Abstract 14258: Modulation of Kynurenine Pathway to Prevent Brain Injury After Cardiac Arrest and Cardiopulmonary Resuscitation in Mice

Introduction: Kynurenine pathway (KP) is emerging as one of the potential components affecting cardiac arrest (CA) outcomes. The aim of this study is to evaluate the effects of KP inhibition through genetic deletion of the rate-limiting enzyme of the KP, indoleamine-2,3-dyoxygenase (IDO) on survival and neurological outcome after CA. Methods and Results: Sixteen adult male wild-type (WT) and IDO-deleted (IDO -/- ) mice were subjected to 8 min untreated CA followed by resuscitation. At baseline heart rate and mean arterial pressure (MAP) did not differ among groups. At the time of return of spontaneous circulation, 30 and 60 min later, MAP was higher in the IDO -/- group compared to the WT one (p=0.0005). IDO -/- mice showed higher survival compared to WT at 7 days after CA (68.5% in IDO -/- vs 37.5% in WT; log rank p=0.036). Neurological function was higher in IDO -/- than in WT mice during the 7 days following CA (p=0.0124). IDO -/- mice also showed an improved locomotor function compared to WT mice (p=0.037). Brain magnetic resonance imaging (MRI) with diffusion tensor imaging (DTI) sequences showed a reduction in fractional anisotropy in the external capsule of the corpus callosum in WT mice compared to IDO -/- mice at 7 days after resuscitation (p=0.015). We then treated additional IDO -/- mice with L-kyn 15 min before CA, to revert the IDO -/- phenotype. Brain MRI with diffusion-weighted imaging (DWI) sequences and histological analysis were performed 24h after CA in WT, IDO -/- , and IDO -/- +L-Kyn mice. Brain MRI revealed restriction of water diffusivity 24h after CA in WT mice. IDO-deletion reduced water diffusion abnormalities while the beneficial effect was reverted in the L-kyn group (p=0.01). Degenerating neurons in the frontal cortex, represented as Fluoro-Jade B positive cells, were more numerous in WT compared to IDO -/- mice; L-kyn halted this IDO deletion-induced reduction in degenerating cells (p=0.05). Conclusion: KP inhibition improves survival and neurological outcome after CA. The neuroprotective effect of IDO-deletion was associated with preservation of brain white matter microintegrity and with reduction of cerebral cytotoxic edema. Reversal of these beneficial effects by L-kyn administration in IDO -/- mice further confirm the KP role in CA outcome.

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Activation of the kynurenine pathway predicts mortality and neurological outcome in cardiac arrest patients: A validation study

Journal of Critical Care ◽

10.1016/j.jcrc.2021.09.025 ◽

2022 ◽

Vol 67 ◽

pp. 57-65

Author(s):

Nina Loretz ◽

Christoph Becker ◽

Seraina Hochstrasser ◽

Kerstin Metzger ◽

Katharina Beck ◽

...

Keyword(s):

Cardiac Arrest ◽

Validation Study ◽

Neurological Outcome ◽

Kynurenine Pathway

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Our experiences with therapeutic hypothermia

Medicinski pregled ◽

10.2298/mpns0710431p ◽

2007 ◽

Vol 60 (9-10) ◽

pp. 431-435 ◽

Cited By ~ 1

Author(s):

Milovan Petrovic ◽

Ilija Srdanovic ◽

Gordana Panic ◽

Tibor Canji ◽

Tihomir Miljevic

Keyword(s):

Cardiac Arrest ◽

Therapeutic Hypothermia ◽

Neurological Outcome ◽

Mild Hypothermia ◽

Acute Myocarditis ◽

Neuroprotective Effect ◽

Sudden Cardiac Arrest ◽

Neurological Recovery ◽

Global Cerebral Ischemia ◽

Resuscitation Guidelines

Introduction. The single most important clinically relevant cause of global cerebral ischemia is cardiac arrest. The estimated rate of sudden cardiac arrest is between 40 and 130 cases per 100.000 people per year. Almost 80% of patients initially resuscitated from cardiac arrest remain comatose for more than one hour. One year after cardiac arrest only 10-30% of these patients survive with good neurological outcome. The ability to survive anoxic no-flow states is dramatically increased with protective and preservative hypothermia. The results of clinical studies show a marked neuroprotective effect of mild hypothermia in resuscitation. Material and Methods. In our clinic, 12 patients were treated with therapeutic hypothermia. A combination of intravascular and external method of cooling was used according to the ILCOR (International Liaison Committee on Resuscitation) guidelines. The target temperature was 33oC, while the duration of cooling was 24 hours. After that, passive rewarming was allowed. All patients also received other necessary therapy. Results. Six patients (50%) had a complete neurological recovery. Two patients (16.6%) had partial neurological recovery. Four patients (33.3%) remained comatose. Five patients (41.66%) survived, while 7 (58.33%) patients died. The main cause of cardiac arrest was acute myocardial infarction (91.6%). One patient had acute myocarditis. Conclusion. Mild resuscitative hypothermia after cardiac arrest improves neurological outcome and reduces mortality in comatose survivors. .

