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Genetic Influences on Patient-Oriented Outcomes in Traumatic Brain Injury: A Living Systematic Review of Non-Apolipoprotein E Single-Nucleotide Polymorphisms.

ABSTRACT: There is a growing literature on the impact of genetic variation on outcome in traumatic brain injury (TBI). Whereas a substantial proportion of these publications have focused on the apolipoprotein E (APOE) gene, several have explored the influence of other polymorphisms. We undertook a systematic review of the impact of single-nucleotide polymorphisms (SNPs) in non-apolipoprotein E (non-APOE) genes associated with patient outcomes in adult TBI). We searched EMBASE, MEDLINE, CINAHL, and gray literature from inception to the beginning of August 2017 for studies of genetic variance in relation to patient outcomes in adult TBI. Sixty-eight articles were deemed eligible for inclusion into the systematic review. The SNPs described were in the following categories: neurotransmitter (NT) in 23, cytokine in nine, brain-derived neurotrophic factor (BDNF) in 12, mitochondrial genes in three, and miscellaneous SNPs in 21. All studies were based on small patient cohorts and suffered from potential bias. A range of SNPs associated with genes coding for monoamine NTs, BDNF, cytokines, and mitochondrial proteins have been reported to be associated with variation in global, neuropsychiatric, and behavioral outcomes. An analysis of the tissue, cellular, and subcellular location of the genes that harbored the SNPs studied showed that they could be clustered into blood-brain barrier associated, neuroprotective/regulatory, and neuropsychiatric/degenerative groups. Several small studies report that various NT, cytokine, and BDNF-related SNPs are associated with variations in global outcome at 6-12 months post-TBI. The association of these SNPs with neuropsychiatric and behavioral outcomes is less clear. A definitive assessment of role and effect size of genetic variation in these genes on outcome remains uncertain, but could be clarified by an adequately powered genome-wide association study with appropriate recording of outcomes.

SUBMITTER: Zeiler FA

PROVIDER: S-EPMC8054522 | biostudies-literature | 2021 Apr

REPOSITORIES: biostudies-literature

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Genetic Influences on Patient-Oriented Outcomes in Traumatic Brain Injury: A Living Systematic Review of Non-Apolipoprotein E Single-Nucleotide Polymorphisms.

Zeiler Frederick A FA McFadyen Charles C Newcombe Virginia F J VFJ Synnot Anneliese A Donoghue Emma L EL Ripatti Samuli S Steyerberg Ewout W EW Gruen Russel L RL McAllister Thomas W TW Rosand Jonathan J Palotie Aarno A Maas Andrew I R AIR Menon David K DK

Journal of neurotrauma 20190607 8

There is a growing literature on the impact of genetic variation on outcome in traumatic brain injury (TBI). Whereas a substantial proportion of these publications have focused on the apolipoprotein E (APOE) gene, several have explored the influence of other polymorphisms. We undertook a systematic review of the impact of single-nucleotide polymorphisms (SNPs) in non-apolipoprotein E (non-APOE) genes associated with patient outcomes in adult TBI). We searched EMBASE, MEDLINE, CINAHL, and gray li ...[more]

PMID: 29799308

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Project description:BackgroundTraumatic Brain Injury (TBI) is a major cause of disability and mortality, to which there is currently no comprehensive treatment. Blood Brain Barrier (BBB) dysfunction is well documented in human TBI patients, yet the molecular mechanisms that underlie this neurovascular unit (NVU) pathology remains unclear. The apolipoprotein-E (apoE) protein has been implicated in controlling BBB integrity in an isoform dependent manner, via suppression of Cyclophilin A (CypA)-Matrix metallopeptidase-9 (MMP-9) signaling cascades, however the contribution of this pathway in TBI-induced BBB permeability is not fully investigated.MethodsWe exposed C57Bl/6 mice to controlled cortical impact and assessed NVU and BBB permeability responses up to 21 days post-injury. We pharmacologically probed the role of the CypA-MMP-9 pathway in BBB permeability after TBI using Cyclosporin A (CsA, 20 mg/kg). Finally, as the apoE4 protein is known to be functionally deficient compared to the apoE3 protein, we used humanized APOE mice as a clinically relevant model to study the role of apoE on BBB injury and repair after TBI.ResultsIn C57Bl/6 mice there was an inverse relationship between soluble apoE and BBB permeability, such that damaged BBB stabilizes as apoE levels increase in the days following TBI. TBI mice displayed acute pericyte loss, increased MMP-9 production and activity, and reduced tight-junction expression. Treatment with the CypA antagonist CsA in C57Bl/6 mice attenuates MMP-9 responses and enhances BBB repair after injury, demonstrating that MMP-9 plays an important role in the timing of spontaneous BBB repair after TBI. We also show that apoe mRNA is present in both astrocytes and pericytes after TBI. We report that APOE3 and APOE4 mice have similar acute BBB responses to TBI, but APOE3 mice display faster spontaneous BBB repair than APOE4 mice. Isolated microvessel analysis reveals delayed pericyte repopulation, augmented and sustained MMP-9 expression at the NVU, and impaired stabilization of Zonula Occludens-1, Occludin and Claudin-5 expression at tight junctions in APOE4 mice after TBI compared to APOE3 mice.ConclusionsThese data confirm apoE as an important modulator of spontaneous BBB stabilization following TBI, and highlights the APOE4 allele as a risk factor for poor outcome after TBI.

