Glial fibrillary acidic protein as a marker of astrocytic activation in the cerebrospinal fluid of patients with amyotrophic lateral sclerosis

Benninger, Felix; Glat, Micaela; Offen, Daniel; Steiner, Israel

doi:10.1016/j.jocn.2015.10.008

Cited by 21 publications

(18 citation statements)

References 39 publications

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“…In the last decade research on hereditary neurodegenerative disorders has shifted from a neuron-centric view toward the recognition of destructive mechanisms arising from central nervous system glial cells, which likewise express the respective mutant proteins ( Lobsiger and Cleveland, 2007 ; Phatnani and Maniatis, 2015 ). Consistent with this hypothesis, a parallel rise of neuronal and glial markers has been reported in other neurodegenerative diseases, such as amyotrophic lateral sclerosis ( Benninger et al, 2016 ). Specifically in FRDA, dysfunction in glial cells, most importantly astrocytes, has recently gained increasing attention.…”

Section: Discussionsupporting

confidence: 64%

“…The Food and Drug Administration defines biomarkers as objectively measurable characteristics that are indicators of physiological and pathological processes or reflect response to therapeutic interventions ( Biomarkers Definitions Working Group, 2001 ). Over the past decade, several brain-derived proteins have emerged as promising candidate markers for neurodegeneration in a variety of acute and chronic neurological diseases ( Zetterberg et al, 2013 ; Burman et al, 2014 ; Benninger et al, 2016 ; Byrne et al, 2017 ). These include the astrocytic intermediate filament protein, glial fibrillary acidic protein (GFAP) ( Yang and Wang, 2015 ); the neuron-specific cytoskeletal protein neurofilament-light chain (NfL) ( Liu et al, 2004 ); a cytoplasmatic neuronal enzyme, ubiquitin C-terminal hydrolase L1 (UCHL1) ( Wilkinson et al, 1989 ); and the microtubule associated protein tau ( Binder et al, 1985 ).…”

Section: Introductionmentioning

confidence: 99%

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Plasma Markers of Neurodegeneration Are Raised in Friedreich’s Ataxia

Zeitlberger

Thomas‐Black

García-Moreno

et al. 2018

Front. Cell. Neurosci.

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Background: Friedreich’s ataxia (FRDA) is the most common autosomal recessive ataxia. Disease-modifying treatments are not available yet; however, several compounds are currently under investigation. As a result, there is a growing need for the identification of robust and easily accessible biomarkers for the monitoring of disease activity and therapeutic efficacy. The simultaneous measurement of multiple brain-derived proteins could represent a time- and cost-efficient approach for biomarker investigation in pathologically complex neurodegenerative diseases like FRDA.Objectives: To investigate the role of plasma neurofilament-light chain (NfL), glial fibrillary acidic protein (GFAP), total tau (t-tau) and ubiquitin C-terminal hydrolase L1(UCHL1) as biomarkers in FRDA. Additionally, NfL measurements derived from the novel multiplex assay were compared to those from an established NfL singleplex assay.Methods: In this study, an ultrasensitive Single molecule array (Simoa) 4-plex assay was used for the measurement of plasma NfL, GFAP, t-tau, and UCHL1 in 33 FRDA patients and 13 age-matched controls. Differences in biomarker concentrations between these groups were computed and associations with genetic and disease related parameters investigated. Additionally, the agreement between NfL measurements derived from the 4-Plex and an established Simoa NfL singleplex assay was assessed.Results: Mean plasma NfL, GFAP and UCHL1 levels were significantly higher in FRDA patients than in controls (NfL: p < 0.001; GFAP: p = 0.006, and UCHL1: p = 0.020). Conversely, there was no significant difference in concentrations of t-tau in the patient and control group (p = 0.236). None of the proteins correlated with the GAA repeat length or the employed measures of disease severity. The individual NfL values derived from the two assays showed a strong concordance (rc = 0.93). Although the mean difference of 1.29 pg/mL differed significantly from 0 (p = 0.006), regression analysis did not indicate the presence of a proportional bias.Conclusion: This is the first study demonstrating that NfL, GFAP, and UCHL1 levels are raised in FRDA, potentially reflecting ongoing neuronal degeneration and glial activation. Further studies are required to determine their role as marker for disease activity and progression. Furthermore, the novel 4-plex assay appears to be a valid tool to simultaneously measure brain-derived proteins at extremely low concentrations in the peripheral circulation.

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Section: Discussionsupporting

confidence: 64%

Section: Introductionmentioning

confidence: 99%

Plasma Markers of Neurodegeneration Are Raised in Friedreich’s Ataxia

Zeitlberger

Thomas‐Black

García-Moreno

et al. 2018

Front. Cell. Neurosci.

