Contribution of O4+ oligodendrocyte precursors and astrocytes to the glial ensheathment of vessels in the rabbit myelinated streak

The barrier properties and glial ensheathment of blood vessels in the retinal myelinated streak of adult New Zealand White rabbits were characterized at the ultrastructural level by intravascular injection of horseradish peroxidase (HRP) and immuno‐electron microscopy with monoclonal antibody O4 and antibodies to glial fibrillary acidic protein (GFAP). Vessels within the myelinated streak did not leak HRP, and they exhibited tight junctions between adjacent endothelial cells. However, unlike their adult counterparts, the retinal blood vessels at postnatal day 18 exhibited substantial endocytotic activity. Both GFAP⁺ astrocytes and O4⁺ cells were evident surrounding the preretinal blood vessels of the myelinated streak. Furthermore, O4⁺ cells exhibited features indicative of high synthetic activity, including a large proportion of extended chromatin and prominent nucleoli within the nucleus, as well as a well‐developed Golgi apparatus and numerous mitochondria in the cytoplasm. O4⁺ cells also exhibited variable quantities of heterochromatin, indicative of early stages of cellular differentiation. These observations are consistent with previous data showing that O4⁺ cells in the myelinated streak include oligodendrocyte precursor cells, pre‐oligodendrocytes, and immature oligodendrocytes (Morcos Y, Chan‐Ling T. Glia 21:163–182, 1997). The present data indicate that the preretinal vessels of the myelinated streak possess barrier properties typical of microvasculature in the central nervous system, and that both O4⁺ cells and astrocytes contribute to the glial ensheathment of these vessels. These vessels thus differ markedly from the leaky preretinal vessels associated with pathological conditions such as retinopathy of prematurity. GLIA 27:1–14, 1999. © 1999 Wiley‐Liss, Inc.     

Cerebral hypoperfusion and glucose hypometabolism: Key pathophysiological modulators promote neurodegeneration,cognitive impairment,and Alzheimer's disease

Aging, hypertension, diabetes, hypoxia/obstructive sleep apnea (OSA), obesity, vitamin B12/folate deficiency, depression, and traumatic brain injury synergistically promote diverse pathological mechanisms including cerebral hypoperfusion and glucose hypometabolism. These risk factors trigger neuroinflammation and oxidative‐nitrosative stress that in turn decrease nitric oxide and enhance endothelin, Amyloid‐β deposition, cerebral amyloid angiopathy, and blood–brain barrier disruption. Proinflammatory cytokines, endothelin‐1, and oxidative‐nitrosative stress trigger several pathological feedforward and feedback loops. These upstream factors persist in the brain for decades, upregulating amyloid and tau, before the cognitive decline. These cascades lead to neuronal Ca²⁺ increase, neurodegeneration, cognitive/memory decline, and Alzheimer's disease (AD). However, strategies are available to attenuate cerebral hypoperfusion and glucose hypometabolism and ameliorate cognitive decline. AD is the leading cause of dementia among the elderly. There is significant evidence that pathways involving inflammation and oxidative‐nitrosative stress (ONS) play a key pathophysiological role in promoting cognitive dysfunction. Aging and several comorbid conditions mentioned above promote diverse pathologies. These include inflammation, ONS, hypoperfusion, and hypometabolism in the brain. In AD, chronic cerebral hypoperfusion and glucose hypometabolism precede decades before the cognitive decline. These comorbid disease conditions may share and synergistically activate these pathophysiological pathways. Inflammation upregulates cerebrovascular pathology through proinflammatory cytokines, endothelin‐1, and nitric oxide (NO). Inflammation‐triggered ONS promotes long‐term damage involving fatty acids, proteins, DNA, and mitochondria; these amplify and perpetuate several feedforward and feedback pathological loops. The latter includes dysfunctional energy metabolism (compromised mitochondrial ATP production), amyloid‐β generation, endothelial dysfunction, and blood–brain‐barrier disruption. These lead to decreased cerebral blood flow and chronic cerebral hypoperfusion‐ that would modulate metabolic dysfunction and neurodegeneration. In essence, hypoperfusion deprives the brain from its two paramount trophic substances, viz., oxygen and nutrients. Consequently, the brain suffers from synaptic dysfunction and neuronal degeneration/loss, leading to both gray and white matter atrophy, cognitive dysfunction, and AD. This Review underscores the importance of treating the above‐mentioned comorbid disease conditions to attenuate inflammation and ONS and ameliorate decreased cerebral blood flow and hypometabolism. Additionally, several strategies are described here to control chronic hypoperfusion of the brain and enhance cognition. © 2016 Wiley Periodicals, Inc.     

