ABSTRACT
The evolution of neuromyelitis optica spectrum disorder (NMOSD) from a rare, incurable and misunderstood disease with almost universally poor outcomes to its present state in just over a decade is unprecedented in neurology and possibly in medicine. Our knowledge of NMOSD biology has led to the recognition of wider phenotypes, new disease mechanisms, and thus clinical trials of new and effective treatments. This article aims to update readers on the recent developments in NMOSD with particular emphasis on clinical advances, the 2015 diagnostic criteria, biomarkers, imaging, and therapeutic interventions.
Subject(s)
Neurologists/psychology , Neuromyelitis Optica , Aquaporin 4/immunology , Cytokines/metabolism , Glial Fibrillary Acidic Protein/metabolism , Humans , Immunoglobulin G/blood , Immunologic Factors/therapeutic use , Myelin-Oligodendrocyte Glycoprotein/immunology , Neuroimaging , Neuromyelitis Optica/blood , Neuromyelitis Optica/diagnosis , Neuromyelitis Optica/drug therapyABSTRACT
BACKGROUND: Encephalitis is parenchymal brain inflammation, commonly due to herpes simplex virus (HSV). Key host inflammatory mediators and their relationship to blood-brain barrier (BBB) permeability, neuroimaging changes, and disease outcome are poorly understood. METHODS: We measured levels of 38 mediators in serum (n = 78) and cerebrospinal fluid (n = 37) specimens from patients with encephalitis, including 17 with disease due to HSV infection. Outcome measures were Glasgow coma and outcome scores; CSF to serum albumin ratio, reflecting BBB permeability; and, in patients with HSV infection, magnetic resonance imaging-based temporal lobe volume. RESULTS: Serum interleukin 1 receptor antagonist (IL-1RA) levels were elevated in patients with a good outcome (P= .004). Among patients infected with HSV, the ratio of CSF IL-1ß to IL-1RA was associated with a worse outcome (P= .009); a ratio of ≥0.55 pg/mL had high specificity and sensitivity for a poor outcome (100% and 83%;P= .015). Temporal lobe volume had a negative correlation with serum IL-1RA level (P= .012) and a positive correlation with serum IL-1α level (P= .0003) and CSF IL-1ß level (P= .007). A normal coma score was associated with an elevated interleukin 10 (IL-10) level in serum specimens from HSV-infected patients (P= .007) and CSF specimens from all patients (P= .016); the IL-10 level correlated inversely with BBB permeability (P= .005). CONCLUSIONS: A proinflammatory cytokine response is associated with greater clinical severity, BBB permeability, and neuroimaging damage during encephalitis. IL-1 antagonists should be investigated as adjunctive treatment in encephalitis.
Subject(s)
Blood-Brain Barrier , Capillary Permeability , Encephalitis, Herpes Simplex/immunology , Inflammation Mediators , Interleukin-1/metabolism , Albumins/cerebrospinal fluid , Cohort Studies , Encephalitis, Herpes Simplex/blood , Encephalitis, Herpes Simplex/cerebrospinal fluid , England , Glasgow Coma Scale , Humans , Inflammation Mediators/blood , Inflammation Mediators/cerebrospinal fluid , Interleukin 1 Receptor Antagonist Protein/blood , Interleukin 1 Receptor Antagonist Protein/cerebrospinal fluid , Interleukin-1/blood , Interleukin-1/cerebrospinal fluid , Interleukin-10/blood , Interleukin-10/cerebrospinal fluid , Interleukin-1beta/blood , Interleukin-1beta/cerebrospinal fluid , Magnetic Resonance Imaging , Neuroimaging , Prospective Studies , Serum Albumin/analysis , Simplexvirus/immunology , Temporal Lobe/pathologyABSTRACT
GAP-43 has been studied in the rodent and mammalian brain and shown to be present specifically in areas undergoing axonal elongation and synapse formation. GAP-43 was cloned using the baculovirus expression system and purified. A sandwich ELISA was developed using the recombinant GAP-43 as standard and validated. CSF GAP-43 levels were analysed in benign intracranial hypertension, movement disorders, multiple sclerosis, neuropathy, CNS infections, motor neuron disease, and headache (neurological controls). GAP-43 levels were low in all disorders analysed (in particular motor neuron disease; p=0.001, and movement disorders and multiple sclerosis; p<0.0001) compared to controls, aside from CNS infections. GAP-43 is preferentially reduced in the CSF of neurological disorders associated with neurodegeneration.
