Blood-brain Barrier Disturbance Research Articles

The Pathologic Cascade of Cerebrovascular Lesions in SHRSP: Is Erythrocyte Accumulation an Early Phase?

Cerebral small vessel disease (CSVD) is associated with vessel wall changes, microbleeds, blood-brain barrier (BBB) disturbances, and reduced cerebral blood flow (CBF). As spontaneously hypertensive stroke-prone rats (SHRSP) may be a valid model of some aspects of human CSVD, we aimed to identify whether those changes occur in definite temporal stages and whether there is an initial phenomenon beyond those common vascular alterations. Groups of 51 SHRSP were examined simultaneously by histologic (Hematoxylin-Eosin, IgG-Immunohistochemistry, vessel diameter measurement) and imaging methods (Magnetic Resonance Imaging, 201-Thallium-Diethyldithiocarbamate/99m-Technetium-HMPAO Single Photon Emission Computed Tomography conducted as pilot study) at different stages of age. Vascular pathology in SHRSP proceeds in definite stages, whereas an age-dependent accumulation of erythrocytes in capillaries and arterioles represents the homogeneous initial step of the disease. Erythrocyte accumulations are followed by BBB disturbances and microbleeds, both also increasing with age. Microthromboses, tissue infarctions with CBF reduction, and disturbed potassium uptake represent the final stage of vascular pathology in SHRSP. Erythrocyte accumulations--we parsimoniously interpreted as stases--without cerebral tissue damage represent the first step of vascular pathology in SHRSP. If that initial phenomenon could be identified in patients, these erythrocyte accumulations might be a promising target for implementing prophylactic and therapeutic strategies in human CSVD.

Blood-Brain Barrier Breakdown and Blood-Brain Communication in Neurological and Psychiatric Diseases

Blood-Brain Barrier Breakdown and Blood-Brain Communication in Neurological and Psychiatric Diseases

Nitric oxide production by endothelin‐1 enhances astrocytic migration via the tyrosine nitration of matrix metalloproteinase‐9

The deleterious effects of endothelin-1 (ET-1) in the central nervous system (CNS) include disturbance of water homeostasis and blood-brain barrier (BBB) integrity. In the CNS, ischemic injury elicits ET-1 release from astrocytes, behaving through G-protein coupled ET receptors. These considerations raise the question of whether ET-1 influences cellular functions of astrocytes, the major cell type that provides structural and functional support for neurons. Uncontrolled nitric oxide (NO) production has been implicated in sterile brain insults, neuroinflammation, and neurodegenerative diseases, which involve astrocyte activation and neuronal death. However, the detailed mechanisms of ET-1 action related to NO release on rat brain astrocytes (RBA-1) remain unknown. In this study, we demonstrate that exposure of astrocytes to ET-1 results in the inducible nitric oxide synthase (iNOS) up-regulation, NO production, and matrix metalloproteinase-9 (MMP-9) activation in astrocytes. The data obtained with Western blot, reverse transcription-PCR (RT-PCR), and immunofluorescent staining analyses showed that ET-1-induced iNOS expression and NO production were mediated through an ET(B)-dependent transcriptional activation. Engagement of G(i/o)--and G(q) -coupled ET(B) receptors by ET-1 led to activation of c-Src-dependent phosphoinositide 3-kinase (PI3K)/Akt and p42/p44 mitogen-activated protein kinase (MAPK) and then activated transcription factor nuclear factor-κB (NF-κB). The activated NF-κB was translocated into nucleus and thereby promoted iNOS gene transcription. Ultimately, NO production stimulated by ET-1 enhanced the migration of astrocytes through the tyrosine nitration of MMP-9. Taken together, these results suggested that in astrocytes, activation of NF-κB by ET(B)-dependent c-Src, PI3K/Akt, and p42/p44 MAPK signalings is necessary for ET-1-induced iNOS gene up-regulation.