Blood–brain barrier opening with focused ultrasound in experimental models of Parkinson's disease

Parkinson's disease has many symptomatic treatments, but there is no neuroprotective therapy currently available. The evolution of this disease is inexorably progressive, and halting or stopping the neurodegenerative process is a major unmet need. Parkinson's disease motor features at onset are typically limited to 1 body segment, that is, focal signs, and the nigrostriatal degeneration is highly asymmetrical and mainly present in the caudal putamen. Thus, clinically and neurobiologically the process is fairly limited early in its evolution. Tentatively, this would allow the possibility of intervening to halt neurodegeneration at the most vulnerable site. The recent use of new technologies such as focused ultrasound provides interesting prospects. In particular, the possibility of transiently opening the blood–brain barrier to facilitate penetrance of putative neuroprotective agents is a highly attractive approach that could be readily applied to Parkinson's disease. However, because there are currently effective treatments available (ie, dopaminergic pharmacological therapy), more experimental evidence is needed to construct a feasible and practical therapeutic approach to be tested early in the evolution of Parkinson's disease patients. In this review, we provide the current evidence for the application of blood–brain barrier opening in experimental models of Parkinson's disease and discuss its potential clinical applicability. © 2019 International Parkinson and Movement Disorder Society     

Blood–brain barrier and traumatic brain injury

The blood–brain barrier (BBB) is an anatomical microstructural unit, with several different components playing key roles in normal brain physiological regulation. Formed by tightly connected cerebrovascular endothelial cells, its normal function depends on paracrine interactions between endothelium and closely related glia, with several recent reports stressing the need to consider the entire gliovascular unit in order to explain the underlying cellular and molecular mechanisms. Despite that, with regard to traumatic brain injury (TBI) and significant events in incidence and potential clinical consequences in pediatric and adult ages, little is known about the actual role of BBB disruption in its diverse pathological pathways. This Mini‐Review addresses the current literature on possible factors affecting gliovascular units and contributing to posttraumatic BBB dysfunction, including neuroinflammation and disturbed transport mechanisms along with altered permeability and consequent posttraumatic edema. Key mechanisms and its components are described, and promising lines of basic and clinical research are identified, because further knowledge on BBB pathological interference should play a key role in understanding TBI and provide a basis for possible therapeutic targets in the near future, whether through restoration of normal BBB function after injury or delivering drugs in an increased permeability context, preventing secondary damage and improving functional outcome. © 2013 Wiley Periodicals, Inc.     

Pathology of the cerebral artery in Binswanger's disease in the aged: Observation by serial sections and morphometry of the cerebral arteries

Binswanger's disease (BD) is not rare in the aged. The aim of the present study was to compare the etiopathogenesis of BD of the aged (aged‐BD) with that of classic‐BD, with the aid of morphometry of the arterial medial thickness and reconstruction of the cerebral medullary arteries using serial sections from five autopsy cases. The age range of the aged‐BD cases was 73–89 years. The mean heart weight of these cases was 296 g, in contrast to 391 g of the five age‐matched cases of hypertension without diffuse myelin loss and atrophy of the cerebral white matter (HT). Although significant medial hypertrophy of the subarachnoid and medullary arteries was not found in all aged‐BD cases, differently from classic‐BD, all five cases of aged‐BD commonly presented significantly widespread loss of the medial smooth muscle cells (SMC) of the medullary arteries as compared with HT, similar to the case in classic‐BD. The etiopathogenesis of aged‐BD is common to that of classic‐BD; stiffening caused by hypertensive changes of the medullary artery, especially SMC loss, is responsible for the diffuse myelin loss and atrophy of the cerebral white matter of BD, rather than grade of hypertension itself or hypertensive medial hypertrophy. As the mechanism of such an especially severe involvement of the cerebral medullary artery in BD, some genetic abnormality in the functional response or vulnerability to hypertension of the artery should be considered.     

