“I used to think the brain was the most wonderful organ in my body. Then I realized who was telling me this.” – Emo Philips

The complexity of the structure and operation of a human brain is almost unfathomable. Our brains are the headquarters of the human experience: storing, sorting and reorganizing memories and even experiences that occurred before or outside of our cognitive memory; determining how we react to circumstances internally and externally; and controlling not just our functions, but our feelings, perceptions and understanding of life. A change in the brain changes the very essence of a person’s identity.

Three areas where brain changes are receiving intense attention are Alzheimer’s Disease; brain injuries incurred through contact sports, such as boxing and American football; and brain injuries incurred during military service. Although a relationship between the brain injuries from contact sports and military service seems obvious, the link with Alzheimer’s Disease (or AD) may be just as substantial. When Traumatic Brain Injury (or TBI) produces a degenerative neurological cycle, the disease is referred to as Chronic Traumatic Encephalopathy (or CTE). The diseases are so similar, that some cases of CTE have been mistakenly diagnosed as AD. The research in all three areas seem to be leading scientists to investigate the same functions on the cellular and molecular level in the brain.

Although NFL brain injury studies have garnered the most media attention, traumatic brain injury (TBI) is a leading cause of death and disability in children and young adults. Yes, that kid who bangs his head on the wall may be doing severe damage to his brain. It also affects approximately 400,000 of the 2 million US military personnel who have deployed to Iraq and Afghanistan.

Much of the recent research has been sponsored by the VA, the National Institutes of Health, the Alzheimer’s Association and the and the NFL. With TBI, the shock wave travels at different speeds through gray matter and white matter. The different speeds of travel tend to focus destructive energy where the gray matter and white matter are joined. This is the area where abnormalities have been found in the brains of affected athletes and military personnel.

Testing a football helmet in 1912

 

To better understand brain degeneration, consider some healthy nervous system functions at the cellular level. The following explanation is admittedly an oversimplification, but should suffice for our purposes. Nerve cells constantly construct and deconstruct small rigid hollow tubes (microtubules) which are used to connect them to other nerve cells and to transport nutrients. They send energy packages through these tubes (mitochondria) and signals cross the gaps between cells (synapses) by sending, receiving and then changing chemical messengers.It is possible that these microtubules are what are most severely damaged during TBI. Proteins, called tau-proteins, are abundant in nerve cells but rare in other cells and are responsible for the assembly and stability of these microtubules. Tau-proteins are relatively simple proteins, and have several different structures (isomers). One way the structures differ is whether components are attached on the same (cis) or opposite (trans) sides of a stable molecular bond. An illustration of these structures is provided using a simple molecular structure (1,2-dichloroethene) below.

Cl            Cl                                                        Cl             H

\         /                                                             \         /

C = C                                                                  C = C

/         \                                                              /         \

H             H                                                       H              Cl

Cis-1,2 dichloroethene                      Trans-1,2 dichloroethene

The trans-tau-protein builds healthy microtubules. This is possibly due to the linear nature of its structure from one attaching component to the next. The cis-tau-protein causes twisted microtubules to be built, possibly because of the attachment locations are on the same side of the body of the molecule, which produces a curved connection. If 1,2-dichlorethene molecules were to attach to each other by replacing the Chlorine atoms with a bond, the trans-isomer would produce a string, but the cis-isomer would be twisted. A mixture of cis-isomers and trans-isomers would produce strings with twists everyplace a cis-isomer occurred. A bunch of twisted microtubules is called a tangle.

Tangles are found in the brains affected by AD or CTE. Tangles are not suitable transports for a nerve cell’s energy packets, so the nerve cell does not properly communicate with its neighbors and eventually dies of starvation. Although scientists are not certain of the origin, some abnormal clusters of proteins between brain cells, called plaques, are also found in brains affected by AD or CTE. These could be the remnants of tangles from dead brain cells.

If a brain experiences a traumatic injury, from a percussive blast or a sudden jarring, it can begin to produce the cis-tau-protein within as little as 12 hours. More frequent and more severe TBI experiences increase production of the cis-tau-protein. A relatively mild TBI (a mild concussion) may produce temporarily higher levels of the cis-tau-protein. This implies the body may have some mechanism for removing the disease-causing protein. Stress is also reported to sometimes cause increased production of the toxic protein, possibly because the body uses the same source hormone (cortisol) to deal with stress and fatigue as it uses to fight inflammation. The production of the toxic protein is particularly dangerous when the brain is not allowed to rest and provided water and proper nutrition immediately following an injury. Additionally, the use of some medicines, particularly opioids, also increase the production of the cis-tau-protein.

