Juvenile Traumatic Brain Injury Induces Long-Term Perivascular Matrix Changes Alongside Amyloid-Beta Accumulation

In our juvenile traumatic brain injury (jTBI) model, emergence of cognitive dysfunctions was observed up to 6 months after trauma. Here we hypothesize that early brain injury induces changes in the neurovascular unit (NVU) that would be associated with amyloid-beta (Aβ) accumulation. We investigated NVU changes for up to 6 months in a rat jTBI model, with a focus on the efflux protein P-glycoprotein (P-gp) and on the basement membrane proteins perlecan and fibronectin, all known to be involved in Aβ clearance. Rodent-Aβ staining is present and increased after jTBI around cerebral blood microvessels, and the diameter of those is decreased by 25% and 34% at 2 and 6 months, respectively, without significant angiogenesis. P-glycoprotein staining in endothelium is decreased by 22% and parallels an increase of perlecan and fibronectin staining around cerebral blood vessels. Altogether, these results strongly suggest that the emergence of long-term behavioral dysfunctions observed in rodent jTBI may be related to endothelial remodeling at the blood–brain barrier alongside vascular dysfunction and altered Aβ trafficking. This study shows that it is important to consider jTBI as a vascular disorder with long-term consequences on cognitive functions.

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Annexin A2 Deficiency Exacerbates Neuroinflammation and Long-Term Neurological Deficits after Traumatic Brain Injury in Mice

International Journal of Molecular Sciences ◽

10.3390/ijms20246125 ◽

2019 ◽

Vol 20 (24) ◽

pp. 6125 ◽

Cited By ~ 5

Author(s):

Ning Liu ◽

Yinghua Jiang ◽

Joon Yong Chung ◽

Yadan Li ◽

Zhanyang Yu ◽

...

Keyword(s):

Traumatic Brain Injury ◽

Brain Injury ◽

Inflammatory Response ◽

Neurovascular Unit ◽

Annexin A2 ◽

Tissue Loss ◽

Neurological Deficits ◽

Endogenous Factors ◽

The Brain

Our laboratory and others previously showed that Annexin A2 knockout (A2KO) mice had impaired blood–brain barrier (BBB) development and elevated pro-inflammatory response in macrophages, implying that Annexin A2 (AnxA2) might be one of the key endogenous factors for maintaining homeostasis of the neurovascular unit in the brain. Traumatic brain injury (TBI) is an important cause of disability and mortality worldwide, and neurovascular inflammation plays an important role in the TBI pathophysiology. In the present study, we aimed to test the hypothesis that A2KO promotes pro-inflammatory response in the brain and worsens neurobehavioral outcomes after TBI. TBI was conducted by a controlled cortical impact (CCI) device in mice. Our experimental results showed AnxA2 expression was significantly up-regulated in response to TBI at day three post-TBI. We also found more production of pro-inflammatory cytokines in the A2KO mouse brain, while there was a significant increase of inflammatory adhesion molecules mRNA expression in isolated cerebral micro-vessels of A2KO mice compared with wild-type (WT) mice. Consistently, the A2KO mice brains had a significant increase in leukocyte brain infiltration at two days after TBI. Importantly, A2KO mice had significantly worse sensorimotor and cognitive function deficits up to 28 days after TBI and significantly larger brain tissue loss. Therefore, these results suggested that AnxA2 deficiency results in exacerbated early neurovascular pro-inflammation, which leads to a worse long-term neurologic outcome after TBI.

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Rapid disruption of the cortical microcirculation after mild traumatic brain injury

10.1101/788455 ◽

2019 ◽

Author(s):

Ellen D. Witkowski ◽

Şefik Evren Erdener ◽

Kıvılcım Kılıç ◽

Sreekanth Kura ◽

Jianbo Tang ◽

...

Keyword(s):

Traumatic Brain Injury ◽

Brain Injury ◽

Vascular Dysfunction ◽

Metabolic Stress ◽

Time Lapse ◽

Post Injury ◽

Injury Model ◽

Time Lapse Imaging

AbstractTraumatic brain injury (TBI) is a major source of cognitive deficits affecting millions annually. The bulk of human injuries are mild, causing little or no macroscopic damage to neural tissue, yet can still lead to long-term neuropathology manifesting months or years later. Although the cellular stressors that ultimately lead to chronic pathology are poorly defined, one notable candidate is metabolic stress due to reduced cerebral blood flow (CBF), which is common to many forms of TBI. Here we used high-resolution in vivo intracranial imaging in a rodent injury model to characterize deficits in the cortical microcirculation during both acute and chronic phases after mild TBI. We found that CBF dropped precipitously during immediate post-injury periods, decreasing to less than half of baseline levels within minutes and remaining suppressed for 1.5-2 hours. Repeated time-lapse imaging of the cortical microvasculature revealed further striking flow deficits in the capillary network, where 18% of vessels were completely occluded for extended periods after injury, and an additional >50% showed substantial stoppages. Decreased CBF was paralleled by extensive vasoconstriction that is likely to contribute to loss of flow. Our data indicate a major role for vascular dysfunction in even mild forms of TBI, and suggest that acute post-injury periods may be key therapeutic windows for interventions that restore flow and mitigate metabolic stress.

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Faculty Opinions recommendation of A lack of amyloid beta plaques despite persistent accumulation of amyloid beta in axons of long-term survivors of traumatic brain injury.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1122919.580019 ◽

2008 ◽

Author(s):

George Perry

Keyword(s):

Traumatic Brain Injury ◽

Brain Injury ◽

Amyloid Beta ◽

Long Term Survivors

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Ribonuclease-1 treatment after traumatic brain injury preserve the integrity of the neurovascular unit, decreases inflammatory response and delays secondary brain damage in mice

10.21203/rs.3.rs-956514/v1 ◽

2021 ◽

Author(s):

Tobias J. Krämer ◽

Per Hübener ◽

Bruno Pöttker ◽

Christina Gölz ◽

Axel Neulen ◽

...