Systemic and central immunity in Alzheimer's disease: therapeutic implications

Clinical pharmaceutical trials aimed at modulating the immune system in Alzheimer's Disease have largely focused on either dampening down central proinflammatory innate immunity or have manipulated adaptive immunity to facilitate the removal of centrally deposited beta amyloid. To date, these trials have had mixed clinical therapeutic effects. However, a number of clinical studies have demonstrated disturbances of both systemic and central innate immunity in Alzheimer's Disease and attention has been drawn to the close communication pathways between central and systemic immunity. This paper highlights the need to take into account the potential systemic effects of drugs aimed at modulating central immunity and the possibility of developing novel therapeutic approaches based on the manipulation of systemic immunity and its communication with the central nervous system.     

Human apolipoprotein E ?4 expression impairs cerebral vascularization and blood–brain barrier function in mice

Human apolipoprotein E (APOE) exists in three isoforms ɛ2, ɛ3, and ɛ4, of which APOE4 is the main genetic risk factor of Alzheimer''s disease (AD). As cerebrovascular defects are associated with AD, we tested whether APOE genotype has an impact on the integrity and function of the blood–brain barrier (BBB) in human APOE-targeted replacement mice. Using the quantitative in situ brain perfusion technique, we first found lower (13.0% and 17.0%) brain transport coefficient (Clup) of [³H]-diazepam in APOE4 mice at 4 and 12 months, compared with APOE2 and APOE3 mice, reflecting a decrease in cerebral vascularization. Accordingly, results from immunohistofluorescence experiments revealed a structurally reduced cerebral vascularization (26% and 38%) and thinner basement membranes (30% and 35%) in 12-month-old APOE4 mice compared with APOE2 and APOE3 mice, suggesting vascular atrophy. In addition, APOE4 mice displayed a 29% reduction in [³H]-d-glucose transport through the BBB compared with APOE2 mice without significant changes in the expression of its transporter GLUT1 in brain capillaries. However, an increase of 41.3% of receptor for advanced glycation end products (RAGE) was found in brain capillaries of 12-month-old APOE4 mice. In conclusion, profound divergences were observed between APOE genotypes at the cerebrovascular interface, suggesting that APOE4-induced BBB anomalies may contribute to AD development.     

The case for blood-brain barrier dysfunction in the pathogenesis of Alzheimer's disease

Alzheimer's disease (AD) is a neurodegenerative disease that leads to a progressive loss of integrative and memory capacities of the brain. This is the predominant form of neurodegenerative dementia, with a growing prevalence of between 1 in 50 and 1 in 100 in North America. Numerous hypotheses related to the etiology of AD have developed over the years. However, among the various published hypotheses, the predominant one is related to the progressive and prominent accumulation of central nervous system β-amyloid peptide and the ensuing brain burden created. It is, therefore, important to consider the homeostatic mechanisms underlying β-amyloid transport dynamics between the brain and blood vascular compartments. As well, there is a dynamic interrelationship between soluble and insoluble forms of the peptide. Factors that underlie and regulate these dynamic processes are likely relevant to the end accumulation of β-amyloid peptide in the brain compartment and ultimately in insoluble forms, which is characteristic of, and significant for, the pathophysiology of the Alzheimer's brain. Significantly, and in particular relation to the amyloid burden theory mentioned above, it has been postulated that a dysfunctioning blood-brain barrier (BBB) may play a significant, if not critical, role in the pathogenesis of AD. By allowing the influx of injurious materials or agents into the brain or by impeding or blocking the efflux of those materials and/or agents, BBB-related neuronopathies and their associated sequelae could, and do, ensue.     

