Concussion is a serious traumatic brain injury (TBI) that occurs frequently in athletes participating in high-impact sports, car accident victims and individuals who have fallen. An aspect of TBI that is gaining increasing interest is the broken blood-brain barrier (BBB) or “leaky brain,” which can also occur along with concussion or in lieu of it. Repair of the BBB is essential for concussed patients and support of the BBB in athletes is vital for the prevention or lessening of TBI.
The blood brain barrier (BBB) is a physical barrier between the brain and the circulating blood, formed by the arrangement of endothelial cells and tight junctions that line the capillaries, which supply blood to the brain. It is a highly selective barrier that restricts the movement of all soluble proteins greater than 400 Da from the blood across to the brain. Acting like a filter, the BBB protects the brain from infections, the products of infections such as lipopolysaccharides (LPS), and toxic chemicals, etc., that circulate in the blood. The BBB naturally permits the passage of essential metabolites, small hydrophobic (lipid soluble) molecules like oxygen, carbon-dioxide, hormones, etc.
The presence of BBB autoantigens may indicate a breakdown of the BBB. BBB protein autoantigens that have persisted for an extended period following repetitive BBB disruptions may cause neuronal cell death, the release of neural antigens, and an early cognitive decline. TBI is a multifaceted pathology involving excitotoxicity, free radical formation, brain swelling, and the entry of locally produced molecules such as cytokines, chemokines, and other molecules (Figure 1).
The target tissue damage is primarily determined by genetics and exposure to environmental factors, leading to various clinical conditions including:
When the BBB is damaged it provides a gateway for environmental triggers to infiltrate the brain and nervous system. Due to the similarity between some of these triggers and neurological tissues, neuro-reactive antibodies can be formed. Neuronal autoantibodies contribute to the onset of neurological diseases. Known cross-reactions between neurological tissues and environmental triggers include:
Patients with circulating antibodies to the above environmental triggers who experience BBB breakage are at the risk of reactive antibodies infiltrating the brain and causing neurological tissue damage. The more circulating antibodies, the greater the potential damage to nervous system tissues can occur (see Figure 2a and Figure 2b). Once antibodies made against environmental triggers cause damage to these tissues, autoantibodies can be produced against the neurological tissues, which will further contribute to the neuroautoimmune process.
Increasing data over recent years has linked the BBB and vasculature involvement in course of pathophysiology of many neurological issues. Inflammation induced by environmental triggers is a known cause of BBB disruption. Inflammatory disorders such as meningitis and encephalitis, and autoimmune diseases like multiple sclerosis, epilepsy and Alzheimer’s disease may be initiated due to BBB breakdown.
The repeated head trauma and TBI associated with some sports, such as football, have also been shown to induce BBB permeability, followed by antibody production against BBB proteins. A cell-mediated response resulting in autoantibodies to BBB indicates a pathological alteration of the protective brain barrier.12 As shown in Figure 1, such a result may manifest itself in pre- and post-synaptic dysregulation of neurotransmitters.[13, 14]
The BBB works efficiently to prevent brain infections. However viruses can penetrate the barrier by attaching onto circulating cells of the immune system. Systemic LPS enhances both immune cell and free virus transport across the intact BBB. LPS acts at the luminal surface of the brain microvascular endothelial cell monolayer, which induces abluminal secretion of cytokines and other factors that in turn act on pericytes; the pericytes then secrete substances that enhance viral transcytosis across the BBB.
In an animal study, wheat germ agglutinin (WGA), a lectin protein from wheat, was injected into the subjects. Banks and colleagues showed by both in vivo and in vitro studies that free HIV-1 can be taken up by brain endothelial cells and cross the BBB. When WGA binds to sialic acid and N-acetylglucosamine, it induces vesicle-mediated internalization of WGA by brain endothelial cells, a process called adsorptive endocytosis.[20, 21] Lectin-induced vesicles provide the mechanism by which enveloped viruses in general are internalized by cells. Banks’ study results strongly suggest that glycoprotein gp120 or gp120/gp41 induces adsorptive endocytosis and the uptake of HIV-1 by brain endothelial cells. This action explains how free, blood-borne viruses can infect the CNS while the BBB remains intact.
BBB dysregulation plays a role in many neurological disorders. BBB breakdown may precede, accelerate, exacerbate or contribute to chronic disease processes in neurodegenerative disorders of the adult and aging nervous system. Examples include, but are not limited to:
A simple blood draw can assess antibodies to BBB, as well as several environmental triggers of neuroautoimmunity that can invade the brain and nervous system during BBB breakdown. This assessment can identify potential problems in athletes at risk for TBI. Problems can be addressed prior to a TBI, and thus, if a TBI occurs, less neurological tissue damage will result. This simple screening tool can also measure BBB health and the safe time to return to play. The Array 20 – Blood-Brain Barrier Permeability Screen is exclusively available at Cyrex Laboratories, LLC.
Thank you to Cyrex Laboratories, LLC for contributing to our Summit Sponsor Showcase! We look forward to future blogs from our sponsors leading up to The Concussion Health Summit. Register today to attend the Summit and join the conversation discussing the latest knowledge and technology regarding concussion management.
The Early Bird Discount and the Hyatt Regency Hotel "Cut-Off Date" to reserve your hotel rooms ends on Thursday, July 6th. There are three ways to register: online, email/fax or mail. Click here to register.
Concussion Health Updates
Here's what we've added to Concussion health lately...