Animal models of traumatic brain injury: a review of pathophysiology to biomarkers and treatments

Petersen, Abigail; Soderstrom, Matthew; Saha, Biswajit; Sharma, Pushpa

doi:10.1007/s00221-021-06178-6

Cited by 37 publications

(25 citation statements)

References 83 publications

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“…Clinically relevant models are required for the development of novel TBI therapy alternatives. It is possible to imitate diverse injury processes, such as more localized or generalized damage, caused by focal brain contusion, or diffuse axonal injury (DAI), thanks to the range of models that have been used [ 33 ]. The controlled cortical impact (CCI) model, the lateral and central fluid percussion injury (FPI) models, and the weight drop/impact accelerations (I/A) model are probably the most widely utilized animal models in the treatment of TBI globally.…”

Section: Reviewmentioning

confidence: 99%

Management and Treatment of Traumatic Brain Injuries

Jha¹,

Ghewade²

2022

Cureus

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Traumatic brain injuries (TBI) are one of the main reasons for death in recent years worldwide or globally. They are the number one cause of death for both civilians and military members. It affects how the brain functions and is currently one of the crucial concerns of global public health issues. TBI is increasing worldwide because of the increasing dependency on motorized vehicles and machinery. One of the reasons for TBI is the expanding human population. It is the major cause of death and disability in the world. In young adults around the world, it is the main cause of mortality and morbidity. Its complicated etiology and pathogenesis include primarily primary and secondary injury types. Neuroinflammation is also focused on TBI to be cured. The neuroprotection of the injured brain has received tremendous attention during TBI treatment. In this review, we will first discuss the definition of traumatic brain injury, its causes, and the symptoms experienced by patients of various age groups. Finally, treatment methods and advances in treatment will be discussed. In this review, the aftereffects of traumatic brain damage are also covered. Ferroptosis and choline phospholipids are also emphasized as important components of the treatment of traumatic brain damage in this review.

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Section: Reviewmentioning

confidence: 99%

Management and Treatment of Traumatic Brain Injuries

Jha¹,

Ghewade²

2022

Cureus

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“…Phosphorylated tau protein (p-tau) is a key pathogenic molecule that plays an important role in development of neurofibrillary degeneration . It was experimentally demonstrated that mild TBI leads to tau protein hyperphosphorylation, which induces the loss of intercellular connectivity and neuronal death . Tauopathies develop undetected before the onset of clinical signs and become apparent after a long period of latency .…”

Section: Introductionmentioning

confidence: 99%

“…10,11 It was experimentally demonstrated that mild TBI leads to tau protein hyperphosphorylation, which induces the loss of intercellular connectivity and neuronal death. [12][13][14][15] Tauopathies develop undetected before the onset of clinical signs and become apparent after a long period of latency. 16,17 P-tau 181 is considered a promising biomarker for early detection of AD, frontotemporal lobar degeneration, and TBI of all severities.…”

Section: Introductionmentioning

confidence: 99%

Association of Nonconcussive Repetitive Head Impacts and Intense Physical Activity With Levels of Phosphorylated Tau₁₈₁ and Total Tau in Plasma of Young Elite Soccer Players

et al. 2023

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ImportanceHead impacts resulting in traumatic brain injury (TBI) lead to the elevation of phosphorylated tau protein (p-tau181) in plasma. To our knowledge, this study is the first to investigate dynamics of p-tau181 levels and the ratio of p-tau181 to total tau in individuals after nonconcussive head impacts.ObjectiveTo determine the association of repetitive low-intensity head impacts on p-tau181 and total tau protein levels in the plasma of young adult elite soccer players and assess the possible association of head impacts with focused attention and cognitive flexibility.Design, Setting, and ParticipantsIn this cohort study, young elite soccer players performed intense physical activity with and without heading the ball. The study was conducted at a university facility in Slovakia from October 1, 2021, to May 31, 2022. Eligible participants were selected based on similarities in demographic variables, excluding those with a history of TBI.Main Outcomes and MeasuresThe primary study outcomes were the levels of total tau protein and p-tau181 in plasma samples and the cognitive status of the study participants.ResultsA total of 37 male athletes participated in the study (mean [SD] age: exercise group, 21.6 [1.6] years; heading group, 21.2 [1.5] years). We found significantly elevated levels of total tau and p-tau181 in the plasma of soccer players 1 hour after physical exercise (tau, 1.4-fold; 95% CI, 1.2-1.5; P &lt; .001; p-tau181, 1.4-fold; 95% CI, 1.3-1.5, P &lt; .001) and repetitive head impacts (tau, 1.3-fold; 95% CI, 1.2-1.4; P &lt; .001; p-tau181, 1.5-fold; 95% CI, 1.4-1.7 P &lt; .001). The ratio of p-tau181 to tau was significantly higher 1 hour after exercise and heading training, and remained elevated specifically in the heading group even after 24 hours (1.2-fold; 95% CI, 1.1-1.3; P = .002). Performance in cognitive tests revealed a significant decline in focused attention and cognitive flexibility after physical exercise and heading training; physical exercise of higher intensity without heading training was associated with a greater negative cognitive performance than heading only.Conclusions and RelevanceIn this cohort study of young elite soccer players, the elevation of p-tau181 and tau was observed after acute intense physical activity and nonconcussive repetitive head impacts. The increase of p-tau181 levels relative to tau after 24 hours indicated an acute enrichment of phosphorylated tau fraction in the periphery when compared with preimpact levels; an imbalance of tau proteins may have long-lasting consequences in the brain of head-impacted individuals.