CNS pericytes: Concepts,misconceptions, and a way out

Rouget, in 1873 , was the first to describe a population of cells surrounding capillaries, which he regarded as contractile elements. Fifty years later, Zimmermann termed these cells “pericytes” and distinguished three subtypes along the vascular tree. Since then, the discussion concerning the contractile ability of pericytes has never ceased. Current concepts of pericyte biology rather suggest critical roles in the maintenance of homeostasis, blood–brain barrier (BBB) integrity, angiogenesis, and neovascularization. In addition, data from models of brain pathology suggest that novel pericytes are recruited from the bone marrow, but their respective precursor remains enigmatic. Recent data also suggest an important role in the regulation of cerebral blood flow, thus confirming Rouget's original idea. However, comparison of data from different studies is often constrained by the fact that pericytes were questionably identified. Although a clear‐cut definition exists, defining pericytes as part of the vascular wall being enclosed in its basement membrane, pericytes are often mixed up with adjacent cell types of the vascular wall, the perivascular space, and the juxtavascular parenchyma. In fact, their identification is difficult—if not impossible—in standard histological sections. An unambiguous distinction, however, is possible at the ultrastructural level and in semi‐thin sections, where their location within the vascular basement membrane can be displayed. Using these techniques in combination with immunological staining methods allows demarking their unique morphology and location. Here, we review original papers describing pericytes, briefly outline their topography within the vascular compartments, describe methods for their identification, and summarize current concepts of their function. © 2009 Wiley‐Liss, Inc.     

帕金森病患者24小时动态血压变化及其影响因素的临床研究

目的研究帕金森病(PD)患者动态血压变化特点及其相关的影响因素。方法采用无创性携带式动态血压监测仪行24 h动态血压监测,评估81例PD患者(PD组)和59名正常对照者(对照组)的动态血压变化节律,同时进行PD非运动症状问卷调查,探讨病理性血压节律的相关影响因素。结果①PD组患者血压节律倾向于非杓型血压;卧位血压升高的发生率较正常对照组高(P=0.001)。②PD组24 h平均血压、24 h平均收缩压、夜间平均血压、夜间平均收缩压、夜间平均舒张压均较对照组升高(P0.05);夜间平均动脉血压下降水平[MABP(%)]较对照组明显降低(P0.05)。③PD患者夜间血压变异系数(CV)与病程(P=0.019)、H-Y分级(P=0.047)、UPDRS评分(P=0.031)、心血管症状相关(P=0.016)、睡眠/疲劳(P=0.049)因素呈正相关。结论 PD患者血压节律偏向于非杓型血压,并广泛存在夜间血压升高现象,病理性血压节律可能是自主神经功能受损的潜在指标。     

Focused ultrasound opening of the blood–brain barrier for treatment of Parkinson's disease

The expanding landscape of options for Parkinson's disease (PD) therapeutics calls for novel ways to improve delivery of treatments to counteract neurodegeneration or enhance symptomatic control. This unmet need is particularly relevant for opportunities in gene therapy, which, in recent PD clinical trials, has required invasive neurosurgical approaches into the CNS. One of the promising techniques to bring new therapies into the brain for PD therapeutics involves an evolving technology, focused ultrasound. Focused ultrasound has been used to alleviate tremor by thermal ablation with high‐energy sonication. Using similar equipment but much lower sonication energy, focused ultrasound assisted with micro‐bubbles can temporarily open the blood–brain barrier at specific brain targets to facilitate real‐time magnetic resonance–guided delivery of therapeutic agents. To explore the current status and future of focused ultrasound in transvascular therapeutics for PD, a November 2018 workshop reviewed its accomplishments and challenges. This report summarizes key points of discussion and provides further background to the promising roles focused ultrasound offers. © 2019 International Parkinson and Movement Disorder Society     

The rise of pericytes in neurovascular research

The popularity of pericyte research is increasing, and this was not more evident than at the recent 2019 Brain meeting in Yokohama which featured a large number of presentations focused on brain pericyte research, including the Presidential Symposium. In this article, we will provide a history of brain pericyte research, present the results of our analysis showing a substantial increase in brain pericyte research presented at Brain meetings since 2005, suggest reasons for their increased popularity, and comment on what the future holds for brain pericyte research.     

