Elevated glial fibrillary acidic protein levels in the cerebrospinal fluid of patients with narcolepsy

Glial fibrillary acidic protein (GFAP) is an established indicator of astrogliosis. Therefore, variable cerebrospinal fluid (CSF) concentrations of this protein might reflect disease-specific pathologic profiles. In patients with narcolepsy, a loss of hypocretin-1 (hcrt-1) neurons in the brain and low concentrations of hcrt-1 in CSF have been reported. We performed a commercially available enzyme-linked immunosorbent assay to investigate if GFAP also is altered in the CSF of these patients. Here we detected significantly higher CSF levels of GFAP in patients with low hcrt-1 levels, of which the majority had a diagnosis of narcolepsy and cataplexy (NC); however, this finding was not observed in patients with hcrt-1 levels that were within reference range. In conclusion, GFAP may be useful as an additional disease biomarker in patients with narcolepsy, and this hypothesis should be investigated in larger studies.     

Analysis of cerebrospinal fluid glial fibrillary acidic protein after seizures in children

PURPOSE: To evaluate pediatric seizure patients for astrocytic injury by measuring cerebrospinal fluid (CSF) glial fibrillary acidic protein (GFAP), determine risk factors for GFAP elevation after seizures, and compare seizure-induced astrocyte injury with neuronal injury by concurrent measurement of CSF neuron-specific enolase (NSE). METHODS: CSF obtained from pediatric patients (n = 52) within 24 h of seizure was assayed for GFAP and NSE. Retrospective chart review was performed for seizure type, duration, and etiology. RESULTS: Overall, children with seizures had elevated CSF GFAP compared with controls (p = 0.0075), but no elevation of NSE (p = 0.1437). No effect of seizure type or etiology was found, but a significant positive effect of seizure duration (p = 0.0010) and status epilepticus (p = 0.0296) was seen on CSF GFAP. Individually, seven children (13%) had elevated GFAP (>440 pg/ml); in five children, the increased GFAP was not accompanied by elevations in NSE (<12 ng/ml). Five children with elevated GFAP had symptomatic etiologies for their seizures, but the etiology of one child with elevated GFAP was cryptogenic, and one had febrile seizures. CONCLUSIONS: Elevation of CSF GFAP after seizures suggests that astrocytic injury may occur in a subgroup of children, primarily in the context of prolonged seizures and symptomatic etiologies. Increased GFAP levels may occur in patients with normal NSE, suggesting that GFAP may be a more sensitive marker of brain injury in some cases.     

Quantification of regional glial fibrillary acidic protein levels in Alzheimer's disease

OBJECTIVES: Our objectives were to quantify glial fibrillary acidic protein (GFAP) in brains of Alzheimer's disease (AD) cases, and non-AD controls to determine the regions with the most severe gliosis in AD. MATERIAL AND METHODS: In a case control design, we used an enzyme-linked immunosorbent assay (ELISA) to quantify GFAP in frozen brain from four areas of neocortex in 10 AD cases, 10 age-matched controls, and 10 younger controls from the Honolulu-Asia Aging Study autopsy archive. RESULTS: Median age at death was 83.5 years for cases and age-matched controls, and 77 years for younger controls. For the AD cases compared with the age-matched controls, levels of GFAP in occipital (P=0.01), parietal (P=0.028), and temporal lobes (P=0.004) (but not frontal) were significantly higher in the cases. The median GFAP excess in AD cases compared with age matched controls was highest in the temporal lobe. CONCLUSIONS: Regional quantification of GFAP reveals that the glial response is most prominent in the temporal lobe in AD.     

Proteomic analysis of glial fibrillary acidic protein in Alzheimer's disease and aging brain

Chronic inflammation is known to play an important role in the heterogeneous pathogenesis of Alzheimer's disease (AD). Activated astrocytes expressing glial fibrillary acidic protein (GFAP) are closely associated with AD pathology, such as tangles, neuritic plaques and amyloid depositions. Altogether, 46 soluble isoforms of GFAP were separated and most of them quantified by two-dimensional immunoblotting in frontal cortices of AD patients and age-matched controls. A 60% increase in the amount of more acidic isoforms of GFAP was observed in AD and these isoforms were both phosphorylated and N-glycosylated, while more basic isoforms were O-glycosylated and exhibited no quantitative differences between post-mortem AD and control brains. These data highlight the importance of exploring isoform-specific levels of proteins in pathophysiological conditions since modifications of proteins determine their activity state, localization, turnover and interaction with other molecules. Mechanisms, structures and functional consequences of modification of GFAP isoforms remain to be clarified.     

