Blood-brain barrier breakdown,neuroinflammation, and cognitive decline in older adults

Introduction

Blood-brain barrier (BBB) breakdown is observed in older versus younger adults and in late-onset Alzheimer's disease versus age-matched controls, but its causes and consequences in aging are unclear. We tested the hypothesis that BBB breakdown is associated with cognitive decline and inflammation in nondemented elders.

Blood-brain barrier breakdown following gliotoxic drug injection in the brainstem of Wistar rats

Ethidium bromide (EB) causes local astrocytic disappearance, with glia limitans disruption and supposed blood-brain barrier (BBB) breakdown The aim of this study was to investigate the BBB integrity after the injection of 0.1% EB (group E) or 0.9% saline solution (group C) into cisterna pontis of Wistar rats. Brainstem fragments were collected from 24 hours to 31 days post-injection for ultrastructural study and GFAP immuno-histochemical staining. Some animals received colloidal carbon ink by intravenous route at the same periods. In rats from group C, there was no sign of astrocyte loss and no leakage of ink from blood vessels in the injection site. In group E, astrocyte disappearance began at 48 hours and some areas were still devoid of astrocytic processes 31 days after. Leakage of carbon particles was seen from 48 hours to 7 days in the EB-induced lesions. Tight junctions did not show any detectable ultrastructural change due to the lack of perivascular astrocytes.     

Blood-brain barrier opening to horseradish peroxidase in acute arterial hypertension

Summary Acute arterial hypertension was induced in male Wistar rats using two experimental techniques: (1) i.v. injection of Aramine and (2) infusion of physiological saline as a bolus via internal carotid artery. Horseradish peroxidase (HRP) was injected i.v. prior to both experimental procedures and subsequently localized in the brain by light and electron microscopy. In the saline infusion (pressure pulse) model, colloidal lanthanum was also applied as a diffusion tracer following fixation of the cerebral endothelium.In the Aramine model, extravasation of HRP correlated with abrupt elevation of blood pressure. In the pressure pulse model HRP extravasation was consistently visualized in the affected hemisphere. Electron microscopy showed consistent labeling of plasmalemmal vesicles by HRP in segments of cerebral endothelium. However, HRP was also clearly visualized in junctional pools suggesting focal opening of endothelial tight junctions as a pathway for extravasation of this tracer in both hypertensive models. Colloidal lanthanum not transported by plasmalemmal vesicles across endothelium after fixation of the brain also bypassed consecutive membrane appositions of endothelial tight junctions indicating existance of interendothelial pathways to macromolecules in acute arterial hypertension.Supported in part by Medical Research Council of Canada Grant MA-5958Dr. Z. Nagy, Assistant Professor at the Psychiatric Clinic, Semmelweis Medical School, Budapest, Hungary, held a Medical Research Council of Canada Fellowship at the Montreal Neurological Institute, McGill University, during the course of this study     

Blood-brain barrier breakdown and repair following gliotoxic drug injection in the brainstem of streptozotocin-diabetic rats

Ethidium bromide (EB) causes local astrocytic disappearance, with glia limitans disruption and blood-brain barrier (BBB) breakdown. The aim of this study was to evaluate the BBB integrity after the injection of 0.1% EB or 0.9% saline solution into the cisterna pontis of Wistar rats submitted or not to the streptozotocin diabetogenic model. Brainstem sections were collected from 24 hours to 31 days post-injection for ultrastructural analysis and glial fibrillary acidic protein immunohistochemical staining. Some animals received colloidal carbon ink by intravenous route at the same periods. In rats injected with EB, results revealed astrocyte disappearance and leakage of carbon particles beginning at 48 hours and persisting for 7 days in non-diabetic rats and for 15 days in the diabetic ones, although, in both groups, several areas remained devoid of astrocytic processes up to 31 days. In rats injected with saline, there was no sign of astrocytic loss or carbon particles leakage.     