Keyword(s):

Traumatic Brain Injury ◽

Brain Injury ◽

Vascular Dysfunction ◽

Neurovascular Unit ◽

Mechanical Damage ◽

Inflammatory Cells ◽

Systemic Circulation ◽

Lesion Volume ◽

Secondary Damage ◽

Functional Benefit

Abstract Traumatic brain injury (TBI) involves primary mechanical damage and delayed secondary damage caused by vascular dysfunction and neuroinflammation. Intracellular components released into the parenchyma and systemic circulation, termed danger-associated molecular patterns (DAMPs), are major drivers of vascular dysfunction and neuroinflammation. These DAMPs include cell-free RNAs (cfRNAs), which damage the blood–brain barrier (BBB), thereby promoting edema, procoagulatory processes, and infiltration of inflammatory cells. We tested the hypothesis that intraperitoneal injection of Ribonuclease-1 (RNase1, two doses of 20, 60, or 180 µg/kg) at 30 min and 12h after controlled-cortical-impact (CCI) can reduce secondary lesion expansion compared to vehicle treatment 24h and 120h post-CCI. The lowest total dose (40 µg/kg) was most effective at reducing lesion volume (−31% RNase 40µg/kg vs. vehicle), brain water accumulation (−5.5%), and loss of BBB integrity (−21.6%) at 24h post-CCI. RNase1 also reduced perilesional leukocyte recruitment (−53.3%) and microglial activation (−18.3%) at 120h post-CCI, but there was no difference in lesion volume at this time and no functional benefit. Treatment with RNase1 in the early phase following TBI stabilizes the BBB and impedes leukocyte immigration, thereby suppressing neuroinflammation. RNase1-treatment may be a novel approach to delay brain injury to extend the window for treatment opportunities after TBI.

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Cognitive Communicative Challenges in TBI: Assessment and Intervention in the Long Term

Perspectives on Neurophysiology and Neurogenic Speech and Language Disorders ◽

10.1044/nnsld21.1.33 ◽

2011 ◽

Vol 21 (1) ◽

pp. 33-42 ◽

Cited By ~ 8

Author(s):

Lori G. Cook ◽

Roberta DePompei ◽

Sandra B. Chapman

Keyword(s):

Traumatic Brain Injury ◽

Brain Injury ◽

Cognitive Skills ◽

Early Brain Injury ◽

Higher Order ◽

Pediatric Traumatic Brain Injury ◽

School Environments ◽

Educational Functioning ◽

The Subject

Neurocognitive stall is defined as a failure or lag in achieving later emerging cognitive milestones, representing an increasing “gap” in neurocognitive, social, and educational functioning after early brain injury (Chapman, 2006). This paper provides an overview of the subject in regard to pediatric traumatic brain injury (TBI), briefly discussing both ineffective and proactive methods for detecting and monitoring later emerging deficits associated with neurocognitive stall. The paper concludes with discussion of an emerging intervention to mitigate impairments in higher-order cognitive skills and enhance learning efficiency, including suggestions for use in rehabilitation settings and within school environments.

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Traumatic Brain Injury: A Trauma Surgeon's Perspective

Perspectives on Neurophysiology and Neurogenic Speech and Language Disorders ◽

10.1044/nnsld22.3.82 ◽

2012 ◽

Vol 22 (3) ◽

pp. 82-89

Author(s):

Oscar D. Guillamondegui

Keyword(s):

Traumatic Brain Injury ◽

Brain Injury ◽

Multidisciplinary Approach ◽

Trauma Team ◽

The United States ◽

Long Term Outcomes ◽

Term Care ◽

Injured Brain ◽

The Moment

Traumatic brain injury (TBI) is a serious epidemic in the United States. It affects patients of all ages, race, and socioeconomic status (SES). The current care of these patients typically manifests after sequelae have been identified after discharge from the hospital, long after the inciting event. The purpose of this article is to introduce the concept of identification and management of the TBI patient from the moment of injury through long-term care as a multidisciplinary approach. By promoting an awareness of the issues that develop around the acutely injured brain and linking them to long-term outcomes, the trauma team can initiate care early to alter the effect on the patient, family, and community. Hopefully, by describing the care afforded at a trauma center and by a multidisciplinary team, we can bring a better understanding to the armamentarium of methods utilized to treat the difficult population of TBI patients.

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Prosodic Impairment Associated With Traumatic Brain Injury

Perspectives on Neurophysiology and Neurogenic Speech and Language Disorders ◽

10.1044/nnsld19.3.97 ◽

2009 ◽

Vol 19 (3) ◽

pp. 97-102

Author(s):

Billy Irwin

Keyword(s):

Traumatic Brain Injury ◽

Brain Injury ◽

Detailed Analysis ◽

Acoustic Characteristics ◽

Individual Variations

Abstract Purpose: This article discusses impaired prosody production subsequent to traumatic brain injury (TBI). Prosody may affect naturalness and intelligibility of speech significantly, often for the long term, and TBI may result in a variety of impairments. Method: Intonation, rate, and stress production are discussed in terms of the perceptual, physiological, and acoustic characteristics associated with TBI. Results and Conclusions: All aspects of prosodic production are susceptible to the effects of damage resulting from TBI. There are commonly associated prosodic impairments; however, individual variations in specific aspects of prosody require detailed analysis.

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