Targeting the Cerebrovascular System: Next-Generation Biomarkers and Treatment for Mild Traumatic Brain Injury

Baker, Tamara L.; Agoston, Denes V.; Brady, Rhys D.; Major, Brendan; McDonald, Stuart J.; Mychasiuk, Richelle; Wright, David K.; Yamakawa, Glenn R.; Sun, Mujun; Shultz, Sandy R.

doi:10.1177/10738584211012264

Cited by 19 publications

(16 citation statements)

References 180 publications

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“…The kinetic forces at the time of mTBI, as well as the secondary injury cascades that follow, can result in deformation, dysfunction, and injury to the cerebrovascular system that may manifest in cerebral blood flow changes, perivascular neuroinflammation, blood brain barrier (BBB) damage, and microhemorrhage ( Bonne et al, 2003 ; Marchi et al, 2013 ; Wang et al, 2014 ; Long et al, 2015 ; Tagge et al, 2018 ; Baker et al, 2021 ). Notably, evidence from both animal and human studies indicate that cerebrovascular injury is associated with mTBI symptoms and functional deficits ( Bonne et al, 2003 ; Wang et al, 2014 ; Huang et al, 2015 ; Long et al, 2015 ).…”

Section: Introductionmentioning

confidence: 99%

Treatment with vascular endothelial growth factor-A worsens cognitive recovery in a rat model of mild traumatic brain injury

Sun

Baker

Wilson

et al. 2022

Front. Mol. Neurosci.

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Mild traumatic brain injury (mTBI) is a common and unmet clinical issue, with limited treatments available to improve recovery. The cerebrovascular system is vital to provide oxygen and nutrition to the brain, and a growing body of research indicates that cerebrovascular injury contributes to mTBI symptomatology. Vascular endothelial growth factor-A (VEGF-A) is a potent promoter of angiogenesis and an important modulator of vascular health. While indirect evidence suggests that increased bioavailability of VEGF-A may be beneficial after mTBI, the direct therapeutic effects of VEGF-A in this context remains unknown. This study therefore aimed to determine whether intracerebroventricular administration of recombinant VEGF-A could improve recovery from mTBI in a rat model. Male and female Sprague–Dawley rats were assigned to four groups: sham + vehicle (VEH), sham + VEGF-A, mTBI + VEH, mTBI + VEGF-A. The mTBI was induced using the lateral impact model, and treatment began at the time of the injury and continued until the end of the study. Rats underwent behavioral testing between days 1 and 10 post-injury, and were euthanized on day 11 for post-mortem analysis. In males, the mTBI + VEGF-A group had significantly worse cognitive recovery in the water maze than all other groups. In females, the VEGF treatment worsened cognitive performance in the water maze regardless of mTBI or sham injury. Analysis of hippocampal tissue found that these cognitive deficits occurred in the presence of gene expression changes related to neuroinflammation and hypoxia in both male and female rats. These findings indicate that the VEGF-A treatment paradigm tested in this study failed to improve mTBI outcomes in either male or female rats.

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Section: Introductionmentioning

confidence: 99%

Treatment with vascular endothelial growth factor-A worsens cognitive recovery in a rat model of mild traumatic brain injury

Sun

Baker

Wilson

et al. 2022

Front. Mol. Neurosci.

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“…The observed VEGF increase in human SH-SY5Y cells after sAPPα exposure is in line with data showing that VEGF is able to improve the cognitive decline in Tg2576 AD mouse model [ 217 ]. Besides the importance of this vascular factor in AD, Cerebrovascular Injury (CVI) is a recognised hallmark of TBI that affects function and integrity of the cerebrovascular system, contributing to neuronal dysfunction and neurodegeneration [ 218 ]. VEGF has been reported to mediate TBI amelioration [ 219 ], suggesting that new vasculogenic therapies targeting VEGF and its expression could be a feasible approach for vascular-related brain injuries typical of AD and TBI.…”

Section: Resultsmentioning

confidence: 99%

The Labyrinthine Landscape of APP Processing: State of the Art and Possible Novel Soluble APP-Related Molecular Players in Traumatic Brain Injury and Neurodegeneration

