Dataset Information

Deletion of the WNK3-SPAK kinase complex in mice improves radiographic and clinical outcomes in malignant cerebral edema after ischemic stroke.

ABSTRACT: The WNK-SPAK kinase signaling pathway controls renal NaCl reabsorption and systemic blood pressure by regulating ion transporters and channels. A WNK3-SPAK complex is highly expressed in brain, but its function in this organ remains unclear. Here, we investigated the role of this kinase complex in brain edema and white matter injury after ischemic stroke. Wild-type, WNK3 knockout, and SPAK heterozygous or knockout mice underwent transient middle cerebral artery occlusion. One cohort of mice underwent magnetic resonance imaging. Ex-vivo brains three days post-ischemia were imaged by slice-selective spin-echo diffusion tensor imaging magnetic resonance imaging, after which the same brain tissues were subjected to immunofluorescence staining. A second cohort of mice underwent neurological deficit analysis up to 14 days post-transient middle cerebral artery occlusion. Relative to wild-type mice, WNK3 knockout, SPAK heterozygous, and SPAK knockout mice each exhibited a >50% reduction in infarct size and associated cerebral edema, significantly less demyelination, and improved neurological outcomes. We conclude that WNK3-SPAK signaling regulates brain swelling, gray matter injury, and demyelination after ischemic stroke, and that WNK3-SPAK inhibition has therapeutic potential for treating malignant cerebral edema in the setting of middle cerebral artery stroke.

SUBMITTER: Zhao H

PROVIDER: S-EPMC5381450 | biostudies-literature | 2017 Feb

REPOSITORIES: biostudies-literature

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Deletion of the WNK3-SPAK kinase complex in mice improves radiographic and clinical outcomes in malignant cerebral edema after ischemic stroke.

Zhao Hanshu H Nepomuceno Rachel R Gao Xin X Foley Lesley M LM Wang Shaoxia S Begum Gulnaz G Zhu Wen W Pigott Victoria M VM Falgoust Lindsay M LM Kahle Kristopher T KT Yang Sung-Sen SS Lin Shih-Hua SH Alper Seth L SL Hitchens T Kevin TK Hu Shaoshan S Zhang Zhongling Z Sun Dandan D

Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism 20160720 2

The WNK-SPAK kinase signaling pathway controls renal NaCl reabsorption and systemic blood pressure by regulating ion transporters and channels. A WNK3-SPAK complex is highly expressed in brain, but its function in this organ remains unclear. Here, we investigated the role of this kinase complex in brain edema and white matter injury after ischemic stroke. Wild-type, WNK3 knockout, and SPAK heterozygous or knockout mice underwent transient middle cerebral artery occlusion. One cohort of mice unde ...[more]

PMID: 26861815

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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

Deletion of the WNK3-SPAK kinase complex in mice improves radiographic and clinical outcomes in malignant cerebral edema after ischemic stroke.

Publications

Deletion of the WNK3-SPAK kinase complex in mice improves radiographic and clinical outcomes in malignant cerebral edema after ischemic stroke.

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