On bloodvessel branching analysis for the detection of Alzheimer's disease

Alzheimer’s Disease (AD) is increasingly prevalent in modern society and methods for its diagnosis are only just starting to emerge. Given images of brain tissue, we show how Alzheimer’s disease can be detected from the branching structures of blood vessels. This is achieved by a new approach which counts the branching points and derives measures which are suited to the analysis of small branching structures. The measures are formulated to be rotation, scale and position invariant and are deployed in tandem with more standard measures. Analysis on a database comprised of brain tissue samples from subjects who are normal, with Alzheimer’s and age matched normal has shown capability to classify correctly images of brain tissue from subjects afflicted with Alzheimer’s disease.<br/

Clearance of interstitial fluid (ISF) and CSF (CLIC) group-part of Vascular Professional Interest Area (PIA): Cerebrovascular disease and the failure of elimination of Amyloid-β from the brain and retina with age and Alzheimer\u27s disease-Opportunities for Therapy

Two of the key functions of arteries in the brain are (1) the well-recognized supply of blood via the vascular lumen and (2) the emerging role for the arterial walls as routes for the elimination of interstitial fluid (ISF) and soluble metabolites, such as amyloid beta (Aβ), from the brain and retina. As the brain and retina possess no conventional lymphatic vessels, fluid drainage toward peripheral lymph nodes is mediated via transport along basement membranes in the walls of capillaries and arteries that form the intramural peri-arterial drainage (IPAD) system. IPAD tends to fail as arteries age but the mechanisms underlying the failure are unclear. In some people this is reflected in the accumulation of Aβ plaques in the brain in Alzheimer\u27s disease (AD) and deposition of Aβ within artery walls as cerebral amyloid angiopathy (CAA). Knowledge of the dynamics of IPAD and why it fails with age is essential for establishing diagnostic tests for the early stages of the disease and for devising therapies that promote the clearance of Aβ in the prevention and treatment of AD and CAA. This editorial is intended to introduce the rationale that has led to the establishment of the Clearance of Interstitial Fluid (ISF) and CSF (CLIC) group, within the Vascular Professional Interest Area of the Alzheimer\u27s Association International Society to Advance Alzheimer\u27s Research and Treatment

Vital Functions Contribute to the Spread of Extracellular Fluids in the Brain: Comparison Between Life and Death

Vascular pulsations, contractions of vascular smooth muscle cells and breathing have been reported to foster movement and clearance of interstitial and cerebrospinal fluids from the brain. The aim of this study was to estimate the contribution of these vital functions. We compared the spread of an injected hydrophilic tracer (Fluoro-Emerald, a 10 kDa fluorescein-coupled dextran amine) in the brains of live anesthetized and sacrificed rats at 30 and 90 min after injection. To determine the overall pattern of distribution of tracers, we created 3D-reconstructions of the horizontal transections of the whole brain. Immunofluorescence staining with laminin and collagen IV was performed to determine the pattern of distribution of tracer in relation to the cerebrovascular basement membranes. We found that diffusion was widely restricted to the periventricular region in sacrificed rats with no spread to the contralateral hemisphere, while the bulk flow occurred along the vasculature and reached the surface and the contralateral hemisphere as soon as 30 min after injection in live anesthetized animals. The tracer appeared to be localized along the vascular basement membranes and along fiber tracts as reported previously. Thus, our data indicate that vital functions are essential for the remote movement of extracellular fluids within the cerebral parenchyma

Blood vessel feature description for detection of Alzheimers disease

We describe how image analysis can be used to detect the presence of Alzheimer’s disease. The data are images of brain tissue collected from subjects with and without Alzheimer’s disease. The analysis concentrates on the shape and structure of the blood vessels which are known to be affected by amyloid beta, whose drainage is affected by Alzheimer’s disease. The structure is analysed by a new approach which measures the influence of the blood vessels’ branching structures. Their density and tortuosity are analysed in conjunction with a boundary description derived using Fourier descriptors. These measures form a feature vector which is derived from the images of brain tissue, and the discrimination capability shows that it is possible to detect the presence of Alzheimer’s disease using these measures and in an automated way. These measures also show that shape information is influenced by the vessels’ branchingstructure, as known to be consistent with Alzheimer’s disease evolution

Cerebrovascular Smooth Muscle Cells as the Drivers of Intramural Periarterial Drainage of the Brain

The human brain is the organ with the highest metabolic activity but it lacks a traditional lymphatic system responsible for clearing waste products. We have demonstrated that the basement membranes of cerebral capillaries and arteries represent the lymphatic pathways of the brain along which intramural periarterial drainage (IPAD) of soluble metabolites occurs. Failure of IPAD could explain the vascular deposition of the amyloid-beta protein as cerebral amyloid angiopathy (CAA), which is a key pathological feature of Alzheimer\u27s disease. The underlying mechanisms of IPAD, including its motive force, have not been clarified, delaying successful therapies for CAA. Although arterial pulsations from the heart were initially considered to be the motive force for IPAD, they are not strong enough for efficient IPAD. This study aims to unravel the driving force for IPAD, by shifting the perspective of a heart-driven clearance of soluble metabolites from the brain to an intrinsic mechanism of cerebral arteries (e.g., vasomotion-driven IPAD). We test the hypothesis that the cerebrovascular smooth muscle cells, whose cycles of contraction and relaxation generate vasomotion, are the drivers of IPAD. A novel multiscale model of arteries, in which we treat the basement membrane as a fluid-filled poroelastic medium deformed by the contractile cerebrovascular smooth muscle cells, is used to test the hypothesis. The vasomotion-induced intramural flow rates suggest that vasomotion-driven IPAD is the only mechanism postulated to date capable of explaining the available experimental observations. The cerebrovascular smooth muscle cells could represent valuable drug targets for prevention and early interventions in CAA

