Cobbers on the Brain – Page 62 – Student Commentary on the Neurological Sciences

The Good, the Bad & the Ugly

Posted on November 2, 2020 by / 0 Comment

The Good – A snack

I recently opened the door to my refrigerator and delightfully found a tub of ice cream waiting, practically begging to-be consumed. A smile crept across my face as I pulled the tub out of the freezer for the third time that day when suddenly I remembered an article we had read in my neurochemistry course on Alzheimer’s disease and inflammation. The smile quickly faded, and the ice cream was placed back into the freezer. What does inflammation have to do with Alzheimer’s and how does that have any relevance to my third bowl of ice cream in an afternoon you may ask. I’m here to tell you, more than you think.

The Bad – Alzheimer’s

Alzheimer’s disease is a neurodegenerative condition characterized by loss of memory and other important mental capacities. These malfunctions occur as a result of decreased brain cell connections due to neuronal cell death. Neurons contain a diverse array of cellular machinery and proteins significant to their health and proper functioning. Two of the primary issues in Alzheimer’s are neurofibrillary tangles and beta-amyloid plaques. These result due to issues with the proteins tau and beta-peptide oligomers both of which accumulate and coagulate resulting in neuron and tissue death. The tissues die because coagulation of these proteins blocks the movement of materials inside the cells and the transmission of signals outside and amongst the cells leading to a total loss of function and degeneration of the neurons. But how does that relate to inflammation?

The Ugly – Inflammation

Inflammation specifically chronic low-grade inflammation of tissues recruits cells from the immune system called macrophages (in the body) and microglia (in the brain). This inflammation results in increased activity of a protein abbreviated as PTP1B which has the role of dephosphorylating (deactivating in most cases but not all) other proteins and signaling pathways. This deactivation of important proteins such as IRS1 & IRS2 prevents them from enacting their functions of blocking the over activation of another protein abbreviated as mTOR. When mTOR signaling is improperly regulated then beta-peptide oligomers and tau turn into neurofibrillary tangles and beta-amyloid plaques which develop through a continued long and complex scheme of further improper signaling. MTOR malfunction also leads to insulin resistance which is at the sole of Alzheimer’s disease and its development.

– Insulin Resistance

Insulin is a hormone produced in the pancreas (and brain in small quantities) that plays several important roles both within the body and within the brain. Within the body, insulin regulates the metabolism of carbohydrates, fats, and proteins by promoting the absorption of glucose from the blood. Its resistance is the primary cause of type 2 diabetes. Within the brain, insulin plays a neuroprotective role, regulates synaptic plasticity, long-term memory consolidation, and participates in regulating neuron growth and survival. Insulin resistance within the brain leads to neuron vulnerability, degeneration, and Alzheimer’s disease. Because of insulins diverse and significant roles, having type 2 diabetes puts one at risk for developing Alzheimer’s disease and vice versa.

The Ice Cream

Okay that all makes sense (inflammation leads to beta-amyloid plaques, neurofibrillary tangles, and insulin resistance which causes Alzheimer’s disease) but what relevance does ice cream have? A healthy diet is important and can have a positive impact on the prevention of developing multiple conditions including Alzheimer’s disease and type 2 diabetes. A poorly balanced diet, especially one high in fat can stimulate the body to increase its fat stores. It’s this increase in fat storage that recruits immune cells resulting in inflammation and initiating the cascade of events leading to said conditions. Of course, eating ice cream responsibly is of no concern and certainly won’t lead to the development of type 2 diabetes or Alzheimer’s disease in the average individual, but a consistent pattern of poor diet and numerous other factors such as lack of exercise could contribute to an increased risk of development. There remains much to learn about the link between insulin resistance, type 2 diabetes, and Alzheimer’s disease including Alzheimer’s cause and possible treatment strategies. But, with the knowledge we do have, we can be proactive in an effort to best protect ourselves and those we love. Thanks for reading.

