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Variations in the cerebrospinal fluid proteome following traumatic brain injury and subarachnoid hemorrhage.

ABSTRACT: BACKGROUND:Proteomic analysis of cerebrospinal fluid (CSF) has shown great promise in identifying potential markers of injury in neurodegenerative diseases [1-13]. Here we compared CSF proteomes in healthy individuals, with patients diagnosed with traumatic brain injury (TBI) and subarachnoid hemorrhage (SAH) in order to characterize molecular biomarkers which might identify these different clinical states and describe different molecular mechanisms active in each disease state. METHODS:Patients presenting to the Neurosurgery service at the Louisiana State University Hospital-Shreveport with an admitting diagnosis of TBI or SAH were prospectively enrolled. Patients undergoing CSF sampling for diagnostic procedures were also enrolled as controls. CSF aliquots were subjected to 2-dimensional gel electrophoresis (2D GE) and spot percentage densities analyzed. Increased or decreased spot expression (compared to controls) was defined in terms of in spot percentages, with spots showing consistent expression change across TBI or SAH specimens being followed up by Matrix-Assisted Laser Desorption/Ionization mass spectrometry (MALDI-MS). Polypeptide masses generated were matched to known standards using a search of the NCBI and/or GenPept databases for protein matches. Eight hundred fifteen separately identifiable polypeptide migration spots were identified on 2D GE gels. MALDI-MS successfully identified 13 of 22 selected 2D GE spots as recognizable polypeptides. RESULTS:Statistically significant changes were noted in the expression of fibrinogen, carbonic anhydrase-I (CA-I), peroxiredoxin-2 (Prx-2), both ? and ? chains of hemoglobin, serotransferrin (Tf) and N-terminal haptoglobin (Hp) in TBI and SAH specimens, as compared to controls. The greatest mean fold change among all specimens was seen in CA-I and Hp at 30.7 and -25.7, respectively. TBI specimens trended toward greater mean increases in CA-I and Prx-2 and greater mean decreases in Hp and Tf. CONCLUSIONS:Consistent CSF elevation of CA-I and Prx-2 with concurrent depletion of Hp and Tf may represent a useful combination of biomarkers for the prediction of severity and prognosis following brain injury.

SUBMITTER: Connor DE

PROVIDER: S-EPMC7303909 | biostudies-literature | 2017 Sep

REPOSITORIES: biostudies-literature

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Variations in the cerebrospinal fluid proteome following traumatic brain injury and subarachnoid hemorrhage.

Connor David E DE Chaitanya Ganta V GV Chittiboina Prashant P McCarthy Paul P Scott L Keith LK Schrott Lisa L Minagar Alireza A Nanda Anil A Alexander J Steven JS

Pathophysiology : the official journal of the International Society for Pathophysiology 20170513 3

<h4>Background</h4>Proteomic analysis of cerebrospinal fluid (CSF) has shown great promise in identifying potential markers of injury in neurodegenerative diseases [1-13]. Here we compared CSF proteomes in healthy individuals, with patients diagnosed with traumatic brain injury (TBI) and subarachnoid hemorrhage (SAH) in order to characterize molecular biomarkers which might identify these different clinical states and describe different molecular mechanisms active in each disease state.<h4>Metho ...[more]