Subject(s)
Cloning, Organism , Enzyme-Linked Immunosorbent Assay/methods , GAP-43 Protein/genetics , GAP-43 Protein/metabolism , Nervous System Diseases/diagnosis , Animals , Humans , Mice , Nervous System Diseases/cerebrospinal fluidABSTRACT
A 48-year-old man presented with numbness in fingers and diplopia 1 week after a flu-like illness. He made a full recovery but 8 years later developed progressive and disabling sensory ataxia. He had superimposed acute flare-ups with numbness, double vision and ptosis, all following infections. A blood test showed antidisialosyl antibodies including GD1b, GD3, GT1b and GQ1b in keeping with the diagnosis of chronic ataxic neuropathy, ophthalmoplegia, IgM paraprotein, cold agglutinins and antidisialosyl antibodies (CANOMAD). Initial treatment with monthly courses of intravenous immunoglobulin (IVIg) 0.4 g/kg/day for 5 days every 4 weeks helped temporarily but there were marked disabling fluctuations of symptoms. With IVIg 0.6 g/kg/day weekly his symptoms are stable. He remains mobile and has no eye symptoms without need for any other medication. This case demonstrates that weekly IVIg infusions instead of one 5-day course monthly may be able to avoid fluctuations of symptoms in CANOMAD.
Subject(s)
Anemia, Hemolytic, Autoimmune/therapy , Ataxia/therapy , Immunoglobulins, Intravenous/therapeutic use , Ophthalmoplegia/therapy , Anemia, Hemolytic, Autoimmune/diagnosis , Ataxia/diagnosis , Diagnosis, Differential , Humans , Immunoglobulins, Intravenous/administration & dosage , Male , Middle Aged , Ophthalmoplegia/diagnosis , Treatment OutcomeABSTRACT
Multiple sclerosis (MS) is a CNS disorder characterized by demyelination and neurodegeneration. Although hallmarks of recovery (remyelination and repair) have been documented in early MS, the regenerative capacity of the adult CNS per se remains uncertain with the wide held belief that it is either limited or non-existent. The neural cell adhesion molecule (NCAM) is a cell adhesion molecule that has been widely implicated in axonal outgrowth, guidance and fasciculation. Here, we used in vitro and in vivo of MS to investigate the role of NCAM in disease progression. We show that in health NCAM levels decrease over time, but this occurs acutely after demyelination and remains reduced in chronic disease. Our findings suggest that depletion of NCAM is one of the factors associated with or possibly responsible for disease progression in MS.
Subject(s)
Disease Progression , Multiple Sclerosis/metabolism , Multiple Sclerosis/pathology , Neural Cell Adhesion Molecules/antagonists & inhibitors , Neural Cell Adhesion Molecules/cerebrospinal fluid , Adult , Amino Acid Sequence , Animals , Female , Humans , Male , Mice , Mice, Inbred C57BL , Middle Aged , Molecular Sequence Data , Multiple Sclerosis/cerebrospinal fluid , Neural Cell Adhesion Molecules/biosynthesis , Pregnancy , Rats , Rats, Sprague-Dawley , Young AdultABSTRACT
INTRODUCTION: It has still not been clearly established whether the cognitive deficits of idiopathic normal pressure hydrocephalus (iNPH) are caused by a disturbance in cerebrospinal fluid (CSF) dynamics or an underlying metabolic disturbance. OBJECTIVE: To identify the possible associations between biochemical markers, the neuroimaging characteristics, and cognitive deficits of patients undergoing investigations for possible iNPH. METHODS: A CSF sample obtained during a lumbar puncture from 10 patients with iNPH was analyzed for several biochemical markers (lactate, 8-isoprostane, vascular endothelial growth factor [VEGF], neurofilament heavy protein, glial fibrillary acidic protein, amyloid beta 1-42, and total tau). All patients underwent a battery of neuropsychological testing and imaging as part of their selection process for their suitability for CSF diversion surgical procedure. Volumetric analysis of imaging was carried out measuring the ventricular volume (VV), intracranial volume (ICV), periventricular lucencies, deep white matter hyperintensities, and white matter (WM) volume, as well as their ratios. RESULTS: A significant negative correlation of preoperative symptom duration and total tau levels (R = -0.841, P = .002) was found. There was a significant positive correlation (R = 0.648, P = .043) between the levels of VEGF and the VV/ICV ratio. There was a significant positive correlation of the levels of glial fibrillary acidic protein and the VV/deep white matter hyperintensities ratio (R = 0.828, P = .006). A significant negative correlation was observed between the levels of neurofilament heavy protein and the VV/ICV ratio (R = -0.657, P = .039) and the WM volume (R = -0.778, P = .023). Lactate levels were lower for patients performing in the normal range on the Recognition Memory Test for faces. Patients who performed better in the Recognition Memory Test words test had higher ICV volumes. All the patients in this study showed below normal performance when the subcortical function was assessed. CONCLUSION: The positive correlation of VEGF with the severity of ventriculomegaly may indicate that this is because of the transmantle pressure gradient; this response may not be because of hypoxia but represents an attempt at neuroregeneration. The degree of reactive gliosis correlates inversely with the severity of WM lesions. Neuronal degeneration is negatively correlated with the volume of the WM in these patients. The small association of volumetry and the cognitive profile of these patients may be consistent with a direct biochemical disturbance being responsible for the cognitive deficit observed. Ongoing studies with set protocols for neuropsychological assessment and volumetric analysis are warranted to further elucidate on the preliminary results of the current study.
