Glial Fibrillary Astrocytic Protein Research Articles

Effects of HZE-Particle Exposure Location and Energy on Brain Inflammation and Oxidative Stress in Rats.

Astronauts on exploratory missions will be exposed to particle radiation of high energy and charge (HZE particles), which have been shown to produce neurochemical and performance deficits in animal models. Exposure to HZE particles can produce both targeted effects, resulting from direct ionization of atoms along the particle track, and non-targeted effects (NTEs) in cells that are distant from the track, extending the range of potential damage beyond the site of irradiation. While recent work suggests that NTEs are primarily responsible for changes in cognitive function after HZE exposures, the relative contributions of targeted and non-targeted effects to neurochemical changes after HZE exposures are unclear. The present experiment was designed to further explore the role of targeted and non-targeted effects on HZE-induced neurochemical changes (inflammation and oxidative stress) by evaluating the effects of exposure location and particle energy/linear energy transfer (LET). Forty-six male Sprague-Dawley rats received head-only or body-only exposures to 56Fe particles [600 MeV/n (75 cGy) or 1,000 MeV/n (100 cGy)] or 48Ti particles [500 MeV/n (50 cGy) or 1,100 MeV/n (75 cGy)] or no irradiation (0 cGy). Twenty-four h after irradiation, rats were euthanized, and the brain was dissected for analysis of HZE-particle-induced neurochemical changes in the hippocampus and frontal cortex. Results showed that exposure to 56Fe and 48Ti ions produced changes in measurements of brain inflammation [glial fibrillary astrocyte protein (GFAP)], oxidative stress [NADPH-oxidoreductase-2 (NOX2)] and antioxidant enzymes [superoxide dismutase (SOD), glutathione S-transferase (GST), nuclear factor erythroid 2-related factor 2 (Nrf2)]. However, radiation effects varied depending upon the specific measurement, brain region, and exposure location. Although overall exposures of the head produced more detrimental changes in neuroinflammation and oxidative stress than exposures of the body, body-only exposures also produced changes relative to no irradiation, and the effect of particle energy/LET on neurochemical changes was minimal. Results indicate that both targeted and non-targeted effects are important contributors to neurochemical changes after head-only exposure. However, because there were no consistent neurochemical changes as a function of changes in track structure after head-only exposures, the role of direct effects on neuronal function is uncertain. Therefore, these findings, although in an animal model, suggest that NTEs should be considered in the estimation of risk to the central nervous system (CNS) and development of countermeasures.

Insulin and insulin-like growth factor-I receptors in astrocytes exert different effects on behavior and Alzheimer´s-like pathology

Background: Pleiotropic actions of insulin and insulin-like growth factor I (IGF-I) in the brain are context- and cell-dependent, but whether this holds for their receptors (insulin receptor (IR) and IGF-I receptor (IGF-IR), respectively), is less clear. Methods: We compared mice lacking IR or IGF-IR in glial fibrillary astrocytic protein (GFAP)-expressing astrocytes in a tamoxifen-regulated manner, to clarify their role in this type of glial cells, as the majority of data of their actions in brain have been obtained in neurons. Results: We observed that mice lacking IR in GFAP astrocytes (GFAP IR KO mice) develop mood disturbances and maintained intact cognition, while at the same time show greater pathology when cross-bred with APP/PS1 mice, a model of familial Alzheimer´s disease (AD). Conversely, mice lacking IGF-IR in GFAP astrocytes (GFAP-IGF-IR KO mice) show cognitive disturbances, maintained mood tone, and show control-dependent changes in AD-like pathology. Conclusions: These observations confirm that the role of IR and IGF-IR in the brain is cell-specific and context-dependent.

Insulin and insulin-like growth factor-I receptors in astrocytes exert different effects on behavior and Alzheimer´s-like pathology.