Cerebrospinal fluid neurofilament and glial fibrillary acidic protein in patients with cerebral vasculitis

Few diseases in clinical medicine cause as much diagnostic consternation as central nervous system (CNS) vasculitis because of its varying modes of presentation and frequently overlapping clinical and pathological features. There are no pathognomonic clinical or laboratory findings. The purpose of the present retrospective study was to validate the use of the light subunit of neurofilament triplet protein (NFL) and glial fibrillary acidic protein (GFAP) as markers of CNS tissue damage for patients with systemic or isolated CNS vasculitis. Levels of cerebrospinal fluid (CSF) NFL and GFAP were measured using ELISAs. Both CSF NFL and CSF GFAP concentrations were significantly higher in a patient group diagnosed with CNS vasculitis (P < 0.01 and P < 0.05, respectively) than in a patient group for whom CNS vasculitis was excluded. In the future, analysis of CSF NFL in particular, but also GFAP, may be a useful complement in the difficult clinical task of diagnosing CNS vasculitis.     

High cerebrospinal fluid concentration of glial fibrillary acidic protein (GFAP) in patients with normal pressure hydrocephalus

The concentration of glial fibrillary acidic protein (GFAP) in lumbar cerebrospinal fluid (CSF) was measured in 12 patients with normal pressure hydrocephalus (NPH) 11 patients with primary degenerative dementia (PDD), 8 patients with various other neurological diseases, and 18 patients without signs of organic nervous disease (controls).

Mean CSF GFAP concentration was significantly higher in NPH patients: 96 ± 23 ng/ml (SEM) when compared with PDD patients: 8.2 ± 1.9 ng/ml (P < 0.01), or with controls: 4.3 ± 0.7 ng/ml (P < 0.01). Only 2 NPH patients had a GFAP concentration within the range of the control group (2–14 ng GFAP/ml CSF). No significant differences were found between the PDD patients and the control group, or between the group of patients with other neurological diseases and the control group.

In addition, a rostro-caudal gradient of GFAP in CSF could be demonstrated. In 6 NPH and 2 PDD patients both ventricular and lumbar CSF samples were investigated. In all cases the ventricular GFAP concentration was higher than the lumbar concentration. The difference was statistically significant (P < 0.01).

Our results suggest that determination of CSF GFAP concentration might be of diagnostic value in discrimination between NPH patients and patients with enlarged ventricles associated with degenerative brain disease.     

Determination of S-100 and glial fibrillary acidic protein concentrations in cerebrospinal fluid after brain infarction

BACKGROUND AND PURPOSE: We initiated the present study to evaluate the clinical value of consecutive concentration determinations of S-100 and glial fibrillary acidic proteins in cerebrospinal fluid from patients with brain infarction. METHODS: We took sequential samples of cerebrospinal fluid from 28 patients within 48 hours, at 7 days, and at 18-21 days after the ictus. We measured astroglial protein concentrations using an enzyme-linked immunosorbent assay and also determined size of the infarction (computed tomography), clinical state of the patient (simplified activities of daily living test), blood-brain barrier dysfunction (cerebrospinal fluid/serum albumin ratio), and a myelin marker (myelin basic protein). RESULTS: We found a transient increase of both proteins in the cerebrospinal fluid during the first week after the ischemic stroke (p less than 0.05). This increment was significantly correlated with the size of the infarction and the clinical state of the patients. CONCLUSIONS: Transient release of astroglial proteins into the cerebrospinal fluid possibly reflects initial focal ischemic damage and, in the later phase, ongoing destruction of astroglial cells in the penumbra zone. We suggest that determinations of cerebrospinal fluid astroglial protein concentrations can be used to estimate ischemic brain damage, which should be of particular value in clinical trials of pharmacological agents, such as calcium antagonists, on stroke patients.     

a-albumin (glial fibrillary acidic protein) in normal and pathological human brain and cerebrospinal fluid

Summary a-albumin, a specific brain protein observed after agar gel electrophoresis and shown to be identical to the later described GFA, has been determined in normal and pathological human central nervous system and cerebrospinal fluid.The outcome of this study underlines the value of the detection of specific proteins of the brain in biological fluids.

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Zusammenfassung a-Albumin, ein spezifisches Gehirnprotein, welches in der Agar-Elektrophorese nachweisbar und identisch mit dem später beschriebenen GFA ist, wurde im normalen und pathologischen zentralen Nervensystem des Patienten und im Liquor bestimmt. Die Ergebnisse der vorliegenden Untersuchung belegen die Wichtigkeit des Nachweises von hirnspezifischen Proteinen in biologischen Flüssigkeiten.