Subject(s)
Cognition Disorders , Hydrocephalus, Normal Pressure , Aged , Aged, 80 and over , Brain/metabolism , Brain/pathology , Brain/physiopathology , Cerebral Ventricles/pathology , Cerebral Ventricles/surgery , Cognition Disorders/cerebrospinal fluid , Cognition Disorders/pathology , Cognition Disorders/physiopathology , Female , Humans , Hydrocephalus, Normal Pressure/cerebrospinal fluid , Hydrocephalus, Normal Pressure/metabolism , Hydrocephalus, Normal Pressure/physiopathology , Male , Middle Aged , Nerve Tissue Proteins/cerebrospinal fluid , Neuroimaging , Prospective StudiesABSTRACT
OBJECT: The prognostic value of CSF biomarkers in patients with idiopathic normal pressure hydrocephalus (iNPH) has not been adequately studied to date. The aim of this study was to identify CSF markers of favorable surgical outcome in patients with iNPH undergoing the insertion of a ventriculoperitoneal shunt. METHODS: Ventricular CSF was collected intraoperatively from 22 patients with iNPH and enzyme-linked immunosorbent assay was used to analyze the levels of amyloid-ß 1-42 (Aß(1-42)) and total tau protein. The Black grading scale was used to assess outcomes at 6 months. Receiver operating characteristic (ROC) curves were obtained and discriminant function analysis was undertaken to provide sensitivity and specificity figures for each marker as well as their combination. RESULTS: The mean age of the patients was 71.45 years (± 9.5 years [SD]). Follow-up was achieved in 21 patients. Seventeen patients had a favorable outcome and 4 patients had unfavorable outcome at 6 months. An Aß(1-42) level of 180 pg/ml had a sensitivity of 35% and a specificity of 20% for predicting a favorable outcome at 6 months. A total tau level of 767 pg/ml will have a sensitivity of 17% and a specificity of 20% for predicting a favorable outcome at 6 months. A combination of Aß(1-42) and total tau levels predicted favorable outcomes with a sensitivity of 80% and specificity of 82.4%. CONCLUSIONS: In this pilot study a combination of Aß(1-42) levels and total tau protein levels predicted favorable surgical outcomes at 6 months with adequate accuracy to be of clinical use. Further study in a larger group with longer follow-up is warranted.
Subject(s)
Amyloid beta-Peptides/cerebrospinal fluid , Hydrocephalus, Normal Pressure/cerebrospinal fluid , Hydrocephalus, Normal Pressure/surgery , Peptide Fragments/cerebrospinal fluid , Ventriculoperitoneal Shunt , tau Proteins/cerebrospinal fluid , Aged , Aged, 80 and over , Biomarkers/cerebrospinal fluid , Enzyme-Linked Immunosorbent Assay , Female , Follow-Up Studies , Humans , Male , Prognosis , Treatment OutcomeABSTRACT
The rostrocaudal gradient (RCG) of markers present in cerebrospinal fluid (CSF) has not been studied adequately due to lack of appropriate control populations and ethical restrictions. The aim of this study is to understand the rostrocaudal gradient of CSF biomarkers. We contacted a study comparing CSF levels of seven biomarkers from cisternal (rostral) and lumbar (caudal) CSF obtained from patients with trigeminal neuralgia and tension-type headache. The RCGs of CSF/serum albumin ratio, 8-isoprostane. GFAP, total tau and beta amyloid protein were higher than one. The RCGs of lactate, VEGF and the heavy chain of neurofilament protein were lower than one. The study provides new values for several commonly examined markers of cisternal CSF. Knowledge of the RCG gradient of different CSF markers is important in interpreting studies reporting ventricular CSF values.