Background: Pleiotropic actions of insulin and insulin-like growth factor I (IGF-I) in the brain are context- and cell-dependent, but whether this holds for their receptors (insulin receptor (IR) and IGF-I receptor (IGF-IR), respectively), is less clear. Methods: We compared mice lacking IR or IGF-IR in glial fibrillary astrocytic protein (GFAP)-expressing astrocytes in a tamoxifen-regulated manner, to clarify their role in this type of glial cells, as the majority of data of their actions in brain have been obtained in neurons. Results: We observed that mice lacking IR in GFAP astrocytes (GFAP IR KO mice) develop mood disturbances and maintained intact cognition, while at the same time show greater pathology when cross-bred with APP/PS1 mice, a model of familial Alzheimer´s disease (AD). Conversely, mice lacking IGF-IR in GFAP astrocytes (GFAP-IGF-IR KO mice) show cognitive disturbances, maintained mood tone, and show control-dependent changes in AD-like pathology. Conclusions: These observations confirm that the role of IR and IGF-IR in the brain is cell-specific and context-dependent.

Elevation of neural injury markers in patients with neurologic sequelae after hospitalization for SARS-CoV-2 infection

SummaryPatients with SARS-CoV-2 infection (COVID-19) risk developing long-term neurologic symptoms after infection. Here, we identify biomarkers associated with neurologic sequelae one year after hospitalization for SARS-CoV-2 infection. SARS-CoV-2-positive patients were followed using post-SARS-CoV-2 online questionnaires and virtual visits. Hospitalized adults from the pre-SARS-CoV-2 era served as historical controls. 40% of hospitalized patients develop neurological sequelae in the year after recovery from acute COVID-19 infection. Age, disease severity, and COVID-19 infection itself was associated with additional risk for neurological sequelae in our cohorts. Glial fibrillary astrocytic protein (GFAP) and neurofilament light chain (NF-L) were significantly elevated in SARS-CoV-2 infection. After adjusting for age, sex, and disease severity, GFAP and NF-L remained significantly associated with longer term neurological symptoms in patients with SARS-CoV-2 infection. GFAP and NF-L warrant exploration as biomarkers for long-term neurologic complications after SARS-CoV-2 infection.

Insulin and insulin-like growth factor-I receptors in astrocytes exert different effects on behavior and Alzheimer´s-like pathology.

Background: Pleiotropic actions of insulin and insulin-like growth factor I (IGF-I) in the brain are context- and cell-dependent, but whether this holds for their receptors (insulin receptor (IR) and IGF-I receptor (IGF-IR), respectively), is less clear. Methods: We compared mice lacking IR or IGF-IR in glial fibrillary astrocytic protein (GFAP)-expressing astrocytes in a tamoxifen-regulated manner, to clarify their role in this type of glial cells, as the majority of data of their actions in brain have been obtained in neurons. Results: We observed that mice lacking IR in GFAP astrocytes (GFAP IR KO mice) develop mood disturbances and maintained intact cognition, while at the same time show greater pathology when cross-bred with APP/PS1 mice, a model of familial Alzheimer´s disease (AD). Conversely, mice lacking IGF-IR in GFAP astrocytes (GFAP-IGF-IR KO mice) show cognitive disturbances, maintained mood tone, and show control-dependent changes in AD-like pathology. Conclusions: These observations confirm that the role of IR and IGF-IR in the brain is cell-specific and context-dependent.

Plasma neurofilament light chain level predicts outcomes in stroke patients receiving endovascular thrombectomy

BackgroundTimely endovascular thrombectomy (EVT) significantly improves outcomes in patients with acute ischemic stroke (AIS) with large vessel occlusion type. However, whether certain central nervous system-specific plasma biomarkers correlate with the outcomes is unknown. We evaluated the temporal changes and prognostic roles of the levels of these biomarkers in patients with AIS undergoing EVT.MethodsWe enrolled 60 patients who received EVT for AIS and 14 controls. The levels of plasma biomarkers, namely neurofilament light chain (NfL), glial fibrillary astrocytic protein (GFAP), tau, and ubiquitin C-terminal hydrolase L1 (UCHL1), were measured with an ultrasensitive single molecule array before, immediately after, and 24 h after EVT (T1, T2, and T3, respectively). The outcomes of interest were death or disability at 90 days (defined as a modified Rankin Scale score of 3–6) and types of hemorrhagic transformation (hemorrhagic infarction or parenchymal hemorrhage).ResultsOf the 180 blood samples from the 60 patients who received EVT, the plasma NfL, GFAP, and UCHL1 levels at T1 were significantly higher than those of the controls, and the levels of all four biomarkers were significantly higher at T3. Patients with parenchymal hemorrhage had a significantly higher rate of increase in GFAP (Pinteraction = 0.005) and UCHL1 (Pinteraction = 0.007) levels compared with those without parenchymal hemorrhage. In a multivariable analysis with adjustment for age, sex, National Institute of Health Stroke Scale score, history of atrial fibrillation, and recanalization status, higher NfL levels at T1 (odds ratio [OR] 2.05; 95% confidence interval [CI], 1.03–4.08), T2 (OR, 2.08; 95% CI, 1.05–4.01), and T3 (OR, 3.94; 95% CI, 1.44–10.79) were independent predictors of death or disability at 90 days.ConclusionAmong patients with AIS who received EVT, those with hemorrhagic transformation exhibited significant increase in plasma GFAP and UCHL1 levels over time. Higher plasma NfL were predictive of unfavorable functional outcomes.

