Tuesday, July 21, 2015

Chronic Traumatic Encephalopathy: Are there ways to mitigate risk?

In recent years, research in to Chronic Traumatic Encephelopathy(CTE) has exploded as the number of professional football players and war veterans who have committed suicide has increased.  The chronic condition, thought to be a consequence of repeated blows to the head in sports such as football and boxing or from blast-exposed military veterans, leads to progressive loss of brain tissue and abnormal brain physiology somewhat similar to that of Alzheimer's disease patients.  The disease is insidious, beginning with mood disturbances and psychotic episodes early on.  In the second stage, memory loss, erratic behavior, and Parkinson's symptoms become increasingly prominent.  Finally, victims of the disease experience dementia, full-blown Parkinson's, and speech and motor dysfunction.  While progression of the disease is often blamed solely on repeated blows to the head sustained as a result of contact sports, oftentimes the symptoms don't appear until a much later time, sometimes a decade or more after retirement.  Making research in to CTE difficult is the fact that the only way to diagnosis it is through examination of the brain after death.

As science in to other chronic disease has progressed, diet has emerged as a potential contributing factor.  Cardiovascular disease, Type 2 diabetes, stroke, and a host of other diseases, particularly autoimmune diseases, are thought to be impacted to a significant degree by diet.  Unfortunately, most of the previous research has been directed towards micronutrients in food that may function as protective against these diseases and not towards the specific mechanisms that may contribute to their progression.  Over the last decade or so, however, science has taken an interesting turn.  Rather than looking at the body as a sterile environment devoid of microorganisms, the body is now seen as an ecosystem teeming with thousands of species of bacteria that not only reside within and on us, but also help perform vital life functions that are required for health.  As it turns out, a defect in one of the functions these bacteria help perform may be an integral step in the progression of chronic traumatic encephalopathy.

Chronic inflammation in modern disease

A common theme that continually presents itself in modern disease is chronic inflammation.  When we become injured, or infected with a pathogenic strain of bacteria, inflammatory cytokines are secreted to begin the healing process or initiate the removal of the unwanted visitors.  The inflammatory process serves us very well when it works in the way that it is meant to work, acutely.  When the inflammatory process is chronic and unabated, it can cause many problems throughout the body.  In a disease like Rheumatoid Arthritis, chronic inflammation presents itself as painful joints.  In a disease such as Type 2 diabetes, chronic inflammation presents itself as dysregulated blood glucose and the damaging effects it has on the body.  In a disease like Alzheimer's disease, chronic inflammation may present itself as progressive mental decline due to changes in brain physiology.  Three of the physiological changes seen in Alzheimer's disease are also seen in chronic traumatic encephalopathy: blood brain barrier permeability, neuroinflammation and resultant hyperphosphorylation of the protein tau.  Many of the symptoms between the conditions are similar as well.  With so many commonalities between the diseases and no good method of diagnosis for CTE, looking at Alzheimer's disease may give us some insight in to chronic traumatic encephalopathy.

While acute inflammation is necessary for survival, chronic inflammation is toxic to neurons.  Immune cells of the brain that are activated by inflammation, microglia and astrocytes,
make a toxic soup that can ultimately kill neurons(1, 2).  Metcalfe and Figueirido-Pereira put forth an Alzheimer's model whereby inflammation activates microglia and astrocytes which generate toxic byproducts that kill neurons and leads to progressively more inflammation as seen below. 

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However, what initiates this event?  Why is the inflammation associated with Alzheimer's disease chronic?  In something like chronic traumatic encephalopathy that may be caused by repeated blows to the head, the damage is evident.  However, Alzheimer's disease is not associated with blows to the head.  A fairly new hypothesis has bacterial infection contributing to chronic inflammation.

Our entire digestive tract, from mouth to anus, is loaded with trillions of bacteria that may, in some way, be triggering the immune system and causing chronic inflammation.  However, in order to cause the damage seen in the brain of someone with Alzheimer's disease, these bacteria would need to make it from the gut in to the bloodstream and from the bloodstream in to the brain, no easy task.  To do this, they would need to bypass the intestinal barrier AND the blood brain barrier.

Bacterial invasion and Alzheimer's disease

Multiple lines of evidence identify a connection between bacterial invasion and Alzheimer's disease(3, 4, 5).  Most of the evidence focuses primarily on bacteria found in the mouth.  Finding bacteria in the brains of people suffering from Alzheimer's disease was a bit of a surprise given that the brain was thought to be tightly segregated from the general circulation by the blood brain barrier.  However, under the proper circumstances, the blood brain barrier can become permeable.  One of these circumstances involves the presence of lipopolysaccharide(LPS), a molecule found in the cell membrane of gram negative bacteria that drives the immune system in animals nuts.  In both CTE and Alzheimer's disease, the blood brain barrier is more permeable than it should be, and we don't know why. 

