scholarly journals Meningeal lymphatic dysfunction exacerbates traumatic brain injury pathogenesis

2019 ◽  
Author(s):  
Ashley C. Bolte ◽  
Mariah E. Hurt ◽  
Igor Smirnov ◽  
Michael A. Kovacs ◽  
Celia A. McKee ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Cognitive Deficits ◽  
Lymphatic System ◽  
Lymphatic Drainage ◽  
Neurological Dysfunction ◽  
Increased Intracranial Pressure ◽  
Post Injury ◽  
Lymphatic Function ◽  
Increased Icp

ABSTRACTTraumatic brain injury (TBI) has emerged as a leading cause of death and disability. Despite being a growing medical issue, the biological factors that promote central nervous system (CNS) pathology and neurological dysfunction following TBI remain poorly characterized. Recently, the meningeal lymphatic system was identified as a critical mediator of drainage from the CNS. In comparison to other peripheral organs, our understanding of how defects in lymphatic drainage from the CNS contribute to disease is limited. It is still unknown how TBI impacts meningeal lymphatic function and whether disruptions in this drainage pathway are involved in driving TBI pathogenesis. Here we demonstrate that even mild forms of brain trauma cause severe deficits in meningeal lymphatic drainage that can last out to at least two weeks post-injury. To investigate a mechanism behind impaired lymphatic function in TBI, we examined how increased intracranial pressure (ICP) influences the meningeal lymphatics, as increased ICP commonly occurs in TBI. We demonstrate that increased ICP is capable of provoking meningeal lymphatic dysfunction. Moreover, we show that pre-existing lymphatic dysfunction mediated by targeted photoablation before TBI leads to increased neuroinflammation and cognitive deficits. These findings provide new insights into both the causes and consequences of meningeal lymphatic dysfunction in TBI and suggest that therapeutics targeting the meningeal lymphatic system may offer strategies to treat TBI.

scholarly journals Meningeal lymphatic dysfunction exacerbates traumatic brain injury pathogenesis

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Ashley C. Bolte ◽  
Arun B. Dutta ◽  
Mariah E. Hurt ◽  
Igor Smirnov ◽  
Michael A. Kovacs ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Lymphatic System ◽  
Lymphatic Drainage ◽  
Cognitive Outcomes ◽  
Increased Intracranial Pressure ◽  
Post Injury ◽  
Lymphatic Function ◽  
Experimental Mouse Model ◽  
Experimental Mouse

Abstract Traumatic brain injury (TBI) is a leading global cause of death and disability. Here we demonstrate in an experimental mouse model of TBI that mild forms of brain trauma cause severe deficits in meningeal lymphatic drainage that begin within hours and last out to at least one month post-injury. To investigate a mechanism underlying impaired lymphatic function in TBI, we examined how increased intracranial pressure (ICP) influences the meningeal lymphatics. We demonstrate that increased ICP can contribute to meningeal lymphatic dysfunction. Moreover, we show that pre-existing lymphatic dysfunction before TBI leads to increased neuroinflammation and negative cognitive outcomes. Finally, we report that rejuvenation of meningeal lymphatic drainage function in aged mice can ameliorate TBI-induced gliosis. These findings provide insights into both the causes and consequences of meningeal lymphatic dysfunction in TBI and suggest that therapeutics targeting the meningeal lymphatic system may offer strategies to treat TBI.

scholarly journals A combination antioxidant therapy to inhibit NOX2 and activate Nrf2 decreases secondary brain damage and improves functional recovery after traumatic brain injury

2017 ◽  
Vol 38 (10) ◽  
pp. 1818-1827 ◽  
Author(s):  
Raghavendar Chandran ◽  
TaeHee Kim ◽  
Suresh L Mehta ◽  
Eshwar Udho ◽  
Vishal Chanana ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Motor Function ◽  
Neurological Dysfunction ◽  
Vehicle Group ◽  
Lesion Volume ◽  
Post Injury ◽  
Cortical Contusion ◽  
Nrf2 Activator