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Although the role of genetics in the production of the tau proteins is not fully understood, it is believed to play an important role in the production of the different types of tau proteins. The reason the misshapen tau proteins are formed is not fully understood. Tau proteins are resistant to heat and relatively stable. Since the rise in the proteins in the brain is delayed following trauma, the trauma probably does not convert the proteins from one form to another, but it is possible that either the higher production of tau proteins when the brain is repairing recently damaged microtubules may reduce the stability of the type of tau protein produced through either greater diversity in production or the increased production overwhelming any natural mechanism which normally removes, inhibits or limits the cis-tau-protein. Once the cis-tau-protein is produced and in higher concentrations in the nervous system, it appears the nervous system becomes trapped in an increasing cis-tau-protein production cycle. This causes the brain to enter a degenerative cycle, with the cis-tau-proteins slowly and progressively destroying brain cells.

CTE progresses through four stages. The first stage is associated with headaches, loss of attention and concentration. Some people have short-term memory losses, depression, feel aggression, are explosive and have some executive dysfunctions. By stage 2, mood swings, headaches and short-term memory loss are frequently experienced. Some patients in stage 2 have executive function problems, impulsive behaviors, and have suicidal thoughts or make suicidal statements.

Stage 3 is marked by attention and concentration problems, memory loss, explosive behavior, executive dysfunction, depression, aggression, mood swings, and difficulties with visual-spatial relationships. People in stage 3 are considered cognitively impaired. Stage 4 is full-blown dementia and the individuals have severe cognitive problems and memory loss, with the prior problems growing more profound and the addition of paranoia, language difficulties and difficulty walking normally. Substance abuse is a sign and symptom of all the stages.

Until recently the diagnosis of AD and CTE was based on behaviors and autopsies on the brains of deceased patients. Some highly sensitive MRIs and the use of specially designed low radioactive dyes have been used to diagnose CTE on living patients. Washington University in St. Louis has been a leader in the research on CTE diagnosis for military personnel. They use a very sensitive MRI to detect the build-up of the cis-tau-protein in the brain. In 2012, Boston University announced the results of a study of 85 donated brains of athletes and veterans who suffered repeated head injuries and found CTE in 68 of them.

Brains affected by Alzheimer’s and CTE have many similarities, even on a microscopic level.

Although some medications are used to reduce the speed at which Alzheimer’s progresses, the current medications have met with limited success and are not standard treatments for CTE. Per the Mayo Clinic, the current treatment for CTE is limited to preventing more brain injuries. Although some behavioral success has been reported from cognitive behavioral therapy (CBT), the impact of CBT on the brain chemistry is not likely to be adequate to fully treat these diseases. Two medical treatments do show promise: Cannabidiol (CBD) and a cis-tau-protein destroying antibody. Cannabidiol is a non-psychoactive component of marijuana and has been shown to inhibit the overproduction of the tau protein. (Esposito, G., Filippis, D., Carnuccia, R. et al. Journal of Molecular Medicine (2006) 84:253).

In 2014, Sheng Yuan published a PhD thesis in Pharmacology which included studies on Cannabidiol receptors in dementia. He described several neuroprotective properties of CBD, including stimulating neurological repairs and reducing oxidative stress, neurotoxins and inflammation. There are three groups of cannabinoids: endocannabinoids, which are naturally synthesized in the human body; phytocannabinoids, which are extracted from plants; and synthetic cannabinoids; which are produced under chemical synthesis and structural modification. Researchers are attempting to synthesize a cannabinoid which is more readily accepted by the brain than the phytocannabinoid, CBD.  Marijuana also contains THC, which is a psychoactive substance and has a higher affinity for both cannabinoid receptors found in humans.

CBD oil has reportedly been used to successfully treat seizures and other neurological problems and is available over-the-counter in some states, but it is still technically banned by federal law and listed as a schedule 1 drug by the DEA, meaning it is considered as having no medicinal value and highly subject to abuse. Therefore, it is difficult to get any federal approval for studies of CBD’s potential uses or benefits. Furthermore, the DEA could prosecute someone purchasing CBD through the mail or transporting it across state lines with the same force as if the substance were LSD or heroin. Reports by those who have taken CBD vary from no noticed change to significant improvement. In rare cases, people who have used CBD oil report feeling mild-mood and mind-altering effects. The most common side effect of ingested CBD oil is mild digestive upset. Some effects may be unknown or undetected for years.

On the more traditional track, scientists at Beth Israel Medical Center and Harvard University announced on July 15, 2015, they had developed an antibody for possible early intervention of CTE and AD. It is reported to prevent the development of debilitating neurodegenerative diseases from repetitive contact sport injuries or exposure to military blasts. The antibody selectively detects and destroys the cis-tau-protein.  It has been successfully tested on laboratory mice with TBI induced from stress, contact sport simulated injuries and military blast simulated injuries.

The initial indications are the medicine could be used to prevent TBI from developing into AD or CTE and the antibody reverses some of the damage in the brains of the mice used for testing. However, the development of this into a medical treatment regime is subject to financial backing and in the United States it is also subjected to the rigorous FDA drug approval process. Years or decades may pass before the treatment is available, if ever.

Sincere thanks to Randall Stevenson, Sr. for his research and dedication that contributed to the content in this article.

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