Prognostic significance of age in traumatic brain injury

Dhandapani, SS; Manju, D; Sharma, Bharati; Mahapatra, AK

doi:10.4103/0976-3147.98208

Cited by 78 publications

(60 citation statements)

References 21 publications

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“…Likewise, in a study of 5,612 TBI patients, Hukkelhoven et al found that the percent mortality within 6 mo of primary injuries increased with age, 21% at <35 y and 52% at >55 y (28). Also, in a study of 244 TBI patients, Dhandapani et al found that the percent mortality within 1 mo of primary injuries was significantly associated with increasing age, 15% at <18 y, 44% at 18-59 y, and 52% at >59 y (29). These similarities between flies in our TBI model and human TBI patients strongly indicate that flies and humans incur TBI through similar cellular and molecular mechanisms.…”

Section: Discussionmentioning

confidence: 99%

A Drosophila model of closed head traumatic brain injury

Katzenberger¹,

Loewen

Wassarman³

et al. 2013

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

119

233

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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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Section: Discussionmentioning

confidence: 99%

A Drosophila model of closed head traumatic brain injury

Katzenberger¹,

Loewen

Wassarman³

et al. 2013

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

119

233

View full text Add to dashboard Cite

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“…In humans and flies, the probability of mortality following TBI is associated with age and blood/hemolymph glucose level, which is influenced by diet (Susman et al 2002; Hukkelhoven et al 2003; Griesdale et al 2009; Dhandapani et al 2012; Katzenberger et al 2013, 2015a; Wang et al 2013; Borsage et al 2015; Chong et al 2015). Furthermore, studies of repetitive primary injuries in mammals and flies indicate that the time between primary injuries can affect the probability of mortality (Kanayama et al 1996; Friess et al 2009; Meehan et al 2012; Huang et al 2013; Weil et al 2014; Bolton Hall et al 2016) (Figure 1 and Figure 3).…”

Section: Discussionmentioning

confidence: 99%

“…Among individuals that sustain similar primary injuries, older individuals have a higher probability of mortality than younger individuals, suggesting that biological processes that change during aging promote secondary injuries (Hukkelhoven et al 2003; Dhandapani et al 2012). Also, in a rat TBI model, fasting compared with feeding ad libitum following primary injuries is neuroprotective, suggesting that dietary intake enhances biological processes that promote secondary injuries (Davis et al 2008).…”

mentioning

confidence: 99%

Age and Diet Affect Genetically Separable Secondary Injuries that Cause Acute Mortality Following Traumatic Brain Injury in Drosophila

Katzenberger

Ganetzky

Wassarman

2016

G3 Genes|Genomes|Genetics

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Outcomes of traumatic brain injury (TBI) vary because of differences in primary and secondary injuries. Primary injuries occur at the time of a traumatic event, whereas secondary injuries occur later as a result of cellular and molecular events activated in the brain and other tissues by primary injuries. We used a Drosophila melanogaster TBI model to investigate secondary injuries that cause acute mortality. By analyzing mortality percentage within 24 hr of primary injuries, we previously found that age at the time of primary injuries and diet afterward affect the severity of secondary injuries. Here, we show that secondary injuries peaked in activity 1–8 hr after primary injuries. Additionally, we demonstrate that age and diet activated distinct secondary injuries in a genotype-specific manner, and that concurrent activation of age- and diet-regulated secondary injuries synergistically increased mortality. To identify genes involved in secondary injuries that cause mortality, we compared genome-wide mRNA expression profiles of uninjured and injured flies under age and diet conditions that had different mortalities. During the peak period of secondary injuries, innate immune response genes were the predominant class of genes that changed expression. Furthermore, age and diet affected the magnitude of the change in expression of some innate immune response genes, suggesting roles for these genes in inhibiting secondary injuries that cause mortality. Our results indicate that the complexity of TBI outcomes is due in part to distinct, genetically controlled, age- and diet-regulated mechanisms that promote secondary injuries and that involve a subset of innate immune response genes.

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“…Some are directly related to the injury, but others, including environmental factors, pre-date the injury [10][11][12][13]. Co-morbidities such as substance abuse and pre-morbid demographic characteristics such as age, education and employment are important for outcome [14][15][16][17][18][19][20][21][22]. A systematic review of prospective cohort studies investigating prognostic factors at least 1 year after injury found strong evidence that pre-injury unemployment and pre-injury substance abuse predict disability and non-productivity in patients with TBI [23].…”

Section: Introductionmentioning

confidence: 99%