ABSTRACT
Following an intraventricular hemorrhage (IVH), red blood cell lysis and hemoglobin (Hb) oxidation with the release of heme can cause sterile neuroinflammation. In this study, we measured Hb derivates and cellular adhesion molecules ICAM-1 and VCAM-1 with cell-free miRNAs in cerebrospinal fluid (CSF) samples obtained from Grade-III and Grade-IV preterm IVH infants (IVH-III and IVH-IV, respectively) at multiple time points between days 0-60 after the onset of IVH. Furthermore, human choroid plexus epithelial cells (HCPEpiCs) were incubated with IVH and non-IVH CSF (10 v/v %) for 24 h in vitro to investigate the IVH-induced inflammatory response that was investigated via: (i) HMOX1, IL8, VCAM1, and ICAM1 mRNAs as well as miR-155, miR-223, and miR-181b levels by RT-qPCR; (ii) nuclear translocation of the NF-κB p65 subunit by fluorescence microscopy; and (iii) reactive oxygen species (ROS) measurement. We found a time-dependent alteration of heme, IL-8, and adhesion molecules which revealed a prolonged elevation in IVH-IV vs. IVH-III with higher miR-155 and miR-181b expression at days 41-60. Exposure of HCPEpiCs to IVH CSF samples induced HMOX1, IL8, and ICAM1 mRNA levels along with increased ROS production via the NF-κB pathway activation but without cell death, as confirmed by the cell viability assay. Additionally, the enhanced intracellular miR-155 level was accompanied by lower miR-223 and miR-181b expression in HCPEpiCs after CSF treatment. Overall, choroid plexus epithelial cells exhibit an abnormal cell phenotype after interaction with pro-inflammatory CSF of IVH origin which may contribute to the development of later clinical complications in preterm IVH.
Subject(s)
Cerebral Hemorrhage/pathology , Choroid Plexus/metabolism , Systemic Inflammatory Response Syndrome/pathology , C-Reactive Protein/cerebrospinal fluid , C-Reactive Protein/metabolism , Case-Control Studies , Cerebral Hemorrhage/complications , Cerebral Hemorrhage/congenital , Cerebral Hemorrhage/metabolism , Choroid Plexus/pathology , Cohort Studies , Cytokines/cerebrospinal fluid , Cytokines/metabolism , Epithelial Cells/metabolism , Epithelial Cells/pathology , Female , Heme/metabolism , Hemoglobins/metabolism , Humans , Hungary , Infant, Newborn , Infant, Premature , Intercellular Adhesion Molecule-1/cerebrospinal fluid , Intercellular Adhesion Molecule-1/metabolism , Male , Systemic Inflammatory Response Syndrome/congenital , Systemic Inflammatory Response Syndrome/etiology , Systemic Inflammatory Response Syndrome/metabolism , Vascular Cell Adhesion Molecule-1/cerebrospinal fluid , Vascular Cell Adhesion Molecule-1/metabolismABSTRACT
OBJECTIVE: Our objective is to explore whether blood-cerebrospinal fluid (CSF) barrier biomarkers differ in episodic migraine (EM) or chronic migraine (CM) from controls. BACKGROUND: Reports of blood-brain barrier and blood-cerebrospinal fluid barrier (BCSFB) disruption in migraine vary. Our hypothesis is that investigation of biomarkers associated with blood, CSF, brain, cell adhesion, and inflammation will help elucidate migraine pathophysiology. METHODS: We recruited 14 control volunteers without headache disorders and 42 individuals with EM or CM as classified using the International Classification of Headache Disorders, 3rd edition, criteria in a cross-sectional study located at our Pasadena and Stanford headache research centers in California. Blood and lumbar CSF samples were collected once from those diagnosed with CM or those with EM during two states: during a typical migraine, before rescue therapy, with at least 6/10 level of pain (ictal); and when migraine free for at least 48 h (interictal). The average number of headaches per month over the previous year was estimated by those with EM; this enabled comparison of biomarker changes between controls and three headache frequency groups: <2 per month, 2-14 per month, and CM. Blood and CSF biomarkers were determined using antibody-based methods. RESULTS: Antimigraine medication was only taken by the EM and CM groups. Compared to controls, the migraine group had significantly higher mean CSF-blood quotients of albumin (Qalb : mean ± standard deviation (SD): 5.6 ± 2.3 vs. 4.1 ± 1.9) and fibrinogen (Qfib mean ± SD: 1615 ± 99.0 vs. 86.1 ± 55.0). Mean CSF but not plasma soluble vascular cell adhesion molecule-1 (sVCAM-1) levels were significantly higher in those with more frequent migraine: (4.5 ng/mL ± 1.1 in those with <2 headache days a month; 5.5 ± 1.9 with 2-14 days a month; and 7.1 ± 2.9 in CM), while the Qfib ratio was inversely related to headache frequency. We did not find any difference in individuals with EM or CM from controls for CSF cell count, total protein, matrix metalloproteinase-9, soluble platelet-derived growth factor receptor ß, tumor necrosis factor-alpha, interferon-gamma, interleukin (IL)-6, IL-8, IL-10, or C-reactive protein. CONCLUSIONS: The higher Qalb and Qfib ratios may indicate that the transport of these blood-derived proteins is disturbed at the BCSFB in persons with migraine. These changes most likely occur at the choroid plexus epithelium, as there are no signs of typical endothelial barrier disruption. The most striking finding in this hypothesis-generating study of migraine pathophysiology is that sVCAM-1 levels in CSF may be a biomarker of higher frequency of migraine and CM. An effect from migraine medications cannot be excluded, but there is no known mechanism to suggest they have a role in altering the CSF biomarkers.
