Elevated Glial Fibrillary Acidic Protein Levels Research Articles

Plasma neurofilament light outperforms glial fibrillary acidic protein in differentiating behavioural variant frontotemporal dementia from primary psychiatric disorders

ObjectiveTimely, accurate distinction between behavioural variant frontotemporal dementia (bvFTD) and primary psychiatric disorders (PPD) is a clinical challenge. Blood biomarkers such as neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP) have shown promise. Prior work has shown NfL helps distinguish FTD from PPD. Few studies have assessed NfL together with GFAP. MethodsWe investigated plasma GFAP and NfL levels in participants with bvFTD, bipolar affective disorder (BPAD), major depressive disorder (MDD), treatment-resistant schizophrenia (TRS), healthy controls (HC), adjusting for age and sex. We compared ability of GFAP and NfL to distinguish bvFTD from PPD. ResultsPlasma GFAP levels were significantly (all p < 0.001) elevated in bvFTD (n = 22, mean (M) = 273 pg/mL) compared to BPAD (n = 121, M = 96 pg/mL), MDD (n = 42, M = 105 pg/mL), TRS (n = 82, M = 67.9 pg/mL), and HC (n = 120, M = 76.8 pg/mL). GFAP distinguished bvFTD from all PPD with an area under the curve (AUC) of 0.85, 95 % confidence interval [0.76, 0.95]. The optimal cut-off of 105 pg/mL was associated with 73 % specificity and 86 % sensitivity. NfL had AUC 0.95 [0.91, 0.99], 13.3 pg/mL cut-off, 88 % specificity, 86 % sensitivity, and was superior to GFAP (p = 0.02863) and combination of GFAP and NfL (p = 0.04726). ConclusionsThis study found elevated GFAP levels in bvFTD compared to a large cohort of PPD, but NfL levels exhibited better performance in this distinction. These findings extend the literature on GFAP in bvFTD and build evidence for plasma NfL as a useful biomarker to assist with distinguishing bvFTD from PPD. Utilisation of NfL may improve timely and accurate diagnosis of bvFTD.

Mode of administration influences plasma levels of active Centella asiatica compounds in 5xFAD mice while markers of neuroinflammation remain unaltered.

A water extract of Centella asiatica (L.) Urban [Apiaceae] (CAW) has demonstrated cognitive-enhancing effects in mouse models of Alzheimer's disease and aging, the magnitude of which is influenced by whether CAW is delivered in the drinking water or the diet. These cognitive benefits are accompanied by improvements in oxidative stress and mitochondrial function in the brain, two pathways related to the neuroinflammatory response. The effect of CAW on neuroinflammation, however, has not been directly studied. Here, we investigated the effect of CAW on neuroinflammation in 5xFAD mice and compared plasma levels of CAW's active compounds following two modes of CAW administration. Eight-to-nine-month-old male and female 5xFAD mice and their wild-type littermates were administered CAW in their diet or drinking water (0 or 1,000 mg/kg/day) for five weeks. Immunohistochemistry was performed for β-amyloid (Aβ), glial fibrillary acidic protein (GFAP), and Griffonia simplicifolia lectin I (GSL I) in the cortex and hippocampus. Gene expression of inflammatory mediators (IL-6, TNFα, IL-1β, TREM2, AIF1, CX3CR1, CX3CL1, CD36, C3AR1, RAGE, CCR6, CD3E) was measured in the deep grey matter. CAW decreased cortical Aβ plaque burden in female 5xFAD mice administered CAW in the drinking water but had no effect on Aβ plaques in other treatment groups. CAW did not impact elevated levels of GFAP or GSL I in 5xFAD mice, regardless of sex, brain region, or mode of CAW administration. In the deep grey matter, CAW increased C3AR1 expression in 5xFAD females administered CAW in the drinking water and decreased IL-1β expression in 5xFAD males administered CAW in the diet. CAW had no effect, however, on gene expression levels of any other inflammatory mediator in the deep grey, for either sex or mode of CAW administration. Mice administered CAW in the drinking water versus the diet had significantly higher plasma levels of CAW compounds. CAW had little impact on the neuroinflammatory markers selected for evaluation in the present study, suggesting that the cognitive benefits of CAW may not be mediated by an anti-inflammatory effect or that additional molecular markers are needed to fully characterize the effect of CAW on neuroinflammation.

