Proteasome Biology Is Compromised in White Matter After Asphyxic Cardiac Arrest in Neonatal Piglets

Therapeutic hypothermia provides incomplete neuroprotection after hypoxia-ischemia (HI)-induced brain injury in neonates. We previously showed that cortical neuron and white matter apoptosis are promoted by hypothermia and early rewarming in a piglet model of HI. The unfolded protein response (UPR) may be one of the potential mediators of this cell death. Here, neonatal piglets underwent HI or sham surgery followed by 29 h of normothermia, 2 h of normothermia + 27 h of hypothermia or 18 h of hypothermia + rewarming. Piglets recovered for 29 h. Immunohistochemistry for endoplasmic reticulum to nucleus signaling-1 protein (ERN1), a marker of UPR activation, was used to determine the ratios of ERN1+ macroglia and neurons in the motor subcortical white matter and cerebral cortex. The ERN1+ macroglia were immunophenotyped as oligodendrocytes and astrocytes by immunofluorescent colabeling. Temperature (p = 0.046) and HI (p < 0.001) independently affected the ratio of ERN1+ macroglia. In sham piglets, sustained hypothermia (p = 0.011) and rewarming (p = 0.004) increased the ERN1+ macroglia ratio above that in normothermia. HI prior to hypothermia diminished the UPR. Ratios of ERN1+ macroglia correlated with white matter apoptotic profile counts in shams (r = 0.472; p = 0.026), thereby associating UPR activation with white matter apoptosis during hypothermia and rewarming. Accordingly, macroglial cell counts decreased in shams that received sustained hypothermia (p = 0.009) or rewarming (p = 0.007) compared to those in normothermic shams. HI prior to hypothermia neutralized the macroglial cell loss. Neither HI nor temperature affected ERN1+ neuron ratios. In summary, delayed hypothermia and rewarming activate the macroglial UPR, which is associated with white matter apoptosis. HI may decrease the macroglial endoplasmic reticulum stress response after hypothermia and rewarming.

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Prognostication of neurologic outcome using gray-white-matter-ratio in comatose patients after cardiac arrest

BMC Neurology ◽

10.1186/s12883-021-02480-6 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Konrad Kirsch ◽

Stefan Heymel ◽

Albrecht Günther ◽

Kathleen Vahl ◽

Thorsten Schmidt ◽

...

Keyword(s):

Cardiac Arrest ◽

White Matter ◽

Circulatory Arrest ◽

Cerebral Performance Category ◽

Time Interval ◽

Performance Category ◽

Neurologic Outcomes ◽

Ischaemic Brain ◽

Cerebral Performance Category Score ◽

Category Score

Abstract Background This study aimed to assess the prognostic value regarding neurologic outcome of CT neuroimaging based Gray-White-Matter-Ratio measurement in patients after resuscitation from cardiac arrest. Methods We retrospectively evaluated CT neuroimaging studies of 91 comatose patients resuscitated from cardiac arrest and 46 non-comatose controls. We tested the diagnostic performance of Gray-White-Matter-Ratio compared with established morphologic signs of hypoxic-ischaemic brain injury, e. g. loss of distinction between gray and white matter, and laboratory parameters, i. e. neuron-specific enolase, for the prediction of poor neurologic outcomes after resuscitated cardiac arrest. Primary endpoint was neurologic function assessed with cerebral performance category score 30 days after the index event. Results Gray-White-Matter-Ratio showed encouraging interobserver variability (ICC 0.670 [95% CI: 0.592–0.741] compared to assessment of established morphologic signs of hypoxic-ischaemic brain injury (Fleiss kappa 0.389 [95% CI: 0.320–0.457]) in CT neuroimaging studies. It correlated with cerebral performance category score with lower Gray-White-Matter-Ratios associated with unfavourable neurologic outcomes. A cut-off of 1.17 derived from the control population predicted unfavourable neurologic outcomes in adult survivors of cardiac arrest with 100% specificity, 50.3% sensitivity, 100% positive predictive value, and 39.3% negative predictive value. Gray-White-Matter-Ratio prognostic power depended on the time interval between circulatory arrest and CT imaging, with increasing sensitivity the later the image acquisition was executed. Conclusions A reduced Gray-White-Matter-Ratio is a highly specific prognostic marker of poor neurologic outcomes early after resuscitation from cardiac arrest. Sensitivity seems to be dependent on the time interval between circulatory arrest and image acquisition, with limited value within the first 12 h.

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Abstract 14621: Whole Body Periodic Acceleration (pGz) Induces Anti-Inflammatory Signaling in Brain After Hypoxic Injury

Circulation ◽

10.1161/circ.132.suppl_3.14621 ◽

2015 ◽

Vol 132 (suppl_3) ◽

Author(s):

Jose A Adams ◽

Anna Pastuszko ◽

Peter Pastuszko ◽

David Wilson ◽

Vinay Nadkarni

Keyword(s):