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“…Nevertheless, there is still no consensus about a unique pathway, and ALS pathophysiology is supposed to be multifactorial [3][4][5]. In this way, inflammation and microglial activation are considered important components in ALS pathogenesis since inflammatory response accompanies motor neuron death [6][7][8].…”

Section: Introductionmentioning

confidence: 99%

Evaluation of Chitotriosidase and CC-Chemokine Ligand 18 as Biomarkers of Microglia Activation in Amyotrophic Lateral Sclerosis

et al. 2018

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Background: The development of biomarkers for use in diagnosing, monitoring disease progression and analyzing therapeutic trials response in amyotrophic lateral sclerosis (ALS) is essential. Objective: The aim of this study was to identify inflammatory factors in plasma or cerebrospinal fluid (CSF) from patients with ALS with particular attention to specific markers of microglia activation as chitotriosidase (ChT) and chemokine (C-C motif) ligand 18 (CCL18) to determine its potential as ALS biomarkers. Methods: We studied CSF and plasma samples from 32 patients and 42 healthy controls. We assayed the ChT activity by a spectrofluorometric method and protein levels of other inflammatory biomarkers (tumor necrosis factor [TNF]-alpha, interleukin [IL]-6 and CCL18) by enzyme-linked immunosorbent assay. CHIT1 gene polymorphism in exon 10 (c.1049_1072dup24) encoding inactive ChT enzyme was genotyped in all subjects. Results: ChT activity and TNF-alpha protein levels were significantly higher in CSF of ALS patients, but we found no correlation with the severity and progression of the disease. Nevertheless, we did not found any differences in CCL18 or IL-6 protein levels between both groups in CSF or plasma. In our sample, only 3% of subjects were homozygous carriers for the CHIT1 exon 10 duplication associated with defective enzyme. Conclusions: High ChT activity in CSF of patients with ALS may reflect microglia activation and could be a potential biomarker of the disease. We did not find any significant difference regarding CCL-18, another specific marker of microglia activation that is related with M2-like microglia phenotype. Deepening the understanding of the activation state of microglia (M1 and M2) may contribute to the knowledge about the specific role of neuroinflammation in ALS and future therapeutic strategies.

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“…For instance, cerebrospinal fluid (CSF) levels of specific molecules, such as neurofilament proteins and Cystatin C, have been proposed as possible biomarkers in ALS. Interestingly, a recent study examined GFAP concentration in a small cohort of ALS patients, suggesting that GFAP might serve as a potential biomarker ( 20 ).…”

Section: Discussionmentioning

confidence: 99%

“…GFAP levels were also high in serum samples from the patients that exhibit motor and sensory neurological pathologies ( 11 ). In the case of ALS, GFAP has been shown to be increased in the cerebrospinal fluid from patients ( 20 ). This is reasonable based on the fact that astrocyte activation is one of the critical hallmarks that occur during the process of motor neuron degeneration in ALS ( 21 , 22 ).…”

Section: Introductionmentioning

confidence: 99%

Blood Level of Glial Fibrillary Acidic Protein (GFAP) Does not Correlate With Disease Progression in a Rat Model of Familial ALS (SOD1G93A Transgenic)

2018

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Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by specific loss of motor neurons in the spinal cord and brain stem. Currently, there are limited options for treating ALS and further investigation of the disease etiology and ALS disease progression need to be completed. There is an urgent need to identify biomarkers to detect and study disease progression in ALS. Glial fibrillary acidic protein (GFAP) is an intermediate filament protein that is expressed by a number of cells related to the central nervous system including glial cells and ependymal cells. Recent studies indicated that significant levels of GFAP protein were detected in peripheral tissues, such as skeletal muscle. In this study, we hypothesized that levels of GFAP in blood represent a biomarker of disease progression in ALS. To test this specific hypothesis, we used a rat model of familial ALS (SOD1G93A transgenic), which has been extensively used to understand the complexity of this devastating disease. Disease progression in a cohort of male and female SOD1G93A transgenic rats was monitored by motor function, and blood samples were collected when these animals reached disease end-stage. We measured GFAP protein levels by ELISA and found no correlation between GFAP concentration and disease progression in either serum and plasma samples of SOD1G93A transgenic. Further investigation would be required in order to implicate blood GFAP as a potential biomarker for ALS.

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Glial fibrillary acidic protein as a marker of astrocytic activation in the cerebrospinal fluid of patients with amyotrophic lateral sclerosis

Cited by 21 publications

References 39 publications

Plasma Markers of Neurodegeneration Are Raised in Friedreich’s Ataxia

Plasma Markers of Neurodegeneration Are Raised in Friedreich’s Ataxia

Evaluation of Chitotriosidase and CC-Chemokine Ligand 18 as Biomarkers of Microglia Activation in Amyotrophic Lateral Sclerosis

Blood Level of Glial Fibrillary Acidic Protein (GFAP) Does not Correlate With Disease Progression in a Rat Model of Familial ALS (SOD1G93A Transgenic)

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