Subject(s)
Blood-Brain Barrier , Fibrinogen/cerebrospinal fluid , Inflammation , Migraine Disorders , Vascular Cell Adhesion Molecule-1/cerebrospinal fluid , Adult , Biomarkers/blood , Biomarkers/cerebrospinal fluid , Cross-Sectional Studies , Female , Humans , Inflammation/blood , Inflammation/cerebrospinal fluid , Inflammation/immunology , Male , Middle Aged , Migraine Disorders/blood , Migraine Disorders/cerebrospinal fluid , Migraine Disorders/physiopathologyABSTRACT
Intraventricular hemorrhage (IVH) is a frequent complication of prematurity that is associated with high neonatal mortality and morbidity. IVH is accompanied by red blood cell (RBC) lysis, hemoglobin (Hb) oxidation, and sterile inflammation. Here we investigated whether extracellular Hb, metHb, ferrylHb, and heme contribute to the inflammatory response after IVH. We collected cerebrospinal fluid (CSF) (n = 20) from premature infants with grade III IVH at different time points after the onset of IVH. Levels of Hb, metHb, total heme, and free heme were the highest in CSF samples obtained between days 0 and 20 after the onset of IVH and were mostly non-detectable in CSF collected between days 41 and 60 of post-IVH. Besides Hb monomers, we detected cross-linked Hb dimers and tetramers in post-IVH CSF samples obtained in days 0-20 and 21-40, but only Hb tetramers were present in CSF samples obtained after 41-60 days. Vascular cell adhesion molecule-1 (VCAM-1) and interleukin-8 (IL-8) levels were higher in CSF samples obtained between days 0 and 20 than in CSF collected between days 41 and 60 of post-IVH. Concentrations of VCAM-1, intercellular adhesion molecule-1 (ICAM-1), and IL-8 strongly correlated with total heme levels in CSF. Applying the identified heme sources on human brain microvascular endothelial cells revealed that Hb oxidation products and free heme contribute to the inflammatory response. We concluded that RBC lysis, Hb oxidation, and heme release are important components of the inflammatory response in IVH. Pharmacological interventions targeting cell-free Hb, Hb oxidation products, and free heme could have potential to limit the neuroinflammatory response following IVH.
Subject(s)
Brain/pathology , Cerebral Intraventricular Hemorrhage/metabolism , Endothelial Cells/metabolism , Erythrocytes/pathology , Heme/cerebrospinal fluid , Hemoglobins/cerebrospinal fluid , Inflammation/metabolism , Premature Birth/metabolism , Female , Humans , Infant, Newborn , Infant, Premature , Intercellular Adhesion Molecule-1/cerebrospinal fluid , Interleukin-8/cerebrospinal fluid , Male , Neurogenic Inflammation , Oxidation-Reduction , Premature Birth/immunology , Vascular Cell Adhesion Molecule-1/cerebrospinal fluidABSTRACT
BACKGROUND: Cerebrovascular diseases play an important role in dementia. Air pollution is associated with cardiovascular disease, with growing links to neurodegeneration. Prior studies demonstrate associations between fine particulate matter (PM2.5) and biomarkers of endothelial injury in the blood; however, no studies have evaluated these biomarkers in cerebrospinal fluid (CSF). OBJECTIVE: We evaluate associations between short-term and long-term PM2.5 exposure with CSF vascular cell adhesion molecule-1 (VCAM-1) and e-selectin in cognitively normal and mild cognitive impairment (MCI)/Alzheimer's disease (AD) individuals. METHODS: We collected CSF from 133 community volunteers at VA Puget Sound between 2001-2012. We assigned short-term PM2.5 from central monitors and long-term PM2.5 based on annual average exposure predictions linked to participant addresses. We performed analyses stratified by cognitive status and adjusted for key covariates with tiered models. Our primary exposure windows for the short-term and long-term analyses were 7-day and 1-year averages, respectively. RESULTS: Among cognitively normal individuals, a 5 µg/m3 increase in 7-day and 1-year average PM2.5 was associated with elevated VCAM-1 (7-day: 35.4 (9.7, 61.1) ng/ml; 1-year: 51.8 (6.5, 97.1) ng/ml). A 5 µg/m3 increase in 1-year average PM2.5, but not 7-day average, was associated with elevated e-selectin (53.3 (11.0, 95.5) pg/ml). We found no consistent associations among MCI/AD individuals. CONCLUSIONS: We report associations between short-term and long term PM2.5 and CSF biomarkers of vascular damage in cognitively normal adults. These results are aligned with prior research linking PM2.5 to vascular damage in other biofluids as well as emerging evidence of the role of PM2.5 in neurodegeneration.