DPP4 Valorphin Activate NR4As Pathway and OPA1 That Protect from CoQ10 Deficiency, OPA1 Dysfunctions and WMH

Deficiencies in Threonine (Thr), Tryptophan hydroxylase (Tph), Glutamate (Glu), Glutamine (Gln), and Leucine can result from increased polarizability in mTORC1 and its subunits. These deficiencies may lead to disorders in OPA1 repair, which can be a primary cause of Coenzyme Q10 (CoQ10) deficiency disease. CoQ10 is crucial for maintaining the inner mitochondrial membrane and is necessary for the synthesis of the glucocorticoid receptor (GCR). Mitochondrial damage or dysfunction can lead to the accumulation of pro-inflammatory molecules, which may cause mutations in subunits and proteins. Reduced levels of Tryptophan, Glycine (Gly), and Arginine (Arg) can result in decreased Proline synthesis, subsequently reducing tRNA levels. This, in turn, can impair mitochondrial OPA1 repair and function due to decreased GTPase activity. The reduced function of GTPase can lead to decreased IL-17 synthesis and the accumulation of pro-inflammatory molecules, resulting in a reduction in serotonin production, as well as decreased production of GCbeta, oxytocin, and Nrf2. These changes can lead to a decrease in the proliferation of megakaryocytes and, consequently, reduced hematopoiesis, which is associated with white matter hyperintensity. Opioid receptors play a role in producing powerful analgesia, contributing to the function of immune cells, and modulating acquired immune responses, including the function of lymphocytes. Tryptophan, Leucine, and Tyrosine kinases are crucial for activating mitochondrial OPA1 repairs, which are essential for CoQ10 synthesis. Tryptophan (TGG) is necessary for activating Proline, which is essential for both OPA1 function and tRNA production. Additionally, it plays a role in IL17 synthesis and the activation of the NR4As pathway, which includes the activation of GCs-beta, oxytocin, and Nrf2 production, respectively. Cytotoxic edema can result from uncontrolled or uncompensated cation influx, primarily sodium (Na+). This edema occurs due to high levels of potassium (K) and sodium (Na) binding toxicity, leading to coagulation and reduced ATPase and GTPase activity. It starts with a decrease in CoQ10 synthesis and an increase in Plasma Glial Fibrillary Acidic Protein (GFAP), resulting in decreased mineralocorticoid. Increased sodium and potassium binding, associated with decreased anions binding in biological molecules, can be due to reduced GTPase and OPA1 function. This reduction in anions function is the result of a primary Coenzyme Q10 (CoQ10) deficiency, leading to elevated GFAP levels in cognitively normal older adults at risk of Alzheimer's disease. Primary Coenzyme Q10 (CoQ10) deficiency is typically associated with multisystem involvement, including neurologic manifestations such as fatal neonatal encephalopathy with hypoxia, late-onset multiple-system atrophy-like symptoms, dystonia, spasticity, seizures, and intellectual disability. Autoimmune diseases and skin inflammatory disorders can start due to increased cation binding toxicity, which reduces ATPase and GTPase function, characterized by a deficiency in proper GTPase production, leading to a reduction in mitochondrial OPA1 function and a deficiency in GCs-beta synthesis via the NR4As pathway. GFAP is an important neuroinflammation biomarker, and an increase in its levels may indicate OPA1 dysfunction, a decrease in CoQ10, neuroinflammation, and a reduction in the NR4As pathway. The increase in GFAP during acute ischemic stroke can be initiated by increased cation binding to anions, leading to enhanced energy stability and decreased tRNA production, which is proline-dependent. This decrease in tRNAs and GTPase activity can result in a decrease in IL17 production, increased inflammation, decreased blood flow to the brain, and reduced oxygen supply to the brain, ultimately contributing to neuronal damage. A decrease in hemorphin (valorphin) reflects reduced lymphocyte function and a loss of cholinecontaining phospholipids (CCPLs). Valorphin contains Tyrosine, which is essential for kinases production, required for choline kinases synthesis, and crucial for activating tRNAs, serotonin, oxytocin, and Nrf2 via the NR4As pathway, all of which are essential for lymphocyte function and antiinflammatory growth. Nrf2 dysfunction, connected to NR4As and oxytocin dysfunction, plays a significant role in the pathogenesis of vascular cognitive impairment and dementia (VCID).

Blood Biomarkers as Prognostic Indicators for Neurological Injury in COVID-19 Patients: A Systematic Review and Meta-Analysis.

Coronavirus disease 2019 (COVID-19) has been linked to various neurological complications. This meta-analysis assessed the relationship between glial fibrillary acidic protein (GFAP) and neurofilament light chain (NfL) levels in the blood and neurological injury in COVID-19 patients. A comprehensive search of various databases was conducted until 18 August 2023, to find studies reporting GFAP and NfL blood levels in COVID-19 patients with neurological complications. GFAP and NfL levels were estimated between COVID-19 patients and healthy controls, and meta-analyses were performed using RevMan 5.4 software for analysis. In the 21 collected studies, it was found that COVID-19 patients had significantly higher levels of pooled GFAP (SMD = 0.52; 95% CI: 0.31, 0.73; p ≤ 0.001) and NfL (SMD = 0.60; 95% CI: 0.37, 0.82; p ≤ 0.001) when compared to the healthy controls. The pooled GFAP (SMD = 0.86; 95% CI: 0.26, 1.45; p ≤ 0.01) and NfL (SMD = 0.87; 95% CI: 0.48, 1.26; p ≤ 0.001) were significantly higher in non-survivors. These findings indicate a significant association between COVID-19 severity and elevated levels of GFAP and NfL, suggesting that GFAP and NfL could serve as potential diagnostic and prognostic markers for the early detection and monitoring of COVID-19-related neurological injuries.