Sources

https://pubmed.ncbi.nlm.nih.gov/29129775/

https://www.google.com/search?rlz=1C5CHFA_enUS867US867&ei=3w6fX6j-F8Sf_Qby65G4DA&q=insulin&oq=insulin&gs_lcp=CgZwc3ktYWIQAzIHCAAQyQMQQzIECAAQQzIHCAAQsQMQQzIECAAQQzIHCAAQsQMQQzIFCAAQsQMyBQgAELEDMgQIABBDMgUIABCxAzIFCAAQsQM6CAgAELEDEIMBOgIIADoLCC4QsQMQxwEQowI6CAguEMcBEK8BOgoIABCxAxDJAxBDOgoILhCxAxCDARBDUJ3uzQFYpvjNAWDF-80BaAFwAXgAgAGpAogBlwiSAQUwLjYuMZgBAKABAaoBB2d3cy13aXqwAQDAAQE&sclient=psy-ab&ved=0ahUKEwjo6cDFjOLsAhXET98KHfJ1BMcQ4dUDCA0&uact=5

https://www.mayoclinic.org/diseases-conditions/alzheimers-disease/symptoms-causes/syc-20350447?utm_source=Google&utm_medium=abstract&utm_content=Alzheimers-disease&utm_campaign=Knowledge-panel

Disease/Health

Alzheimer’s: More Risky Than You Think

Posted on November 2, 2020 by / 0 Comment

Alzheimer’s: the complicated disease resulting in memory loss, confusion, and disorientation. Odds are we’ve all heard of this disease and the profound implications it can have on people’s lives, but there may be much more to this issue than we have previously understood.

In the brain:

In Alzheimer’s, there are obviously many things going wrong in the brain, leading to the complex nature of the disease. However, the cause of Alzheimer’s can really be boiled down to one main issue: insulin resistance. Insulin is crucial to the brain’s normal functioning, so issues with it working properly have detrimental results. There are essentially four facets that lead to the insulin resistance seen in Alzheimer’s. These are: inflammation, unchecked PTP1B activity, deregulated mTOR signaling, and abnormal ganglioside metabolism.

The first part of the insulin resistance understanding of Alzheimer’s is inflammation. Inflammation in the brain is known to cause insulin resistance, considering it impairs synaptic functioning and goes hand-in-hand with stress on the endoplasmic reticulum. Next is unchecked PTP1B activity. PTP1B is an enzyme that is an important regulator of the insulin signaling pathway. It is a negative regulator, which is important when working properly, but when unchecked, causes insulin resistance. The third facet of insulin resistance comes from deregulated mTOR signaling. The mTOR signaling pathway is an important regulator of cell metabolism, proliferation, and survival. When mTOR signaling is off, it retroactively inhibits insulin substrates so that they are no longer able to bind to their receptor. This once again leads to the insulin resistance seen in Alzheimer’s. Finally, ganglioside metabolism is abnormal in Alzheimer’s. These gangliosides, specific molecules containing a glycosphingolipid and one or more acids, promote the aggregation of amyloid-beta protein plaques that run wild in Alzheimer’s.

With all of the previous implications considered, we can see that insulin resistance is an important contributor to Alzheimer’s and may be a significant system to target when thinking about future treatments and therapies. What’s also quite fascinating is that all four of those causes are also linked to the insulin resistance seen in type 2 diabetes. Many of us likely did not know that type 2 diabetes and Alzheimer’s are so interconnected in causes and mechanisms. Here is a figure that summarizes these concepts:

Image source: Vieira MNN, Lima-Filho RAS, De Felice FG. Connecting Alzheimer’s disease to diabetes: Underlying mechanisms and potential therapeutic targets. Neuropharmacology. 2018 Jul 1;136(Pt B):160-171. doi: 10.1016/j.neuropharm.2017.11.014. Epub 2017 Nov 10. PMID: 29129775.

Outside the brain:

Now that we’ve taken a look at what exactly is contributing to Alzheimer’s within the brain, it’s also important to keep in mind the factors that come from outside the brain and body: from the environment.

The most important risk factor for Alzheimer’s is increasing age (which many of us might have guessed!) but other environmental risk factors are not well understood, though they are quite prevalent. One study suggests that half of the individual differences seen in Alzheimer’s risk levels may be environmental. In other words, half of any one person’s chances to develop this disease could be attributed to environmental causes, which is insane! Obviously with findings this significant, there needs to be a better understanding of environmental factors in Alzheimer’s. It is crucial to understand the full Alzheimer’s exposome, which is another word for the complex gene-environment interactions that lead to individuals’ higher or lower susceptibility and onset of Alzheimer’s.

There are several environmental factors known to have a role in Alzheimer’s risk. Some main ones are exercise, traumatic brain injury, blood pressure, smoking, education, and air pollution. Interestingly, researchers have found that the onset of dementia was a decade earlier in individuals with these environmental risks. A whole decade! Obviously with environmental factors having this significant of a shift in the onset curve, we must begin to think about how our lifestyle shapes our life outcome.