Subject(s)
Air Pollutants/adverse effects , Biomarkers/cerebrospinal fluid , Particulate Matter/adverse effects , Vascular System Injuries/cerebrospinal fluid , Vascular System Injuries/psychology , Aged , Aged, 80 and over , Air Pollution/adverse effects , Alzheimer Disease/cerebrospinal fluid , Cognition , Cohort Studies , E-Selectin/analysis , Environmental Exposure , Female , Humans , Male , Middle Aged , Particle Size , Vascular Cell Adhesion Molecule-1/cerebrospinal fluidABSTRACT
OBJECTIVE: To measure CSF levels of biomarkers reflecting microglia and astrocytes activation, neuroinflammation, and cerebrovascular changes and study their associations with the core biomarkers of Alzheimer disease (AD) pathology (ß-amyloid [Aß] and tau), structural imaging correlates, and clinical disease progression over time. METHODS: The study included cognitively unimpaired elderly (n = 508), patients with mild cognitive impairment (MCI, n = 256), and patients with AD dementia (n = 57) from the longitudinal Swedish BioFINDER cohort. CSF samples were analyzed for YKL-40, interleukin (IL)-6, IL-7, IL-8, IL-15, IP-10, monocyte chemoattractant protein 1, intercellular adhesion molecule 1 (ICAM-1), vascular adhesion molecule 1 (VCAM-1), placental growth factor, and fms-related tyrosine kinase 1 (Flt-1). MRI data were available from 677 study participants. Longitudinal clinical assessments were conducted in control individuals and patients with MCI (mean follow-up 3 years, range 1-6 years). RESULTS: CSF levels of YKL-40, ICAM-1, VCAM-1, IL-15, and Flt-1 were increased during the preclinical, prodromal, and dementia stages of AD. High levels of these biomarkers were associated with increased CSF levels of total tau, with the associations, especially for YKL-40, being stronger in Aß-positive individuals. The results were similar for associations between phosphorylated tau and YKL-40, ICAM-1, and VCAM-1. High levels of the biomarkers were also associated with cortical thinning (primarily in the precuneus and superior parietal regions) and with subsequent cognitive deterioration in patients without dementia as measured with Mini-Mental State Examination (YKL-40) and Clinical Dementia Rating Sum of Boxes (YKL-40, ICAM-1, VCAM-1 and IL-15). Finally, higher levels of CSF YKL-40, ICAM-1, and Flt-1 increased risk of development of AD dementia in patients without dementia. CONCLUSIONS: Neuroinflammation and cerebrovascular dysfunction are early events occurring already at presymptomatic stages of AD and contribute to disease progression.
Subject(s)
Biomarkers/cerebrospinal fluid , Cerebrovascular Disorders/cerebrospinal fluid , Cerebrovascular Disorders/etiology , Cognitive Dysfunction/complications , Encephalitis/cerebrospinal fluid , Encephalitis/etiology , Aged , Aged, 80 and over , Amyloid beta-Peptides/cerebrospinal fluid , Apolipoprotein E4/genetics , Cerebrovascular Disorders/diagnostic imaging , Chitinase-3-Like Protein 1/cerebrospinal fluid , Cognitive Dysfunction/diagnostic imaging , Cytokines/cerebrospinal fluid , Encephalitis/diagnostic imaging , Female , Humans , Intercellular Adhesion Molecule-1/cerebrospinal fluid , Magnetic Resonance Imaging , Male , Middle Aged , Placenta Growth Factor/cerebrospinal fluid , Vascular Cell Adhesion Molecule-1/cerebrospinal fluid , Vascular Endothelial Growth Factor Receptor-1/cerebrospinal fluid , tau Proteins/cerebrospinal fluidABSTRACT
BACKGROUND: This study sought to evaluate gender and APOE genotype-related differences in the concentrations of cerebrospinal fluid (CSF) biomarkers for Alzheimer's disease (AD) and cerebrovascular injury across the life span of cognitively normal adults. METHODS: CSF amyloid beta1-42 (Aß42), phospho-tau-181 (p-tau181), and total tau were measured in 331 participants who were between the ages of 21 and 100. CSF E-selectin and vascular cell adhesion protein 1 (VCAM1) were measured in 249 participants who were between the ages of 50 and 100. RESULTS: CSF total tau and p-tau181 increased with age over the adult life span (p < 0.01) with no gender differences in those increases. CSF Aß42 concentration varied according to age, gender, and APOE genotype (interaction of age × gender × Îµ4, p = 0.047). CSF VCAM1, but not E-selectin, increased with age (p < 0.01), but both were elevated in men compared to women (p < 0.01). CONCLUSIONS: Female APOE-ε4 carriers appear at higher risk for AD after age 50. In contrast, men may experience a relatively higher rate of cerebrovascular injury in middle and early old age.