Neurological and psychiatric manifestations of systemic lupus erythematosus and antiphospholipid syndrome

Neurological or psychiatric symptoms are present in 60% of the cases with systemic lupus erythematosus. Direct lesions of nervous system are associated with the presence of antibodies, vasculitis, thrombosis and impairments mediated by cytokines. Damages caused by injuries of other organs or those due to therapy are known as indirect causes. In the complex pathogenesis the primary cause is neuronal dysfunction mediated by autoantibodies, vasculopathia and coagulopathia. Until now, more than 20 antibodies have been identified in association with damages of the nervous system. These antibodies may impair neurons or astrocytes and may promote thrombotic processes in vessels of the brain. Activation of endothelial cells and disturbance of blood-brain barrier are also pathogenic factors. In patients with systemic lupus erythematosus the most frequent psychiatric manifestations are organic psychosyndrome, particularly deterioration of cognitive functions, and depression, while the most common neurological syndromes are epilepsy and ischemic stroke. In the pathogenesis of antiphospholipid syndrome β2-glycoprotein I plays the most important role; binding to its antibody the complex may interact with cells and modify haemostatic actions. The most frequent neurological manifestations of antiphospholipid syndrome are headache and ischemic stroke.

Effects of levetiracetam on blood-brain barrier disturbances following hyperthermia-induced seizures in rats with cortical dysplasia

Aims The mechanisms underlying the changes in blood-brain barrier (BBB) integrity and the generation of seizures in childhood associated with preexisting brain lesions like cortical dysplasia (CD) are poorly understood. We investigated the effects of levetiracetam (LEV) on BBB integrity and the survival during hyperthermic seizures in rats with CD. Main methods Pregnant rats were exposed to 145 cGy of gamma-irradiation on embryonic day 17. On postnatal day 28, hyperthermia-induced seizures were evoked in offspring with CD. To show the functional and morphological alterations in BBB integrity, quantitative analysis of sodium fluorescein (NaFlu) extravasation, immunohistochemistry and electron microscopy were performed. Key findings Seizure scores and mortality rates were decreased by LEV during hyperthermia-induced seizures in rats with CD (P < 0.01). Increased NaFlu extravasation into brain by hyperthermia-induced seizures in animals with CD was decreased by LEV (P < 0.01). While glial fibrillary acidic protein (GFAP) immunoreactivity slightly increased in brain sections of animals with CD during hyperthermia-induced seizures, LEV led to GFAP immunoreactivity comparable to that of controls. Decreased occludin immunoreactivity and expression in CD plus hyperthermia-induced seizures was increased by LEV. Opening of tight junctions and abundance of pinocytotic vesicles representing ultrastructural evidences of BBB impairment and severe perivascular edema were observed in animals with CD exposed to hyperthermia-induced seizures and LEV treatment led to the attenuation of these findings. Significance These results indicate that LEV may present a novel approach for the protection of the BBB besides its antiepileptic impact on hyperthermic seizures in the setting of CD.

NEUROBID—an EU-funded project to study the developing brain barriers

Brain diseases are one of the most prevalent groups of diseases in Europe with estimated annual costs amounting to €386 billion. Data collected by the WHO suggest that brain diseases are responsible for 35% of Europe's total disease burden. In the treatment of neurological disease, the blood brain barrier (BBB) still represents an obstacle for the delivery of drugs to the brain and thus a major challenge for the development of therapeutic regimens. Understanding the molecular basis and functioning of the BBB in health and disease, including transport mechanisms across the BBB, therefore holds significant potential for future strategies to prevent and ameliorate neurological disease.Recent research indicates that some neurological disorders have a developmental etiologic component. The major goal of the NEUROBID project is thus to understand the molecular mechanisms and function of the BBB in health and disease both in the developing brain and the adult central nervous system. With an interdisciplinary consortium from the fields of developmental neurobiology and BBB research, NEUROBID aims to (i) understand the involvement of normal and disturbed BBB function in normal and abnormal brain development and (ii) to develop novel strategies for drug delivery to the brain. Unique transport mechanisms across the BBB will be used to target potential therapeutic macromolecular and cellular agents specifically to the brain barriers and transport them into the brain. The main target disorders of NEUROBID are non-inherited neurodevelopmental disorders arising from perinatal adverse exposure, such as cerebral palsy, and classic adult neurological disorders such as multiple sclerosis and stroke.In the long term, NEUROBID hopes to pave the way for new treatment strategies and thus reduce the economic and social burden of neurological disease.

