Sex Differences in Traumatic Brain Injury: What We Know and What We Should Know

Gupte, Raeesa; Brooks, William M.; Vukas, Rachel; Pierce, Janet D.; Harris, J. Ieuan

doi:10.1089/neu.2018.6171

Cited by 341 publications

(316 citation statements)

References 299 publications

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“…Hormonal differences between males and females might be expected to cause sex-specific responses to bTBI; however, there is currently no consensus as to whether sex acts as a biological variable in CNS injury pathogenesis. 25 The studies described here found that sex did not have a significant effect on the visual outcomes analyzed: survival of RGCs, RGC complex layer thickness, and RGC function. To determine whether deleting IL-1 pathway components protected the retina from bTBI-induced damage, visual outcomes were compared in wild-type (WT) versus mice with null mutations in genes encoding IL-1α, IL-1β, or IL-1RI.…”

mentioning

confidence: 58%

“…Although more recent studies have begun using both male and female mice, some studies report that females fare better than males, and vice versa, while still others have found no difference between the sexes or had unclear results. 25 CNS anatomy, cellular pathways, and drug responses can be affected by sex, 36 – 38 but the specific parameters being analyzed could additionally produce different conclusions, depending on the effect of sex hormones. Indeed, sex-specific responses to the injury, the reparative processes that occur later, and responses to therapeutic interventions could result in distinctly different patterns of neuroprotection or neurodegeneration.…”

Section: Discussionmentioning

confidence: 99%

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Sex Does Not Influence Visual Outcomes After Blast-Mediated Traumatic Brain Injury but IL-1 Pathway Mutations Confer Partial Rescue

Evans

Boehme

et al. 2020

Invest. Ophthalmol. Vis. Sci.

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Purpose In a mouse model of blast-mediated traumatic brain injury (bTBI), interleukin-1 (IL-1)-pathway components were tested as potential therapeutic targets for bTBI-mediated retinal ganglion cell (RGC) dysfunction. Sex was also evaluated as a variable for RGC outcomes post-bTBI. Methods Male and female mice with null mutations in genes encoding IL-1α, IL-1β, or IL-1RI were compared to C57BL/6J wild-type (WT) mice after exposure to three 20-psi blast waves given at an interblast interval of 1 hour or to mice receiving sham injury. To determine if genetic blockade of IL-1α, IL-1β, or IL-1RI could prevent damage to RGCs, the function and structure of these cells were evaluated by pattern electroretinogram and optical coherence tomography, respectively, 5 weeks following blast or sham exposure. RGC survival was also quantitatively assessed via immunohistochemical staining of BRN3A at the completion of the study. Results Our results showed that male and female WT mice had a similar response to blast-induced retinal injury. Generally, constitutive deletion of IL-1α, IL-1β, or IL-1RI did not provide full protection from the effects of bTBI on visual outcomes; however, injured WT mice had significantly worse visual outcomes compared to the injured genetic knockout mice. Conclusions Sex does not affect RGC outcomes after bTBI. The genetic studies suggest that deletion of these IL-1 pathway components confers some protection, but global deletion from birth did not result in a complete rescue.

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mentioning

confidence: 58%

Section: Discussionmentioning

confidence: 99%

Sex Does Not Influence Visual Outcomes After Blast-Mediated Traumatic Brain Injury but IL-1 Pathway Mutations Confer Partial Rescue

Evans

Boehme

et al. 2020

Invest. Ophthalmol. Vis. Sci.

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“…To date, all animal studies investigating the relationship between the NLRP3 inflammasome and TBI have exclusively utilized male rodents. It is becoming increasingly appreciated that males and females can have different biological and behavioral responses to TBI [111]. Of particular relevance, there is some evidence that the nature of neuroinflammatory responses after TBI may differ between sexes.…”

Section: Biological Sex and The Nlrp3 Inflammasomementioning

confidence: 99%

The NLRP3 inflammasome in traumatic brain injury: potential as a biomarker and therapeutic target