Subject(s)
Alzheimer Disease/cerebrospinal fluid , Alzheimer Disease/genetics , Biomarkers/cerebrospinal fluid , Sex Characteristics , Vascular Diseases/cerebrospinal fluid , Vascular Diseases/genetics , Adult , Aged , Aged, 80 and over , Aging/cerebrospinal fluid , Aging/genetics , Amyloid beta-Peptides/cerebrospinal fluid , Apolipoprotein E4/genetics , E-Selectin/metabolism , Female , Genotype , Humans , Male , Middle Aged , Peptide Fragments/cerebrospinal fluid , Vascular Cell Adhesion Molecule-1/cerebrospinal fluid , Young Adult , tau Proteins/cerebrospinal fluidABSTRACT
The choroid plexus epithelium is a secretory epithelium par excellence. However, this is perhaps not the most prominent reason for the massive interest in this modest-sized tissue residing inside the brain ventricles. Most likely, the dominant reason for extensive studies of the choroid plexus is the identification of this epithelium as the source of the majority of intraventricular cerebrospinal fluid. This finding has direct relevance for studies of diseases and conditions with deranged central fluid volume or ionic balance. While the concept is supported by the vast majority of the literature, the implication of the choroid plexus in secretion of the cerebrospinal fluid was recently challenged once again. Three newer and promising areas of current choroid plexus-related investigations are as follows: 1) the choroid plexus epithelium as the source of mediators necessary for central nervous system development, 2) the choroid plexus as a route for microorganisms and immune cells into the central nervous system, and 3) the choroid plexus as a potential route for drug delivery into the central nervous system, bypassing the blood-brain barrier. Thus, the purpose of this review is to highlight current active areas of research in the choroid plexus physiology and a few matters of continuous controversy.
Subject(s)
Cerebrospinal Fluid/physiology , Choroid Plexus/physiology , Epithelium/physiology , Ion Channels/metabolism , Signal Transduction/physiology , Animals , Biological Transport , Blood-Brain Barrier , Choroid Plexus/ultrastructure , Gene Expression , Humans , Hydrogen-Ion Concentration , Intercellular Adhesion Molecule-1/cerebrospinal fluid , Intercellular Adhesion Molecule-1/genetics , Ion Channels/antagonists & inhibitors , Ion Channels/genetics , Membrane Transport Modulators/pharmacology , Vascular Cell Adhesion Molecule-1/cerebrospinal fluid , Vascular Cell Adhesion Molecule-1/geneticsABSTRACT
OBJECTIVE: Hippocampal sclerosis of aging (HS-Aging) is a common cause of dementia in older adults. We tested the variability in cerebrospinal fluid (CSF) proteins associated with previously identified HS-Aging risk single nucleotide polymorphisms (SNPs). METHODS: Alzheimer's Disease Neuroimaging Initiative cohort (ADNI; n=237) data, combining both multiplexed proteomics CSF and genotype data, were used to assess the association between CSF analytes and risk SNPs in four genes (SNPs): GRN (rs5848), TMEM106B (rs1990622), ABCC9 (rs704180), and KCNMB2 (rs9637454). For controls, non-HS-Aging SNPs in APOE (rs429358/rs7412) and MAPT (rs8070723) were also analyzed against Aß1-42 and total tau CSF analytes. RESULTS: The GRN risk SNP (rs5848) status correlated with variation in CSF proteins, with the risk allele (T) associated with increased levels of AXL Receptor Tyrosine Kinase (AXL), TNF-Related Apoptosis-Inducing Ligand Receptor 3 (TRAIL-R3), Vascular Cell Adhesion Molecule-1 (VCAM-1) and clusterin (CLU) (all p<0.05 after Bonferroni correction). The TRAIL-R3 correlation was significant in meta-analysis with an additional dataset (p=5.05×10-5). Further, the rs5848 SNP status was associated with increased CSF tau protein - a marker of neurodegeneration (p=0.015). These data are remarkable since this GRN SNP has been found to be a risk factor for multiple types of dementia-related brain pathologies.
Subject(s)
Aging/cerebrospinal fluid , Biomarkers/cerebrospinal fluid , Dementia/genetics , Hippocampus/pathology , Intercellular Signaling Peptides and Proteins/genetics , Aged , Aged, 80 and over , Amyloid beta-Peptides/cerebrospinal fluid , Clusterin/cerebrospinal fluid , Databases, Factual , Dementia/cerebrospinal fluid , Female , GPI-Linked Proteins/cerebrospinal fluid , Genetic Predisposition to Disease , Genome-Wide Association Study , Humans , Male , Polymorphism, Single Nucleotide , Progranulins , Receptors, Tumor Necrosis Factor, Member 10c/cerebrospinal fluid , Regression Analysis , Risk Factors , Sclerosis , Vascular Cell Adhesion Molecule-1/cerebrospinal fluid , tau Proteins/cerebrospinal fluidABSTRACT
Metastasis to the central nervous system (CNS) is the primary obstacle in leukemia treatment. Matrix metalloproteinase-9 (MMP-9), chemokine ligand-2 (CCL2) and soluble vascular adhesion molecule-1 (sVCAM-1) play crucial roles in tumor cell adhesion, motivation and survival, but their roles in leukemia CNS metastasis remain to be elucidated. We investigated the prognostic significance of serum and cerebrospinal fluid (CSF) MMP-9, CCL2 and sVCAM-1 in leukemia patients to explore their potential as predictive biomarkers of the development of CNS leukemia (CNSL). MMP-9, CCL2 and sVCAM-1 were measured in paired CSF and serum samples collecting from 33 leukemia patients with or without CNS metastasis. Other risk factors related to CNSL prognosis were also analyzed. sVCAM-1Serum and CCL2Serum/CSF were significantly higher in the CNSL group than in the non-CNSL group and the controls (p < 0.05). MMP-9Serum was insignificantly lower in the CNSL group than in the non-CNSL group and the controls (p > 0.05). No differences were found for the sVCAM-1Serum, CCL2Serum, and MMP-9Serum levels between non-CNSL patients and controls (p > 0.05). MMP-9CSF was significantly higher in the CNSL group than both the non-CNSL and the control groups (p < 0.05). The indexes of sVCAM-1, CCL2, and MMP-9 in the CNSL group were lower than in the controls (p < 0.05). Positive correlations were determined between the MMP-9CSF and the ALBCSF/BBB value/WBCCSF, between sVCAM-1Serum and the WBCCSF/BBB value. Negative correlations existed between MMP-9Serum and the ALBCSF/BBB value/WBCCSF, and between the CCL2 index and ALBCSF. sVCAM-1Serum was positively associated with event-free survival (EFS), and patients with higher levels of ALBCSF, MMP-9CSF/Serum, CCL2CSF/Serum, and sVCAM-1CSF/Serum had shorter EFS. MMP-9CSF, CCL2CSF and sVCAM-1CSF are the first three principal components analyzed by cluster and principal component analysis. Our data suggest that MMP-9, CCL2 and sVCAM-1 in the CSF may be more potent than serum in predicting the possibility of leukemia metastatic CNS and the outcome of CNSL patients.