Development of an ultrasensitive microfluidic assay for the analysis of Glial fibrillary acidic protein (GFAP) in blood.

Introduction: A rapid and reliable detection of glial fibrillary acidic protein (GFAP) in biological samples could assist in the diagnostic evaluation of neurodegenerative disorders. Sensitive assays applicable in the routine setting are needed to validate the existing GFAP tests. This study aimed to develop a highly sensitive and clinically applicable microfluidic immunoassay for the measurement of GFAP in blood. Methods: A microfluidic GFAP assay was developed and validated regarding its performance. Subsequently, serum and cerebrospinal fluid (CSF) of Alzheimer's disease (AD), Multiple Sclerosis (MS) and control patients were analyzed with the established assay, and levels were compared to the commercial GFAP Simoa discovery kit. Results: The developed GFAP assay showed a good performance with a recovery of 85% of spiked GFAP in serum and assay variations below 15%. The established assay was highly sensitive with a calculated lower limit of quantification and detection of 7.21pg/mL and 2.37pg/mL, respectively. GFAP levels were significantly increased in AD compared to control patients with advanced age (p = 0.002). However, GFAP levels revealed no significant increase in MS compared to control patients in the same age range (p = 0.140). Furthermore, serum GFAP levels evaluated with the novel microfluidic assay strongly correlated with Simoa concentrations (r = 0.88 (95% CI: 0.81-0.93), p < 0.0001). Conclusion: We successfully developed a sensitive and easy-to-use microfluidic assay to measure GFAP in blood. Furthermore, we could confirm previous findings of elevated GFAP levels in AD by applying the assay in a cohort of clinically characterized patients.

Serum glial fibrillary acidic protein (GFAP) predicts outcome after intracerebral and subarachnoid hemorrhage.

Intracerebral and subarachnoid hemorrhage are critical conditions with a high mortality, and the outcome for the individual patient is notoriously difficult to predict. Biomarkers that reflect disease severity and predict outcome are therefore warranted. Blood samples from 40 patients with intracerebral, 46 patients with subarachnoid hemorrhage, and 70 healthy individuals were collected. Levels of glial fibrillary acidic protein (GFAP) and neuroglobin were measured by ultra-sensitive single molecule array and enzyme-linked immunosorbent assay, respectively. Clinical information including mortality and functional outcome was recorded. Blood levels of GFAP and neuroglobin in intracerebral and subarachnoid hemorrhage patients were significantly elevated when compared to healthy individuals (all p < 0.0001). GFAP levels were significantly higher in patients dying or with poor functional outcome than in healthy individuals (all p ≤ 0.01). GFAP levels separated survivors from non-survivors with an area under receiver operating characteristics (AUROC) = 0.78 (confidence interval (CI) 0.59-0.98) for intracerebral hemorrhage and 0.82 (CI 0.69-0.94) for subarachnoid hemorrhage patients. The Akaike and Bayesian information criteria (AIC/BIC) for mortality/poor outcome prediction improved when combining GFAP levels with hematoma volume (p = 0.04/p < 0.01), National Institutes of Health Stroke Scale (NIHSS) (p = 0.09/p < 0.01), Hunt-Hess (p < 0.05/p = 0.21), or Fischer score (p < 0.05/p = 0.02). Elevated GFAP levels at admission to hospital predicted mortality and poor outcome in our cohort of intracerebral and subarachnoid hemorrhage patients. Neuroglobin levels did not provide additional information. Combining GFAP measurements with clinical disease severity scores increased outcome prediction precision. This may suggest that GFAP measurement could improve prognostication in patients with intracerebral or subarachnoid hemorrhage. This sub-trial was not registered.

Relative stabilities of wild-type and mutant glial fibrillary acidic protein in patients with Alexander disease

Alexander disease (AxD) is an often fatal astrogliopathy caused by dominant gain-of-function missense mutations in the glial fibrillary acidic protein (GFAP) gene. The mechanism by which the mutations produce the AxD phenotype is not known. However, the observation that features of AxD are displayed by mice that express elevated levels of GFAP from a human WT GFAP transgene has contributed to the notion that the mutations produce AxD by increasing accumulation of total GFAP above some toxic threshold rather than the mutant GFAP being inherently toxic. A possible mechanism for accumulation of GFAP in AxD patients is that the mutated GFAP variants are more stable than the WT, an attribution abetted by observations that GFAP complexes containing GFAP variants are more resistant to solvent extraction. Here we tested this hypothesis by determining the relative levels of WT and mutant GFAP in three individuals with AxD, each of whom carried a common but different GFAP mutation (R79C, R239H, or R416W). Mass spectrometry analysis identified a peptide specific to the mutant or WT GFAP in each patient, and we quantified this peptide by comparing its signal to that of an added [15N]GFAP standard. In all three individuals, the level of mutant GFAP was less than that of the WT. This finding suggests that AxD onset is due to an intrinsic toxicity of the mutant GFAP instead of it acting indirectly by being more stable than WT GFAP and thereby increasing the total GFAP level.