Uncontrolled oxidative stress contributes to the secondary neuronal death that promotes long-term neurological dysfunction following traumatic brain injury (TBI). Surprisingly, both NADPH oxidase 2 (NOX2) that increases and transcription factor Nrf2 that decreases reactive oxygen species (ROS) are induced after TBI. As the post-injury functional outcome depends on the balance of these opposing molecular pathways, we evaluated the effect of TBI on the motor and cognitive deficits and cortical contusion volume in NOX2 and Nrf2 knockout mice. Genetic deletion of NOX2 improved, while Nrf2 worsened the post-TBI motor function recovery and lesion volume indicating that decreasing ROS levels might be beneficial after TBI. Treatment with either apocynin (NOX2 inhibitor) or TBHQ (Nrf2 activator) alone significantly improved the motor function after TBI, but had no effect on the lesion volume, compared to vehicle control. Whereas, the combo therapy (apocynin + TBHQ) given at either 5 min/24 h or 2 h/24 h improved motor and cognitive function and decreased cortical contusion volume compared to vehicle group. Thus, both the generation and disposal of ROS are important modulators of oxidative stress, and a combo therapy that prevents ROS formation and potentiates ROS disposal concurrently is efficacious after TBI.

A-125 The Impact of Bilingualism on Symbol Digit Modalities Test Performance Following Traumatic Brain Injury

2021 ◽  
Vol 36 (6) ◽  
pp. 1175-1175
Author(s):  
Raelynn Munoz ◽  
Daniel W Lopez-Hernandez ◽  
Rachel A Rugh-Fraser ◽  
Jasman Sidhu ◽  
Pavel Y Litvin ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Cognitive Deficits ◽  
Test Performance ◽  
Oral Performance ◽  
Neurocognitive Performance ◽  
Post Injury ◽  
Cognitive Speed ◽  
The Impact ◽  
Larger Sample

Abstract Objective Traumatic brain injury (TBI) survivors exhibit cognitive deficits. Research suggests that multilingualism can influence neurocognitive performance. We examined the effects of TBI and bilingualism/monolingualism on a test of attention and cognitive speed (i.e., Symbol Digit Modalities Test; SDMT). Method The sample consisted of 55 healthy comparison (27 Spanish-English bilinguals; 28 English-monolinguals), 34 acute TBI (14 Spanish-English bilinguals; 23 English-monolinguals), and 27 chronic TBI (13 Spanish-English bilinguals; 12 English-monolinguals) participants. Acute TBI participants were tested 6 months post-injury; chronic TBI participants were tested 12 months or more post-injury. A series of 3X2 ANOVAs were conducted to determine the effect of TBI and language on SDMT written and oral performance. Results ANOVAs revealed the healthy comparison group outperformed both TBI groups on SDMT written, p = 0.000, ηp2 = 0.21. Also, the healthy comparison and chronic TBI groups outperformed the acute TBI group on SDMT oral, p = 0.000, ηp2 = 0.13. Interaction effects emerged between TBI and bilingualism/monolingualism. On SDMT written and oral, acute TBI English-monolinguals outperformed acute TBI Spanish-English bilinguals; meanwhile, chronic TBI Spanish-English bilinguals outperformed chronic TBI English-monolinguals, p < 0.05, ηp2 = 0.09–0.10. Conclusion The acute TBI group performed worse than healthy comparison adults on both SDMT tasks. Furthermore, the chronic TBI group demonstrated better SDMT oral abilities compared to the acute TBI group. Relative to monolinguals with TBI, our findings suggest better cognitive recovery of attention and cognitive speed in bilingual TBI participants. Future studies with larger sample sizes should examine if learning English first or second impacts Spanish-English bilingual TBI survivors’ SDMT performance compared to English-monolingual TBI survivors.

scholarly journals Traumatic Brain Injury in Aged Mice Induces Chronic Microglia Activation, Synapse Loss, and Complement-Dependent Memory Deficits

2018 ◽  
Vol 19 (12) ◽  
pp. 3753 ◽  
Author(s):  
Karen Krukowski ◽  
Austin Chou ◽  
Xi Feng ◽  
Brice Tiret ◽  
Maria-Serena Paladini ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Cognitive Deficits ◽  
Brain Lesion ◽  
Clinical Intervention ◽  
Memory Deficits ◽  
Cell Number ◽  
Post Injury ◽  
Synapse Loss ◽  
Immune System Activation