Project description:Background: Disruption in cerebrovascular reactivity following traumatic brain injury (TBI) is a known phenomenon that may hold prognostic value and clinical relevance. Ultimately, improved knowledge of this process and more robust means of continuous assessment may lead to advances in precision medicine following TBI. One such method is transcranial Doppler (TCD), which has been employed to evaluate cerebrovascular reactivity following injury utilizing a continuous time-series approach. Objective: The present study undertakes a scoping review of the literature on the association of continuous time-domain TCD based indices of cerebrovascular reactivity, with global functional outcomes, cerebral physiologic correlates, and imaging evidence of lesion change. Design: Multiple databases were searched from inception to November 2020 for articles relevant to the association of continuous time-domain TCD based indices of cerebrovascular reactivity with global functional outcomes, cerebral physiologic correlates, and imaging evidence of lesion change. Results: Thirty-six relevant articles were identified. There was significant evidence supporting an association with continuous time-domain TCD based indices and functional outcomes following TBI. Indices based on mean flow velocity, as measured by TCD, were most numerous while more recent studies point to systolic flow velocity-based indices encoding more prognostic utility. Physiologic parameters such as intracranial pressure, cerebral perfusion pressure, Carbon Dioxide (CO2) reactivity as well as more established indices of cerebrovascular reactivity have all been associated with these TCD based indices. The literature has been concentrated in a few centres and is further limited by the lack of multivariate analysis. Conclusions: This systematic scoping review of the literature identifies that there is a substantial body of evidence that cerebrovascular reactivity as measured by time-domain TCD based indices have prognostic utility following TBI. Indices based on mean flow velocities have the largest body of literature for their support. However, recent studies indicate that indices based on systolic flow velocities may contain the most prognostic utility and more closely follow more established measures of cerebrovascular reactivity. To a lesser extent, the literature supports some associations between these indices and cerebral physiologic parameters. These indices provide a more complete picture of the patient's physiome following TBI and may ultimately lead to personalized and precise clinical care. Further validation in multi-institution studies is required before these indices can be widely adopted clinically.

Project description:Non-invasive brain stimulation has been widely investigated as a potential treatment for a range of neurological and psychiatric conditions, including brain injury. However, the behavioural effects of brain stimulation are variable, for reasons that are poorly understood. This is a particular challenge for traumatic brain injury, where patterns of damage and their clinical effects are heterogeneous. Here we test the hypothesis that the response to transcranial direct current stimulation following traumatic brain injury is dependent on white matter damage within the stimulated network. We used a novel simultaneous stimulation-MRI protocol applying anodal, cathodal and sham stimulation to 24 healthy control subjects and 35 patients with moderate/severe traumatic brain injury. Stimulation was applied to the right inferior frontal gyrus/anterior insula node of the salience network, which was targeted because our previous work had shown its importance to executive function. Stimulation was applied during performance of the Stop Signal Task, which assesses response inhibition, a key component of executive function. Structural MRI was used to assess the extent of brain injury, including diffusion MRI assessment of post-traumatic axonal injury. Functional MRI, which was simultaneously acquired to delivery of stimulation, assessed the effects of stimulation on cognitive network function. Anodal stimulation improved response inhibition in control participants, an effect that was not observed in the patient group. The extent of traumatic axonal injury within the salience network strongly influenced the behavioural response to stimulation. Increasing damage to the tract connecting the stimulated right inferior frontal gyrus/anterior insula to the rest of the salience network was associated with reduced beneficial effects of stimulation. In addition, anodal stimulation normalized default mode network activation in patients with poor response inhibition, suggesting that stimulation modulates communication between the networks involved in supporting cognitive control. These results demonstrate an important principle: that white matter structure of the connections within a stimulated brain network influences the behavioural response to stimulation. This suggests that a personalized approach to non-invasive brain stimulation is likely to be necessary, with structural integrity of the targeted brain networks an important criterion for patient selection and an individualized approach to the selection of stimulation parameters.

Dataset Information

Genetic Influences on Patient-Oriented Outcomes in Traumatic Brain Injury: A Living Systematic Review of Non-Apolipoprotein E Single-Nucleotide Polymorphisms.

Publications

Genetic Influences on Patient-Oriented Outcomes in Traumatic Brain Injury: A Living Systematic Review of Non-Apolipoprotein E Single-Nucleotide Polymorphisms.

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