Consensus statement for diagnosis of subcortical small vessel disease

Vascular cognitive impairment (VCI) is the diagnostic term used to describe a heterogeneous group of sporadic and hereditary diseases of the large and small blood vessels. Subcortical small vessel disease (SVD) leads to lacunar infarcts and progressive damage to the white matter. Patients with progressive damage to the white matter, referred to as Binswanger’s disease (BD), constitute a spectrum from pure vascular disease to a mixture with neurodegenerative changes. Binswanger’s disease patients are a relatively homogeneous subgroup with hypoxic hypoperfusion, lacunar infarcts, and inflammation that act synergistically to disrupt the blood–brain barrier (BBB) and break down myelin. Identification of this subgroup can be facilitated by multimodal disease markers obtained from clinical, cerebrospinal fluid, neuropsychological, and imaging studies. This consensus statement identifies a potential set of biomarkers based on underlying pathologic changes that could facilitate diagnosis and aid patient selection for future collaborative treatment trials.     

Loss of nocturnal blood pressure fall in various extrapyramidal syndromes

Cardiovascular autonomic dysfunction has frequently been reported in some patients with extrapyramidal syndromes, especially multiple system atrophy (MSA) but also Parkinson's disease (PD). However, there are only few reports on the prevalence of cardiovascular autonomic dysfunction progressive in supranuclear palsy (PSP). Moreover, the relation of detailed cardiovascular testing and easy to assess 24‐hour ambulatory blood pressure (BP) is not known. Our study evaluates 24‐hour ambulatory BP monitoring in patients with PD, PSP, MSA, and corresponding controls (Con) and relates the findings to the results of comprehensive cardiovascular autonomic testing. Twenty‐three patients with PD, 25 patients with PSP, 25 patients with MSA, and 26 corresponding controls were studied by 24‐hour ambulatory BP monitoring (ABPM) in comparison to cardiovascular autonomic testing. Patients with PD, PSP, and MSA presented frequently with a pathological nocturnal BP regulation (no decrease or even an increase of nocturnal BP) in comparison to the control group (PD 48%, PSP 40%, MSA 68% vs. Con 8%). In MSA and PD patients, the frequent pathological BP increase during night was closely correlated to orthostatic hypotension. Since loss of nocturnal BP fall is frequent in patients with extrapyramidal syndromes, even if they are free of subjective autonomic dysfunction, we recommend 24‐hour ABPM as an easy to perform screening test, especially if detailed autonomic testing is not available. Pathological loss of nocturnal BP fall may account for increased cardiovascular mortality in extrapyramidal syndromes. © 2009 Movement Disorder Society     

Lymphocyte migration through the blood–brain barrier (BBB) in feline immunodeficiency virus infection is significantly influenced by the pre‐existence of virus and tumour necrosis factor (TNF)‐α within the central nervous system (CNS): studies using an in vitro feline BBB model

Aims: In human immunodeficiency virus infection, macrophage‐tropic and lymphotropic viruses exist in the host. Central nervous system (CNS) infection is an early and ongoing event, important to understand when developing strategies to treat infection. Some knowledge exists on macrophage‐tropic virus interactions with the blood–brain barrier (BBB), and the aim of this study was to investigate lymphotropic lentivirus interactions with the BBB. Methods: Interactions of the lymphotropic feline immunodeficiency virus (FIV) with an in vitro model of the feline BBB were evaluated in scenarios to mimic in vivo infections. Results: Cell‐free FIV crossed the BBB in very low quantities, and in the presence of tumour necrosis factor (TNF)‐α, BBB integrity was unaffected. However, cell‐associated FIV readily crossed the BBB, but BBB integrity was not significantly altered. Transmigration of uninfected and infected lymphocytes increased in response to TNF‐α, accompanied by a moderate disruption of barrier integrity and an upregulation of vascular cell adhesion molecule‐1 rather than intercellular adhesion molecule‐1. Significant enhancement of migration and disruption of BBB tight junctions occurred when infected cells and TNF‐α were added to the brain side of the BBB and this enhancement was not mediated through additional TNF‐α production. Conclusions: Small quantities of virus in the brain together with TNF‐α have the potential to stimulate greater cell and viral entry into the CNS and this is likely to involve important factors other than further TNF‐α production. Lymphotropic lentivirus entry to the CNS is governed by many factors similar to macrophage‐tropic strains.     