Cerebral amyloid angiopathy in the aetiology and immunotherapy of Alzheimer disease

Amyloid is deposited in the walls of arteries and capillaries as cerebral amyloid angiopathy (CAA) in the brains of older individuals and of those with Alzheimer disease (AD). CAA in AD reflects an age-related failure of elimination of amyloid-beta (Aβ) from the brain along perivascular lymphatic drainage pathways. In the absence of conventional lymphatic vessel in the brain, interstitial fluid and solutes drain from the brain to cervical lymph nodes along narrow basement membranes in the walls of capillaries and arteries, a pathway that is largely separate from the cerebrospinal fluid. In this review we focus on the pathology and pathogenesis of CAA, its role in the aetiology of AD and its impact on immunotherapy for AD. The motive force for lymphatic drainage of the brain appears to be generated by arterial pulsations. Failure of elimination of Aβ along perivascular pathways coincides with a reduction in enzymic degradation of Aβ, reduced absorption of Aβ into the blood and age-related stiffening of artery walls that appears to reduce the motive force for lymphatic drainage. Reduced clearances of Aβ and CAA are associated with the accumulation of insoluble and soluble Aβs in the brain in AD and the probable loss of homeostasis of the neuronal environment due to retention of soluble metabolites within the brain. Tau metabolism may also be affected. Immunotherapy has been successful in removing insoluble plaques of Aβ from the brain in AD but with little effect on cognitive decline. One major problem is the increase in CAA in immunised patients that probably prevents the complete removal of Aβ from the brain. Increased knowledge of the physiology and structural and genetic aspects of the lymphatic drainage of Aβ from the brain will stimulate the development of therapeutic strategies for the prevention and treatment of AD

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

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

Quantitative proteomic profiling of white matter in cases of cerebral amyloid angiopathy reveals upregulation of extracellular matrix proteins and clusterin

Aims: Cerebral amyloid angiopathy (CAA) is the accumulation of amyloid beta (Aβ) in the walls of cerebral arterioles, arteries and capillaries. Changes in the white matter in CAA are observed as hyperintensities and dilated perivascular spaces on MRI suggesting impairment of fluid drainage but the pathophysiology behind these changes is poorly understood. We tested the hypothesis that proteins associated with clearance of Aβ peptides are upregulated in the white matter in cases of CAA.Methods: In this study, we compare the quantitative proteomic profile of white matter from post-mortem brains of patients with CAA and age-matched controls in order to gain insight into the cellular processes and key molecules involved in the pathophysiology of CAA.Results: Our proteomic analysis resulted in the profiling of 3,734 proteins (peptide FDR p&lt;0.05). Of these, 189 were differentially expressed in CAA vs. control. Bioinformatics analysis of these proteins showed significant enrichment of proteins related to cell adhesion | cell-matrix interaction, mitochondrial dysfunction and hypoxia. Upregulated proteins in CAA included EMILIN2, COL4A2, TLN1, CLU, HSPG2. Downregulated proteins included DSP, IDE, HBG1.Conclusions: The present study reports an in-depth quantitative proteomic profiling of white matter from patients with CAA, highlighting extracellular matrix proteins and clusterin as key molecules in the pathophysiology of white matter changes in cases of CAA

Cerebrovascular Smooth Muscle Cells as the Drivers of Intramural Periarterial Drainage of the Brain

The human brain is the organ with the highest metabolic activity but it lacks a traditional lymphatic system responsible for clearing waste products. We have demonstrated that the basement membranes of cerebral capillaries and arteries represent the lymphatic pathways of the brain along which intramural periarterial drainage (IPAD) of soluble metabolites occurs. Failure of IPAD could explain the vascular deposition of the amyloid-beta protein as cerebral amyloid angiopathy (CAA), which is a key pathological feature of Alzheimer's disease. The underlying mechanisms of IPAD, including its motive force, have not been clarified, delaying successful therapies for CAA. Although arterial pulsations from the heart were initially considered to be the motive force for IPAD, they are not strong enough for efficient IPAD. This study aims to unravel the driving force for IPAD, by shifting the perspective of a heart-driven clearance of soluble metabolites from the brain to an intrinsic mechanism of cerebral arteries (e.g., vasomotion-driven IPAD). We test the hypothesis that the cerebrovascular smooth muscle cells, whose cycles of contraction and relaxation generate vasomotion, are the drivers of IPAD. A novel multiscale model of arteries, in which we treat the basement membrane as a fluid-filled poroelastic medium deformed by the contractile cerebrovascular smooth muscle cells, is used to test the hypothesis. The vasomotion-induced intramural flow rates suggest that vasomotion-driven IPAD is the only mechanism postulated to date capable of explaining the available experimental observations. The cerebrovascular smooth muscle cells could represent valuable drug targets for prevention and early interventions in CAA