Blood-brain barrier biology and methodology

The blood-brain barrier (BBB) is formed by epithelial-like high resistance tight junctions within the endothelium of capillaries perfusing the vertebrate brain. Because of the presence of the BBB, circulating molecules gain access to brain cells only via one of two processes: (i) lipid-mediated transport of small molecules through the BBB by free diffusion, or (ii) catalyzed transport. The latter includes carrier-mediated transport processes for low molecular weight nutrients and water soluble vitamins or receptor-mediated transport for circulating peptides (e.g., insulin), plasma proteins (e.g., transferrin), or viruses. While BBB permeability, per se, is controlled by the biochemical properties of the plasma membranes of the capillary endothelial cells, overall brain microvascular biology is a function of the paracrine interactions between the capillary endothelium and the other two major cells comprising the microcirculation of brain, i.e., the capillary pericyte, which shares the basement membrane with the endothelial cell, and the astrocyte foot process, which invests 99% of the abluminal surface of the capillary basement membrane in brain. Microvascular functions frequently ascribed to the capillary endothelium are actually executed by either the capillary pericyte or the capillary astrocyte foot process. With respect to BBB methodology, there are a variety of in vivo methods for studying biological transport across this important membrane. The classical physiologic techniques may now be correlated with modern biochemical and molecular biological approaches using freshly isolated animal or human brain capillaries. Isolated brain capillary endothelial cells can also be grown in tissue culture to form an 'in vitro BBB' model. However, BBB research cannot be performed using only the in vitro BBB model, but rather it is necessary to correlate observations made with the in vitro BBB model with in vivo studies.     

Blood-brain barrier P-glycoprotein function is not impaired in early Parkinson's disease

The cause of Parkinson's disease (PD) is unknown. Genetic susceptibility and exposure to environmental toxins contribute to specific neuronal loss in PD. Decreased blood-brain barrier (BBB) P-glycoprotein (P-gp) efflux function has been proposed as a possible causative link between toxin exposure and PD neurodegeneration. In the present study BBB P-gp function was investigated in vivo in 10 early stage PD patients and 8 healthy control subjects using (R)-[(11)C]-verapamil and PET. Cerebral volume of distribution (V(d)) of verapamil was used as measure of P-gp function. Both region of interest (ROI) analysis and voxel analysis using statistical parametric mapping (SPM) were performed to assess regional brain P-gp function. In addition, MDR1 genetic polymorphism was assessed. In the present study, a larger variation in V(d) of (R)-[(11)C]-verapamil was seen in the PD group as compared to the control group. However, decreased BBB P-gp function in early stage PD patients could not be confirmed.     

急性脑血管病伴偏身舞蹈症

目的对急性脑血管病伴偏身舞蹈症的发病机制、临床特点、影像学及治疗预后进行分析。方法以"脑卒中"或"偏身舞蹈症"为关键词,以中国期刊全文数据库为数据库,对2003年至2008年15篇国内杂志发表194例患者的临床资料进行回顾性分析。结果脑卒中后部分病人以偏身舞蹈症为主要表现和首发症状,多好发于有动脉硬化基础的老年人,以基底节病变最常见,156例脑梗死患者中基底节病变占91.0%,38例脑出血患者中基底节病变占97.4%。脑部病灶小,临床表现轻,预后取决于原发病。结论急性脑血管病是偏侧舞蹈症的主要病因之一,病灶部位以基底节为主,氟哌啶醇治疗效果较好。     

血脑屏障--解剖与生理

由血液运载的物质在进入脑组织的途中需通过一道屏障,人们对它的认识至少已经过一个世纪。Lewandowsky和Goldman观察到只有将酸性活体染剂注入到蛛网膜下腔才能使脑组织染色,而注入到血流中却不能,于是人们找到了血脑屏障(blood-brainbarrier,BBB)存在的证据。实际上,广义上的血脑屏障包括三部分:血-脑屏障,血-脑脊液屏障(blood-cerebrospinalfluidbarrier,BLB)和脑脊液-脑屏障(brain-CSFbarrier,LBB),其中血-脑屏障和血-脑脊液屏障解剖结构有类似之处,生理和病理意义重大。我们这里主要回顾具有典型意义的血-脑屏障(图1)。脑是人体最…     