A Systematic Review of the Usefulness of Glial Fibrillary Acidic Protein for Predicting Acute Intracranial Lesions following Head Trauma.

The extensive use of computed tomography (CT) after acute head injury is costly and carries potential iatrogenic risk. This systematic review examined the usefulness of blood-based glial fibrillary acidic protein (GFAP) for predicting acute trauma-related CT-positive intracranial lesions following head trauma. The main objective was to summarize the current evidence on blood-based GFAP as a potential screening test for acute CT-positive intracranial lesions following head trauma. We screened MEDLINE, EMBASE, PsychInfo, CINAHL, Web of Science, the Cochrane Database, Scopus, Clinical Trials, OpenGrey, ResearchGate, and the reference lists of eligible publications for original contributions published between January 1980 and January 2017. Eligibility criteria included: (i) population: human head and brain injuries of all severities and ages; (ii) intervention: blood-based GFAP measurement ≤24 h post-injury; and (iii) outcome: acute traumatic lesion on non-contrast head CT ≤24 h post-injury. Three authors completed the publication screening, data extraction, and quality assessment of eligible articles. The initial search identified 4,706 articles, with 51 eligible for subsequent full-text assessment. Twenty-seven articles were ultimately included. Twenty-four (89%) studies reported a positive association between GFAP level and acute trauma-related intracranial lesions on head CT. The area under the receiver operating characteristic curve for GFAP prediction of intracranial pathology ranged from 0.74 to 0.98 indicating good to excellent discrimination. GFAP seemed to discriminate mass lesions and diffuse injury, with mass lesions having significantly higher GFAP levels. There was considerable variability between the measured GFAP averages between studies and assays. No well-designed diagnostic studies with specific GFAP cutoff values predictive of acute traumatic intracranial lesions have been published. Intracranial CT-positive trauma lesions were associated with elevated GFAP levels in the majority of studies. Methodological heterogeneity in GFAP assessments and the lack of well-designed diagnostic studies with commercially validated GFAP platforms hinder the level of evidence, and variability in levels of GFAP with no clearly established cutoff for abnormality limit the clinical usefulness of the biomarker. However, blood-based GFAP holds promise as a means of screening for acute traumatic CT-positive lesion following head trauma.

Lithium Decreases Glial Fibrillary Acidic Protein in a Mouse Model of Alexander Disease.

Alexander disease is a fatal neurodegenerative disease caused by mutations in the astrocyte intermediate filament glial fibrillary acidic protein (GFAP). The disease is characterized by elevated levels of GFAP and the formation of protein aggregates, known as Rosenthal fibers, within astrocytes. Lithium has previously been shown to decrease protein aggregates by increasing the autophagy pathway for protein degradation. In addition, lithium has also been reported to decrease activation of the transcription factor STAT3, which is a regulator of GFAP transcription and astrogliogenesis. Here we tested whether lithium treatment would decrease levels of GFAP in a mouse model of Alexander disease. Mice with the Gfap-R236H point mutation were fed lithium food pellets for 4 to 8 weeks. Four weeks of treatment with LiCl at 0.5% in food pellets decreased GFAP protein and transcripts in several brain regions, although with mild side effects and some mortality. Extending the duration of treatment to 8 weeks resulted in higher mortality, and again with a decrease in GFAP in the surviving animals. Indicators of autophagy, such as LC3, were not increased, suggesting that lithium may decrease levels of GFAP through other pathways. Lithium reduced the levels of phosphorylated STAT3, suggesting this as one pathway mediating the effects on GFAP. In conclusion, lithium has the potential to decrease GFAP levels in Alexander disease, but with a narrow therapeutic window separating efficacy and toxicity.

Cerebrospinal fluid biomarkers in facial nerve palsy caused by Varicella Zoster virus