Spatial diversity of blood–brain barrier alteration and macrophage invasion in experimental autoimmune encephalomyelitis: A comparative MRI study

Inflammation plays a central role in the development of numerous disorders of the central nervous system (CNS) such as multiple sclerosis (MS). For a long time it was assumed that recruitment of macrophages into the CNS and breakdown of the blood–brain barrier (BBB) are closely linked. In the present study we challenge this concept. We used small superparamagnetic iron oxide particles (SPIO)-enhanced T2-weighted (T2-w) magnetic resonance imaging (MRI) on a routine 1.5 T MRI unit to follow macrophage infiltration in experimental autoimmune encephalomyelitis (EAE), the animal model of MS. After an initial SPIO-enhanced MRI, gadofluorine M (Gf), an experimental contrast agent which proved to be more sensitive in detecting BBB leakage than gadolinium (Gd)–DTPA (Bendszus, M., Ladewig, G., Jestaedt, L., Misselwitz, B., Solymosi, L., Toyka, K.V., Stoll, G., Gadofluorine-M enhancement allows more sensitive detection of inflammatory CNS lesions than T2-w imaging: a quantitative MRI study. Brain 2008; 1-12), was applied to the same animals followed by a second scan. Areas with SPIO-induced signal loss on T2-w MRI indicative of recent macrophage infiltration were matched with areas showing Gf enhancement as a measure of BBB disturbance. Overall 87 EAE lesions showed iron-related signal loss, while 57 lesions showed Gf enhancement. By direct comparison we could detect concomitant SPIO-induced signal loss and Gf enhancement only in a small minority of lesions. In conclusion, our findings show macrophage infiltration in the CNS during EAE in areas with a closed BBB for humoral factors. This holds true despite the use of a more sensitive MR contrast agent for BBB disruption than Gd-DTPA. Our experimental observations may have implications for disease monitoring in MS patients by MRI which guides treatment decisions.

11C-Methionin-PET in der Neuroonkologie

11 C-Methionine PET provides unique information in the diagnosis of brain tumours. In comparison to 18 F-FDG PET, due to low uptake in normal brain tissue and inflammatory cells, high contrast is obtained for the diagnosis of low-grade tumours and differentiation against inflammatory changes. When compared to MRT, one major advantage of PET with radioactive labelled amino acids is the realistic reflection of the biologically active part of the tumour. This part is often larger than the area of blood brain barrier disturbance as outlined by the enhancement of contrast media in MRT - and smaller than the tumour oedema as shown in the T2 weighted images. Hence, 11 C-Methionine PET is able to contribute substantially in planning of surgical or radiation therapy. In the evaluation of treatment results, especially the quantitative information with regard to regional extension and intensity of elevated amino acid uptake can be crucial to establish the necessity and size for re-intervention as the case may be. For clinical research, radio-labelled amino acids can be used - due to their prognostic potential - as a tool to select biologically comparable tumours for a prospective study. From the patients perspective, 11 C-Methionine PET is a simple, non-invasive procedure, with a relatively low radiation exposure.

Conditional deletion of β1‐integrin in astroglia causes partial reactive gliosis

Astrocytes play many pivotal roles in the adult brain, including their reaction to injury. A hallmark of astrocytes is the contact of their endfeet with the basement membrane surrounding blood vessels, but still relatively little is known about the signaling mediated at the contact site. Here, we examine the role of beta1-integrin at this interface by its conditional deletion using different Cre lines. Thereby, the protein was reduced only at postnatal stages either in both glia and neurons or specifically only in neurons. Strikingly, only the former resulted in reactive gliosis, with the hallmarks of reactive astrocytes comprising astrocyte hypertrophy and up-regulation of the intermediate filaments GFAP and vimentin as well as pericellular components, such as Tenascin-C and the DSD-1 proteoglycan. In addition, we also observed to a certain degree a non-cell autonomous activation of microglial cells after conditional beta1-integrin deletion. However, these reactive astrocytes did not divide, suggesting that the loss of beta1-integrin-mediated signaling is not sufficient to elicit proliferation of these cells as observed after brain injury. Interestingly, this partial reactive gliosis appeared in the absence of cell death and blood brain barrier disturbances. As these effects did not appear after neuron-specific deletion of beta1-integrin, we conclude that beta1-integrin-mediated signaling in astrocytes is required to promote their acquisition of a mature, nonreactive state. Alterations in beta1-integrin-mediated signaling may hence be implicated in eliciting specific aspects of reactive gliosis after injury.