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“…It was repeatedly demonstrated in experimental models that mild traumatic brain injury leads to tau protein hyperphosphorylation [12][13][14] . Phosphorylated tau induces primary steps in generation of pair helical filaments and provokes the building of neurofibrillary tangles (NFTs), that block axonal transport which leads to the loss of intercellular connectivity and neuronal death 15,16 .…”

Section: Introductionmentioning

confidence: 99%

Non-concussive Repetitive Head Impacts and Intense Physical Activity Elevate pT181-Tau and pT181/total-Tau in Plasma of Young Adults

Cente

Peráčková

Peráček

et al. 2022

Preprint

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IMPORTANCE Head impacts resulting in traumatic brain injury (TBI) lead to elevation of phosphorylated tau protein in plasma, the biomarkers for patients with acute and chronic TBI. Dynamics of phosphorylated tau protein level (pTau) and ratio of pTau and total tau in subjects after the non-concussive head impact was not yet investigated. OBJECTIVE To determine the acute effect of repetitive low-intensity head impacts on phosphorylated and total tau protein levels in plasma of young adults and to assess the effect of the head impacts on focused attention and cognitive flexibility. DESIGN The study cohort consisted of young professional soccer players performing intense physical activity without heading the ball (n=32) and physical activity including the heading (n=28). SETTING The effect of repetitive non-concussive head impacts was monitored in all athletes evaluating the parameters of physical activity, impact force during heading the ball, together with neuropsychological testing of cognitive attention and cognitive flexibility at multiple time-points before and during a set of controlled training exercises. The total and phosphorylated tau protein levels were determined using an ultrasensitive single molecule assay at 3 time points: before training, 1 h, and 24 h after each training session in a non-fasting state. The psychological scores were collected before and 1 h after the training using Trail Making Test. PARTICIPANTS The study included volunteer male college soccer players. The eligible participants were selected based on the similar demographic variables, such as age, years of performing organized sport, weekly sport activity and body mass index. The subjects with the history of previous TBI were excluded from the study. MAIN OUTCOMES AND MEASURES The primary study outcomes are the levels of total tau protein and tau protein phosphorylated at the Threonine 181 in plasma samples, and cognitive status of the study participants. The study hypothesis was formulated before the data collection. RESULTS We found significantly elevated levels of total tau and phospho-tau protein (pT181) in the plasma of soccer players one hour after physical exercise (Tau: 1.35-fold, 95% CI 1.2-1.5, P = .0001; pT181: 1.4-fold, 95% CI 1.3-1.5, P < .0001) and repetitive head impacts (Tau: 1.3-fold, 95% CI 1.2-1.4, P < .0001; pT181: 1.5-fold, 95% CI 1.4-1.7, P < .0001) in comparison to baseline. The pT181/Tau ratio was significantly higher 1 hour after the exercise and heading training, and remained elevated specifically in the heading group even after 24 hours (1.2-fold, 95% CI 1.1-1.3, P = .0024). Performance in cognitive tests revealed a significant decline in focused attention (TMT-A) and cognitive flexibility (TMT-B) after the physical exercise (TMT-A: 75.16 [95% CI, 68.3-82.01, P < .0001]; TMT-B: 80.26 [95% CI, 69.83-90.68, P < .0001]) and heading training (TMT-A: 33.76 [95% CI, 30.11-37.42, P = .0004]; TMT-B: 63.92 [95% CI, 56.99-70.84, P = .0434]). Nevertheless, the physical exercise of higher intensity without the heading had a more negative impact than heading training (TMT-A: P < .0001; TMT-B: P = .0207). CONCLUSIONS AND RELEVANCE Our study showed, that non-concussive repetitive head impacts elevate pT181-Tau and pT181/total-Tau in plasma of young adults. The increase of pT181-Tau was observed also after the intense physical activity alone, however the elevation of pT181/Tau ratio after 24 hours was highly significant and specific for non-concussive repetitive head impacts. The results support the idea that phosphorylated tau-enriched fraction of tau proteins may have long-lasting consequences in the brain of head-impacted individuals. The possible longitudinal disbalance of tau proteins induced by repetitive head impacts needs to be further investigated in larger and broader cohorts, and over longer period of time.

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Animal models of traumatic brain injury: a review of pathophysiology to biomarkers and treatments

Cited by 37 publications

References 83 publications

Management and Treatment of Traumatic Brain Injuries

Management and Treatment of Traumatic Brain Injuries

Association of Nonconcussive Repetitive Head Impacts and Intense Physical Activity With Levels of Phosphorylated Tau₁₈₁ and Total Tau in Plasma of Young Elite Soccer Players

Non-concussive Repetitive Head Impacts and Intense Physical Activity Elevate pT181-Tau and pT181/total-Tau in Plasma of Young Adults

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Animal models of traumatic brain injury: a review of pathophysiology to biomarkers and treatments

Cited by 37 publications

References 83 publications

Management and Treatment of Traumatic Brain Injuries

Management and Treatment of Traumatic Brain Injuries

Association of Nonconcussive Repetitive Head Impacts and Intense Physical Activity With Levels of Phosphorylated Tau181 and Total Tau in Plasma of Young Elite Soccer Players

Non-concussive Repetitive Head Impacts and Intense Physical Activity Elevate pT181-Tau and pT181/total-Tau in Plasma of Young Adults

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Association of Nonconcussive Repetitive Head Impacts and Intense Physical Activity With Levels of Phosphorylated Tau₁₈₁ and Total Tau in Plasma of Young Elite Soccer Players