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Age-Related Variations in Regional White Matter Volumetry and Microstructure During the Post-adolescence Period: A Cross-Sectional Study of a Cohort of 1,713 University Students

Frontiers in Systems Neuroscience ◽

10.3389/fnsys.2021.692152 ◽

2021 ◽

Vol 15 ◽

Author(s):

Ami Tsuchida ◽

Alexandre Laurent ◽

Fabrice Crivello ◽

Laurent Petit ◽

Antonietta Pepe ◽

...

Keyword(s):

White Matter ◽

University Students ◽

Diffusion Tensor ◽

Brain Mri ◽

Mean Diffusivity ◽

High Angular Resolution ◽

White Matter Volume ◽

Matter Volume ◽

Brain White Matter ◽

Age Related

Human brain white matter undergoes a protracted maturation that continues well into adulthood. Recent advances in diffusion-weighted imaging (DWI) methods allow detailed characterizations of the microstructural architecture of white matter, and they are increasingly utilized to study white matter changes during development and aging. However, relatively little is known about the late maturational changes in the microstructural architecture of white matter during post-adolescence. Here we report on regional changes in white matter volume and microstructure in young adults undergoing university-level education. As part of the MRi-Share multi-modal brain MRI database, multi-shell, high angular resolution DWI data were acquired in a unique sample of 1,713 university students aged 18–26. We assessed the age and sex dependence of diffusion metrics derived from diffusion tensor imaging (DTI) and neurite orientation dispersion and density imaging (NODDI) in the white matter regions as defined in the John Hopkins University (JHU) white matter labels atlas. We demonstrate that while regional white matter volume is relatively stable over the age range of our sample, the white matter microstructural properties show clear age-related variations. Globally, it is characterized by a robust increase in neurite density index (NDI), and to a lesser extent, orientation dispersion index (ODI). These changes are accompanied by a decrease in diffusivity. In contrast, there is minimal age-related variation in fractional anisotropy. There are regional variations in these microstructural changes: some tracts, most notably cingulum bundles, show a strong age-related increase in NDI coupled with decreases in radial and mean diffusivity, while others, mainly cortico-spinal projection tracts, primarily show an ODI increase and axial diffusivity decrease. These age-related variations are not different between males and females, but males show higher NDI and ODI and lower diffusivity than females across many tracts. These findings emphasize the complexity of changes in white matter structure occurring in this critical period of late maturation in early adulthood.

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Diffusion Tensor Imaging to Predict Long-term Outcome after Cardiac Arrest

Anesthesiology ◽

10.1097/aln.0b013e318275148c ◽

2012 ◽

Vol 117 (6) ◽

pp. 1311-1321 ◽

Cited By ~ 68

Author(s):

Charles-Edouard Luyt ◽

Damien Galanaud ◽

Vincent Perlbarg ◽

Audrey Vanhaudenhuyse ◽

Robert D. Stevens ◽

...

Keyword(s):