No: 1680 Presentation at ESCV 2015: Poster 1 Cerebrospinal fluid biomarkers in facial nerve palsy caused by Varicella Zoster virus J. Lindstrom1,∗, A. Grahn1, H. Zetterberg2, M. Studahl1 1 Department of Infectious Diseases, Sahlgrenska University Hospital, Ostra, Goteborg, Sweden 2 Clinical Neurochemistry Laboratory, Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry, Sweden Background: Reactivation of Varicella Zoster virus (VZV) can cause facial nerve palsy with neurological sequels despite treatment with aciclovir and/or corticosteroids. Associated symptoms such as vertigo and loss of hearing are frequent. Facial nerve palsy caused by VZV manifest as Ramsay Hunt syndrome when blisters are present, or as zoster sine herpete without blisters. Neurofilament light protein (NFL), glial fibrillary acidic protein (GFAp) and S-100 are cerebrospinal fluid (CSF) biomarkers that have been used to estimate severity of neuronal damage and prognosis in various CNS diseases. One previous study has been performed on VZV in the central nervous system (CNS), but patients with facial palsy have not been specifically studied. Methods: 28 patientswith VZV facial palsy, diagnosed by detection of VZV DNA in CSF by PCR, were retrospectively identified. GFAp, NFL and S-100 were measured in stored CSF samples and compared with a control group (n=52). Medical records were studied for relevant patient data such as severity of symptoms, treatment and laboratory parameters. Results: CSF concentrations of NFL and GFAp were significantly elevated compared to controls (p<0.01 and p<0.05) and S-100 concentrations were reduced. Additionally, NFL kinetics indicated slightly increasing concentrations in CSF samples drawn more than seven days after onset of neurological symptoms. Viral load (VZV DNA copies/ml) correlated with both NFL (Spearman r=0.51; p<0.01) and GFAp (Spearman r=0.54; p<0.01). No correlations were found between biomarkers and severity of symptoms, clinical outcome at follow-up, or treatment with aciclovir prior to CSF sampling in this small study. Conclusion: In this first study on biomarkers in facial palsy caused by VZV, we identified a pattern of elevated NFL, elevated GFAp and decreased S-100 compared to controls. Increased NFL levels reflect axonal damage, and elevated levels of GFAp, in combination with decreased concentrations of S-100 , indicate astrogliosis rather than damage to the astroglial cell membrane. Biomarkers of neuron and glial cell damage can be used to understand pathogenesis, and in future studies assessment of these biomarkers in relation to treatment and clinical outcome should be explored. http://dx.doi.org/10.1016/j.jcv.2015.07.137 Abstract No: 1682 Presentation at ESCV 2015: Poster 1 False negative influenza A virus subtype H3N2 in Prodesse GenProbe ProFlu+ PCR assay in season 2014–2015 N. Kirkby1,∗, T.N. Thomsen1, R. Trebbien2, K. Vorborg2, J. Ronn2, T.K. Fischer2, C.B. Christiansen1 1 Department of Clinical Microbiology, Rigshospitalet, Copenhagen, Denmark 2 National Influenza Center, Virological Surveillance and Research Department of Microbiological

Increased expression of glial fibrillary acidic protein in prefrontal cortex in psychotic illness

Astrocyte dysregulation has been implicated in the pathophysiology of schizophrenia (SCZ) and bipolar disorder (BPD), however the exact nature of astrocytic alterations remains to be identified. In this study we investigated whether levels of four astrocyte-specific proteins; glial fibrillary acidic protein (GFAP), aldehyde dehydrogenase 1L1 (ALDH1L1), vimentin and excitatory amino acid transporter 1 (EAAT1) are altered in SCZ and BPD. Relative concentrations of GFAP, ALDH1L1, vimentin and EAAT1 were assessed post-mortem in dorsolateral prefrontal cortex in SCZ (n=35), BPD (n=34) and non-psychiatric controls (n=35) by western blotting. The same proteins were also quantified in cingulate cortex of rats administered the antipsychotics haloperidol and clozapine. Elevated levels of GFAP were observed in SCZ and BPD, when compared to controls. GFAP was also significantly increased when comparing individuals with psychotic symptoms against those without. Vimentin, ALDH1L1 and EAAT1 levels did not differ between groups. Rats exposed to antipsychotics did not exhibit significant differences in any astrocytic protein, suggesting that increased GFAP in SCZ is not attributable to antipsychotic treatment. Our findings indicate that astrocyte pathology may be associated with psychotic symptoms. Lack of ALDH1L1 and vimentin variability and increased GFAP levels may imply that astrocyte numbers are unchanged but astrocytes are partially activated, or may indicate a specific dysregulation of GFAP.

Rotenone-induced neurotoxicity in rat brain areas: A study on neuronal and neuronal supportive cells

The present study was conducted to correlate rotenone-induced neurotoxicity with cellular and molecular modifications in neuronal and neuronal supportive cells in rat brain regions. Rotenone was administered (3, 6 and 12μg/μl) intranigrally in adult male Sprague-Dawley rats. After the 7th day of rotenone treatment, specific protein markers for neuronal cells – tyrosine hydroxylase (TH), astroglial cells – glial fibrillary acidic protein (GFAP), microglial cells – CD11b/c, and Iba-1 were evaluated by immunoblotting and immunofluorescence in the striatum (STR) and mid brain (MB). Apoptotic cell death was assessed by caspase-3 gene expression. Higher doses of rotenone significantly lowered TH protein levels and elevated Iba-1 levels in MB. All the doses of rotenone significantly increased GFAP and CD11b/c protein in the MB. In STR, rotenone elevated GFAP levels but did not affect TH, CD11b/c and Iba-1 protein levels. Caspase-3 expression was increased significantly by all the doses of rotenone in MB but in STR only by higher doses (6 and 12μg). It may be suggested that astroglial activation and apoptosis play an important role in rotenone-induced neurotoxicity. MB appeared as more sensitive than STR toward rotenone-induced cell toxicity. The astroglial cells emerged as more susceptible than neuronal and microglial cells to rotenone in STR.