Subject(s)
Central Nervous System Neoplasms/blood , Central Nervous System Neoplasms/cerebrospinal fluid , Leukemia/pathology , Adolescent , Adult , Biomarkers, Tumor/blood , Biomarkers, Tumor/cerebrospinal fluid , Central Nervous System Neoplasms/diagnosis , Central Nervous System Neoplasms/secondary , Chemokine CCL2/blood , Chemokine CCL2/cerebrospinal fluid , Female , Humans , Kaplan-Meier Estimate , Male , Matrix Metalloproteinase 9/blood , Matrix Metalloproteinase 9/cerebrospinal fluid , Principal Component Analysis , Prognosis , ROC Curve , Risk Factors , Sensitivity and Specificity , Vascular Cell Adhesion Molecule-1/blood , Vascular Cell Adhesion Molecule-1/cerebrospinal fluid , Young AdultABSTRACT
Mounting evidence supports the involvement of brain inflammation and the associated blood-brain barrier damage from which spontaneous and recurrent seizures originate. Detection of the soluble form of adhesion molecules (AM) has also been proven to predict outcomes in central nervous system (CNS) disorders. A recent study has shown that expression of AM in brain vessels was upregulated 24 h after kainic acid (KA) induced seizures. The aim of the present study was to investigate soluble AM levels in the cerebrospinal fluid (CSF) and serum of epilepsy patients. Paired CSF and serum samples were analyzed by sandwich enzyme-linked immunosorbent assay (ELISA) to determine the concentrations of soluble vascular cell adhesion molecule-1 (sVCAM-1) and soluble intercellular adhesion molecule-1 (sICAM-1). Increased serum concentrations of sICAM-1 were present in epileptic patients (41 localization-related of unknown etiology, 19 idiopathic generalized). Serum sICAM-1 level in drug-refractory epilepsy was elevated as compared to new diagnosis epilepsy and drug-responsive epilepsy. CSF sVCAM-1 and serum sVCAM-1 concentrations in the epilepsy group were higher as compared to the neurosis group. Moreover, CSF sVCAM-1 and serum sVCAM-1 concentrations in drug-refractory epilepsy were raised as compared to drug-responsive epilepsy and new diagnosis epilepsy. However, there were no significant differences in concentrations of CSF sICAM-1 between the epilepsy and neurosis groups. Our results suggest that sVCAM-1 and sICAM-1 could play an important role in the drug-refractory epilepsy.
Subject(s)
Epilepsy/cerebrospinal fluid , Intercellular Adhesion Molecule-1/cerebrospinal fluid , Vascular Cell Adhesion Molecule-1/cerebrospinal fluid , Adolescent , Adult , Case-Control Studies , Epilepsy/blood , Female , Humans , Intercellular Adhesion Molecule-1/blood , Male , Middle Aged , Vascular Cell Adhesion Molecule-1/bloodABSTRACT
We examined 60 patients with remitting multiple sclerosis (disability 3,5±1.6 EDSS scores). The relative risk of rapid progression of neurologic impairment was associated with the higher levels of matrix metalloproteinase-2, soluble platelet endothelial cell adhesion molecule-1 (sPECAM-1) and soluble vascular cell adhesion molecule-1 (sVCAM-1) in the cerebrospinal fluid. The relative risk of exacerbation of the disease in the next three years was associated with the level of tumor necrosis factor alpha and matrix metalloproteinase-2.