We now see that Alzheimer’s is much more complex than originally understood. Considering insulin resistance, environmental factors, and link to type 2 diabetes, this disease deserves much more recognition and research so we can hopefully work towards a better understanding, and eventually, a cure.

Disease/Health

Estrogen, Insulin Resistance, and Alzheimer’s Disease: A Love Triangle

Posted on October 31, 2020 by / 0 Comment

Insulin Resistance and Alzheimer’s Disease:

The first two members involved in this complicated love triangle are insulin resistance and Alzheimer’s Disease. There is a remarkable link between the two, as insulin resistance increases the likelihood that an individual develops Alzheimer’s Disease, and vice versa. This connection between these two conditions are the result of a variety of overlapping mechanisms at the cellular level that contribute to the development of one or both ailments.

Insulin has numerous beneficial effects throughout the brain including protection for neurons, growth and survival of neurons, and reinforce neuroplasticity, a mechanism that allows for long-term memory consolidation and maintenance. When there is a deficiency in insulin as a result of insulin resistance, these neuroprotective effects are absent and put the brain at higher susceptibility to developing Alzheimer’s Disease.

Estrogen and Insulin Resistance:

The other member in this love triangle is the reproductive hormone, estrogen, that prepares the lining of the uterus for pregnancy, along with a number of body-wide effects. Low levels of estrogen have been linked to insulin resistance in numerous studies, suggesting a prominent role of estrogen in maintaining normal insulin signaling. This deficiency in estrogen that leads to insulin resistance that, as mentioned above, can put an individual at a greater risk of developing Alzheimer’s Disease.

Estrogen and Alzheimer’s Disease:

Decreased levels of estrogen can also directly increase the likelihood of the development of Alzheimer’s Disease, in addition to the role of estrogen in insulin resistance, as demonstrated above. This effect can be seen in the form of estrogen as a neuroprotective agent in the brain. In particular, estrogen helps to prevent the synthesis and accumulation of beta-amyloid (Aß) plaques. These plaques have neurotoxic effects within the brain, as the presence and buildup of these molecules have shown to be a primary root cause of Alzheimer’s Disease.

Clinical Applications:

Menopause is categorized by decreased estrogen levels as those who menstruate age. This stage of reproductive health therefore leads to an increased risk of developing insulin resistance and eventual Alzheimer’s Disease as a result of estrogen deficiency.

Since low estrogen has indeed been linked to insulin resistance, this is largely why post-menopausal women tend to gain weight and have a greater likelihood of developing Type 2 Diabetes. Additionally, menopause as a result of surgical hysterectomies, in which the ovaries are also removed, results in two times greater likelihood of developing Alzheimer’s disease in those who underwent the procedure than those who did not. This increased risk is largely associated with a loss of estrogen. These clinical commonalities further emphasize the role of estrogen in the protection against both insulin resistance, and ultimately, Alzheimer’s Disease.

Estrogen as a Potential Treatment Option

Estrogen is one of the best-studied drugs for potential use in the prevention and/or treatment of Alzheimer’s disease. Estrogen therapy can reduce the cognitive decline observed in women that have gone through either natural or surgical menopause. This form of therapy can therefore help to delay or be used in the treatment of both Alzheimer’s Disease and Type 2 Diabetes. Supplemental estrogen also improves the function of Tacrine, an anticholinesterase drug that is used for the treatment of Alzheimer’s Disease, thus demonstrating that estrogen may enhance existing treatments for Alzheimer’s Disease. Further research regarding the therapeutic effects of estrogen should be pursued, as its positive effects in preventative measures against insulin resistance and Alzheimer’s Disease are invaluable in the fight against these health issues.

Abstract (Featured Image) created by S. Wiger

Disease/Health

Infliximab: Treating Everything From Alzheimer’s to Arthritis

Posted on October 30, 2020 by / 0 Comment

What would you think if I told you the same manmade drug is used to treat Alzheimer’s Disease (AD), Type II Diabetes (T2D), psoriasis, ulcerative colitis, Crohn’s disease, rheumatoid arthritis, and more seemingly unrelated disorders? Are you skeptical that these diseases have enough in common that the same drug is prescribed for them all? Read on to find out how much these disorders have in common on a molecular level and how one drug helps treat them all.