A literature review of the feasibility of glial fibrillary acidic protein as a biomarker for stroke and traumatic brain injury.

Traumatic brain injuries (TBIs) are potentially lethal medical conditions, with symptoms that can overlap with symptoms of injuries outside the brain. In many cases, current diagnostic methods do not fully distinguish acute brain injury from other organ damage. In the management of stroke patients, the choice of treatment depends on whether the stroke is ischemic or hemorrhagic; however, no quick lab diagnostic tests are available to distinguish between the two types of strokes. As a result, patient triage, disposition, and patient management decisions may be delayed for patients with suspected TBI and stroke. Glial fibrillary acidic protein (GFAP), a brain-specific biomarker that is released into the blood following TBI and stroke, is being explored for potential diagnostic and prognostic value in these indications. We therefore conducted a review of MEDLINE-indexed publications from 2004 to 2011 to evaluate the current status of GFAP as a prognostic and diagnostic tool for TBI and stroke within the context of current published guidelines. Our review suggests that GFAP could provide clinically valuable information for the prognosis of TBI and stroke, but it is still at an early stage of development as a biomarker. Several TBI studies have shown elevated GFAP levels following a TBI event to be associated with greater severity of injury, poorer outcomes, and increased mortality. Clinical studies also indicate that GFAP has potential clinical utility in the differential diagnosis of various types of stroke. However, more clinical research will be required to determine the ability of GFAP levels to diagnose TBI in heterogeneous patient populations, as well as the ability of GFAP to differentiate between ischemic stroke (IS), intracerebral hemorrhage (ICH), subarachnoid hemorrhage (SAH), and non-stroke conditions in populations of patients with suspected rather than confirmed stroke. Additional clinical studies will also be required to define the temporal patterns of GFAP release in IS, ICH, SAH, and TBI, and their potential use in the differential diagnosis of these conditions. Finally, such research could demonstrate the ability of GFAP test results to provide unique clinical information that informs management decisions for TBI and stroke patients.

163: Electronic fetal monitoring (EFM) patterns in the second stage of labor: association and test characteristics for fetal acidemia

in the second stage of labor: association and test characteristics for fetal acidemia Alison G. Cahill, Anthony Odibo, Kimberly Roehl, George Macones Washington University in St. Louis, Department of Obstetrics and Gynecology, St. Louis, MO OBJECTIVE: To estimate the association and screening efficacy of EFM patterns prior to delivery and acidemia using NICHD Categories and definitions. STUDY DESIGN: We conducted a 5-year retrospective cohort study of all singleton, non-anomalous gestations delivered at 37 weeks from the second stage of labor. The primary exposure was 30 minutes of EFM immediately prior to delivery, interpreted by 2 dedicated obstetric research nurses, formally trained and re-trained in EFM interpretation, blind to clinical and outcome data. EFM patterns were interpreted using the NICHD nomenclature, including the 3-Category system and feature definitions. EFM was interpreted in 10-minute epochs, and then overall. The primary outcome was acidemia, defined as an umbilical cord gas pH 7.10. Relative risks and 95% confidence intervals, and test characteristics for acidemia were calculated. RESULTS: Of 5,388 patients meeting inclusion criteria, 98.9% (5331) had a pH 7.10 and 1.1% (57) were acidemic. In bivariate analyses of the EFM patterns 30 minutes prior to delivery, baseline tachycardia (RR 3.3, 1.7 6.3) was the only pattern among NICHD-defined EFM Categories or features associated with acidemia; Categories IIII, minimal variability (RR 0.7, 0.3–1.6), marked variability (RR 2.2, 1.0 4.6), repetitive late (RR 1.3, 0.5–3.4) and prolonged decelerations (RR 3.1, 1.2– 8.2) all demonstrated no association. Test characteristics for each EFM Category or features were equally poor (Table). CONCLUSION: The NICHD 3-tiered Category system, as well as specifically defined features such as variability and deceleration types, demonstrate weak or no association with acidemia and do not demonstrate clinically useful test properties for EFM interpretation in the second stage. 164 Glial fibrillary acidic protein as a serum biomarker for the early identification of neonatal periventricular white matter injury in preterm neonates Amanda Stewart, Jacky Jennings, Aylin Tekes, Huisman Thierry, Frances Northington, William Savage, Allen Everett, Ernest Graham Johns Hopkins University School of Medicine, Gynecology and Obstetrics, Division of Maternal-Fetal Medicine, Baltimore, MD, John Hopkins University School of Medicine, Pediatrics, Baltimore, MD, Johns Hopkins University School of Medicine, Pediatric Neuro-Radiology, Baltimore, MD, Johns Hopkins University School of Medicine, Pediatrics, Baltimore, MD, Johns Hopkins University School of Medicine, Pathology-Transfusion Medicine, Baltimore, MD, Johns Hopkins University School of Medicine, Pediatric Cardiology, Baltimore, MD OBJECTIVE: Periventricular white matter injury(PWMI) in preterm infants results in cerebral palsy in 60-100% of survivors. Glial fibrillary acidic protein(GFAP), an abundant white matter protein localized to astrocytes, is normally undetectable in serum and only measureable after CNS injury. We sought to determine if serum GFAP levels can be used to identify neonates developing PWMI. STUDY DESIGN: This is a case control study of all neonates born at a single tertiary care hospital from 4/09 4/11 at 2334 weeks gestation diagnosed with PWMI on a head ultrasound at 6 weeks of life. Each case with PWMI was gestational age matched to a subsequent neonate with a normal head ultrasound. GFAP was measured in cord blood at the time of birth, at NICU admission, and on days 1-4 of life. Paired variables were compared using paired t-tests and McNemar chi square. Wilcoxon rank sum tests were used to compare GFAP levels. RESULTS: During this 2 year period, 21 cases with PWMI occurred. Cases and controls did not differ in birthweight (1077 / 544 grams, 963 / 492 grams) or incidence of cesarean delivery (61.9%, 66.7%). Cases with PWMI had a significantly increased incidence of intraventricular hemorrhage (90.5%, 23.8%, p 0.001), 5 min Apgar 7 (66.7%, 23.8%, p 0.01) and seizures (42.9%, 0%, p 0.004). There was no significant difference in umbilical arterial pH (7.22 /1 0.19, 7.27 / 0.06), or base deficit (4.4 / 6.8, 2.6 / 1.7). GFAP was not significantly different in cord blood, at NICU admission, or day 1, but was significantly increased at days 2-4 of life (p 0.002, 0.0005, 0.04). The 6 cases with cystic PWMI had significantly elevated GFAP levels compared to other cases (p 0.03). Logistic regression of GFAP at day 4 of life showed sensitivity 50%, specificity 78.6%, PPV 75% and NPV 55% in identifying PWMI. CONCLUSION: Serum GFAP levels were significantly elevated on day of life 2-4 in neonates diagnosed with PWMI at 6 weeks. Measurement of GFAP in the perinatal period provides a rapid quantitative way to diagnose white matter injury, and may also correlate with the scale of injury and neurocognitive outcomes. Poster Session I Clinical Obstetrics, Medical-Surgical-Disease, Neonatology, Physiology-Endocrinology www.AJOG.org