Elevated B-cell activating factor BAFF, but not APRIL, correlates with CSF cerebellar autoantibodies in pediatric opsoclonus-myoclonus syndrome

Childhood opsoclonus-myoclonus syndrome (OMS) occurs idiopathic or, in association with a neuroblastoma, as a paraneoplastic syndrome. Since autoantibodies were identified in some patients, an autoimmune pathogenesis has been suspected. While the newly discovered B-cell activating factors BAFF and APRIL are involved in systemic autoimmune diseases, their association with neuroimmunological diseases is hardly understood. We here investigated the BAFF and APRIL levels in serum and cerebrospinal fluid (CSF) of OMS patients and their correlation with surface-binding autoantibodies. BAFF and APRIL were both determined by ELISA, and autoantibodies to cerebellar granular neurons (CGN) have been investigated by flow cytometry in 17 OMS patients, 16 neuroblastoma (NB) patients, 13 controls and 11 children with inflammatory neurological diseases (IND). BAFF, but no APRIL, was elevated in the CSF of OMS children and IND children. However, in contrast to IND patients, OMS patients did not have a blood–brain-barrier disturbance, indicating that BAFF was produced intrathecally in OMS patients, but not in IND patients. CSF BAFF levels showed a correlation with CSF CGN autoantibodies ( r 2 = 0.58, p < 0.05). These data indicate that an activated B-cell system in the cerebrospinal fluid is involved in the pathogenesis of OMS, and BAFF may be a candidate parameter for the activation of B-cell immune system.

Blood-brain barrier disturbance in patients with Alzheimer's disease is related to vascular factors

To investigate the blood-brain barrier (BBB function), serum and cerebrospinal fluid (CSF) from 118 patients with Alzheimer's disease (AD) and 50 healthy controls was analyzed with regard to albumin concentrations. For the AD group, clinical vascular factors were also recorded. The CSF/serum albumin ratio was used as a measure of BBB function. When compared with controls, the AD group showed a higher mean albumin ratio, indicating a decline in BBB function. However, no significant reduction in BBB function was found in AD patients without vascular factors. These findings support the hypothesis that BBB disturbance is related to vascular factors, coexisting with AD. In the control group, no significant correlation between age and albumin ratio was found, which suggests that aging per se is not primarily associated with a decline in BBB function. The present study provides evidence in favour of the conclusion that a reduced BBB function is related neither to AD nor to aging, but to clinical vascular factors.

Acute peripheral facial palsy: CSF findings and etiology

CSF and serum were examined in acute and convalescence phase from 56 patients with acute idiopathic peripheral facial palsy. CSF protein analysis, viral and borrelia serology were performed. Borrelia infection was found in 9/56 cases and was often associated with inflammatory CSF findings. One patient each had serological evidence for a recent or ongoing infection with herpes simplex, varicella zoster, adeno, influenza B, echo and Epstein-Barr virus, but none had specific intrathecal antibody synthesis; 11 patients had a serological pattern compatible with a reactivated Epstein-Barr virus infection. Eleven patients displayed mononuclear CSF pleocytosis. Four of them had a borrelia infection. A disturbed blood-brain barrier was observed in 19 patients. Intrathecal immunoglobulin synthesis as indicated by elevated IgM-indices was found in 16 patients and by IgG indices in three. Nine patients had oligoclonal IgG bands in serum and CSF, three exclusively in CSF. It is concluded that patients with facial palsy often have inflammatory CSF findings, indicating a generalised central nervous system affection, and not only a mononeuritis. The importance of viral infections in the pathogenesis is still obscure. Borrelia is the most common infectious cause of facial palsy.

Liquor:serum quotients of IgG and albumin in patients with meningism, meningitis and multiple sclerosis.

Liquor:serum quotients of IgG and albumin in patients with meningism, meningitis and multiple sclerosis have been studied. Abnormal quotients indicative of disturbed blood-brain barrier function and/or intrathecal IgG synthesis were found in various proportions of all 3 groups of patients. In some patients with aseptic meningitis and meningism, the abnormal quotients were comparable with those found in patients with multiple sclerosis. The reason for this is unknown. An unspecific reaction to febrile illness may be involved. As a consequence, the findings of abnormal liquor:serum quotients of IgG and albumin should be evaluated with great caution in patients with recent or present febrile illness.