     

Interleukin-12 is reduced in cerebrospinal fluid of patients with Alzheimer's disease and frontotemporal dementia

Interleukin-12 is a heterodimeric cytokine produced by activated blood monocytes, macrophages and glial cells. It enhances differentiation and proliferation of T cells and increases production of proinflammatory cytokines, such as Interferon-gamma and Tumor Necrosis Factor-alpha. There is little information about the involvement of IL-12 in the pathophysiology of Alzheimer's disease (AD) and other tauopathies. OBJECTIVES: The objective of our study was to assess the role of IL-12 as a potential marker of immune reactions in patients with AD and frontotemporal dementia (FTD). PATIENTS AND METHODS: We measured by immunoassay cerebrospinal fluid (CSF) IL-12 levels in 19 patients with AD and 7 patients with FTD in comparison with CSF IL-12 levels in 30 patients with non-inflammatory neurological diseases served as neurological control patients (NCTRL). IL-12 levels were correlated with age, age of disease onset, disease duration, MMSE score, and rate of dementia progression. Abeta42 and Total tau (tau(T)) levels in CSF were also measured. RESULTS: Patients with AD had significantly lower CSF IL-12 levels compared with NCTRL patients (p<0.001). Patients with FTD had also lower CSF IL-12 levels compared with NCTRL patients (p<0.05). Age, sex, disease duration and MMSE score did not affect IL-12 levels in any of the groups. In AD a significant positive correlation was noted between IL-12 levels and tau(T) levels (Rs=0.46, p=0.048). CONCLUSIONS: Our findings may suggest a reduced inflammatory reaction during the course of AD and FTD. A neurotrophic role of IL-12 and other proinflammatory cytokines cannot be excluded.     

IL-15 is elevated in cerebrospinal fluid of patients with Alzheimer's disease and frontotemporal dementia

Interleukin-15 is a novel proinflammatory cytokine. It is produced by activated blood monocytes, macrophages, and glial cells. The objective of our study was to assess the role of interleukin-15 as a marker of increased proinflammatory activity in patients with Alzheimer's disease and frontotemporal dementia. We measured cerebrospinal fluid interleukin-15 levels in 17 patients with Alzheimer's disease and 7 patients with frontotemporal dementia in comparison with 17 patients with amyotrophic lateral sclerosis and 15 patients with Parkinson's disease. Patients with Alzheimer's disease and frontotemporal dementia had significantly higher cerebrospinal fluid interleukin-15 levels compared with patients with noninflammatory neurological diseases (P < .05 and P < .01, respectively). In Alzheimer's disease, a significant positive correlation was noted between interleukin-15 levels and age of onset (R = .48, P = .05). Our findings suggest that interleukin-15 may be implicated in the pathophysiology of Alzheimer's disease and frontotemporal dementia.     

Serum and cerebrospinal fluid brain damage markers neurofilament light and glial fibrillary acidic protein correlate with tick-borne encephalitis disease severity—a multicentre study on Lithuanian and Swedish patients

Background and purpose

Our aim was to examine the correlation between biomarkers of neuronal and glial cell damage and severity of disease in patients with tick-borne encephalitis.

Methods

One hundred and fifteen patients with tick-borne encephalitis diagnosed in Lithuania and Sweden were prospectively included, and cerebrospinal fluid (CSF) and serum samples were obtained shortly after hospitalization. Using pre-defined criteria, cases were classified as mild, moderate or severe tick-borne encephalitis. Additionally, the presence of spinal nerve paralysis (myelitis) and/or cranial nerve affection were noted. Concentrations of the brain cell biomarkers glial fibrillary acidic protein (GFAP), YKL-40, S100B, neurogranin, neurofilament light (NfL) and tau were analysed in CSF and, in addition, NfL, GFAP and S100B levels were measured in serum. The Jonckheere-Terpstra test was used for group comparisons of continuous variables and Spearman's partial correlation test was used to adjust for age.

Results

Cerebrospinal fluid and serum concentrations of GFAP and NfL correlated with disease severity, independent of age, and with the presence of nerve paralysis. The markers neurogranin, YKL-40, tau and S100B in CSF and S100B in serum were detected, but their concentrations did not correlate with disease severity.

Conclusions

Neuronal cell damage and astroglial cell activation with increased NfL and GFAP in CSF and serum were associated with a more severe disease, independent of age. Increased GFAP and NfL concentrations in CSF and NfL in serum were also indicative of spinal and/or cranial nerve damage. NfL and GFAP are promising prognostic biomarkers in tick-borne encephalitis, and future studies should focus on determining the association between these biomarkers and long-term sequelae.     