Subject(s)
Multiple Sclerosis/cerebrospinal fluid , Platelet Endothelial Cell Adhesion Molecule-1/cerebrospinal fluid , Tumor Necrosis Factor-alpha/cerebrospinal fluid , Vascular Cell Adhesion Molecule-1/cerebrospinal fluid , Adult , Biomarkers/cerebrospinal fluid , Disease Progression , Female , Humans , Male , Multiple Sclerosis/diagnosis , Severity of Illness IndexABSTRACT
OBJECTIVE: To evaluate the degree of blood-brain barrier disruption in patients with neuromyelitis optica (NMO) and to clarify whether the levels of soluble intercellular adhesion molecule 1 (sICAM-1) and soluble vascular cell adhesion molecule 1 (sVCAM-1) in patients with NMO can be useful biomarkers for blood-brain barrier breakdown. DESIGN: Descriptive historical cohort. SETTING: Department of Neurology, Graduate School of Medicine, Chiba University. PATIENTS: The levels of sICAM-1 and sVCAM-1 in 25 patients with NMO, 21 patients with multiple sclerosis, and 20 patients with other noninflammatory neurologic disorders in the serum and cerebrospinal fluid (CSF) were measured using a multiplexed fluorescent magnetic bead-based immunoassay. MAIN OUTCOME MEASURES: Levels of the soluble adhesion molecules in serum and CSF and their associations with blood-brain barrier disruption. RESULTS: The CSF levels of sICAM-1 and sVCAM-1 increased in patients with NMO compared with patients with multiple sclerosis and other noninflammatory neurologic disorders (P < .001), and serum levels of sICAM-1 increased in patients with NMO compared with healthy control individuals (P = .003). The CSF sICAM-1 levels from patients with NMO were correlated with the albumin quotient (P = .02) and the presence of lesions detected via gadolinium-enhanced magnetic resonance imaging. CONCLUSIONS: Severe blood-brain barrier breakdown occurs in patients with NMO. Measuring adhesion molecules is useful to evaluate this barrier disruption.
Subject(s)
Blood-Brain Barrier/physiopathology , Intercellular Adhesion Molecule-1/blood , Intercellular Adhesion Molecule-1/cerebrospinal fluid , Neuromyelitis Optica , Vascular Cell Adhesion Molecule-1/blood , Vascular Cell Adhesion Molecule-1/cerebrospinal fluid , Adult , Cohort Studies , Female , Humans , Immunoassay/methods , Male , Middle Aged , Multiple Sclerosis/blood , Multiple Sclerosis/cerebrospinal fluid , Multiple Sclerosis/pathology , Neuromyelitis Optica/blood , Neuromyelitis Optica/cerebrospinal fluid , Neuromyelitis Optica/pathology , Statistics as Topic , Up-Regulation/physiologyABSTRACT
Levels of adhesion molecules were measured in 24 patients with multiple sclerosis during the 3-years prospective study. The high level of adhesion molecules sPECAM in the cerebrospinal fluid was associated with the appearance of new foci according to the magnetic resonance imaging data as well as with quick disability.
Subject(s)
Multiple Sclerosis/cerebrospinal fluid , Multiple Sclerosis/diagnosis , Platelet Endothelial Cell Adhesion Molecule-1/cerebrospinal fluid , Vascular Cell Adhesion Molecule-1/cerebrospinal fluid , Adult , Female , Humans , Magnetic Resonance Imaging , Male , Prospective StudiesABSTRACT
OBJECTIVE: Vascular endothelial cell injury contributes to the pathogenesis of viral encephalitis. This study was designed to investigate the roles of vascular endothelial growth factor (VEGF) and vascular cell adhesion molecule-1(VCAM-1) in cerebral spinal fluid (CSF) in the pathogenesis of viral encephalitis and in the evaluation of the severity and the prognosis of viral encephalitis in children. METHODS: CSF VEGF and VCAM-1 levels were measured using ELISA in 65 children with viral encephalitis and 20 age-matched controls (10 cases of epilepsy and 10 cases of congenital abnormality). RESULTS: CSF levels of VEGF and VCAM-1 in the viral encephalitis group in the acute phase were significantly elevated compared with those in the congenital abnormality (P<0.01) and the epilepsy groups (P<0.05). CSF levels of VEGF and VCAM-1 in the viral encephalitis group in the recovery phase decreased significantly and were similar to the levels of the epilepsy group, but remained higher than those in the congenital abnormality group (P<0.05). There was a positive correlation between CSF levels of VEGF and VCAM-1 in the viral encephalitis group in the acute and recovery phases. CSF levels of VEGF and VCAM-1 were positively correlated to CSF protein contents and the degree of MRI abnormality in the viral encephalitis group. CONCLUSIONS: VEGF and VCAM-1 may participate in the pathogenesis of viral encephalitis. Detection of the two parameters may be helpful to the evaluation of the severity and prognosis of viral encephalitis.