Cardiac Arrest ◽

Diffusion Coefficient ◽

Diffusion Tensor Imaging ◽

White Matter ◽

Apparent Diffusion Coefficient ◽

Diffusion Tensor ◽

Brain Magnetic Resonance Imaging ◽

Unfavorable Outcome ◽

Resonance Imaging ◽

Apparent Diffusion

Background Prognostication in comatose survivors of cardiac arrest is a major clinical challenge. The authors' objective was to determine whether an assessment with diffusion tensor imaging, a brain magnetic resonance imaging sequence, increases the accuracy of 1 yr functional outcome prediction in cardiac arrest survivors. Methods Prospective, observational study in two intensive care units. Fifty-seven comatose survivors of cardiac arrest underwent brain magnetic resonance imaging. Fractional anisotropy (FA), a diffusion tensor imaging value, was measured in predefined white matter regions, and apparent diffusion coefficient was assessed in predefined grey matter regions. Prediction of unfavorable outcome at 1 yr was compared using four prognostic models: FA global, FA selected, apparent diffusion coefficient, and clinical classifiers. Results Of the 57 patients included in the study, 49 had an unfavorable outcome at 12 months. Areas under the receiver operating characteristic curve (95% CI) to predict unfavorable outcome for the FA global, FA selected, clinical, and apparent diffusion coefficient models were 0.92 (0.82-0.98), 0.96 (0.87-0.99), 0.78 (0.65-0.88), and 0.86 (0.74-0.94), respectively. The FA selected model had the best overall accuracy for predicting outcome, with a score above 0.44 having 94% (95% CI, 83-99%) sensitivity and 100% (95% CI, 63-100%) specificity for the prediction of unfavorable outcome. Conclusion Quantitative diffusion tensor imaging indicates that white matter damage is widespread after cardiac arrest. A prognostic model based on FA values in selected white matter tracts seems to predict accurately 1 yr functional outcome. These preliminary results need to be confirmed in a larger population.

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The presence of antiautonomic membrane receptor antibodies do not correlate with brain lesions in Chagas' disease

Arquivos de Neuro-Psiquiatria ◽

10.1590/s0004-282x2009000400011 ◽

2009 ◽

Vol 67 (3a) ◽

pp. 633-638 ◽

Cited By ~ 2

Author(s):

Marco O. Py ◽

Leonardo Maciel ◽

Roberto C. Pedrosa ◽

Jose H. M. Nascimento ◽

Emiliano Medei

Keyword(s):

Brain Mri ◽

Brain Magnetic Resonance Imaging ◽

White Matter Lesions ◽

Brain Lesions ◽

Autonomic System ◽

System Function ◽

Beta Adrenergic ◽

Brain White Matter ◽

Magnetic Resonance Imaging Mri ◽

Parasympathetic Dysfunction

We previously demonstrated correlation between parasympathetic dysfunction and brain white matter lesions in chronic chagasic patients. OBJECTIVE: To correlate serum functional circulating antibodies with beta adrenergic (Ab-β), muscarinic (Ab-M) or muscarinic and beta adrenergic (Ab-Mβ) activity, the autonomic system function and brain lesions in chronic chagasic patients. METHOD: In fifteen consecutive chagasic patients, the autonomic nervous system was evaluated and brain magnetic resonance imaging (MRI) was performed. The sera of all patients were tested to the presence of circulating functional antibodies. RESULTS: Sera from 11 of 15 chronic chagasic patients had some activity (Ab-β: 7; Ab-M: 1; Ab-Mβ: 3); however, there was no significant correlation between the presence of antibodies and the autonomic system function or the presence of hyperintensities in MRI. CONCLUSION: The mechanism involved in the genesis of hyperintense lesions seen in brain MRI of chronic chagasic patients is still unresolved, although apparently related to parasympathetic dysfunction.

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Diffusion tensor imaging of brain white matter in Huntington gene mutation individuals

Arquivos de Neuro-Psiquiatria ◽

10.1590/0004-282x20170085 ◽

2017 ◽

Vol 75 (8) ◽

pp. 503-508 ◽

Cited By ~ 4

Author(s):

Roberta Arb Saba ◽

James H. Yared ◽

Thomas M. Doring ◽

Med Phys ◽

Vanderci Borges ◽

...

Keyword(s):

Diffusion Tensor Imaging ◽

White Matter ◽

Gene Mutation ◽

Fractional Anisotropy ◽

Diffusion Tensor ◽

Brain Magnetic Resonance Imaging ◽

White Matter Integrity ◽

Brain White Matter ◽

Potential Biomarker ◽

Significant Difference

ABSTRACT Objective To evaluate the role of the involvement of white matter tracts in huntingtin gene mutation patients as a potential biomarker of the progression of the disease. Methods We evaluated 34 participants (11 symptomatic huntingtin gene mutation, 12 presymptomatic huntingtin gene mutation, and 11 controls). We performed brain magnetic resonance imaging to assess white matter integrity using diffusion tensor imaging, with measurement of fractional anisotropy. Results We observed a significant decrease of fractional anisotropy in the cortical spinal tracts, corona radiate, corpus callosum, external capsule, thalamic radiations, superior and inferior longitudinal fasciculus, and inferior frontal-occipital fasciculus in the Huntington disease group compared to the control and presymptomatic groups. Reduction of fractional anisotropy is indicative of a degenerative process and axonal loss. There was no statistically significant difference between the presymptomatic and control groups. Conclusion White matter integrity is affected in huntingtin gene mutation symptomatic individuals, but other studies with larger samples are required to assess its usefulness in the progression of the neurodegenerative process.