Subject(s)
Biomarkers/cerebrospinal fluid , Brain/anatomy & histology , Adult , Aged , Female , Humans , Male , Middle Aged , Reference Standards , Spinal Puncture , Tension-Type Headache/cerebrospinal fluid , Trigeminal Neuralgia/cerebrospinal fluidABSTRACT
Neural cell adhesion molecule (NCAM) is important for neuronal growth and repair. Here we describe the development and validation of a sensitive ELISA for NCAM using commercially available reagents. The measurable range of NCAM ELISA is 16-500 ng/mL, with a constant coefficient-of variation and good parallelism between the reference standard curve and CSF. CSF NCAM was measured in 36 benign-intracranial hypertension, 51 multiple sclerosis, 27 neuropathy, 37 Alzheimer's disease, 12 cognitive impairment, 15 motoneurone disease, 13 meningitis, 17 encephalitis, and 17 control cases. Significant reductions were found between controls and multiple sclerosis, Alzheimer's disease and meningitis.
Subject(s)
Enzyme-Linked Immunosorbent Assay/methods , Nervous System Diseases/cerebrospinal fluid , Neural Cell Adhesion Molecules/cerebrospinal fluid , Adolescent , Adult , Aged , Aged, 80 and over , Albumins/cerebrospinal fluid , Analysis of Variance , Blood-Brain Barrier/physiopathology , Female , Humans , Male , Middle Aged , Nervous System Diseases/classification , Young AdultABSTRACT
It is crucially important to detect subarachnoid haemorrhage (SAH) in all patients in whom it has occurred to select patients for angiography and preventative surgery. A computerized tomography (CT) scan is positive in up to 98% of patients with SAH presenting within 12 h, but is positive in only 50% of those presenting within one week. Cerebrospinal fluid (CSF) bilirubin spectrophotometry can be used to determine the need for angiography in those few CT-negative patients in whom clinical suspicion of SAH remains high; it may remain positive up to two weeks after the event. A lumbar puncture (LP) should only be performed >12 h after the onset of presenting symptoms. Whenever possible collect sequential specimens. Always ensure that the least blood-stained CSF sample taken (usually the last) is sent for bilirubin analysis. Protect the CSF from light and avoid vacuum tube transport systems, if possible. Always use spectrophotometry in preference to visual inspection. All CSF specimens are precious and should always be analysed unless insufficient sample is received. Centrifuge the specimen at >2000 rpm for 5 min as soon as possible after receipt in the laboratory. Store the supernatant at 4 degrees C in the dark until analysis. An increase in CSF bilirubin is the key finding, which supports the occurrence of SAH but is not specific for this. In most positive cases, bilirubin will occur with oxyhaemoglobin.
Subject(s)
Bilirubin/cerebrospinal fluid , Subarachnoid Hemorrhage/cerebrospinal fluid , Subarachnoid Hemorrhage/diagnosis , Bilirubin/blood , Bilirubin/metabolism , Decision Trees , Humans , Methemoglobin/metabolism , Practice Guidelines as Topic , Quality Control , United KingdomABSTRACT
BACKGROUND: UK National External Quality Assessment Service (NEQAS) Specialist Advisory Group for EQA of CSF Proteins and Biochemistry was interested in current practice for the biochemical investigation of cerebrospinal fluid (CSF) in the UK. METHODS: A questionnaire was sent to laboratories via regional audit committees and the results collated. RESULTS: Most laboratories were analysing CSF in a satisfactory manner. There was some variation in the reference ranges used for glucose, protein and lactate. There was concern about the rejection policies of some laboratories on these unrepeatable samples and the wavelengths used to measure bilirubin. The survey revealed the lack of spectrophotometric scanning for haem pigments and bilirubin in some hospitals. CONCLUSIONS: The current practice for the measurement of CSF samples in the UK is satisfactory in most laboratories responding to the questionnaire. National agreement on reference ranges for glucose, protein and lactate should be achievable. Those performing spectrophotometric scanning of the CSF were doing so in concordance with the national guidelines. Some hospitals in the UK may not have responded to the questionnaire because they did not offer spectrophotometric scanning.