Early Blood Biomarkers Distinguish Inflammation from Neonatal Hypoxic-Ischemia Encephalopathy.

Neonatal hypoxic-ischemic encephalopathy is the most common cause of neurological disability in infancy. Superimposed inflammation may further worsen neurological outcomes. Reliable biomarkers which are both sensitive to hypoxic-ischemia and inflammation are critically needed. We tested plasma osteopontin (OPN) and glial fibrillary astrocytic protein (GFAP) within the reported therapeutic window (90min after hypoxic-ischemic (HI) injury) in neonatal rats with different HI severity and inflammation. Two different HI severity groups (mild-HI with 75min hypoxia and severe-HI with 150min hypoxia) were established. Inflammation-sensitized HI brain injury induced by lipopolysaccharide (LPS) further increased apoptotic neurons and infarct volumes. In HI alone groups, OPN was significantly decreased (p < 0.001) but GFAP was slightly increased (p < 0.05) at 90min after HI either in mild-HI or severe-HI compared with naïve group. In LPS-sensitized HI groups, both OPN and GFAP were significantly increased either in LPS-mild-HI or LPS-severe-HI groups compared with the naïve group (all p < 0.05). Induced inflammation by LPS exaggerated neonatal HI brain injury. The plasma OPN and GFAP levels may be useful to differentiate HI alone groups from inflammation-sensitized HI groups or naïve group.

Use of 3D Distance Mapping to examine Neuro‐Glia‐Vascular Plasticity in Rodent Models of Cardiovascular Disease

Regulating cerebral blood flow to supply oxygen and nutrients and remove waste products is of utmost importance for neuronal health. The brain’s capillary network responds to acute local increases of neuronal activity with vasodilation of upstream arterioles (neurovascular coupling, NVC). NVC mechanisms are impaired in a number of neurodegenerative and cardiovascular diseases. A compounding factor in these diseases is the remodelling of capillary networks. A reduced density of capillaries and/or changes in the arrangement of capillaries so that the parenchyma is not adequately supplied can exacerbate these conditions. We set out to develop novel tools to analyse the architecture of cerebral microvascular networks and assess neuronal‐glial‐vascular plasticity in rodent models of hypertension, cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) and impaired endothelial Ca2+ signalling (TRPV4‐KO).Animals (mice or rats) were transcardially perfused with a liposome‐encapsulated fluorescent dye (DiI) and brains were harvested and fixed in 4 % paraformaldehyde. Transparency of the tissue was increased using the SeeDB protocol and the microvasculature was imaged in 2 mm thick coronal brain slabs using 2‐photon microscopy. Subsequently, slabs were cryopreserved, re‐sectioned at 80 μm thickness and processed for immunofluorescence (glial fibrillary astrocytic protein, Gfap). Slices were imaged using scanning confocal microscopy. Imaging volumes were taken in the rostro‐caudal axis to a depth of ~1 mm. They were deconvolved, attenuation‐corrected and scaled to equal length voxels. Then, fluorescent structures were converted into 3D objects (Volumetry G9 ‐ GWH) and non‐vessel particulates were filtered. Then, expanding boundary shells were used at every voxel in parenchymal space. Once the expanding boundary shells collided with a vessel, the distance (radius) was converted to a color and a new imaging volume containing the distance mapping results was created. The proportion of parenchymal voxels located at different distances from their closest blood vessel was calculated.We found that in both mice and rats, overall vessel density was the highest in the paraventricular nucleus of the hypothalamus (10–20 % of voxels), followed by cortex (~ 10 %) and hippocampus (~ 5 %). 90 % of the parenchymal volume in the cortex was within 26 μm of a blood vessel compared to &gt; 34 μm in the hippocampus. Interestingly, Gfap staining was intense in the hippocampus but not in the cortex. In disease models, we found that aged mice (CADASIL, CADASIL control and TRPV4‐KO) had a lower vessel density than younger animals especially in cortex and PVN. In contrast, it was hippocampal vessel density in the dentate gyrus that was lower in spontaneously hypertensive rats than in controls.In summary, we describe a simple, yet powerful method to assess the relationship of capillary networks and parenchymal volume and show that rodent models of cardiovascular diseases are associated with plasticity of the neuro‐glia‐vascular unit.Support or Funding InformationR01 HL133211