Transient Widespread Blood—Brain Barrier Alterations after Cerebral Photothrombosis as Revealed by Gadofluorine M-Enhanced Magnetic Resonance Imaging

Magnetic resonance imaging (MRI) is a powerful tool to assess brain lesions, but currently available contrast agents are limited in the assessment of cellular and functional alterations. By use of the novel MRI contrast agent gadofluorine M (Gf) we report on imaging of transient and widespread changes of blood-brain barrier (BBB) properties as a consequence of focal photothrombotic brain lesions in rats. After i.v. application, Gf led to bright contrast in the lesions, but also the entire ipsilateral cortex on T1-weighted MRI. In contrast, enhancement after application of gadolinium diethylenetriamine-pentaacetic acid (Gd-DTPA), a common clinical indicator of BBB leakage was restricted to the lesions. Remote Gf enhancement was restricted in time to the first 24 h after photothrombosis and corresponded to a transient breakdown of the BBB as revealed by extravasation of the dye Evans blue. In conclusion, our study shows that Gf can visualize subtle disturbances of the BBB in three dimensions not detectable by Gd-DTPA. Upon entry into the central nervous system Gf most likely is locally trapped by interactions with extracellular matrix proteins. The unique properties of Gf hold promise as a more sensitive contrast agent for monitoring BBB disturbances in neurologic disorders, which appear more widespread than anticipated previously.

A new method for determining blood–brain barrier integrity based on intracardiac perfusion of an Evans Blue–Hoechst cocktail

A new method for determining brain regions with blood–brain barrier (BBB) alterations is described. In this method, mice were perfused intracardially with Evans Blue (EB) and Hoechst tracers added in a standard formaldehyde fixative solution. This cocktail method was tested after a localized cryolesion induced in the brain had produced an edematous brain region with disrupted BBB in the animals. The results were then compared with the intravenous and intraperitoneal administration of the tracers prior to intracardiac perfusion. When using the cocktail method, red EB fluorescence locates the cryoinjured brain region while the Hoechst tracer stains the nuclei in that same region. EB and Hoechst fluorescence can also be observed in the choroid plexus and circumventricular organs, where there is no functional BBB. The cocktail gives more intense EB staining in zones of disrupted BBB than that given by traditional methods which use this tracer. The Hoechst tracer is also more useful when administered in the cocktail, since when administrated intravenously it stains all the brain nuclei. The cocktail method permits the immunostaining of brain sections, enabling researchers to characterize and analyze structural and cellular changes in regions where BBB disturbances are present. Thus, immunohistochemistry has been used here to determine the nature of intense EB fluorescent cells that appear in the perilesional rim, which were identified here as neuronal cells.

The relation of cerebrospinal fluid and plasma glycine levels in propionic acidaemia, a ‘ketotic hyperglycinaemia’

The characteristic elevation of plasma glycine concentrations observed in propionic acidaemia (PA) and other 'ketotic hyperglycinaemias' has been attributed to secondary inhibition of the hepatic glycine cleavage system (GCS) by accumulating CoA derivatives of branched-chain amino acid metabolites. In nonketotic hyperglycinaemia (NKH), cerebrospinal fluid (CSF) and plasma glycine levels and their ratio are increased due to primary deficiency of central nervous system (CNS) as well as hepatic GCS. Whether the GCS in the CNS is also inhibited in PA is unclear, as there are scant data available on CSF glycine levels in this disorder. We studied the relation of CSF and plasma glycine levels in 6 paired samples from 4 PA patients, including one PA patient with bacterial meningitis who underwent ventriculoperitoneal shunting and multiple CSF analyses (n = 26). In contrast to the CSF glycine levels which were generally elevated in all four PA patients, the CSF/plasma glycine concentration ratios in paired samples were normal (0.016-0.029), with the exception of a single sample (0.132) with extremely high CSF protein concentration (2010 mg/L) during the course of meningitis indicating a disturbed blood-brain barrier. This finding of normal CSF/plasma glycine ratio in PA suggests that the observed elevations of CSF glycine levels are a reflection of the concurrent hyperglycinaemia resulting from secondary inhibition of hepatic GCS, but that brain GCS is not affected, in contrast to the situation in NKH. The neurological sequelae in PA are therefore unlikely to be related to disturbed glycine metabolism.

Brain infarct caused by trauma-induced intracranial pressure elevation. Clinical and computerized x-ray tomography findings

Of 327 patients admitted to hospital with signs of trauma-induced raised intracranial pressure 41 had infarcts demonstrated by computed tomography (CT). The most common site was the area supplied by the posterior cerebral artery, usually ipsilaterally. Experience so far indicates that the infarcts are most commonly caused by transient, dynamically produced occlusion of the artery, more rarely by venous congestion, resulting from the raised intracranial pressure. Comparison of the morbidity and mortality rate of patients with and without infarction after trauma with signs of raised intracranial pressure indicates that an infarct clearly worsens prognosis. Infarcts can be easily distinguished from contusional foci by CT, although both have decreased density, because the former spread within the supply area of a vessel and, similarly to embolic or arteriosclerotic infarcts, produce contrast enhancement after administration of contrast media as an expression of a disturbed blood-brain barrier.