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Is treatment-resistant schizophrenia associated with distinct neurobiological callosal connectivity abnormalities?

CNS Spectrums ◽

10.1017/s1092852920001753 ◽

2020 ◽

pp. 1-5

Author(s):

Idaiane Batista Assunção-Leme ◽

André Zugman ◽

Luciana Monteiro de Moura ◽

João Ricardo Sato ◽

Cinthia Higuchi ◽

...

Keyword(s):

Time Course ◽

Diffusion Tensor ◽

Brain Mri ◽

Mean Diffusivity ◽

Significant Feature ◽

Antipsychotic Treatment ◽

Treatment Resistant ◽

Adequate Treatment ◽

Brain White Matter ◽

Potential Biomarker

Abstract Background. Resistance to antipsychotic treatment affects up to 30% of patients with schizophrenia. Although the time course of development of treatment-resistant schizophrenia (TRS) varies from patient to patient, the reasons for these variations remain unknown. Growing evidence suggests brain dysconnectivity as a significant feature of schizophrenia. In this study, we compared fractional anisotropy (FA) of brain white matter between TRS and non–treatment-resistant schizophrenia (non-TRS) patients. Our central hypothesis was that TRS is associated with reduced FA values. Methods. TRS was defined as the persistence of moderate to severe symptoms after adequate treatment with at least two antipsychotics from different classes. Diffusion-tensor brain MRI obtained images from 34 TRS participants and 51 non-TRS. Whole-brain analysis of FA and axial, radial, and mean diffusivity were performed using Tract-Based Spatial Statistics (TBSS) and FMRIB’s Software Library (FSL), yielding a contrast between TRS and non-TRS patients, corrected for multiple comparisons using family-wise error (FWE) < 0.05. Results. We found a significant reduction in FA in the splenium of corpus callosum (CC) in TRS when compared to non-TRS. The antipsychotic dose did not relate to the splenium CC. Conclusion. Our results suggest that the focal abnormality of CC may be a potential biomarker of TRS.

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Natural Molecules and Neuroprotection: Kynurenic Acid, Pantethine and α-Lipoic Acid

International Journal of Molecular Sciences ◽

10.3390/ijms22010403 ◽

2021 ◽

Vol 22 (1) ◽

pp. 403

Author(s):

Fanni Tóth ◽

Edina Katalin Cseh ◽

László Vécsei

Keyword(s):

Neurodegenerative Diseases ◽

Lipoic Acid ◽

Kynurenic Acid ◽

Biological Activities ◽

Neuroprotective Effect ◽

Structural Diversity ◽

Kynurenine Pathway ◽

Glutamate Excitotoxicity ◽

Neuroprotective Agents ◽

Starting Point

The incidence of neurodegenerative diseases has increased greatly worldwide due to the rise in life expectancy. In spite of notable development in the understanding of these disorders, there has been limited success in the development of neuroprotective agents that can slow the progression of the disease and prevent neuronal death. Some natural products and molecules are very promising neuroprotective agents because of their structural diversity and wide variety of biological activities. In addition to their neuroprotective effect, they are known for their antioxidant, anti-inflammatory and antiapoptotic effects and often serve as a starting point for drug discovery. In this review, the following natural molecules are discussed: firstly, kynurenic acid, the main neuroprotective agent formed via the kynurenine pathway of tryptophan metabolism, as it is known mainly for its role in glutamate excitotoxicity, secondly, the dietary supplement pantethine, that is many sided, well tolerated and safe, and the third molecule, α-lipoic acid is a universal antioxidant. As a conclusion, because of their beneficial properties, these molecules are potential candidates for neuroprotective therapies suitable in managing neurodegenerative diseases.

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Mechanical circulatory support for refractory out-of-hospital cardiac arrest: a Danish nationwide multicenter study

Critical Care ◽

10.1186/s13054-021-03606-5 ◽

2021 ◽

Vol 25 (1) ◽

Author(s):

Sivagowry Rasalingam Mørk ◽

Carsten Stengaard ◽

Louise Linde ◽

Jacob Eifer Møller ◽

Lisette Okkels Jensen ◽

...