Herpes Simplex Virus Type-1 Infection Impairs Adult Hippocampal Neurogenesis via Amyloid-β Protein Accumulation

We previously reported that Herpes simplex virus type-1 (HSV-1) infection of cultured neurons triggered intracellular accumulation of amyloid-β protein (Aβ) markedly impinging on neuronal functions. Here, we demonstrated that HSV-1 affects in vitro and in vivo adult hippocampal neurogenesis by reducing neural stem/progenitor cell (NSC) proliferation and their neuronal differentiation via intracellular Aβ accumulation. Specifically, cultured NSCs were more permissive for HSV-1 replication than mature neurons and, once infected, they exhibited reduced proliferation (assessed by 5'-bromo-deoxyuridine incorporation, Ki67 immunoreactivity, and Sox2 mRNA expression) and impaired neuronal differentiation in favor of glial phenotype (evaluated by immunoreactivity for the neuronal marker MAP2, the glial marker glial fibrillary astrocyte protein, and the expression of the proneuronal genes Mash1 and NeuroD1). Similarly, impaired adult neurogenesis was observed in the subgranular zone of hippocampal dentate gyrus of an in vivo model of recurrent HSV-1 infections, that we recently set up and characterized, with respect to mock-infected mice. The effects of HSV-1 on neurogenesis did not depend on cell death and were due to Aβ accumulation in infected NSCs. Indeed, they were: (a) reverted, in vitro, by the presence of either β/γ-secretase inhibitors preventing Aβ production or the specific 4G8 antibody counteracting the action of intracellular Aβ; (b) not detectable, in vivo, in HSV-1-infected amyloid precursor protein knockout mice, unable to produce and accumulate Aβ. Given the critical role played by adult neurogenesis in hippocampal-dependent memory and learning, our results suggest that multiple virus reactivations in the brain may contribute to Alzheimer's disease phenotype by also targeting NSCs. Stem Cells 2019;37:1467-1480.

Usefulness of serum interleukin-33 as a prognostic marker of severe traumatic brain injury

BackgroundInterleukin-33 is recently identified as a brain injury biomarker. We determined whether serum interlerukin-33 concentrations are associated with inflammation, severity and prognosis after traumatic brain injury (TBI). MethodsWe detected serum interlerukin-33 concentrations of 102 healthy controls and 102 severe TBI patients, as well as serum concentrations of 3 inflammatory biomarkers (interleukin-6, tumor necrosis factor-alpha and C-reactive protein) and 7 cell-specific proteins (myelin basic protein, glial fibrillary astrocyte protein, S100B, neuron-specific enolase, phosphorylated axonal neurofilament subunit H, Tau and ubiquitin carboxyl-terminal hydrolase L1) in 102 severe TBI patients. The recorded poor prognosis variables included acute lung injury, acute traumatic coagulopathy, progressive hemorrhagic injury, posttraumatic cerebral infarction and six-month mortality and poor outcome (Glasgow score of 1–3). ResultsMedian interlerukin-33 concentration of patients (692 pg/mL) was substantially raised, as compared to controls. Interlerukin-33 concentrations were significantly correlated with Glasgow coma scale (GCS) score and the preceding biomarkers concentrations. Interlerukin-33 concentration > 692 pg/mL emerged as an independent prognostic predictor and its discriminatory capability exceeded those of the above-mentioned inflammatory biomarkers concentrations and was in the range of GCS scores and the aforementioned cell-specific proteins concentrations. ConclusionAscending serum interlerukin-33 concentrations could reflect inflammation, severity and worse prognosis following TBI.