Molecular causes of AD and T2D

First, let’s look at what is happening on the molecular level in AD and T2D. As you may know, T2D is characterized by insulin resistance—an inability to produce or process insulin the way the body is supposed to. This results in T2D disease progression, especially increased blood sugar (hyperglycemia). However, insulin also plays an important role in the brain. It helps protect neurons, the brain’s cells, and is an important player in learning and memory pathways. In this way, insulin resistance has been shown to contribute to AD disease progression as well. The two disorders have a high comorbidity, meaning the often occur together, and a similar molecular cause: inflammation.

When functioning normally, insulin in the brain binds to insulin receptors located on the neuron’s cell membrane. These receptors, once activated, phosphorylate proteins called IRS1 and IRS2, which means that phosphate molecules are put on the proteins. This in turn activates IRS1 and IRS2 which go off to cause more activation and signaling cascades resulting in insulin’s aforementioned activities in the brain, like facilitating learning and memory.

However, in AD, this signaling chain is interrupted. Cells called macrophages, which play an important role in the immune system and in causing programmed cell death, become active. These macrophages secrete proinflammatory cytokines, which are chemicals that cause inflammation. One important proinflammatory cytokine in AD is called TNF-α. High concentrations of TNF-α cause significant inflammation, which interrupts the insulin signaling pathway by preventing insulin receptors from initiating IRS1 and IRS2 phosphorylation. This is how insulin resistance happens in the brain. TNF-α prevents the whole chain of signaling events meant to occur after insulin is released, keeping those important functions like learning and memory from occurring as they should.

Where Infliximab comes in

The drug Infliximab counters this inflammatory insulin resistance pathway. Infliximab is a monoclonal antibody, meaning a manmade (not naturally occurring) drug that acts as an antibody by binding to and neutralizing an antigen, the harmful substance targeted. The antigen targeted by Infliximab is TNF-α. The drug binds to TNF-α and neutralizes it so it cannot cause inflammation and in turn insulin resistance.

Infliximab is highly specific to TNF-α, so it doesn’t bind to any other TNFs (other like TNF-β exist), which is useful because they have their own functions in the cell beyond inflammation that could be harmful if interrupted.

Because it interrupts this inflammatory pathway that contributes to AD and T2D disease pathology, Infliximab has been used experimentally to treat the disorders with relative success. The drug is already prescribed to treat a wide variety of other disorders, as mentioned above: Crohn’s disease, psoriasis, ulcerative colitis, etc. Its mechanism of action works to treat each disorder because inflammation is a key component of them all. It’s clear that mitigating inflammation in the brain and body can be useful in treating or even preventing a wide array of serious disorders.

So, should I just start taking it now?

Definitely not! First of all, Infliximab is not a preventative drug meant to keep you from developing AD or T2D. This drug is prescribed in severe cases of the aforementioned disorders for which other treatments have not been successful. Infliximab can have some pretty serious side effects including causing infections, leukemia, and demyelinating central nervous system disorders. It’s also administered by shot every 6-8 weeks and costs about $900 a dose—not something you should go for if it hasn’t been prescribed by a doctor.

If you’re looking for a preventative measure to counteract inflammation in hopes of delaying or preventing disease onset, you should take a look at a few other “Cobbers on the Brain” posts to see how things like antioxidants and CBD can work to fight inflammation and potentially protect against developing AD, T2D, and other inflammation disorders.

Disease/Health

My head hurts…Now What?

Posted on October 28, 2020 by / 0 Comment

WHAAAM!!!!

Congratulations. Whether from a head-to-head athletic collision, tripping backward on slippery ice, or the result of an unfortunate car accident, you have just joined the millions of Americans who will experience a concussion in a typical year.

I understand you might have questions, and they’re good ones (what was I doing running on ice, why am I in this ridiculous thought experiment, can’t you think of a better attention-grabber) but the important thing right now is to rest and recover. In fact, you probably shouldn’t be reading this short article, in fact, you probably shouldn’t be doing anything at all…you see, our treatment options for concussion are limited to rest…and Tylenol for headaches. Yes, you heard me right, one of the most common neurological injuries has the same treatment options as a twisted ankle—minus the ice. Put another way, there are no current drugs available to help treat concussion.

I know this may sound shocking and/or disheartening, but, before you go, I’d like to share one glimmer of hope, because there’s some promising new research for treating concussion. To understand how this drug, called ILB, works we’ll need a super short primer on the neuroscience of concussion.

