Reframing the Biological Basis of Neuroprotection Using Functional Genomics: Differentially Weighted, Time-Dependent Multifactor Pathogenesis of Human Ischemic Brain Damage

Kofke, W. Andrew; Ren, Yue; Augoustides, John; Li, Hongzhe; Nathanson, Katherine L.; Siman, Robert; Meng, Qing Cheng; Bu, Weiming; Yandrawatthana, Sukanya; Kositratna, Guy; Kim, Cecilia; Bavaria, Joseph E.

doi:10.3389/fneur.2018.00497

Cited by 7 publications

(4 citation statements)

References 109 publications

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“…We performed a retrospective cohort study of 98 patients prospectively enrolled in an observational study on adult patients undergoing non-emergent cardiac surgery: deep hypothermic cardiac arrest aortic surgery or aortic valve replacement surgery. [ 20 ] The protocol was approved by the institutional biomedical review board and subjects provided written informed consent for the study including having their medical records used in research. Subjects with genotyping for the SNP, rs10830963, of MTNR1B were included.…”

Section: Methodsmentioning

confidence: 99%

Does the melatonin receptor 1B gene polymorphism have a role in postoperative delirium?

et al. 2018

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IntroductionPatients undergoing cardiac surgery are at high risk for postoperative delirium, which is associated with longer hospital and intensive care lengths of stays, increased morbidity and mortality. Because sleep disturbances are common in delirium, melatonin has been an area of interest in the treatment of delirium. The rs10830963 single nucleotide polymorphism of the melatonin receptor 1B gene can cause pathological dysfunction of this receptor and is associated with delayed morning offset of melatonin. We hypothesized patients undergoing aortic cardiac surgery who have the risk genotype of a melatonin receptor 1B polymorphism would have a higher incidence of postoperative delirium.MethodsNinety-eight patients undergoing aortic root or valve surgery underwent analysis for melatonin receptor 1B single nucleotide polymorphism, rs10830963. Using a validated method, CHART-DEL, all charts were retrospectively reviewed and scored for the presence of delirium while blinded to the results of the melatonin receptor 1B gene polymorphism.ResultsGenotyping for melatonin receptor 1B polymorphism was acceptable in 76 subjects of European descent of which 18 (23.7%) had delirium. Four of seven subjects with the risk genotype had delirium versus only 20.3% of subjects without the risk genotype. This carried an odds ratio of 5.2 (1.0, 26.1), p = 0.050.ConclusionThis observation suggests a role of the risk genotype of a melatonin receptor 1B polymorphism in the development of postoperative delirium. These hypotheses generating results warrant further prospective studies in a larger cohort group with delirium, circadian rhythm and melatonin assessments.

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Section: Methodsmentioning

confidence: 99%

Does the melatonin receptor 1B gene polymorphism have a role in postoperative delirium?

et al. 2018

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“…This requires reframing neuroprotection research. Neuroprotection based on functional genomics and utilizing a systems biology approach may ultimately provide improved outcomes for patients 22…”

Section: Resultsmentioning

confidence: 99%

Precision Medicine in Acute Brain Injury: A Narrative Review

Mahajan

Kapoor²,

Prabhakar³

2020

Journal of Neurosurgical Anesthesiology

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Over the past few years, the concept of personalized medicine has percolated into the management of different neurological conditions. Improving outcomes after acute brain injury (ABI) continues to be a major challenge. Unrecognized individual multiomic variations in addition to multiple interacting processes may explain why we fail to observe comprehensive improvements in ABI outcomes even when applied treatments appear to be beneficial logically. The provision of clinical care based on a multiomic approach may revolutionize the management of traumatic brain injury, delayed cerebral ischemia after subarachnoid hemorrhage, acute ischemic stroke, and several other neurological diseases. The challenge is to incorporate all the information obtained from genomic studies, other omic data, and individual variability into a practical tool that can be used to assist clinical decision-making. The effective execution of such strategies, which is still far away, requires the development of protocols on the basis of these complex interactions and strict adherence to management protocols. In this review, we will discuss various omics and physiological targets to guide individualized patient management after ABI.

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“…Moreover, nodes with higher ICSs are often informative with respect to reaction interplay and reversibility of the ability of DAMPs to induce cell injury 29 . The notion of multiple adverse protein pathways is important as it could potentially help to develop future targeted therapeutic strategies, enabling a multifaceted, individualized treatment approach for ABI 30,31 . Moreover, genetics studies have begun to identify individual differences in polymorphisms that could affect recovery and cognitive and social processing outcomes after traumatic brain injury 32 …”

Section: Discussionmentioning

confidence: 99%

vCSF Danger-associated Molecular Patterns After Traumatic and Nontraumatic Acute Brain Injury: A Prospective Study

Santacruz

Vincent

Duitama

et al. 2023

Journal of Neurosurgical Anesthesiology

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Background: Danger-associated molecular patterns (DAMPs) may be implicated in the pathophysiological pathways associated with an unfavorable outcome after acute brain injury (ABI). Methods:We collected samples of ventricular cerebrospinal fluid (vCSF) for 5 days in 50 consecutive patients at risk of intracranial hypertension after traumatic and nontraumatic ABI. Differences in vCSF protein expression over time were evaluated using linear models and selected for functional network analysis using the PANTHER and STRING databases. The primary exposure of interest was the type of brain injury (traumatic vs. nontraumatic), and the primary outcome was the vCSF expression of DAMPs. Secondary exposures of interest included the occurrence of intracranial pressure Z 20 or ≥ 30 mm Hg during the 5 days post-ABI, intensive care unit (ICU) mortality, and neurological outcome (assessed using the Glasgow Outcome Score) at 3 months post-ICU discharge. Secondary outcomes included associations of these exposures with the vCSF expression of DAMPs.Results: A network of 6 DAMPs (DAMP_ trauma ; protein-protein interaction [PPI] P = 0.04) was differentially expressed in patients with ABI of traumatic origin compared with those with nontraumatic ABI. ABI patients with intracranial pressure ≥ 30 mm Hg differentially expressed a set of 38 DAMPS (DAMP_ ICP30 ; PPI P < 0.001). Proteins in DAMP_ ICP30 are involved in cellular proteolysis, complement pathway activation, and post-translational modifications. There were no relationships between DAMP expression and ICU mortality or unfavorable versus favorable outcomes.Conclusions: Specific patterns of vCSF DAMP expression differentiated between traumatic and nontraumatic types of ABI and were associated with increased episodes of severe intracranial hypertension.

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Reframing the Biological Basis of Neuroprotection Using Functional Genomics: Differentially Weighted, Time-Dependent Multifactor Pathogenesis of Human Ischemic Brain Damage

Cited by 7 publications

References 109 publications

Does the melatonin receptor 1B gene polymorphism have a role in postoperative delirium?

Does the melatonin receptor 1B gene polymorphism have a role in postoperative delirium?

Precision Medicine in Acute Brain Injury: A Narrative Review

vCSF Danger-associated Molecular Patterns After Traumatic and Nontraumatic Acute Brain Injury: A Prospective Study

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