Dataset Information

Quantitative mass spectrometric analysis of the mouse cerebral cortex after ischemic stroke.

ABSTRACT: Ischemic strokes result in the death of brain tissue and a wave of downstream effects, often leading to lifelong disabilities or death. However, the underlying mechanisms of ischemic damage and repair systems remain largely unknown. In order to better understand these mechanisms, TMT-isobaric mass tagging and mass spectrometry were conducted on brain cortex extracts from mice subjected to one hour of middle cerebral artery occlusion (MCAO) and after one hour of reperfusion. In total, 2,690 proteins were identified and quantified, out of which 65% of the top 5% of up- and down-regulated proteins were found to be significant (p < 0.05). Network-based gene ontology analysis was then utilized to cluster all identified proteins by protein functional groups and cellular roles. Although three different cellular functions were identified-organelle outer membrane proteins, cytosolic ribosome proteins, and spliceosome complex proteins-several functional domains were found to be common. Of these, organelle outer membrane proteins were downregulated whereas cytosolic ribosome and spliceosome complex proteins were upregulated, indicating that major molecular events post-stroke were translation-associated and subsequent signaling pathways (e.g., poly (ADP-ribose) (PAR) dependent cell death). By approaching stroke analyses via TMT-isobaric mass tagging, the work herein presents a grand scope of protein-based molecular mechanisms involved with ischemic stroke recovery.

SUBMITTER: Agarwal A

PROVIDER: S-EPMC7173877 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Quantitative mass spectrometric analysis of the mouse cerebral cortex after ischemic stroke.

Agarwal Ank A Park Seongje S Ha Shinwon S Kwon Ji-Sun JS Khan Mohammed Repon MR Kang Bong Gu BG Dawson Ted M TM Dawson Valina L VL Andrabi Shaida A SA Kang Sung-Ung SU

PloS one 20200421 4

Ischemic strokes result in the death of brain tissue and a wave of downstream effects, often leading to lifelong disabilities or death. However, the underlying mechanisms of ischemic damage and repair systems remain largely unknown. In order to better understand these mechanisms, TMT-isobaric mass tagging and mass spectrometry were conducted on brain cortex extracts from mice subjected to one hour of middle cerebral artery occlusion (MCAO) and after one hour of reperfusion. In total, 2,690 prote ...[more]

PMID: 32315348

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Project description:IntroductionMalignant cerebral edema develops in a small subset of patients with hemispheric strokes, precipitating deterioration and death if decompressive hemicraniectomy (DHC) is not performed in a timely manner. Predicting which stroke patients will develop malignant edema is imprecise based on clinical data alone. Head computed tomography (CT) imaging is often performed at baseline and 24-h. We determined the incremental value of incorporating imaging-derived features from serial CTs to enhance prediction of malignant edema.MethodsWe identified hemispheric stroke patients at three sites with NIHSS ≥ 7 who had baseline as well as 24-h clinical and CT imaging data. We extracted quantitative imaging features from baseline and follow-up CTs, including CSF volume, intracranial reserve (CSF/cranial volume), as well as midline shift (MLS) and infarct-related hypodensity volume. Potentially lethal malignant edema was defined as requiring DHC or dying with MLS over 5-mm. We built machine-learning models using logistic regression first with baseline data and then adding 24-h data including reduction in CSF volume (ΔCSF). Model performance was evaluated with cross-validation using metrics of recall (sensitivity), precision (predictive value), as well as area under receiver-operating-characteristic and precision-recall curves (AUROC, AUPRC).ResultsTwenty of 361 patients (6%) died or underwent DHC. Baseline clinical variables alone had recall of 60% with low precision (7%), AUROC 0.59, AUPRC 0.15. Adding baseline intracranial reserve improved recall to 80% and AUROC to 0.82 but precision remained only 16% (AUPRC 0.28). Incorporating ΔCSF improved AUPRC to 0.53 (AUROC 0.91) while all imaging features further improved prediction (recall 90%, precision 38%, AUROC 0.96, AUPRC 0.66).ConclusionIncorporating quantitative CT-based imaging features from baseline and 24-h CT enhances identification of patients with malignant edema needing DHC. Further refinements and external validation of such imaging-based machine-learning models are required.

Project description:Background and Purpose- Cerebral edema (CED) develops in the hours to days after stroke; the resulting increase in brain volume may lead to midline shift (MLS) and neurological deterioration. The time course and implications of edema formation are not well characterized across the spectrum of stroke. We analyzed displacement of cerebrospinal fluid (ΔCSF) as a dynamic quantitative imaging biomarker of edema formation. Methods- We selected subjects enrolled in a stroke cohort study who presented within 6 hours of onset and had baseline and ≥1 follow-up brain computed tomography scans available. We applied a neural network-based algorithm to quantify hemispheric CSF volume at each imaging time point and modeled CSF trajectory over time (using a piecewise linear mixed-effects model). We evaluated ΔCSF within the first 24 hours as an early biomarker of CED (defined as developing MLS on computed tomography beyond 24 hours) and poor outcome (modified Rankin Scale score, 3-6). Results- We had serial imaging in 738 subjects with stroke, of whom 91 (13%) developed CED with MLS. Age did not differ (69 versus 70 years), but baseline National Institutes of Health Stroke Scale was higher (16 versus 7) and baseline CSF volume lower (132 versus 161 mL, both P<0.001) in those with CED. ΔCSF was faster in those developing MLS, with the majority seen by 24 hours (36% versus 11% or 2.4 versus 0.8 mL/h; P<0.0001). Risk of CED almost doubled for every 10% ΔCSF within 24 hours (odds ratio, 1.76 [95% CI, 1.46-2.14]), adjusting for age, glucose, and National Institutes of Health Stroke Scale. Risk of neurological deterioration (1.6-point increase in National Institutes of Health Stroke Scale at 24 hours) and poor outcome (adjusted odds ratio, 1.34 [95% CI, 1.15-1.56]) was also greater for every 10% increase in ΔCSF. Conclusions- CSF volumetrics provides quantitative evaluation of early edema formation. ΔCSF from baseline to 24-hour computed tomography is a promising early biomarker for the development of MLS and worse neurological outcome.

Dataset Information

Quantitative mass spectrometric analysis of the mouse cerebral cortex after ischemic stroke.

Publications

Quantitative mass spectrometric analysis of the mouse cerebral cortex after ischemic stroke.

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