Tau protein level in cerebrospinal fluid is increased in patients with early multiple sclerosis

Axonal damage has been proposed as the major substrate of permanent clinical disability in multiple sclerosis. Tau protein, a microtubule-associated protein localised in neuronal axons, may serve as a biochemical surrogate marker to evaluate axonal damage in vivo. We intended to determine the extent of axonal damage in different stages and clinical subtypes of MS by investigating cerebrospinal fluid tau concentrations. Tau was measured using an immunoassay in 35 patients with relapsing-remitting MS, eight patients with secondary progressive MS, nine patients with primary progressive MS, 50 patients with clinically isolated syndrome suggestive of early MS and 46 normal controls. Cerebrospinal fluid tau was significantly elevated in MS compared with normal controls (median 206.0 pg/mL versus 152.0 pg/mL; P = 0.002). No significant difference among different subtypes of MS could be detected, although highest levels were found in very early disease stages. There was a significant elevation of CSF tau among patients with gadolinium-enhancing brain lesions in magnetic resonance imaging (P = 0.02) and a tendency towards higher CSF tau levels in patients with pronounced intrathecal IgG synthesis, supporting the notion that axonal damage is influenced by inflammatory activity.     

Acetylcholinesterase activity in cerebrospinal fluid of patients with Alzheimer's disease and senile dementia

Acetylcholinesterase (AChE) in the cerebrospinal fluid (CSF) from patients with Alzheimer-type dementia and control subjects was analyzed by centrifugation on a sucrose density gradient, and by column chromatography on Sephadex G-200. The sedimentation coefficient and molecular weight of CSF AChE were calculated as 10S and 380,000, respectively, which corresponded to those of G4 isozyme in the brain. Other isozymes of AChE were not detected in the CSF of either patients with Alzheimer-type dementia or the controls. Sufficient activity of AChE was observed in the CSF of a patient with familial pseudocholinesterase deficiency, although the pseudocholinesterase activity was not found either in the serum or in the CSF. CSF AChE activity in control subjects increased with advancing age (P less than 0.02). AChE activity in the CSF was significantly lower in patients with presenile dementia (Alzheimer's disease), compared with age-matched control subjects (P less than 0.001). However, AChE activity in the CSF showed a wide variation among patients of Alzheimer-type dementia with a late onset (senile dementia).     

首发抑郁症患者血清胶质纤维酸性蛋白浓度与认知功能的关系

目的:探讨首发抑郁症患者血清胶质纤维酸性蛋白(GFAP)浓度与认知功能的关系。方法:以酶联免疫吸附技术测定首发抑郁症患者(患者组)45例和正常人(对照组)45名血清GFAP浓度,使用威斯康星卡片分类测验检测两组的认知功能,分析血清GFAP浓度和认知功能损害的关系。结果:患者组血清GFAP浓度较对照组显著升高(t=12.72,P0.05);患者组血清GFAP浓度与HAMD总分及各因子分相关无统计学意义,与HAMA因子躯体化焦虑呈负相关(r=0.312,P0.05);患者组正确数、完成分类数较对照组少(t=-3.349,t=-3.349;P均0.05);持续错误数,随机错误数较对照组多(t=4.333,P0.05);患者组血清GFAP浓度与正确数、完成分类数呈负相关(r=0.527,r=0.527;P均0.01),与持续错误数呈正相关(r=0.450,P0.01);患者组血清GFAP浓度和病程之间相关无统计学意义(r=0.129,P0.05)。结论:首发抑郁症患者存在血清GFAP浓度升高,认知功能损害,血清GFAP浓度越高,认知功能损害越严重。     

胶质纤维酸性蛋白在老年痴呆大鼠海马中的表达

为探讨慢性缺血痴呆鼠学习减退与海马内星形胶质细胞表达的关系,基于老年大鼠慢性脑缺血痴呆模型,采用免疫组化技术及迷宫实验,定量分析海马星形胶质细胞变化与学习能力、记忆能力的关系。结果发现,慢性缺血痴呆鼠海马CAl区GFAP阳性细胞数目明显增多,胞体肥大,突起增粗、变长,与对照组相比有显著意义(P<0.05),Y型迷宫测试结果显示,痴呆组大鼠的学习、记忆能力与对照组相比,明显下降。提示海马星形胶质细胞可能参与慢性缺血痴呆大鼠的学习记忆功能。     

Juvenile Alexander disease with a novel mutation in glial fibrillary acidic protein gene

Early-onset (infantile) Alexander disease is associated with mutations in the glial fibrillary acidic protein (GFAP) gene and two hot spots correlate to the severe phenotype. No molecular mechanisms have been elucidated in late-onset (juvenile) Alexander disease. The authors report a novel GFAP mutation in a patient with juvenile Alexander disease. The authors discuss similar molecular mechanisms in another intermediate filament disease and propose a possible molecular pathogenesis in juvenile Alexander disease.