Serum ST2 as a potential prognostic biomarker for traumatic brain injury

BackgroundST2, a receptor of interleukin-33, is involved in inflammation. We discerned the relationship between serum soluble ST2 (sST2) concentrations, inflammation, severity and prognosis following traumatic brain injury (TBI). MethodsWe measured serum sST2, interleukin-6, tumor necrosis factor-alpha, C-reactive protein, myelin basic protein, glial fibrillary astrocyte protein, S100B, neuron-specific enolase, phosphorylated axonal neurofilament subunit H, Tau and ubiquitin carboxyl-terminal hydrolase L1 concentrations in 106 healthy controls and 106 severe TBI patients. We recorded long-term prognosis (i.e., 6-month mortality and functional outcome) and in-hospital major adverse events, including in-hospital mortality, acute lung injury, acute traumatic coagulopathy, progressive hemorrhagic injury and posttraumatic cerebral infarction. ResultssST2 concentrations were significantly higher in patients than in controls and were significantly correlated with Glasgow coma scale (GCS) score and the preceding biomarkers concentrations. Serum sST2 was an independent prognostic predictor and its predictive ability significantly exceeded those of serum interleukin-6, tumor necrosis factor-alpha and C-reactive protein concentrations and was similar to those of GCS scores and serum concentrations of other remaining biomarkers. Moreover, sST2 concentrations significantly improved predictive ability of GCS score. ConclusionIncreased serum sST2 concentrations are significantly related to inflammation, severity and prognosis, substantialized ST2 as a potential prognostic biomarker for TBI.

Serum GFAP level: A novel adjunctive diagnostic test in differentiate epileptic seizures from psychogenic attacks

PurposeThere has been increasing interest in the use of different biomarkers to help distinguish psychogenic from epileptic seizures, in patients presenting acutely with seizure-like events. In the present study, we measured serum glial fibrillary astrocytic protein (GFAP) levels in patients presenting with such events who were subsequently diagnosed as epileptic seizures (ESs) or psychogenic non-epileptic seizures (PNESs) and compared GFAP levels obtained with those found in healthy subjects. MethodsSixty-three patients with seizures (43 with ES and 20 with PNES), and 19 healthy subjects participated in the study. Venous blood samples were obtained within the first 6 h after seizures and serum GFAP levels were measured by protein quantification (ELIZA kit) with an electrochemical luminescence immunoassay. ResultsSerum GFAP levels were significantly higher in patients with ES compared to PNES or healthy controls. A cut-off point of 2.71 ng/ml was found optimally to differentiate ES from PNES (sensitivity 72%, specificity 59%). ConclusionOur study suggests that post-seizure serum GFAP levels could be used in future studies better to understand the underlying mechanism of seizures and may offer as an adjunctive diagnostic test in differentiating ES from PNES.

Comparison of plasma copeptin and multiple biomarkers for assessing prognosis of patients with aneurysmal subarachnoid hemorrhage

BackgroundIncreased plasma copeptin concentrations are related to poor prognosis after aneurysmal subarachnoid hemorrhage (aSAH). The aim of this study was to assess prognostic significance of plasma copeptin detection compared with glial fibrillary astrocyte protein, myelin basic protein, S100B, phosphorylated axonal neurofilament subunit H, neuron-specific enolase, tau and ubiquitin carboxyl-terminal hydrolase L1 in aSAH. MethodsWe detected plasma concentrations of the aforementioned biomarkers in 105 healthy controls using ELISA. Their predictive ability for symptomatic cerebral vasospasm and 6-month poor outcome (Glasgow Outcome Scale score of 1–3) were compared. ResultsPlasma concentrations of the preceding biomarkers were highly correlated with World Federation of Neurological Surgeons subarachnoid hemorrhage scale (WFNS) scores as well as were significantly higher in patients with symptomatic cerebral vasospasm than in those without symptomatic cerebral vasospasm and in patients with poor outcome than in those with good outcome. In terms of area under receiver operating characteristic curve, their predictive value for symptomatic cerebral vasospasm and 6-month poor outcome was in the range of WFNS scores. Plasma copeptin concentration, but not plasma concentrations of other biomarkers, statistically significantly improved the predictive performance of WFNS scores. ConclusionsCopeptin in plasma might have the potential to be a useful prognostic biomarker for aSAH.

