Sex and genetic associations with cerebrospinal fluid dopamine and metabolite production after severe traumatic brain injury

Wagner, Amy K.; Ren, Dianxu; Conley, Yvette P.; Ma, Xiecheng; Kerr, Mary Margaret; Zafonte, Ross; Puccio, Ava M.; Marion, Donald W.; Dixon, C. Edward

doi:10.3171/jns.2007.106.4.538

Cited by 42 publications

(33 citation statements)

References 57 publications

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“…31 In rats, a lack of sex differences in MWM performance has also been reported post-CCI. 28,93 Further, estrous cycle stage at time of injury had no impact on post-TBI cognitive performance in rats. 28 Thus, it appears that use of the MWM for cognitive testing post-TBI does not discriminate between males and females for many species and strains of rodents.…”

Section: Tucker Et Almentioning

confidence: 93%

Performance of Male and Female C57BL/6J Mice on Motor and Cognitive Tasks Commonly Used in Pre-Clinical Traumatic Brain Injury Research

Tucker

McCabe

2016

Journal of Neurotrauma

129

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To date, clinical trials have failed to find an effective therapy for victims of traumatic brain injury (TBI) who live with motor, cognitive, and psychiatric complaints. Pre-clinical investigators are now encouraged to include male and female subjects in all translational research, which is of particular interest in the field of neurotrauma given that circulating female hormones (progesterone and estrogen) have been demonstrated to exert neuroprotective effects. To determine whether behavior of male and female C57BL6/J mice is differentially impaired by TBI, male and cycling female mice were injured by controlled cortical impact and tested for several weeks with functional assessments commonly employed in pre-clinical research. We found that cognitive and motor impairments post-TBI, as measured by the Morris water maze (MWM) and rotarod, respectively, were largely equivalent in male and female animals. However, spatial working memory, assessed by the y-maze, was poorer in female mice. Female mice were generally more active, as evidenced by greater distance traveled in the first exposure to the open field, greater distance in the y-maze, and faster swimming speeds in the MWM. Statistical analysis showed that variability in all behavioral data was no greater in cycling female mice than it was in male mice. These data all suggest that with careful selection of tests, procedures, and measurements, both sexes can be included in translational TBI research without concern for effect of hormones on functional impairments or behavioral variability.

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Section: Tucker Et Almentioning

confidence: 93%

Performance of Male and Female C57BL/6J Mice on Motor and Cognitive Tasks Commonly Used in Pre-Clinical Traumatic Brain Injury Research

Tucker

McCabe

2016

Journal of Neurotrauma

129

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“…There is also evidence that gender alters the dopaminergic system, and that oestradiol levels act in combination with genetic variants in the dopamine system to affect cognitive measures in an inverted-U manner (Jacobs and D'Esposito, 2011). Experimentally, animal models of TBI have demonstrated gender-specific altered response to catecholaminergic therapies, with female rats displaying little cognitive benefit but excessive motor response when treated with doses of methylphenidate that are therapeutic for males (Wagner et al , 2007). …”

Section: Stratifying Patient Treatment Based On Catecholaminergic Funmentioning

confidence: 99%

Catecholamines and cognition after traumatic brain injury

Jenkins

Mehta

Sharp

2016

Brain

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“…TBI results in several acute secondary injury cascades, that include aseptic inflammation (Kumar et al, 2015, 2016), excitotoxicity (Wagner et al, 2005), monaminergic dysfunction (Wagner et al, 2007), neurotrophin abnormalities (Failla et al, 2016), and stress induced steroidogenesis (Wagner et al, 2011a; Santarsieri et al, 2014) that result in blood brain barrier disruption and CNS damage (Wagner et al, 2011b; Goyal et al, 2013); representative biomarkers for each of these pathways have been identified in CSF and serum for clinical populations with moderate/severe TBI. However, individual biomarker studies have limitations with predicting therapeutic treatment response (Maas et al, 2010), which may be due to the focus of current research on single biomarker relationships, rather than the interactions of several.…”

Section: Introductionmentioning

confidence: 99%

Cerebrospinal Fluid Cortisol Mediates Brain-Derived Neurotrophic Factor Relationships to Mortality after Severe TBI: A Prospective Cohort Study

Munoz

Kumar

et al. 2017

Front. Mol. Neurosci.

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Distinct regulatory signaling mechanisms exist between cortisol and brain derived neurotrophic factor (BDNF) that may influence secondary injury cascades associated with traumatic brain injury (TBI) and predict outcome. We investigated concurrent CSF BDNF and cortisol relationships in 117 patients sampled days 0–6 after severe TBI while accounting for BDNF genetics and age. We also determined associations between CSF BDNF and cortisol with 6-month mortality. BDNF variants, rs6265 and rs7124442, were used to create a gene risk score (GRS) in reference to previously published hypothesized risk for mortality in “younger patients” (<48 years) and hypothesized BDNF production/secretion capacity with these variants. Group based trajectory analysis (TRAJ) was used to create two cortisol groups (high and low trajectories). A Bayesian estimation approach informed the mediation models. Results show CSF BDNF predicted patient cortisol TRAJ group (P = 0.001). Also, GRS moderated BDNF associations with cortisol TRAJ group. Additionally, cortisol TRAJ predicted 6-month mortality (P = 0.001). In a mediation analysis, BDNF predicted mortality, with cortisol acting as the mediator (P = 0.011), yielding a mediation percentage of 29.92%. Mediation effects increased to 45.45% among younger patients. A BDNF*GRS interaction predicted mortality in younger patients (P = 0.004). Thus, we conclude 6-month mortality after severe TBI can be predicted through a mediation model with CSF cortisol and BDNF, suggesting a regulatory role for cortisol with BDNF's contribution to TBI pathophysiology and mortality, particularly among younger individuals with severe TBI. Based on the literature, cortisol modulated BDNF effects on mortality after TBI may be related to known hormone and neurotrophin relationships to neurological injury severity and autonomic nervous system imbalance.

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Sex and genetic associations with cerebrospinal fluid dopamine and metabolite production after severe traumatic brain injury

Abstract: In addition to systemic administration of DA, inherent factors such as sex and DAT genotype affect post-TBI CSF DA and DA metabolite levels, a phenomenon that may modulate susceptibility to DA-mediated oxidative injury.

Cited by 42 publications

References 57 publications

Performance of Male and Female C57BL/6J Mice on Motor and Cognitive Tasks Commonly Used in Pre-Clinical Traumatic Brain Injury Research

Performance of Male and Female C57BL/6J Mice on Motor and Cognitive Tasks Commonly Used in Pre-Clinical Traumatic Brain Injury Research

Catecholamines and cognition after traumatic brain injury

Cerebrospinal Fluid Cortisol Mediates Brain-Derived Neurotrophic Factor Relationships to Mortality after Severe TBI: A Prospective Cohort Study

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