Keyword(s):

Logistic Regression ◽

Cardiac Arrest ◽

Survival Rate ◽

Neurological Outcome ◽

Mechanical Circulatory Support ◽

Circulatory Support ◽

Good Neurological Outcome ◽

Factors Associated ◽

National Consensus ◽

Hospital Cardiac Arrest

Abstract Background Mechanical circulatory support (MCS) with either extracorporeal membrane oxygenation or Impella has shown potential as a salvage therapy for patients with refractory out-of-hospital cardiac arrest (OHCA). The objective of this study was to describe the gradual implementation, survival and adherence to the national consensus with respect to use of MCS for OHCA in Denmark, and to identify factors associated with outcome. Methods This retrospective, observational cohort study included patients receiving MCS for OHCA at all tertiary cardiac arrest centers (n = 4) in Denmark between July 2011 and December 2020. Logistic regression and Kaplan–Meier survival analysis were used to determine association with outcome. Outcome was presented as survival to hospital discharge with good neurological outcome, 30-day survival and predictors of 30-day mortality. Results A total of 259 patients were included in the study. Thirty-day survival was 26%. Sixty-five (25%) survived to hospital discharge and a good neurological outcome (Glasgow–Pittsburgh Cerebral Performance Categories 1–2) was observed in 94% of these patients. Strict adherence to the national consensus showed a 30-day survival rate of 30% compared with 22% in patients violating one or more criteria. Adding criteria to the national consensus such as signs of life during cardiopulmonary resuscitation (CPR), pre-hospital low-flow < 100 min, pH > 6.8 and lactate < 15 mmol/L increased the survival rate to 48%, but would exclude 58% of the survivors from the current cohort. Logistic regression identified asystole (RR 1.36, 95% CI 1.18–1.57), pulseless electrical activity (RR 1.20, 95% CI 1.03–1.41), initial pH < 6.8 (RR 1.28, 95% CI 1.12–1.46) and lactate levels > 15 mmol/L (RR 1.16, 95% CI 1.16–1.53) as factors associated with increased risk of 30-day mortality. Patients presenting signs of life during CPR had reduced risk of 30-day mortality (RR 0.63, 95% CI 0.52–0.76). Conclusions A high survival rate with a good neurological outcome was observed in this Danish population of patients treated with MCS for OHCA. Stringent patient selection for MCS may produce higher survival rates but potentially withholds life-saving treatment in a significant proportion of survivors.

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Does Targeted Temperature Management Improve Neurological Outcome in Extracorporeal Cardiopulmonary Resuscitation (ECPR)?

Journal of Intensive Care Medicine ◽

10.1177/08850666211018982 ◽

2021 ◽

pp. 088506662110189

Author(s):

Merry Huang ◽

Aaron Shoskes ◽

Migdady Ibrahim ◽

Moein Amin ◽

Leen Hasan ◽

...

Keyword(s):

Cardiac Arrest ◽

Cardiopulmonary Resuscitation ◽

Neurological Outcome ◽

Targeted Temperature Management ◽

Temperature Management ◽

Survival Outcomes ◽

Pool Data ◽

Good Neurological Outcome ◽

Extracorporeal Cardiopulmonary Resuscitation ◽

Over Time

Purpose: Targeted temperature management (TTM) is a standard of care in patients after cardiac arrest for neuroprotection. Currently, the effectiveness and efficacy of TTM after extracorporeal cardiopulmonary resuscitation (ECPR) is unknown. We aimed to compare neurological and survival outcomes between TTM vs non-TTM in patients undergoing ECPR for refractory cardiac arrest. Methods: We searched PubMed and 5 other databases for randomized controlled trials and observational studies reporting neurological outcomes or survival in adult patients undergoing ECPR with or without TTM. Good neurological outcome was defined as cerebral performance category <3. Two independent reviewers extracted the data. Random-effects meta-analyses were used to pool data. Results: We included 35 studies (n = 2,643) with the median age of 56 years (interquartile range [IQR]: 52-59). The median time from collapse to ECMO cannulation was 58 minutes (IQR: 49-82) and the median ECMO duration was 3 days (IQR: 2.0-4.1). Of 2,643, 1,329 (50.3%) patients received TTM and 1,314 (49.7%) did not. There was no difference in the frequency of good neurological outcome at any time between TTM (29%, 95% confidence interval [CI]: 23%-36%) vs. without TTM (19%, 95% CI: 9%-31%) in patients with ECPR ( P = 0.09). Similarly, there was no difference in overall survival between patients with TTM (30%, 95% CI: 22%-39%) vs. without TTM (24%, 95% CI: 14%-34%) ( P = 0.31). A cumulative meta-analysis by publication year showed improved neurological and survival outcomes over time. Conclusions: Among ECPR patients, survival and neurological outcome were not different between those with TTM vs. without TTM. Our study suggests that neurological and survival outcome are improving over time as ECPR therapy is more widely used. Our results were limited by the heterogeneity of included studies and further research with granular temperature data is necessary to assess the benefit and risk of TTM in ECPR population.

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