Assessment of Serum UCH-L1 and GFAP in Acute Stroke Patients.

A rapid and reliable diagnostic test to distinguish ischemic from hemorrhagic stroke in patients presenting with stroke-like symptoms is essential to optimize management and triage for thrombolytic therapy. The present study measured serum concentrations of ubiquitin C-terminal hydrolase (UCH-L1) and glial fibrillary astrocytic protein (GFAP) in acute stroke patients and healthy controls and investigated their relation to stroke severity and patient characteristics. We also assessed the diagnostic performance of these markers for the differentiation of intracerebral hemorrhage (ICH) from ischemic stroke (IS). Both UCH-L1 and GFAP concentrations were significantly greater in ICH patients than in controls (p < 0.0001). However, exclusively GFAP differed in ICH compared with IS (p < 0.0001). GFAP yielded an AUC of 0.86 for differentiating between ICH and IS within 4.5hrs of symptom onset with a sensitivity of 61% and a specificity of 96% using a cut-off of 0.34ng/ml. Higher GFAP levels were associated with stroke severity and history of prior stroke. Our results demonstrate that blood UCH-L1 and GFAP are increased early after stroke and distinct biomarker-specific release profiles are associated with stroke characteristics and type. We also confirmed the potential of GFAP as a tool for early rule-in of ICH, while UCH-L1 was not clinically useful.

Neural differentiation of human umbilical cord mesenchymal stem cells by cerebrospinal fluid.

Wharton's jelly (WJ) is the gelatinous connective tissue from the umbilical cord. It is composed of mesenchymal stem cells, collagen fibers, and proteoglycans. The stem cells in WJ have properties that are interesting for research. For example, they are simple to harvest by noninvasive methods, provide large numbers of cells without risk to the donor, the stem cell population may be expanded in vitro, cryogenically stored, thawed, genetically manipulated, and differentiated in vitro. In our study, we investigated the effect of human cerebrospinal fluid (CSF) on neural differentiation of human WJ stem cells. The cells in passage 2 were induced into neural differentiation with different concentrations of human cerebrospinal fluid. Differentiation along with neural lineage was documented by expression of three neural markers: Nestin, Microtubule-Associated Protein 2 (MAP2), and Glial Fibrillary Astrocytic Protein (GFAP) for 21 days. The expression of the identified genes was confirmed by Reverse Transcriptase PCR (RT-PCR). Treatment with 100 and 200μg/ml CSF resulted in the expression of GFAP and glial cells marker on days 14 and 21. The expression of neural-specific genes following CSF treatment was dose-dependent and time-dependent. Treatment of the cells with a twofold concentration of CSF, led to the expression of MAP2 on day 14 of induction. No expression of GFAP was detected before day 14 or MAP2 before day 21, which shows the importance of the treatment period. In the present study, expression analysis for the known neural markers: Nestin, GFAP, and MAP2 using RT-PCR were performed. The data demonstrated that CSF could play a role as a strong inducer. RT-PCR showed that cerebrospinal fluid promotes the expression of Nestin, MAP2, and GFAP mRNA in a dose-dependent manner, especially at a concentration of 200 μl/ml. In summary, CSF induces neurogenesis of WJ stem cells that encourages tissue engineering applications with these cells for treatments of neurodegenerative defects and traumatic brain injury.