Blood-brain barrier disruption in multiple sclerosis

The blood-brain barrier (BBB) is a complex organization of cerebral endothelial cells (CEC), pericytes and their basal lamina, which are surrounded and supported by astrocytes and perivascular macrophages. Collectively these cells separate and form the compartments of the cerebral vascular space and the cerebral interstitium under normal conditions. Without the BBB, the 'interior milieu' of the central nervous system (CNS) would be flooded by humoral neurotransmitters and formed blood elements that upset normal CNS functions and lead to vascular/neural injury. Dysregulation of the BBB and transendothelial migration of activated leukocytes are among the earliest cerebrovascular abnormalities seen in multiple sclerosis (MS) brains and parallel the release of inflammatory cytokines/chemokines. Mechanisms for breakdown of the BBB in MS are incompletely understood, but appear to involve direct effects of these cytokines/ chemokines on endothelial regulation of BBB components, as well as indirect cytokine/chemokine-dependent leukocyte mediated injury. Unique endothelial structural features of the BBB include highly organized endothelial tight junctions, the absence of class II major histocompatibility complex, abundant mitochondria and a highly developed transport system in CEC. Exposure of endothelium to proinflammatory cytokines (IFN-gamma, TNF-alpha and IL-1beta) interrupts the BBB by disorganizing cell-cell junctions, decreases the brain solute barrier, enhances leukocyte endothelial adhesion and migration as well as increases expression of class II MHC and promotes shedding of endothelial 'microparticles' (EMP). In this review we examine interactions between cytokines/chemokines, activated leukocytes, adhesion molecules and activated CEC in the pathogenesis of BBB failure in MS.     

Blood-brain barrier to ammonia in humans

We have developed a method to evaluate the diffusion of ammonia across the blood-brain barrier (BBB) in normal humans, based on measures of CBF and the regional cerebral metabolic rate for ammonia, obtained by positron emission tomography. The extraction fraction for ammonia passing through the cerebral capillary bed was a reciprocal function of CBF. The product of the BBB surface area and ammonia permeability, calculated from the Renkin-Crone model, was 0.32 +/- 0.19 cm3 g-1 min-1 (+/- SD) in gray matter and 0.24 +/- 0.16 cm3 g-1 min-1 in white matter. From literature values of the expected capillary surface area ratio, a gray-to-white matter ammonia permeability ratio of 0.37:1.0 was calculated. We speculate that astrocytes may mediate this unexpected difference in permeability, and that the permeability of the BBB to ammonia may be important in the pathogenesis of hyperammonemic brain dysfunction.     

Blood-brain barrier dysfunction in Binswanger’s disease; an immunohistochemical study

Binswanger’s disease is pathologically characterized by a combination of diffuse cerebrovascular white matter lesions and lacunar infarcts in the basal ganglia and white matter. Although a blood-brain barrier (BBB) dysfunction has been implicated in the pathogenesis of these white matter (WM) lesions, few authors have addressed this problem. In the present study, we describe BBB dysfunction and its regional differences in the brains of Binswanger’s disease patients. Twelve brains from Binswanger’s disease patients (group III) were examined and compared with those from five patients with non-neurological disease (group I) and five cortical infarct patients without significant WM lesions (group II). Immunohistochemistry was performed for glial fibrillary acidic protein and vimentin as astroglial cell markers, and for immunoglobulins, complements and fibrinogen as extravasated serum protein markers. The grading scores for IgG extravasation were significantly higher in group III as compared to group I, in both the periventricular WM and the subcortical WM (P < 0.01). In group III, the scores in the periventricular WM and subcortical WM were significantly higher than in the subcortical U fibers and cerebral cortex (P < 0.01 for the periventricular WM; P < 0.001 for the subcortical WM), respectively. Clasmatodendritic astroglia, which had swollen cell bodies and large cytoplasmic vacuoles with disintegrated processes, incorporated the serum components IgG, IgM, C3d, C1q and fibrinogen, both in the periventricular WM and subcortical WM in 5 out of 12 (42%) Binswanger’s disease brains. These results indicate that WM lesions in Binswanger’s disease are accompanied by BBB dysfunction, although it remains uncertain whether BBB dysfunction is secondary to either chronic cerebral ischemia or arterial hypertension. Received: 25 April 1997 / Revised, accepted: 21 July 1997     

Leucocyte aggregation in acute cerebrovascular disease

We evaluated leucocyte aggregation in 26 patients with ischemic stroke and in 10 patients with transient ischemic attacks (TIA), previously untreated, within 24 h from the onset of symptoms. The evaluation was also performed in 30 healthy subjects matched for age and sex. Leucocyte aggregation was significantly higher in patients than in controls (p < 0.01 post hoc Tukey test). Within patients, those with stroke showed a significantly higher aggregation than those with TIA (p = 0.01 post hoc Tukey test). Moreover, stroke patients with the poorest outcome showed significantly higher values of leucocyte aggregation. These results indicate an involvement of leucocytes in cerebral ischemia and suggest that changes in their aggregability may play a role in the evolution of the disease.