LPS levels in circulation are greatly influenced by diet as there are many species of bacteria found in the digestive tract that contain LPS in their cell wall.  So rather than being the consequence of a single strain of bacteria triggering the damage associated with Alzheimer's disease, it may be the cumulative effects of LPS from multiple types of bacteria chronically stimulating the immune system as they breach the intestinal barrier.  In fact, injection of LPS in to the brains of mice causes the same pathology as Alzheimer's disease: increases in blood brain barrier integrity, amyloid beta production and hyperphosphorylation of the protein tau(6, 7, 8).  While amyloid beta production is only sometimes seen in chronic traumatic encephalopathy, blood brain barrier permeability and hyperphosphorylation of tau are almost always present.  Rather than focusing on the bacteria, it becomes more important to focus on the integrity of the intestinal and blood brain barriers.

Further bolstering the notion that bacterial infection and the resultant chronic inflammation associated with it may have a causal impact on the neurodegeneration seen in Alzheimer's disease and CTE is the effect LPS has on tau.  Tau is a protein that is responsible for stabilizing microtubules, components of nerve cells that are important for proper function.  When tau becomes hyperphosporylated, it is unable to stabilize microtubules and the unbound tau clumps together.  In the presence of LPS, neurons form these same tangles(6, 8, 9).  Neuroinflammation is thought to be a primary factor that increases phosphorylation of tau and leads to the pathology seen in Alzheimer's disease and CTE, but the exact mechanisms by which this happen are just now garnering attention from researchers.

Immunoexcitotoxicity in Chronic Traumatic Encephalopathy

One of the more interesting aspects of CTE is something referred to as immunoexcitotoxicity, which also happens to support the presence of bacterial infection in CTE.  Excitotoxicity refers to the process by which neurons are damaged or killed by overstimulating receptors for the excitatory neurotransmitter glutamate secreted during injury.  When microglia and astrocytes encounter pro-inflammatory cytokines they release excitotoxins, particularly glutamate.  These excitotoxins in turn cause the release of pro-inflammatory cytokines in a vicious cycle(12).  In fact, both events are necessary for the damage seen in CTE.  LPS on it's own will not induce neurodegeneration unless glutamate receptors are also activated.  Subtoxic levels of LPS or glutamate on their own will not induce neurodegeneration, but when combined are fully toxic to neurons, hence the term immunoexcitotoxicity.

Obviously, it makes no sense for immune cells to destroy that which they are meant to protect.  The problem isn't the mere presence of microglia, which are thought to contribute more to the damage seen in CTE than astrocytes.  Most immune cells exist in multiple states dependent on what the environment commands them to do and microglia are no different.  Under optimal circumstances, microglia exist in a dormant state where they don't do much of anything until activated.  Once activated by inflammation due to damage or bacterial invasion, they enter a primed state and eventually progress to a fully activated state where they do their thing until the damage is contained.  Once the damage is contained, the microglia enter a reparative phase where they clean up the collateral damage they caused to healthy structures by secreting neuroprotective chemicals.  However, sometimes the microglia remain in a primed state, causing them to overreact to even minor stimuli and not repair the collateral damage.  This can occur due to repeated blows to the head or the presence of LPS in the brain.  Even systemic immune system activation that doesn't reach the brain can enhance immunoexcitotoxicity by keeping microglia chronically activated(12).  The combination of repeated traumatic brain injury and chronic systemic inflammation can likely leave microglia in a chronically primed state, leading to a never-ending barrage of pro-inflammatory cytokines and glutamate.  Essentially, damage to the brain is never fully healed, the collateral damage is never cleaned up, and this is all because the microglia never receive the signal to repair the damage.

So how do we work around this problem?  Should professional football players, mixed martial artists, and boxers just quit their day jobs?  I'm not altogether sure this is necessary.  While it is believed that people with CTE experience repeated blows to the head, very few people who experience repeated blows to the head develop CTE, at least as far as we know.  Perhaps what we are looking at in people who eventually experience CTE isn't specifically due to repeated blows to the head, but chronic inflammation due to stimulation by LPS that never allows the brain injury to heal properly.  In other words, the traumatic brain injury causes significant damage, but if LPS is kept in check and sufficient time is given, maybe the primed microglia enter their reparative state, repair the collateral damage, and re-enter their dormant state.  While repeated brain injury is obviously not a good thing and can leave microglia primed for long periods of time, one would think the outcome would be better if the prior damage was fully healed, even if microglia remain primed.  At the very least this should limit the collateral damage.

Now that I've laid out the mechanisms we may be seeing in chronic traumatic encephalopathy, let's look at factors that may be important and how we can mitigate the damage through diet and lifestyle. We'll do that after the jump.