Comparison of the performances of copeptin and multiple biomarkers in long-term prognosis of severe traumatic brain injury

Enhanced blood levels of copeptin correlate with poor clinical outcomes after acute critical illness. This study aimed to compare the prognostic performances of plasma concentrations of copeptin and other biomarkers like myelin basic protein, glial fibrillary astrocyte protein, S100B, neuron-specific enolase, phosphorylated axonal neurofilament subunit H, Tau and ubiquitin carboxyl-terminal hydrolase L1 in severe traumatic brain injury. We recruited 102 healthy controls and 102 acute patients with severe traumatic brain injury. Plasma concentrations of these biomarkers were determined using enzyme-linked immunosorbent assay. Their prognostic predictive performances of 6-month mortality and unfavorable outcome (Glasgow Outcome Scale score of 1–3) were compared. Plasma concentrations of these biomarkers were statistically significantly higher in all patients than in healthy controls, in non-survivors than in survivors and in patients with unfavorable outcome than with favorable outcome. Areas under receiver operating characteristic curves of plasma concentrations of these biomarkers were similar to those of Glasgow Coma Scale score for prognostic prediction. Except plasma copeptin concentration, other biomarkers concentrations in plasma did not statistically significantly improve prognostic predictive value of Glasgow Coma Scale score. Copeptin levels may be a useful tool to predict long-term clinical outcomes after severe traumatic brain injury and have a potential to assist clinicians.

Prognostic significance of plasma copeptin detection compared with multiple biomarkers in intracerebral hemorrhage

BackgroundHigher plasma copeptin concentrations have been associated with poor clinical outcomes after intracerebral hemorrhage. This study was designed to compare plasma concentrations of copeptin and other biomarkers like myelin basic protein, glial fibrillary astrocyte protein, S100B, neuron-specific enolase, phosphorylated axonal neurofilament subunit H, tau and ubiquitin carboxyl-terminal hydrolase L1 for analysis of their prognostic prediction. MethodsWe measured plasma concentrations of these biomarkers in 118 healthy controls and in 118 acute patients with a comparison analysis for their prediction of 6-month mortality and unfavorable outcome (modified Rankin Scale score>2). ResultsPlasma concentrations of these biomarkers were statistically significantly higher in all patients than in healthy controls, in non-survivors than in survivors and in patients with unfavorable outcome than with favorable outcome. Areas under receiver operating characteristic curves of plasma concentrations of these biomarkers were similar to those of the National Institute of Health Stroke Scale score for prognostic prediction. Plasma copeptin concentration statistically significantly improved the prognostic predictive value of the National Institute of Health Stroke Scale score, but other biomarkers did not. ConclusionsCopeptin may help in the prediction of long-term clinical outcomes after intracerebral hemorrhage.

Autonomic dysfunction in adult-onset alexander disease

Alexander disease (AxD) is an astrogliopathy, resulting from a mutation in the glial fibrillary astrocytic protein gene. Different clinical subtypes have been described, including infantile, juvenile, and adult onset, based upon the age at which symptoms begin. Patients with the adult-onset form, develop a progressive, spastic paraparesis, palatal myoclonus, ataxia, and bulbar weakness. Autonomic nervous system (ANS) dysfunction has been reported as a potential manifestation of adult-onset AxD, but has not been well characterized. We report a case of adult-onset AxD with symptomatic orthostatic hypotension (OH) and heat intolerance that underwent formal autonomic testing. In addition, a comprehensive literature search was conducted to review the frequency and pattern of autonomic dysfunction in this patient population. A 51-year-old patient was diagnosed with AxD at the age of 47, following an 8-year history of vertigo, intermittent diplopia, and sleep disturbance. The patient developed symptoms of OH, erectile dysfunction, and heat intolerance soon after his diagnosis. Autonomic testing demonstrated OH on tilt-table testing (47mmHg decrease in BP with 18 BPM heart rate increment) with absent late phase II and IV responses during the Valsalva maneuver, severe cardiovagal impairment, and preserved postganglionic sympathetic sudomotor function. These findings were interpreted as being consistent with central autonomic failure. The most common autonomic symptoms reported in other AxD cases include constipation, urinary incontinence, and sphincter dysfunction. To our knowledge, this is the first report of formal autonomic testing in AxD. Signs and symptoms of ANS impairment can occur in patients with AxD, and can include orthostatic hypotension and bowel/bladder dysfunction. Autonomic testing in our patient suggests impairment in central autonomic pathways.