Traumatic brain injury (TBI) is of particular concern for the aging community since there is both increased incidence of TBI and decreased functional recovery in this population. In addition, TBI is the strongest environmental risk factor for development of Alzheimer’s disease and other dementia-related neurodegenerative disorders. Critical changes that affect cognition take place over time following the initial insult. Our previous work identified immune system activation as a key contributor to cognitive deficits observed in aged animals. Using a focal contusion model in the current study, we demonstrate a brain lesion and cavitation formation, as well as prolonged blood–brain barrier breakdown. These changes were associated with a prolonged inflammatory response, characterized by increased microglial cell number and phagocytic activity 30 days post injury, corresponding to significant memory deficits. We next aimed to identify the injury-induced cellular and molecular changes that lead to chronic cognitive deficits in aged animals, and measured increases in complement initiation components C1q, C3, and CR3, which are known to regulate microglial–synapse interactions. Specifically, we found significant accumulation of C1q on synapses within the hippocampus, which was paralleled by synapse loss 30 days post injury. We used genetic and pharmacological approaches to determine the mechanistic role of complement initiation on cognitive loss in aging animals after TBI. Notably, both genetic and pharmacological blockade of the complement pathway prevented memory deficits in aged injured animals. Thus, therapeutically targeting early components of the complement cascade represents a significant avenue for possible clinical intervention following TBI in the aging population.

scholarly journals Long-Term Cognitive Deficits After Traumatic Brain Injury Associated With Microglia Activation

2021 ◽  
Author(s):  
Esber Saba ◽  
Mona Karout ◽  
Leila Nasralla ◽  
Firas Kobeissy ◽  
Hala Darwish ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Learning And Memory ◽  
Cognitive Deficits ◽  
Head Injuries ◽  
Spatial Learning And Memory ◽  
Post Injury ◽  
Color Flow ◽  
Injured Brain ◽  
The Central Nervous System

Abstract Traumatic Brain Injury (TBI) is the most prevalent of all head injuries, and based on the severity of the injury, it may result in chronic neurologic and cognitive deficits. Microglia play an essential role in homeostasis and diseases of the central nervous system. We hypothesize that microglia may play a beneficial or detrimental role in TBI depending on their state of activation and duration.In the present study, we evaluated whether TBI results in a spatiotemporal change in microglia phenotype and whether it affects sensory-motor or learning and memory functions in male C57BL/6 mice. We used a panel of neurological and behavioral tests and a multi-color flow cytometry-based data analysis followed by unsupervised clustering to evaluate isolated microglia from injured brain tissue. We characterized several microglial phenotypes and their association with cognitive deficits. TBI results in a spatiotemporal increase in highly activated microglia that correlated negatively with spatial learning and memory at 35 days post-injury. These observations could define therapeutic windows and accelerate translational research to improve patient outcomes.

scholarly journals Acute cognitive deficits after traumatic brain injury predict Alzheimer's disease-like degradation of the human default mode network

2020 ◽  
Author(s):  
Andrei Irimia ◽  
Alexander S Maher ◽  
Nikhil N Chaudhari ◽  
Nahian F Chowdhury ◽  
Elliot B Jacobs
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Cognitive Deficits ◽  
Default Mode Network ◽  
Brain Connectivity ◽  
The Elderly ◽  
Post Injury ◽  
Default Mode

Traumatic brain injury (TBI) and Alzheimer's disease (AD) are prominent neurological conditions whose neural and cognitive commonalities are poorly understood. The extent of TBI-related neurophysiological abnormalities has been hypothesized to reflect AD-like Neurodegeneration because TBI can increase vulnerability to AD. However, it remains challenging to prognosticate AD risk partly because the functional relationship between acute posttraumatic sequelae and chronic AD-like degradation remains elusive. Here, functional magnetic resonance imaging (fMRI), network theory, and machine learning (ML) are leveraged to study the extent to which geriatric mild TBI (mTBI) can lead to AD-like alteration of resting-state activity in the default mode network (DMN). This network is found to contain modules whose extent of AD-like, posttraumatic degradation can be accurately prognosticated based on the acute cognitive deficits of geriatric mTBI patients with cerebral microbleeds. Aside from establishing a predictive physiological association between geriatric mTBI, cognitive impairment, and AD-like functional degradation, these findings advance the goal of acutely forecasting mTBI patients' chronic deviations from normality along AD-like functional trajectories. The association of geriatric mTBI with AD-like changes in functional brain connectivity as early as ~6 months post-injury carries substantial implications for public health because TBI has relatively high prevalence in the elderly.