Subject(s)
Bilirubin/cerebrospinal fluid , Cerebrospinal Fluid/chemistry , Cerebrospinal Fluid/metabolism , Clinical Laboratory Techniques/standards , Glucose/cerebrospinal fluid , Lactic Acid/cerebrospinal fluid , Medical Audit/methods , Clinical Laboratory Techniques/statistics & numerical data , Data Collection , Hospitals/standards , Humans , Proteins/analysis , Quality Assurance, Health Care , Reference Values , Reproducibility of Results , Spectrophotometry/methods , Surveys and Questionnaires , United KingdomABSTRACT
Huntington's disease (HD) causes widespread CNS changes and systemic abnormalities including endocrine and immune dysfunction. HD biomarkers are needed to power clinical trials of potential treatments. We used multiplatform proteomic profiling to reveal plasma changes with HD progression. Proteins of interest were evaluated using immunoblotting and ELISA in plasma from 2 populations, CSF and R6/2 mice. The identified proteins demonstrate neuroinflammation in HD and warrant further investigation as possible biomarkers.
Subject(s)
Blood Proteins/analysis , Central Nervous System/metabolism , Encephalitis/blood , Huntington Disease/blood , Proteomics , Animals , Biomarkers/blood , Blotting, Western , Electrophoresis, Gel, Two-Dimensional , Encephalitis/immunology , Enzyme-Linked Immunosorbent Assay , Humans , Huntington Disease/immunology , Interleukin-6/blood , Mice , Protein Array AnalysisABSTRACT
There is a need for biomarkers of onset and progression in Huntington's disease (HD), as current outcome measures lack the reliability to enable the efficient conduct of disease-modifying trials. Neurofilament heavy chain (NfH) is a neuron-specific protein for the neuro-axonal compartment that has been proposed as a marker for axonal injury, degeneration and loss and its clinical use as a biomarker has been suggested in several neurodegenerative diseases. We used an enzyme-linked immunosorbent assay to quantify NfH levels in plasma in control subjects, premanifest HD mutation carriers and subjects with early and moderate manifest HD. We found no correlation between plasma NfH level and disease stage, or calculated parameters based on CAG repeat length, the major determinant of disease course in HD, and no evidence that NfH may be a predictor of disease onset. We conclude that plasma NfH concentration is not a useful biomarker of onset or progression in HD.
Subject(s)
Axons/metabolism , Brain Chemistry/physiology , Brain/metabolism , Huntington Disease/blood , Huntington Disease/diagnosis , Neurofilament Proteins/blood , Adult , Aged , Axons/pathology , Biomarkers/analysis , Biomarkers/blood , Brain/physiopathology , Disease Progression , Early Diagnosis , Enzyme-Linked Immunosorbent Assay , Female , Genetic Carrier Screening/methods , Humans , Huntingtin Protein , Huntington Disease/physiopathology , Male , Middle Aged , Mutation/genetics , Nerve Degeneration/blood , Nerve Degeneration/pathology , Nerve Degeneration/physiopathology , Nerve Tissue Proteins/genetics , Neurofilament Proteins/analysis , Nuclear Proteins/genetics , Predictive Value of Tests , Prognosis , Trinucleotide Repeat Expansion/geneticsABSTRACT
Rhesus monkeys immunized with MOG(34-56), a dominant T-cell epitope from myelin/oligodendrocyte glycoprotein, develop an acute neurological disease resembling acute disseminated encephalomyelitis (ADEM) in humans. The typical large demyelinated lesions and mononuclear infiltrates in the monkey brains are caused by MOG(34-56) T-cells. We show that MOG(34-56)-reactive CD4+ and CD8+ T-cells are induced in monkeys immunized with a peptide from the human CMV major capsid protein (UL86; 981-1003), that shares sequence similarity with MOG(34-56). Monkeys sensitized against the viral peptide and subsequently challenged with MOG(34-56) display histological signs of encephalitis, but do not show overt neurological signs.