Neurobiochemical Markers of Brain Damage in Cerebrospinal Fluid of Acute Ischemic Stroke Patients

Ischemic injury to the central nervous system causes cellular activation and disintegration, leading to release of cell-type-specific proteins into the cerebrospinal fluid (CSF). We investigated CSF concentrations of myelin basic protein (MBP), glial fibrillary astrocytic protein (GFAP), the calcium-binding protein S100B, and neuron-specific enolase (NSE) in acute ischemic stroke patients and their relation to initial stroke severity, stroke location, and long-term stroke outcome. CSF concentrations of MBP, GFAP, S100B, and NSE were assessed in 89 stroke patients on admission (mean 8.7 h after stroke onset) and in 35 controls. We evaluated the relation between CSF concentrations and (a) stroke severity (NIH Stroke Scale [NIHSS] score on admission, infarct volume), (b) stroke location, and (c) stroke outcome (modified Rankin Scale [mRS] score at month 3). MBP concentration was significantly higher in subcortical than in cortical infarcts (median MBP, 1.18 vs 0.66 microg/L, P < 0.001). GFAP and S100B concentrations correlated with the NIHSS score on admission (GFAP, R = 0.35, P = 0.001; S100B, R = 0.29, P = 0.006), infarct volume (GFAP, R = 0.34, P = 0.001; S100B, R = 0.28, P = 0.008), and mRS score at month 3 (R = 0.42, P < 0.001 and R = 0.28, P = 0.007). Concentrations of NSE did not correlate with stroke characteristics. MBP, GFAP, S100B, and NSE display relevant differences in cellular and subcellular origins, which are reflected in their relation to stroke characteristics. MBP is a marker for infarct location. GFAP and S100B correlate with stroke severity and outcome.

Abstract P27: Microglial Activity and Therapeutic Hypothermia Post Cardiac Arrest Resuscitation in Rats

Background Therapeutic hypothermia after cardiac arrest (CA) improves survival and functional outcomes, but its neuroprotective mechanism remains unclear. We previously showed that immediate initiation of hypothermia post-CA led to better neuro-electrical and behavioral recovery. In this study, we quantified the impact of immediate versus conventional hypothermia with stereological technique on microglia (using expression of ionized calcium binding adaptor molecule 1 - Iba1), astrocytes (using expression of glial fibrillary astrocyte protein - GFAP), and neurons (by Cresyl-violet staining with histopathological damage scoring - HDS). Methods Forty-eight rats were randomly divided into 3 groups (n=16 per group), based on normothermia (NT, T=37°C), 6 hours of immediate hypothermia (IH, T=33°C, initiated immediately after CA), or 12 hours of conventional hypothermia (CH, T=33°C, initiated one hour after CA) after CA. Each group was then evenly divided to 2 subgroups (n=8 based on 7 or 9 min asphyxial time). Hypothermia was maintained using surface cooling. Neurological recovery was evaluated using serial Neurological Deficit Score (NDS) calculation. Results Better recovery by NDS 72 hours post-CA was noted in rats treated with IH (median, interquartile range: 72, 63–74), compared to CH (66, 43–70), and NT (51, 0 – 65) (p=0.005). There was a significantly different proportion of ischemic neurons by HDS in cortex (IH: 18.9±2.5%, CH: 33.2±4.4%, NT: 36.2±4.7%, p=0.002) and CA1 (IH: 14.4±2.9%, CH: 24.6±5.4%, NT: 49.2±5.3%, p&lt;0.001). There was significant less Iba-1 expression in CH compared to IH (p=0.042) and NT (p=0.012) in cortex and CA1. There was no difference for GFAP expression in cortex or CA1. Conclusions Immediate hypothermia leads to better functional outcome and lower ischemic neuronal injury in rats after CA. Temperature manipulation seems to affect the immune response to CA, with increased microglial activity in the IH and NT groups compared to CH group in this injury model. The longer hypothermia duration may decrease the microglia activation in response of central nervous system to CA than short duration in this injury model. No difference was noted in the astrocytic activity in the different groups.