O’Brien

Pham

Symons

et al. 2020

J Neuroinflammation

159

108

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There is a great clinical need to identify the underlying mechanisms, as well as related biomarkers, and treatment targets, for traumatic brain injury (TBI). Neuroinflammation is a central pathophysiological feature of TBI. NLRP3 inflammasome activity is a necessary component of the innate immune response to tissue damage, and dysregulated inflammasome activity has been implicated in a number of neurological conditions. This paper introduces the NLRP3 inflammasome and its implication in the pathogenesis of neuroinflammatory-related conditions, with a particular focus on TBI. Although its role in TBI has only recently been identified, findings suggest that priming and activation of the NLRP3 inflammasome are upregulated following TBI. Moreover, recent studies utilizing specific NLRP3 inhibitors have provided further evidence that this inflammasome is a major driver of neuroinflammation and neurobehavioral disturbances following TBI. In addition, there is emerging evidence that circulating inflammasome-associated proteins may have utility as diagnostic biomarkers of neuroinflammatory conditions, including TBI. Finally, novel and promising areas of research will be highlighted, including the potential involvement of the NLRP3 inflammasome in mild TBI, how factors such as biological sex may affect NLRP3 activity in TBI, and the use of emerging biomarker platforms. Taken together, this review highlights the exciting potential of the NLRP3 inflammasome as a target for treatments and biomarkers that may ultimately be used to improve TBI management.

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“…There are significant sex differences in WM development that may influence vulnerability to injury (Ho et al , 2020;Schmied et al , 2020) . Pre-clinical evidence also suggests that sex may moderate severity of outcomes (see review by (Gupte et al , 2019) ). However, most studies of msTBI in children have not had the sample size necessary to examine this effect (Dennis et al , 2018) .…”

Section: Introductionmentioning

confidence: 99%

White Matter Disruption in Pediatric Traumatic Brain Injury: Results from ENIGMA Pediatric msTBI

Dennis

Caeyenberghs

Hoskinson

et al. 2020

Preprint

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Annually, approximately 3 million children around the world experience traumatic brain injuries (TBIs), of which up to 20% are characterized as moderate to severe (msTBI) and/or have abnormal imaging findings. Affected children are vulnerable to long-term cognitive and behavioral dysfunction, as injury can disrupt or alter ongoing brain maturation. Post-injury outcomes are highly variable, and there is only limited understanding of how inter-individual differences in outcomes arise. Small sample sizes have also complicated efforts to better understand factors influencing the impact of TBI on the developing brain. White matter (WM) disruption is a critical aspect of TBI neuropathology and diffusion MRI (dMRI) is particularly sensitive to microstructural abnormalities. Here we present the results of a coordinated analysis of dMRI data across ten cohorts from three countries. We had three primary aims: (1) to characterize the nature and extent of WM disruption across key post-injury intervals (acute/subacute - within 2 months, post-acute - 2-6 months, chronic - 6+ months); (2) evaluate the impact of age and sex on WM in the context of injury; and (3) to examine associations between WM and neurobehavioral outcomes. Based on data from 507 children and adolescents (244 with complicated mild to severe TBI and 263 control children), we report widespread WM disruption across all post-injury intervals. As expected, injury severity was a significant contributor to the pattern and extent of WM degradation, but explained less variance in dMRI measures with increasing time since injury, supporting other research indicating that other factors contribute increasingly to outcomes over time. The corpus callosum appears to be particularly vulnerable to injury, an effect that persists years post-TBI. We also report sex differences in the effect of TBI on the uncinate fasciculus (UNC), a structure with a key role in emotion regulation. Females with a TBI had significantly lower fractional anisotropy (FA) in the UNC than those with no TBI, and this phenomenon was further associated with more frequent parent-reported behavioral problems as measured by the Child Behavior Checklist (CBCL). These effects were not detected in males. With future harmonization of imaging and neurocognitive data, more complex modeling of factors influencing outcomes will be possible and help to identify clinically-meaningful patient subtypes.

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Sex Differences in Traumatic Brain Injury: What We Know and What We Should Know

Cited by 341 publications

References 299 publications

Sex Does Not Influence Visual Outcomes After Blast-Mediated Traumatic Brain Injury but IL-1 Pathway Mutations Confer Partial Rescue

Sex Does Not Influence Visual Outcomes After Blast-Mediated Traumatic Brain Injury but IL-1 Pathway Mutations Confer Partial Rescue

The NLRP3 inflammasome in traumatic brain injury: potential as a biomarker and therapeutic target

White Matter Disruption in Pediatric Traumatic Brain Injury: Results from ENIGMA Pediatric msTBI

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