PMID: 28549769

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Project description:Recently, there have been emerging interests in the area of microvesicles and exosome (MV/E) released from brain cells in relation to neurodegenerative diseases. However, only limited studies focused on MV/E released post-traumatic brain injury (TBI) as they highlight on the mechanistic roles of released proteins. This study sought to examine if CSF samples from severe TBI patients contain MV/E with unique protein contents. First, nanoparticle tracking analysis determined MV/E from TBI have a mode of 74-98 nm in diameter, while control CSF MV/E have a mode of 99-104 nm. Also, there are more MV/E were isolated from TBI CSF (27.8-33.6 × 108/mL) than from control CSF (13.1-18.5 × 108/mL). Transmission electron microscopy (TEM) visualization also confirmed characteristic MV/E morphology. Using targeted immunoblotting approach, we observed the presence of several known TBI biomarkers such as αII-spectrin breakdown products (BDPs), GFAP, and its BDPs and UCH-L1 in higher concentrations in MV/E from TBI CSF than their counterparts from control CSF. Furthermore, we found presynaptic terminal protein synaptophysin and known exosome marker Alix enriched in MV/E from human TBI CSF. In parallel, we conducted nRPLC-tandem mass spectrometry-based proteomic analysis of two control and two TBI CSF samples. Ninety-one proteins were identified with high confidence in MV/E from control CSF, whereas 466 proteins were identified in the counterpart from TBI CSF. MV/E isolated from human CSF contain cytoskeletal proteins, neurite-outgrowth related proteins, and synaptic proteins, extracellular matrix proteins, and complement protein C1q subcomponent subunit B. Taken together, following severe TBI, the injured human brain released increased number of extracellular microvesicles/exosomes (MV/E) into CSF. These TBI MV/E contain several known TBI biomarkers and previously undescribed brain protein markers. It is also possible that such TBI-specific MV/E might contain cell to cell communication factors related to both cell death signaling a well as neurodegeneration pathways.

Project description:Biological aging may occur at different rates than chronological aging due to genetic, social, and environmental factors. DNA methylation (DNAm) age is thought to be a reliable measure of accelerated biological aging which has been linked to an array of poor health outcomes. Given the importance of chronological age in recovery following aneurysmal subarachnoid hemorrhage (aSAH), a type of stroke, DNAm age may also be an important biomarker of outcomes, further improving predictive models. Cerebrospinal fluid (CSF) is a unique tissue representing the local central nervous system environment post-aSAH. However, the validity of CSF DNAm age is unknown, and it is unclear which epigenetic clock is ideal to compute CSF DNAm age, particularly given changes in cell type heterogeneity (CTH) during the acute recovery period. Further, the stability of DNAm age post-aSAH, specifically, has not been examined and may improve our understanding of patient recovery post-aSAH. Therefore, the purpose of this study was to characterize CSF DNAm age over 14 days post-aSAH using four epigenetic clocks. Genome-wide DNAm data were available for two tissues: (1) CSF for N = 273 participants with serial sampling over 14 days post-aSAH (N = 850 samples) and (2) blood for a subset of n = 72 participants at one time point post-aSAH. DNAm age was calculated using the Horvath, Hannum, Levine, and "Improved Precision" (Zhang) epigenetic clocks. "Age acceleration" was computed as the residuals of DNAm age regressed on chronological age both with and without correcting for CTH. Using scatterplots, Pearson correlations, and group-based trajectory analysis, we examined the relationships between CSF DNAm age and chronological age, the concordance between DNAm ages calculated from CSF versus blood, and the stability (i.e., trajectories) of CSF DNAm age acceleration over time during recovery from aSAH. We observed moderate to strong correlations between CSF DNAm age and chronological age (R = 0.66 [Levine] to R = 0.97 [Zhang]), moderate to strong correlations between DNAm age in CSF versus blood (R = 0.69 [Levine] to R = 0.98 [Zhang]), and stable CSF age acceleration trajectories over 14 days post-aSAH in the Horvath and Zhang clocks (unadjusted for CTH), as well as the Hannum clock (adjusted for CTH). CSF DNAm age was generally stable post-aSAH. Although correlated, CSF DNAm age differs from blood DNAm age in the Horvath, Hannum, and Levine clocks, but not in the Zhang clock. Taken together, our results suggest that, of the clocks examined here, the Zhang clock is the most robust to CTH and is recommended for use in complex tissues such as CSF.

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Variations in the cerebrospinal fluid proteome following traumatic brain injury and subarachnoid hemorrhage.

Publications

Variations in the cerebrospinal fluid proteome following traumatic brain injury and subarachnoid hemorrhage.

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