Subject(s)
Capsid Proteins/immunology , Cholesterol/analogs & derivatives , Encephalomyelitis, Autoimmune, Experimental/immunology , Epitopes, T-Lymphocyte/immunology , Glycoproteins/immunology , Macaca mulatta/immunology , Peptide Fragments/immunology , Animals , Antibodies/blood , Brain/pathology , CD4-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/immunology , Capsid Proteins/pharmacology , Cell Line , Cell Proliferation/drug effects , Cholesterol/immunology , Cross Reactions , Encephalomyelitis, Autoimmune, Experimental/pathology , Encephalomyelitis, Autoimmune, Experimental/physiopathology , Female , Humans , Lymphocyte Activation , Male , Monocytes/pathology , Myelin Proteins , Myelin-Associated Glycoprotein/immunology , Myelin-Associated Glycoprotein/pharmacology , Myelin-Oligodendrocyte Glycoprotein , Peptide Fragments/pharmacology , Polyethylene Glycols , Recombinant Proteins/immunology , Spinal Cord/pathologyABSTRACT
S100B belongs to a family of calcium-binding proteins implicated in intracellular and extracellular regulatory activities. This study of serum S100B in primary progressive multiple sclerosis (PPMS) is based on data obtained from a randomized, controlled trial of Interferon beta-1a in subjects with PPMS. The key questions were whether S100B levels were associated with either disability or MRI findings in primary progressive MS and whether Interferon beta-1a has an effect on their S100B levels. Serial serum S100B levels were measured using an ELISA method. The results demonstrated that serum S100B is not related to either disease progression or MRI findings in subjects with primary progressive MS given Interferon beta-1a. Furthermore there is no correlation between S100B levels and the primary and secondary outcome measures.
Subject(s)
Interferon-beta/therapeutic use , Multiple Sclerosis, Chronic Progressive/blood , Multiple Sclerosis, Chronic Progressive/drug therapy , Nerve Growth Factors/blood , S100 Proteins/blood , Adult , Case-Control Studies , Female , Humans , Interferon beta-1a , Magnetic Resonance Imaging , Male , Nerve Growth Factors/metabolism , S100 Calcium Binding Protein beta Subunit , S100 Proteins/metabolismABSTRACT
The findings of various studies reporting temporal changes in CSF total nitrite/nitrate (NOx) levels after subarachnoid hemorrhage (SAH) vary considerably. The study group comprised 10 patients with SAH and 10 control subjects. Total nitrite/nitrate concentration was measured by a vanadium-based assay with the colorimetric Griess reaction. CSF oxyhemoglobin level was assessed by spectrophotometry. After an initial peak (22.6+/-10.1 microM) within first 24 h after SAH, CSF NOx decreased gradually during the period of observation. There was a significant correlation between CSF concentrations of NOx and OxyHb in the entire observation period (R=0.87, p<0.001). When the impact of bleeding into CSF was considered, patients with very good outcome [Glasgow Outcome Scale (GOS)=5] had significantly lower CSF NOx (11.1+/-1.3 microM) than those with worse outcome (GOS<5) (21.8+/-11.2 microM, p<0.01). In conclusion, this study demonstrates that after aneurysm rupture CSF NOx levels correlate with OxyHb. We suggest this as a novel interpretation of other variable findings in relation to NO metabolites in the central nervous system (CNS) post SAH, and hence it could usefully be incorporated into the planning of future studies, correlating NOx with clinical outcome.
Subject(s)
Nitrates/cerebrospinal fluid , Nitrites/cerebrospinal fluid , Oxyhemoglobins/metabolism , Subarachnoid Hemorrhage/cerebrospinal fluid , Subarachnoid Hemorrhage/diagnosis , Adult , Aged , Biomarkers , Female , Humans , Male , Middle Aged , Predictive Value of Tests , Prognosis , VanadiumABSTRACT
BACKGROUND AND PURPOSE: The mechanism underlying the association between possession of the APOEepsilon4 allele and less favorable outcome after subarachnoid hemorrhage (SAH) remains to be determined. After SAH the level of apolipoprotein E (apoE) in the cerebrospinal fluid (CSF) is decreased, and lower levels are associated with more severe injury and less favorable outcome. This study examined serial CSF samples to determine the time course for the decrease in CSF apoE and the relationship between CSF apoE and amyloid beta-protein (Abeta), testing the hypothesis that apoE-Abeta interactions occur in vivo after SAH. METHODS: Enzyme-linked immunosorbent assay was used to assay apoE, Abeta1-40, and Abeta1-42 in serial ventricular CSF samples from 19 patients with SAH and 13 controls. CSF S100B and tau were assayed as surrogate markers of brain injury. RESULTS: There was a sustained decrease in CSF apoE (P<0.001) and Abeta (P<0.001) after SAH in contrast to the observed elevation in CSF S100B (P<0.001) and tau (P<0.001) concentration. There was significant correlation between CSF Abeta concentration and clinical outcome (r=0.65, P<0.01), and the decrease in CSF Abeta concentration correlated significantly with that of apoE (r=0.85, P<0.0001). CONCLUSIONS: After SAH both apoE and Abeta levels decrease in the CSF, supporting the concept that interactions between these proteins occur in vivo. The possibility that apoE and Abeta influence outcome after SAH warrants further investigation.
