Genetic association studies in patients with traumatic brain injury

Dardiotis, Efthimios; Fountas, Kostas N.; Dardioti, Maria; Xiromerisiou, Georgia; Kapsalaki, Eftychia; Τάσιου, Αναστασία; Hadjigeorgiou, Georgios M.

doi:10.3171/2009.10.focus09215

Cited by 109 publications

(86 citation statements)

References 138 publications

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“…[20] Such an explanation would be in keeping with APOE's known role in neuronal repair [20,[26][27][28] as well as prior research demonstrating that the APOE ε4 allele is associated with poor recovery from neuronal insult. [37] Such an explanation would also be in keeping with the extensive literature that suggests that prolonged stress leads to prolonged release of glucocorticoids, which can, in turn, lead to hippocampal atrophy.…”

Section: Discussionmentioning

confidence: 78%

Effect of the Apoe Ε4 Allele and Combat Exposure on PTSD Among Iraq/Afghanistan-Era Veterans

et al. 2015

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Section: Discussionmentioning

confidence: 78%

Effect of the Apoe Ε4 Allele and Combat Exposure on PTSD Among Iraq/Afghanistan-Era Veterans

et al. 2015

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“…For example, as in flies, human studies suggest that age and the severity of primary injury are important factors in CTE development (30,31). In addition, studies in different rodent strains as well as genetic association studies in TBI patients indicate that, as in flies, TBI outcomes depend on genetic background (26,32).…”

Section: Discussionmentioning

confidence: 99%

“…An increasing body of evidence implicates genetic factors in the variable clinical outcomes of TBI in humans (26). To investigate the effect of genetic background on the primary injury threshold in flies, we determined the MI 24 for 42 fly lines (aged 0-7 d) that were subjected to the standard TBI protocol.…”

Section: Age-associated Processes Enhance Neurodegeneration Due To Brainmentioning

confidence: 99%

A Drosophila model of closed head traumatic brain injury

Katzenberger¹,

Loewen

Wassarman³

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

109

222

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Traumatic brain injury (TBI) is a substantial health issue worldwide, yet the mechanisms responsible for its complex spectrum of pathologies remains largely unknown. To investigate the mechanisms underlying TBI pathologies, we developed a model of TBI in Drosophila melanogaster. The model allows us to take advantage of the wealth of experimental tools available in flies. Closed head TBI was inflicted with a mechanical device that subjects flies to rapid acceleration and deceleration. Similar to humans with TBI, flies with TBI exhibited temporary incapacitation, ataxia, activation of the innate immune response, neurodegeneration, and death. Our data indicate that TBI results in death shortly after a primary injury only if the injury exceeds a certain threshold and that age and genetic background, but not sex, substantially affect this threshold. Furthermore, this threshold also appears to be dependent on the same cellular and molecular mechanisms that control normal longevity. This study demonstrates the potential of flies for providing key insights into human TBI that may ultimately provide unique opportunities for therapeutic intervention.concussion | insect | chronic traumatic encephalopathy T raumatic brain injury (TBI) is a leading cause of neurological deficits and mortality worldwide (1, 2). TBI outcomes result from primary and secondary injuries that cause cell damage and death in the brain. Primary injuries occur during the initial impact and are triggered by external mechanical forces that deform the brain, whereas secondary injuries are triggered by cellular and molecular responses that occur over time in reaction to the primary injuries. TBI outcomes are heterogeneous in the human population owing to variation in the location and strength of primary injuries as well as genetic and environmental factors that affect the severity of primary and secondary injuries. This heterogeneity is one of the most significant barriers to the development of therapeutic interventions (3-5). Therefore, research aimed at determining the genetic and environmental factors that affect the severity of primary and secondary injuries is essential for developing treatments for TBI.To investigate the underlying cellular and molecular basis of TBI, we developed a Drosophila melanogaster model. Key advantages of flies are that (i) large numbers of animals can be rapidly and inexpensively analyzed to establish causality between injuries and outcomes, (ii) many molecular and genetic tools are available to investigate the molecules and pathways that underlie injuries, and (iii) outcomes can readily be evaluated over the entire animal lifespan. Thus, flies provide unique opportunities to understand TBI.It is reasonable to expect that TBI can be modeled in flies because Drosophila has already proved to be an extremely useful model for studying other human neurodegenerative disorders (6). In fact, research in flies has already provided novel insights into neurodegeneration, memory, and sleep, all of which are affected in human TBI (6-8)...

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“…Genetic polymorphisms may play a role in the susceptibility of a given individual to adverse outcomes following TBI (Dardiotis et al, 2010). Apolipoprotein E polymorphisms (APOE = gene, apoE = protein) are the most extensively studied genetic factor in neurotrauma research ( Jellinger et al, 2001( Jellinger et al, ,2004Sun and Jiang, 2008;Teasdale et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

Administration of COG1410 Reduces Axonal Amyloid Precursor Protein Immunoreactivity and Microglial Activation after Controlled Cortical Impact in Mice

Jiang

Brody

2012

Journal of Neurotrauma

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Traumatic axonal injury (TAI) accounts for at least 35% of the morbidity and mortality in traumatic brain injury (TBI) patients without space-occupying lesions. It is also believed to be a key determinant of adverse outcomes such as cognitive dysfunction across the spectrum of TBI severity. Previous studies have shown that COG1410, a synthetic peptide derived from the apolipoprotein E (apoE) receptor binding region, has anti-inflammatory effects after experimental TBI, with improvements in cognitive recovery. However, the effects of COG1410 on axonal injury following TBI are not known. The current study evaluated the effects of 1 mg/kg daily COG1410 versus saline administered intravenously starting 30 min after controlled cortical impact (CCI) injury on pericontusional TAI in young, wild-type C57BL6/J male mice. We found that COG1410 did not affect the number of amyloid precursor protein (APP)-immunoreactive axonal varicosities in the pericontusional corpus callosum and external capsule at 24 h, but reduced APP-immunoreactive varicosities by 31% at 3 days ( p = 0.0023), and 36% at 7 days ( p = 0.0009). COG1410 significantly reduced the number of Iba1-positive cells with activated microglial morphology at all three time points by 21-30%. There was no effect of COG1410 on pericontusional white matter volume or silver staining at any time point. This indicates a possible effect of COG1410 on delayed but not immediate TAI. Future studies are needed to investigate the underlying mechanisms, therapeutic time window, and physiological implications of this effect.

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Genetic association studies in patients with traumatic brain injury

Cited by 109 publications

References 138 publications

Effect of the Apoe Ε4 Allele and Combat Exposure on PTSD Among Iraq/Afghanistan-Era Veterans

Effect of the Apoe Ε4 Allele and Combat Exposure on PTSD Among Iraq/Afghanistan-Era Veterans

A Drosophila model of closed head traumatic brain injury

Administration of COG1410 Reduces Axonal Amyloid Precursor Protein Immunoreactivity and Microglial Activation after Controlled Cortical Impact in Mice

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