Cardiac Arrest ◽

Inflammatory Response ◽

The Body ◽

Regulatory Proteins ◽

Whole Body ◽

Hypoxic Injury ◽

Neonatal Piglets ◽

Neuroprotective Strategies ◽

Periodic Acceleration ◽

Pre Treatment

Introduction: Asphyxia is the most common cause of cardiac arrest in children, with devastating complications. Asphyxia Cardiac Arrest (ACA) is associated with a generalized systemic inflammatory response, in addition brain injury after cardiac arrest (CA) has been shown to have an inflammatory component. Effective neuroprotective strategies are desperately needed. pGz is a method which moves the body in a repetitive head to foot motion increasing pulsatile shear stress, inducing endothelial nitric oxide (eNO) and increasing microvascular flow to brain, heart and other vital organs. We have shown that pGz applied as a preconditioning (pre-treatment) prior to brain hypoxia ischemia, induces increase in brain anti-apoptotic proteins, and modulated the inflammatory response. Hypothesis: The objective of this study was to determine whether pGz post-treatment after ACA, also modifies pro inflammatory brain regulatory proteins. Methods: Twelve anesthetized neonatal piglets (weight 2.5-3 kg) were subjected to 30 min of 7% FiO2, followed by 7 min of Apnea and resuscitation with recovery in 21% FiO2. Animals were randomly assigned to; recovery for 3 hr (Hyp-Cont) or recovery with pGz beginning 30min after hypoxia for 3 hr (pGz). Another group(Sham) had surgery and anesthesia but no hypoxia. Protein expression of IL-1β, IL-6, TNFα, eNOS, and p-eNOS in cortex were meassured. Results: Hypoxia induced a 38%, 74% and 10% increase from Sham in IL-1β, IL-6, TNFα respectively. In contrast pGz treated animals only had a 4%, 21% increase in IL-1β, IL-6, and a 14% decrease in TNFα from Sham. Activation of eNOS (p-eNOS/eNOS) doubled in pGz treated. Figure [Mean (± SD)*p< 0.01]. Conclusion: pGz post resuscitation in a piglet model of ACA decreases brain pro-inflammatory regulatory proteins. The latter, taken together with pGz’s induction of anti-apoptotic signaling proteins, suggest that pGz can be a simple, novel neurotherapeutic strategy when applied after cardiac arrest.

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Prognostic values of gray matter to white matter ratios on early brain computed tomography in adult comatose patients after out-of-hospital cardiac arrest of cardiac etiology

Resuscitation ◽

10.1016/j.resuscitation.2015.07.027 ◽

2015 ◽

Vol 96 ◽

pp. 46-52 ◽

Cited By ~ 38

Author(s):

Byung Kook Lee ◽

Kyung Woon Jeung ◽

Kyoung Hwan Song ◽

Yong Hun Jung ◽

Wook Jin Choi ◽

...

Keyword(s):

Computed Tomography ◽

Cardiac Arrest ◽

White Matter ◽

Gray Matter ◽

Brain Computed Tomography ◽

Hospital Cardiac Arrest

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Quantitative Analysis of the Loss of Distinction Between Gray and White Matter in Comatose Patients After Cardiac Arrest

Stroke ◽

10.1161/01.str.31.9.2163 ◽

2000 ◽

Vol 31 (9) ◽

pp. 2163-2167 ◽

Cited By ~ 143

Author(s):

M. T. Torbey ◽

M. Selim ◽

J. Knorr ◽

C. Bigelow ◽

L. Recht

Keyword(s):

Cardiac Arrest ◽

Quantitative Analysis ◽

White Matter

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Clinical Significance of Gray to White Matter Ratio after Cardiopulmonary Resuscitation in Children

Children ◽

10.3390/children9010036 ◽

2022 ◽

Vol 9 (1) ◽

pp. 36

Author(s):

Yun-Young Lee ◽

Insu Choi ◽

Seung-Jae Lee ◽

In-Seok Jeong ◽

Young-Ok Kim ◽

...

Keyword(s):

Cardiac Arrest ◽

White Matter ◽

Cardiopulmonary Resuscitation ◽

Clinical Significance ◽

Predictive Value ◽

Pediatric Patients ◽

Neurologic Outcome ◽

Hounsfield Units ◽

Brain Ct ◽

Medial Cortex

Cardiopulmonary resuscitation (CPR) successfully restores systemic circulation approximately 50% of the time; however, many successfully restored patients have severe neurologic damage. In adults, the gray matter to white matter attenuation ratio (GWR) in brain computed tomography (CT) correlates with the neurologic outcome. However, in children, the clinical significance of GWR still remains unclear. The aim of this study was to evaluate the clinical characteristics of children who underwent CPR for cardiac arrest according to the survival and to demonstrate the differentiation of grey/white matter by Hounsfield units of brain CT and to characterize the attenuations of grey and white matters. Methods: This is a retrospective single-center study. We enrolled those who underwent brain CT within 24 h after return of spontaneous circulation (ROSC) from January 2005 to June 2018. Brain CTs were taken within 24 h of ROSC. We measured the attenuation of grey and white matter in Hounsfield units and calculated GWR. They were compared with healthy controls. Patients were analyzed as follows: survivors vs. non-survivors and better neurologic outcome vs. worse neurologic outcome. Results: Among 100 pediatric patients who had CPR, 56 met inclusion criteria. There were 24 patients who survived and 32 non-survivors. Our study revealed that the incidence of seizure, duration of CPR, and instances of hypothermia were significantly different between survivors and non-survivors. In both survivors and non-survivors, the attenuation of the caudate nucleus, putamen, GWR-basal ganglia, and average GWR were significantly different from controls. In regression analyses, the medial cortex and average GWR were the significant variables to predict survival, and the receiver operating curves revealed areas under curve of 0.733 and 0.666, respectively. Also, the medial cortex 1 was the only variable that predicted the neurologic outcome. Conclusions: There was some predictive survival value of GWR and medial cortex at the centrum semiovale level in early brain CT within 24 h after cardiac arrest. Although we could not find the predictive value of GWR in the neurologic outcome of pediatric patients, we found that the absolute attenuation of the medial cortex was low in patients with worse neurologic outcomes. Further prospective, multicenter studies are needed to determine the predictive value of GWR and the medial cortex.

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