Subject(s)
Encephalitis, Viral/cerebrospinal fluid , Vascular Cell Adhesion Molecule-1/cerebrospinal fluid , Vascular Endothelial Growth Factor A/cerebrospinal fluid , Adolescent , Child , Child, Preschool , Electroencephalography , Encephalitis, Viral/etiology , Female , Humans , Infant , Magnetic Resonance Imaging , Male , Vascular Cell Adhesion Molecule-1/physiology , Vascular Endothelial Growth Factor A/physiologyABSTRACT
OBJECTIVES: In a pilot study we found a correlation of the clinical outcome with adhesion molecule (AM) concentrations in ventricular cerebrospinal fluid (CSF) but not in serum in patients with intracerebral haemorrhage. We now determined the time course of AM concentration in CSF and serum after basal ganglia haemorrhage (BGH) in order to further uncover pathogenetic mechanisms. MATERIALS AND METHODS: We included 11 patients with acute BGH and ventricular tamponade in which an extraventricular drainage had been applied to treat ventricular ballonade. Paired CSF and serum samples were obtained within 8 h after onset of BGH, as well as on the consecutive days 2, 4, 6, and 8, respectively. The concentrations of soluble ICAM-1 (sICAM-1) and VCAM-1 (sVCAM-1) in CSF and serum were measured by enzyme-linked immunosorbent assay. Moreover, we determined blood volume and perifocal oedema by a semi-automated planimetry technique from initial cranial computed tomography scans. RESULTS: sICAM-1 and sVCAM-1 levels in CSF were highest within the first hours after onset of BGH, then decreased significantly (P < 0.005 and <0.05, respectively) on day 2 and slightly increased thereafter. Furthermore, BGH volume was significantly correlated with the concentrations of sICAM-1 (r = 0.63, P < 0.05) and sVCAM-1 (r = 0.66, P < 0.05) in ventricular CSF but not in serum. CONCLUSIONS: Our results might indicate that the local inflammatory reaction is pronounced early after onset of BGH and appears to be restricted to the central nervous system. Moreover, AM concentrations measured early after BGH onset correlated stronger with radiological and clinical data than follow-up measurements.
Subject(s)
Basal Ganglia Hemorrhage/metabolism , Brain Edema/etiology , Intercellular Adhesion Molecule-1/blood , Intercellular Adhesion Molecule-1/cerebrospinal fluid , Vascular Cell Adhesion Molecule-1/blood , Vascular Cell Adhesion Molecule-1/cerebrospinal fluid , Aged , Aged, 80 and over , Basal Ganglia Hemorrhage/complications , Basal Ganglia Hemorrhage/physiopathology , Blood Volume/physiology , Cerebral Ventricles/metabolism , Cerebral Ventricles/physiopathology , Cerebrovascular Circulation/physiology , Female , Humans , Male , Middle Aged , Time FactorsABSTRACT
BACKGROUND: The pathophysiology of ischemic cerebral lesions following aneurysmal subarachnoid hemorrhage (SAH) is poorly understood. There is growing evidence that inflammatory reactions could be involved in the pathogenesis of such delayed occurring ischemic lesions. The aim of this study was to evaluate adhesion molecules with regard to these lesions following SAH. METHODS: Serum and cerebrospinal fluid (CSF) samples were taken daily from 15 patients up to day 9 after SAH and evaluated for intercellular adhesion molecule-1 (ICAM-1) and vascular adhesion molecule-1 (VCAM-1). RESULTS: CSF and serum samples correlated well during nearly the whole time course (p < 0.0001). A secondary increase in ICAM-1 and VCAM-1 in the serum and CSF correlated with an increase in flow velocity in the transcranial Doppler (p > 0.0001 and p < 0.007) but not to a delayed lesion in the CT scan. CONCLUSION: We believe that inflammatory processes are involved in the pathogenesis of cerebral vasospasm but they might only be a part of a multifactorial pathogenesis.
Subject(s)
Aneurysm, Ruptured/blood , Intercellular Adhesion Molecule-1/blood , Intracranial Aneurysm/blood , Subarachnoid Hemorrhage/blood , Vascular Cell Adhesion Molecule-1/blood , Vasospasm, Intracranial/blood , Adolescent , Adult , Aged , Aneurysm, Ruptured/cerebrospinal fluid , Aneurysm, Ruptured/physiopathology , Blood Flow Velocity , Cerebrovascular Circulation , Female , Humans , Intercellular Adhesion Molecule-1/cerebrospinal fluid , Intracranial Aneurysm/cerebrospinal fluid , Intracranial Aneurysm/physiopathology , Male , Middle Aged , Prospective Studies , Subarachnoid Hemorrhage/cerebrospinal fluid , Subarachnoid Hemorrhage/physiopathology , Time Factors , Ultrasonography, Doppler, Transcranial , Vascular Cell Adhesion Molecule-1/cerebrospinal fluid , Vasospasm, Intracranial/cerebrospinal fluid , Vasospasm, Intracranial/physiopathologyABSTRACT
OBJECT: The aim of this study was to explore whether levels of intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) are elevated in the cerebrospinal fluid (CSF) and serum of patients after aneurysmal subarachnoid hemorrhage (SAH). METHODS: This prospective clinical study focused on 21 patients who had recently suffered an SAH due to aneurysmal rupture and 15 control patients with hydrocephalus who had no other central nervous system disease. Cerebrospinal fluid and serum samples obtained within the first 3 days and on the 5th and 7th days of SAH were assayed for ICAM-1 and VCAM-1 by using quantitative enzyme-linked immunosorbent assays. Levels of soluble forms of ICAM-1 (p = 0.00001) and VCAM-1 (p = 0.009) in the patients' CSF and those of ICAM-1 (p = 0.00001) and VCAM-1 (p = 0.00001) in their serum were found to be elevated after SAH compared with levels in the CSF and serum of control patients with hydrocephalus. In addition, when the authors compared the increased levels of adhesion molecules in the CSF and serum of patients after SAH, the only statistically insignificant difference that they found was between the levels of VCAM-1 in serum obtained on Days 5 and 7 after SAH (p = 0.27). CONCLUSIONS: Adhesion molecules are a group of macromolecules that may participate in the inflammatory process, a common pathway leading to vasospasm after SAH. Leukocyte adherence to the vascular endothelium, which is induced by adhesion molecules, has been believed to be the initial signal of the development of vasospasm. The authors have demonstrated the synchronized elevation of two adhesion molecules in both CSF and serum following aneurysmal SAH. Blocking of ICAM-1 as well as VCAM-1 by monoclonal antibodies post-SAH may provide a beneficial effect on vasospasm.
