most common form of dementia and to date there is no cure or efficient prophylaxis. The cognitive decline correlates with the accumulation of amyloid-β (Aβ) in the walls of capillaries and arteries. Our group has demonstrated that interstitial fluid and Aβ are eliminated from the brain along the basement membranes of capillaries and arteries, the intramural periarterial drainage (IPAD) pathway. With advancing age and arteriosclerosis, the stiffness of arterial walls, this pathway fails in its function and Aβ accumulates in the walls of arteries. In this study we tested the hypothesis that arterial pulsations drive IPAD and that a valve mechanism ensures the net drainage in a direction opposite to that of the blood flow. This hypothesis was tested using a mathematical model of the drainage mechanism. We demonstrate firstly that arterial pulsations are not strong enough to produce drainage velocities comparable to experimental observations. Secondly, we demonstrate that a valve mechanism such as directional permeability of the IPAD pathway is necessary to achieve a net reverse flow. The mathematical simulation results are confirmed by assessing the pattern of IPAD in mice using pulse modulators, showing no significant alteration of IPAD. Our results indicate that forces other than the cardiac pulsations are responsible for efficient IPAD
Convective infux/glymphatic system: tracers injected into the CSF enter and leave the brain along separate periarterial basement membrane pathways
Full text linkTracers 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
The fine anatomy of the perivascular compartment in the human brain: relevance to dilated perivascular spaces in cerebral amyloid angiopathy
Full text linkAβ, amyloid beta, CAA, cerebral amyloid angiopathy, CT, computed tomographic scanning, IPAD, intramural periarterial drainage, ISF, interstitial fluid, MRI, magnetic resonance imaging, PVS, perivascular spaces, WMH, white matter hyperintensities.Cerebral white matter hyperintensities (WMH) observed on magnetic resonance imaging (MRI), or low attenuation on computed tomographic scanning (CT), are the most frequent brain imaging finding in patients with small vessel disease or dementia. It has been assumed that WMH are due to arteriosclerosis or blood-brain barrier breakdown, though recently it was demonstrated that WMH have distinct molecular signatures in Alzheimer's disease (AD) where markers of Wallerian degeneration are present, compared to normal ageing [1]
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Full text link“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Appropriate Similarity Measures for Author Cocitation Analysis
Full text linkWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
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