Improvement of cold injury‐induced mouse brain edema by endothelin ETB antagonists is accompanied by decreases in matrixmetalloproteinase 9 and vascular endothelial growth factor‐A

Brain edema is a potentially fatal pathological state that often occurs after brain injuries such as ischemia and trauma. However, therapeutic agents that fundamentally treat brain edema have not yet been established. We previously found that endothelin ET_B receptor antagonists attenuate the formation and maintenance of vasogenic brain edema after cold injury in mice. In this study, the effects of ET_B antagonists on matrixmetalloproteinase (MMP)9 and vascular endothelial growth factor (VEGF)‐A expression were examined in the cold injury model. Cold injury was performed in the left brain of male ddY mice (5–6 weeks old) for the induction of vasogenic edema. Expression of MMP9 and VEGF‐A mRNA in the mouse cerebrum was increased by cold injury. Immunohistochemical observations showed that the MMP9 and VEGF‐A were mainly produced in reactive astrocytes in the damaged cerebrum. Intracerebroventricular administration of BQ788 (10 μg) or IRL‐2500 (10 μg) (selective ET_B antagonists) attenuated brain edema and disruption of the blood–brain barrier after cold injury. BQ788 and IRL‐2500 reversed the cold injury‐induced increases in MMP9 and VEGF‐A expression. The induction of reactive astrocytes producing MMP9 and VEGF‐A in the damaged cerebrum was attenuated by BQ788 and IRL‐2500. These results suggest that attenuations of astrocytic MMP9 and VEGF‐A expression by ET_B antagonists may be involved in the amelioration of vasogenic brain edema.     

Role of matrix metalloproteinase-9 (MMP-9) in striatal blood-brain barrier disruption in a 3-nitropropionic acid model of Huntington's disease

J. Duran‐Vilaregut, J. del Valle, G. Manich, A. Camins, M. Pallàs, J. Vilaplana and C. Pelegrí (2011) Neuropathology and Applied Neurobiology 37, 525–537 Role of matrix metalloproteinase (MMP)‐9 in striatal blood–brain barrier disruption in a 3‐nitropropionic acid model of Huntington's disease Aims: 3‐Nitropropionic acid (3‐NPA) is a natural toxin that, when administered to experimental animals, reproduces the brain lesions observed in Huntington's disease, which mainly consist of selective neurodegeneration of the striatum. The lesions also include severe alterations to the blood–brain barrier (BBB), which increase its permeability to several substances including blood components and exogenous fluorescent dyes, and the concomitant degradation of some of its constituents such as endothelial cells, tight junction proteins and the basement membrane. We studied here the role of matrix metalloproteinases (MMPs)‐2 and ‐9, also called gelatinases A and B, in the degradation of the BBB in the striatal lesions induced by the systemic administration of 3‐NPA to Sprague‐Dawley rats. Methods: 3‐NPA was intraperitoneally administered at a dose of 20 mg/kg once a day for 3 days. MMPs were studied by means of immunohistochemistry and in situ zymography. Results: In 3‐NPA‐treated rats, MMP‐9 was present in most of the degraded blood vessels in the injured striatum, while it was absent in vessels from non‐injured tissue. In the same animals, MMP‐2 staining was barely detected close to degraded blood vessels. The combination of MMP‐9 immunostaining, in situ zymography and inhibitory studies of MMP‐9 confirmed that net gelatinolytic activity detected in the degraded striatal blood vessels could be attributed almost exclusively to the active form of MMP‐9. Conclusion: Our results highlight the prominent role of MMP‐9 in BBB disruption in the striatal injured areas of this experimental model of Huntington's disease.