Glial fibrillary acidic protein as a biomarker for neonatal hypoxic-ischemic encephalopathy treated with whole-body cooling

Glial fibrillary acidic protein (GFAP) is specific to astrocytes in the central nervous system. We hypothesized that serum GFAP would be increased in neonates with hypoxic-ischemic encephalopathy (HIE) treated with whole-body cooling. We measured GFAP at birth and daily for up to 7 days for neonates in the intensive care unit. We compared neonates with HIE treated with whole-body cooling to gestational age-matched controls without neurological injury and neonates with HIE by brain abnormalities on magnetic resonance imaging (MRI). Neonates with HIE had increased GFAP levels compared with controls. Neonates with HIE and abnormal brain imaging had elevated GFAP levels compared with neonates with HIE and normal imaging. Serum GFAP levels during the first week of life were increased in neonates with HIE and were predictive of brain injury on MRI. Biomarkers such as GFAP could help triage neonates with HIE to treatment, measure treatment efficacy, and provide prognostic information.

Plasma glial fibrillary acidic protein levels in children with sickle cell disease

To determine if glial fibrillary acidic protein (GFAP) is associated with brain injury in children with sickle cell disease (SCD), we measured plasma GFAP among cross-sectional groups of unselected children with SCD, subsets of children with SCD and normal brain MRI or MRI evidence of cerebral infarct, healthy pediatric controls, and adults with brain injury. Children with SCD had higher plasma GFAP than healthy pediatric controls (mean concentrations 0.14 ± 0.37 vs. 0.07 ± 0.08 ng/mL; P 5 0.003); also, 16.0% (16/100) of children with SCD and cerebral infarct had GFAP elevations above the 95th percentile of healthy pediatric controls (P 5 0.04). Although not statistically significant, children with SCD and cerebral infarct had more elevated GFAP levels than with SCD and no infarct (16/100, 16.0% vs. 14/168, 8.3%; P 5 0.07). Children with SCD and acute brain ischemia had a higher proportion of elevated GFAP than SCD children with normal MRI (3/6, 50% vs.8.3%; P 5 0.01). GFAP was associated with elevated systolic blood pressure in the preceding year and correlated positively with white blood cell count and negatively with age and performance IQ. Plasma GFAP is elevated among children with SCD and may be associated with subclinical brain injury.