In search of the ‘self’: Holistic rehabilitation in restoring cognition and recovering the ‘self’ following traumatic brain injury: A case report

2021 ◽  
pp. 1-12
Author(s):  
Meenakshi Banerjee ◽  
Shantala Hegde ◽  
T Harish ◽  
Girish B. Kulkarni ◽  
Narasinga Rao
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Cognitive Deficits ◽  
Emotional Regulation ◽  
Anterograde Amnesia ◽  
Depression Score ◽  
The Self ◽  
Future Research ◽  
Post Injury ◽  
Moderate Traumatic Brain Injury

BACKGROUND: Following mild-moderate traumatic brain injury (TBI), an individual experiences a range of emotional changes. It is often difficult for the patient to reconcile with their post-injury persona, and the memory of pre-injury personhood is particularly painful. Insight into one’s cognitive deficits subsequent to injury can lead to an existential crisis and a sense of loss, including loss of self. OBJECTIVE: Restoration of cognitive functions and reconciliation with loss of pre-traumatic personhood employing a holistic method of neuropsychological rehabilitation in a patient suffering from TBI. METHODS: Ms. K.S, a 25-year-old girl, presented with emotional disturbances following TBI. She reported both retrograde and anterograde amnesia. A multidimensional holistic rehabilitation was planned. Treatment addressed cognitive deficits through the basic functions approach. Cognitive behavioural methods for emotional regulation like diary writing helped reduce irritability and anger outbursts. Use of social media created new modes of memory activation and interactions. Compensatory strategies were used to recover lost skills, music based attention training helped foster an individualised approach to the sense of one’s body and self. RESULTS: As a result of these differing strategies, changes were reflected in neuro-psychological tests, depression score and the patient’s self-evaluation. This helped generate a coherent self-narrative. CONCLUSION: Treatment challenges in such cases are increased due to patient’s actual deficits caused by neuronal/biochemical changes. Innovative and multi-pronged rehabilitation strategies which involve everyday activities provided an answer to some of these problems. This method of rehabilitation may provide an optimistic context for future research.

scholarly journals A-126 Clinical Utility of Risk Factors to Predict Self-reported Neurobehavioral Outcome Following Traumatic Brain Injury: PTSD, Sleep, Resilience, and Lifetime Blast Exposure

2020 ◽  
Vol 35 (6) ◽  
pp. 919-919
Author(s):  
Lange R ◽  
Lippa S ◽  
Hungerford L ◽  
Bailie J ◽  
French L ◽  
...  
Keyword(s):  
Risk Factors ◽  
Traumatic Brain Injury ◽  
Risk Factor ◽  
Brain Injury ◽  
Clinical Utility ◽  
Poor Sleep ◽  
Post Injury ◽  
Poor Outcome ◽  
Blast Exposure ◽  
Neurobehavioral Outcome

Abstract Objective To examine the clinical utility of PTSD, Sleep, Resilience, and Lifetime Blast Exposure as ‘Risk Factors’ for predicting poor neurobehavioral outcome following traumatic brain injury (TBI). Methods Participants were 993 service members/veterans evaluated following an uncomplicated mild TBI (MTBI), moderate–severe TBI (ModSevTBI), or injury without TBI (Injured Controls; IC); divided into three cohorts: (1) < 12 months post-injury, n = 237 [107 MTBI, 71 ModSevTBI, 59 IC]; (2) 3-years post-injury, n = 370 [162 MTBI, 80 ModSevTBI, 128 IC]; and (3) 10-years post-injury, n = 386 [182 MTBI, 85 ModSevTBI, 119 IC]. Participants completed a 2-hour neurobehavioral test battery. Odds Ratios (OR) were calculated to determine whether the ‘Risk Factors’ could predict ‘Poor Outcome’ in each cohort separately. Sixteen Risk Factors were examined using all possible combinations of the four risk factor variables. Poor Outcome was defined as three or more low scores (< 1SD) on five TBI-QOL scales (e.g., Fatigue, Depression). Results In all cohorts, the vast majority of risk factor combinations resulted in ORs that were ‘clinically meaningful’ (ORs > 3.00; range = 3.15 to 32.63, all p’s < .001). Risk factor combinations with the highest ORs in each cohort were PTSD (Cohort 1 & 2, ORs = 17.76 and 25.31), PTSD+Sleep (Cohort 1 & 2, ORs = 18.44 and 21.18), PTSD+Sleep+Resilience (Cohort 1, 2, & 3, ORs = 13.56, 14.04, and 20.08), Resilience (Cohort 3, OR = 32.63), and PTSD+Resilience (Cohort 3, OR = 24.74). Conclusions Singularly, or in combination, PTSD, Poor Sleep, and Low Resilience were strong predictors of poor outcome following TBI of all severities and injury without TBI. These variables may be valuable risk factors for targeted early interventions following injury.

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