Subject(s)
Amyloid beta-Peptides/cerebrospinal fluid , Apolipoproteins E/cerebrospinal fluid , Peptide Fragments/cerebrospinal fluid , Subarachnoid Hemorrhage/cerebrospinal fluid , Adolescent , Adult , Biomarkers/cerebrospinal fluid , Disease Progression , Humans , Middle Aged , Nerve Growth Factors/cerebrospinal fluid , S100 Calcium Binding Protein beta Subunit , S100 Proteins/cerebrospinal fluid , Time Factors , tau Proteins/cerebrospinal fluidABSTRACT
There is evidence that apolipoprotein E (apoE) and amyloid beta-protein (Abeta), which are implicated in the pathology of chronic neurodegenerative disorders, are involved in the response of the brain to acute injury; however, human in vivo evidence is sparse. We conducted a prospective observational study to determine the magnitude and time-course of alterations in cerebrospinal fluid (CSF) apoE and Abeta concentrations after traumatic brain injury (TBI), and the relationship of these changes to severity of injury and clinical outcome. Enzyme linked immunosorbant assay (ELISA) was used to assay apoE, Abeta(1-40) and Abeta(1-42) in serial CSF samples from 13 patients with TBI and 13 controls. CSF S100B and tau were assayed as surrogate markers of brain injury. There was a significant decrease in CSF apoE (p < 0.001) and Abeta (p< 0.001) after TBI contrasting the observed elevation in CSF S100B (p < 0.001) and tau (p < 0.001) concentration. There was significant correlation (r = 0.67, p = 0.01) between injury severity and the decrease in Abeta(1-40) concentration after TBI. In vivo, changes in apoE and Abeta concentration occur after TBI and may be important in the response of the human brain to injury.
Subject(s)
Amyloid beta-Peptides/cerebrospinal fluid , Apolipoproteins E/cerebrospinal fluid , Brain Injuries/cerebrospinal fluid , Peptide Fragments/cerebrospinal fluid , Adolescent , Adult , Aged , Analysis of Variance , Female , Humans , Male , Middle Aged , Prospective Studies , Time FactorsABSTRACT
The APOE epsilon4 allele has been associated with unfavorable outcome after several types of acute brain injury, yet the biological mechanisms underlying this observation are poorly understood. Postmortem and experimental brain injury studies suggest the presence of increased amounts of apolipoprotein E (apoE) within the neuropil after acute brain injury. We assayed the concentration of apolipoprotein E in the cerebrospinal fluid (CSF) of non-injured controls and patients with traumatic brain injury (TBI) to determine whether differences exist, and if these differences correlate with injury severity and clinical outcome. CSF apoE and S100B, a marker of injury severity, were measured by enzyme linked immunosorbant assay. CSF was sampled from 27 traumatic brain injury patients (mean age 32, median 25, range 16-65 years) within 3 days of injury, and 28 controls (mean age 40, median 37, range 19-73 years). The TBI patients all had a Glasgow Coma Score (GCS) of less than eight (i.e., severe head injury). Clinical outcome was determined using the Glasgow Outcome Score (GOS). The average concentration of apoE in the CSF of controls was 12.4 mg/L (95% CI: 10.5-14.3 mg/L) and in TBI patients was 3.7 mg/L (95% CI: 2.1-4.1 mg/L; Mann-Whitney: p < 0.0001). In contrast, the concentration of S100B in the CSF of TBI patients was significantly higher than that of controls (Mann-Whitney: p < 0.0001). We speculate that apoE is retained within the parenchyma of the central nervous system in response to injury where in view of previous data, it may have a protective role.