Associations of cortical astrogliosis with cognitive performance and dementia status

We examined 204 decedents of the autopsy component of the Honolulu-Asia Aging Study, a longitudinal cohort study, who had been clinically assessed for dementia. A sensitive ELISA technique was used to quantify glial fibrillary acidic protein (GFAP), a marker for astrogliosis, in four specific cortical brain regions and assess associations between GFAP and 1) a measure of cognitive function, 2) several clinical dementia conditions, and 3) neuritic plaque (NP) and neurofibrillary tangle (NFT) formation. Cognitive function was inversely associated with GFAP in the occipital, parietal and temporal lobes, but not in the frontal lobe. This relationship remained significant when the contribution of NP and NFT counts was removed. Further, compared to brain samples from non-demented individuals, significantly greater GFAP levels were found in samples from individuals diagnosed with Alzheimer's disease, mixed dementia, and vascular mediated dementia. Because elevated levels of GFAP reflect astroglial responses to even subtle forms of neural damage, our data indicate that increments in GFAP may provide independent, supporting evidence for the damage underlying dementia, even in the absence of other evidence of neuropathology such as the presence of NPs or NFTs. Our findings underscore the need to look beyond standard neuropathological measures putatively linked to specific neuropathological conditions in efforts to identify common cellular and molecular processes that contribute to dementia.

Early Abeta accumulation and progressive synaptic loss, gliosis, and tangle formation in AD brain.

Pathologic changes in the Alzheimer disease (AD) brain occur in a hierarchical neuroanatomical pattern affecting cortical, subcortical, and limbic regions. To define the time course of pathologic and biochemical changes-amyloid deposition, amyloid beta-peptide (Abeta) accumulation, neurofibrillary tangle (NFT) formation, synaptic loss, and gliosis-within the temporal association cortex of AD cases of varying disease duration, relative to control brains. Stereologic assessments of amyloid burden and tangle density as well as ELISA-based measurements of Abeta, synaptophysin, and glial fibrillary acidic protein (GFAP) were performed in the superior temporal sulcus from a cohort of 83 AD and 26 nondemented control brains. Relative to control cases, AD brains were characterized by accumulation of NFT and amyloid plaques, increase of tris- and formic acid-extractable Abeta species, reduced levels of synaptophysin, and elevated levels of GFAP. In AD cases, the duration of dementia correlated with the degree of tangle formation, gliosis, and synaptic loss but not with any Abeta measures. Accumulation of Abeta, measured both neuropathologically and biochemically, was markedly increased in AD brains independent of disease duration, even in cases of short duration. These data support distinct processes in the initiation and progression of AD pathology within the temporal cortex: Deposition of Abeta reaches a "ceiling" early in the disease process, whereas NFT formation, synaptic loss, and gliosis continue throughout the course of the illness.

Detection of glial fibrillary acidic protein and neurofilaments in the cerebrospinal fluid of patients with neurocysticercosis.

Neurocysticercosis (NCC) is an infection caused by Taenia solium larval metacestodes in the central nervous system. The glial fibrillary acidic protein (GFAP) and neurofilaments (NFs) can be used as markers of glial and neuronal damage, respectively. We studied the GFAP and NFs of 68, 160 and 200 kDa in the cerebrospinal fluid (CSF) of patients with NCC by Western blotting. Our results showed that patients with NCC had significantly elevated GFAP levels in the CSF compared with the control, whereas NFs of 68, 160 and 200 kDa were not detected in the CFS of NCC patients. We concluded that GFAP could be used as a marker of glial damage in the CFS of NCC patients.

Müller and RPE Cell Response to Photoreceptor Cell Degeneration in Aging Fischer Rats

With increasing age, retinas of male Fischer rats gradually lose photoreceptor cells beginning at the ora serrata and extending to the central retina resulting in a pronounced peripheral retinopathy. In this study, we used immunocytochemical methods for glial fibrillary acidic protein (GFAP) and carbonic anhydrase II (CA II) to study the Müller cell response to age-related photoreceptor cell degeneration in the superior retina. Retinas of Fischer rats were also examined by electron microscopy to investigate retinal pigment epithelial (RPE) cell and Bruch's membrane structural changes with advancing age. Our study showed extensive photoreceptor cell loss in the region of the ora serrata beginning by 16 months, while few photoreceptor cells were found at 23 months. Neovascularization also occurred in the area of the peripheral retinopathy at the level of the RPE cells as determined by electron microscopy, as well as a thickening of Bruch's membrane with initial signs of small breaks. Dense areas of GFAP-immunostaining of Müller cell processes were found in the superior peripheral retina of 16–30 month-old rats where photoreceptor cells were degenerating. After 21 months, Müller cell processes extended into the subretinal space. However, in the central retina, where the photoreceptor cell population was more stable, GFAP-immunolabelled Müller cells were not detected. Immunoblots of retinal homogenates confirmed elevated GFAP levels at 18–30 months when compared to homogenates from retinas of 6-month-old Fischer rats. During photoreceptor cell degeneration, Müller cell processes were also prominently immunostained for CA II, which were seen to occupy the subretinal space at 18–30 months. Our results suggest that Müller cells respond to the age-related peripheral retinopathy in Fischer rats by increasing GFAP content and growth of their processes into the subretinal space to form a glial scar, but only in the area of severe photoreceptor cell loss. In addition, RPE and Bruch's membrane of aged retinas exhibit typical early age-related changes as also reported for aged human eyes.