Subject(s)
Intercellular Adhesion Molecule-1/blood , Intercellular Adhesion Molecule-1/cerebrospinal fluid , Subarachnoid Hemorrhage/blood , Subarachnoid Hemorrhage/cerebrospinal fluid , Vascular Cell Adhesion Molecule-1/blood , Vascular Cell Adhesion Molecule-1/cerebrospinal fluid , Adult , Aged , Biomarkers , Female , Humans , Male , Middle Aged , Predictive Value of Tests , Prognosis , Prospective StudiesABSTRACT
The aim of the present study was to investigate the serum and cerebrospinal fluid (CSF) concentrations of tumor necrosis factor alpha (TNF-alpha) and soluble vascular cell adhesion molecule-1 (sVCAM-1) in patients with primary progressive form of multiple sclerosis (MS) and in patients with connective tissue diseases (CTDs) complicated with central nervous system (CNS) involvement. Stimulation of sVCAM-1 release by TNF-alpha was demonstrated on endothelial cells of brain vessels. We intended to present the TNF-alpha stimulated elevation of sVCAM-1 in the serum and CSF in any cases of CNS lesion. Fifty patients with several CTDs complicated with neuropsychiatric symptoms and 25 MS patients with primary chronic progressive form of the disease were selected. Determinations of TNF-alpha and sVCAM-1 were performed using ELISA methods. TNF-alpha and sVCAM-1 concentrations were elevated in the CSF of all patients, intrathecal synthesis of sVCAM-1 was demonstrated in MS patients. The changes in the TNF-alpha and sVCAM-1 concentrations were independent from the clinical manifestations, immunoserological changes and quality of neuropsychiatric symptoms of the CTDs. The stimulatory effect of TNF-alpha was more pronounced in the CSF of MS patients.
Subject(s)
Connective Tissue Diseases/cerebrospinal fluid , Multiple Sclerosis/cerebrospinal fluid , Tumor Necrosis Factor-alpha/cerebrospinal fluid , Vascular Cell Adhesion Molecule-1/cerebrospinal fluid , Adult , Autoantibodies/blood , Autoantibodies/cerebrospinal fluid , Case-Control Studies , Central Nervous System Diseases/cerebrospinal fluid , Central Nervous System Diseases/etiology , Central Nervous System Diseases/immunology , Connective Tissue Diseases/complications , Connective Tissue Diseases/immunology , Female , Humans , Middle Aged , Multiple Sclerosis/immunology , Solubility , Tumor Necrosis Factor-alpha/metabolism , Vascular Cell Adhesion Molecule-1/bloodSubject(s)
Intercellular Adhesion Molecule-1/cerebrospinal fluid , Subarachnoid Hemorrhage/cerebrospinal fluid , Vascular Cell Adhesion Molecule-1/cerebrospinal fluid , Acute Disease , Enzyme-Linked Immunosorbent Assay , Glasgow Coma Scale , Prospective Studies , Subarachnoid Hemorrhage/mortality , Survival RateABSTRACT
OBJECTIVE: The pathogenesis of moyamoya syndrome is unknown; however, previous studies suggested an inflammatory component. Because adhesion molecules mediate inflammation during cerebral ischemia, we measured the levels of soluble isoforms of the endothelial adhesion molecules vascular cell adhesion molecule Type 1, intercellular adhesion molecule Type 1, and E-selectin in serum and cerebrospinal fluid (CSF) samples from children with moyamoya syndrome. METHODS: Serum and CSF samples were obtained from children with moyamoya syndrome (n = 20) and patients with congenital spinal deformities (n = 20). Soluble vascular cell adhesion molecule Type 1, intercellular adhesion molecule Type 1, and E-selectin levels were measured in enzyme-linked immunoassays. The correlation between the levels of soluble adhesion molecules and the Suzuki angiographic classification was analyzed. CSF/serum albumin index values were also measured, to determine the integrity of the blood-brain barrier. RESULTS: Compared with the control group, children with moyamoya syndrome exhibited significantly elevated CSF levels of soluble vascular cell adhesion molecule Type 1, intercellular adhesion molecule Type 1, and E-selectin. The albumin index for the moyamoya group was 9, which was significantly higher than that for the control group. However, there were no differences in the serum levels of the three soluble adhesion molecules and no correlations between age, Suzuki classification, and serum and CSF levels of adhesion molecules. CONCLUSION: Our study demonstrates increased CSF levels of soluble endothelial adhesion molecules, suggesting that children with moyamoya syndrome have ongoing central nervous system inflammation, with slight impairment of the blood-brain barrier. These soluble adhesion molecules may be clinically useful as indicators of this inflammatory process and may provide some insight into this enigmatic disease process.