Masi

Biundo

Fiou

et al. 2023

IJMS

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Amyloid Precursor Protein (APP) and its cleavage processes have been widely investigated in the past, in particular in the context of Alzheimer’s Disease (AD). Evidence of an increased expression of APP and its amyloidogenic-related cleavage enzymes, β-secretase 1 (BACE1) and γ-secretase, at the hit axon terminals following Traumatic Brain Injury (TBI), firstly suggested a correlation between TBI and AD. Indeed, mild and severe TBI have been recognised as influential risk factors for different neurodegenerative diseases, including AD. In the present work, we describe the state of the art of APP proteolytic processing, underlining the different roles of its cleavage fragments in both physiological and pathological contexts. Considering the neuroprotective role of the soluble APP alpha (sAPPα) fragment, we hypothesised that sAPPα could modulate the expression of genes of interest for AD and TBI. Hence, we present preliminary experiments addressing sAPPα-mediated regulation of BACE1, Isthmin 2 (ISM2), Tetraspanin-3 (TSPAN3) and the Vascular Endothelial Growth Factor (VEGFA), each discussed from a biological and pharmacological point of view in AD and TBI. We finally propose a neuroprotective interaction network, in which the Receptor for Activated C Kinase 1 (RACK1) and the signalling cascade of PKCβII/nELAV/VEGF play hub roles, suggesting that vasculogenic-targeting therapies could be a feasible approach for vascular-related brain injuries typical of AD and TBI.

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“…95 ; García-Colomo et al . 96 ), as well as other various biomarkers, 35 including cerebrovascular 112 and genetic 113 serum and CSF biomarkers. 114…”

Section: Discussionmentioning

confidence: 99%

Repetitive subconcussion results in disrupted neural activity independent of concussion history

Solar,

Ventresca,

Zamyadi

et al. 2024

Preprint

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Concussion is a public health crisis which results in a complex cascade of neurochemical changes in the brain that can have life changing consequences. Subconcussions are considered less serious and were overlooked until recently, but we now realise repetitive subconcussions, such as repetitive head impacts, can lead to serious neurological deficits. Subconcussions are common in contact sports, and the military where certain personnel are exposed to repetitive occupational blast overpressure. Postmortem studies in athletes reveal that cumulative duration of play and force from collisions are better predictors than concussion history for the presence and severity of chronic traumatic encephalopathy — a progressive and fatal neurodegenerative tauopathy, distinct from concussion, thought to be caused by repetitive head impacts, and only diagnosable postmortem — thus, an in vivo predictive biomarker would be game changing. Magnetoencephalography has exceptional temporal sampling for imaging the dynamics of neuronal electrochemical action, and functional MRI shows that functional connectivity is associated with tauopathy patterns. Therefore, both imaging modalities could provide a surrogate biomarker of tauopathy. In this cross-sectional study, we examined the effects of repetitive subconcussion on neuronal activity and functional connectivity using magnetoencephalography and functional MRI, and on neurological symptoms and mental health in a military sample. For magnetoencephalography and outcome analyses, 81 participants were split into ′high′ and ′low′ blast exposure groups using the generalized blast exposure value: n=41 high blast (26.4—65.7 years; 4 females); n=40 low blast (28.0—63.3 years; 8 females). For fMRI, two high blast male participants without data were excluded: n=39 (29.6—65.7 years). Magnetoencephalography revealed disrupted neuronal activity in participants with a greater history of repetitive subconcussions, including: neural slowing (excessive delta activity) in the right frontal and temporal lobes and subcortical regions (hippocampus, amygdala, caudate, pallidum, thalamus), and functional dysconnectivity in the posterior default mode network (low and high gamma). Notably, these irregularities were independent of concussion or traumatic stress history, and magnetoencephalography revealed functional dysconnectivity not detected with functional MRI. Besides regional slowing and functional disconnection in crucial brain hubs, those with greater blast exposure had poorer neurological outcomes in somatic and cognitive domains, with no blast-related differences in mental health and no associations between neurological symptoms and neuronal activity. This study suggests that repetitive subconcussions have insidious effects on the brain and that magnetoencephalography provides a potential avenue for both treatment targets by identifying affected brain regions and in prevention by identifying those at risk of cumulative subconcussive neurotrauma.

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Targeting the Cerebrovascular System: Next-Generation Biomarkers and Treatment for Mild Traumatic Brain Injury

Cited by 19 publications

References 180 publications

Treatment with vascular endothelial growth factor-A worsens cognitive recovery in a rat model of mild traumatic brain injury

Treatment with vascular endothelial growth factor-A worsens cognitive recovery in a rat model of mild traumatic brain injury

The Labyrinthine Landscape of APP Processing: State of the Art and Possible Novel Soluble APP-Related Molecular Players in Traumatic Brain Injury and Neurodegeneration

Repetitive subconcussion results in disrupted neural activity independent of concussion history

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