Contribution of Poly(ADP-Ribose) Polymerase to Postischemic Blood—Brain Barrier Damage in Rats

The nuclear enzyme poly(ADP-ribose) polymerase (PARP) is activated by oxidative stress and plays a significant role in postischemic brain injury. We assessed the contribution of PARP activation to the blood-brain barrier (BBB) disruption and edema formation after ischemia-reperfusion. In male Wistar rats, global cerebral ischemia was achieved by occluding the carotid arteries and lowering arterial blood pressure for 20 mins. The animals were treated with saline or with the PARP inhibitor N-(6-oxo-5,6-dihydrophenanthridin-2-yl)-N, N-dimethylacetamide.HCl (PJ34); (10 mg/kg, i.v.) before ischemia. After 40 mins, 24, and 48 h of reperfusion, the permeability of the cortical BBB was determined after Evans Blue (EB) and Na-fluorescein (NaF) administration. The water content of the brain was also measured. The permeability of the BBB for EB increased after ischemia-reperfusion compared with the nonischemic animals after 24 and 48 h reperfusion but PARP inhibition attenuated this increase at 48 h (nonischemic: 170+/-9, saline: 760+/-95, PJ34: 472+/-61 ng/mg tissue). The extravasation of NaF showed similar changes and PJ34 post-treatment attenuated the permeability increase even at 24 h. PARP inhibition decreased the brain edema seen at 48 h. Because PARP has proinflammatory properties, the neutrophil infiltration of the cortex was determined, which showed lower values after PJ34 treatment. Furthermore, PJ34 treatment decreased the loss of the tight junction protein occludin at 24 and 48 h. The inhibition of PARP activity accompanied by reduced post-ischemic BBB disturbance and decreased edema formation suggests a significant role of this enzyme in the development of cerebral vascular malfunction

Linezolid-Induced Posterior Reversible Leukoencephalopathy Syndrome

To describe a 71-year-old woman who developed clinical and neuroradiological features of posterior reversible leukoencephalopathy syndrome with a compromised blood-brain barrier after 5 days of intravenous linezolid therapy for an infected hip prosthesis. Case report. Academic research. Posterior reversible leukoencephalopathy syndrome was documented using serial cranial magnetic resonance imaging, and the blood-brain barrier disturbance was demonstrated by contrast enhancement of a lesion and by cerebrospinal fluid analysis. Other causes of posterior reversible leukoencephalopathy syndrome, such as renal failure, severe hypertension, inflammatory syndromes, and infectious diseases of the central nervous system, were excluded during hospitalization. After discontinuation of linezolid therapy, the patient's condition improved rapidly. To our knowledge, this is the first report of likely linezolid-induced posterior reversible leukoencephalopathy syndrome with an altered blood-brain barrier after short-term intravenous therapy.

Role of Ischemic Blood-Brain Barrier on Amyloid Plaques Development in Alzheimers Disease Brain

This review demonstrated that ischemic brain injury induces chronic changes in blood-brain barrier in the gray and white matter. This insufficiency of blood-brain barrier may allow entry of uncellular blood components such as different fragments of amyloid precursor protein and cellular blood components like leukocytes and platelets into the brain parenchyma. These blood components may have chronic harmful effects on the ischemic neuronal cells, axons and myelin and can intensify and finish the neuropathology in ischemic brain parenchyma. Pathological accumulation of different toxic fragments of amyloid precursor protein in extracellular space and myelinated axons appears after ischemic blood-brain barrier injury and seem to be concomitant with, but independent of neuronal ischemic cytoplasmic injury. It seems that ischemic blood-brain barrier disturbances may play an important, both direct and indirect role in the pathogenesis of extra- and intracellular space in gray and white matter lesions following ischemic episode. This neuropathology appears to have similar character and distribution as in sporadic Alzheimer's disease. This review presented chronic micro-blood-brain barrier openings in ischemic gray and white matter lesions that probably would act as seeds of future Alzheimer's amyloid plaques.