Your Brain on Concussion

As your skull impacted the hard surface of another person, the ground, or your car window, a couple things happened in a very short amount of time. First, your body went from accelerating to immobile very quickly, causing your brain to slam into your skull and slosh around a bit inside. Zooming in, this force causes trauma to the membranes of your axons (the long, message sending bits of neurons). This in turn causes an imbalance in ion levels in and around the affected neurons, as the microscopic tears in axon membranes allow potassium ions to leave and calcium ions to enter with no regard for typical entrance/exit policies. Calcium, being the potent messenger that it is, goes around turning all sorts of things on and off that it shouldn’t, a bull let into a china shop by an earthquake. This disrupts the delicate neuronal balance even further, forcing membrane pumps to go into overtime trying to reestablish normal ion levels. As you might imagine, pumping a whole bunch of ions against their concentration gradient is tough work (think bailing out a canoe that’s taking on water), so naturally, this process uses up a ton of cellular energy (ATP). Normally, the neuron’s ATP-generating mitochondria (the famous powerhouses of the cell) can handle surges in energy demand, but our dear friend calcium has been sequestered in the mitochondria to prevent it from doing more cellular damage. While temporarily locking calcium in the mitochondria is an effective stop-gap measure, the downside is it hampers energy production. These dysfunctional mitochondria, coupled with increased neuroinflammation and reactive oxygen species (ROS) generation further exacerbate the low-energy crisis in traumatized neurons, culminating in neuron death.

The take-home message from diving into the concussed brain is that physical head trauma leads to a neuronal energy crisis, and prolonged low-energy states increase the amount of cell death and subsequent recovery time.

The trauma-induced energy crisis presents a critical unmet need to produce treatments that help to restore the neuronal energy balance so neurons affected by concussion can heal and repair.

This is where the good news comes in. Hot off the press is a 2020 article demonstrating that dextran sulfate (ILB: a low-weight carbohydrate) restores brain energy after traumatic brain injury (TBI) in rats. Johansson et. al (2020)., use N-acetyl aspartate (NAA) as a proxy energy metabolite (If NAA goes up, then brain metabolism must be up) to measure the effectiveness of the ILB treatment.

This data shows that ILB increases NAA levels (orange and red graphs) in rats following TBI! Yay!

Now, before you rush off and call your doctor for some ILB, a few caveats:

This data is in rats, not humans, rigorous clinical trials are required to ensure the drug’s efficacy and safety in humans
The model was of severe TBI, concussion is categorized as mild TBI so the effect seen may or may not translate—more research needed!
It’s still unclear exactly how ILB causes increased NAA, it could be by directly improving mitochondrial function, lowering neuroinflammation and/or ROS generation, or some combination of the three. In any case, the mechanism of action should be better explained before we go popping ILB pills in humans.

All said, while rest is still the gold standard “treatment” for concussion (because resting your brain prioritizes neuronal healing instead of other physical/mental tasks), ILB represents an exciting new development for concussion treatment! Now turn off your phone and rest your brain!

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Rapamycin: Potentially the answer to Alzheimers – and Aging?

Posted on October 28, 2020 by / 0 Comment

Most everyone has heard of Alzheimer’s Disease, far too often because of personal experience with loved ones. Although everyone associates the disease with someone losing their memory (and rightfully so), a physiological hallmark of Alzheimers is insulin resistance, which is thought of as the state of not having enough insulin, for one reason or another.

Insulin is most commonly known for its role in regulating metabolism. Insulin however, does a whole host of other helpful things for our bodies, including the regulation of synaptic plasticity, being neuroprotective, acting on neuronal growth and survival, and has been proposed to regulate the gene expression required for the ability to consolidate long term memories. All of this alludes to the fact that if we don’t have enough insulin, as seen in Alzheimers, we have a problem.

What can we do?

Insulin resistance has been observed to occur due to an inhibited insulin signalling pathway and an overactive pathway that leads that resistance called mTOR1 (mammalian target of rapamycin). However, with a drug called Rapamycin, mTOR can be inhibited and insulin resistance is abolished. Now, this doesn’t solve Alzheimers, but it’s certainly a step in the right direction for treatment if nothing else.

Some researchers however are suggesting that rapamycin has additional beneficial effects than simply increasing insulin (although this still might be the mechanism, the benefits are broader than simply treating Alzheimers). One of the positive effects of rapamycin that was found was that, when intermittently administered, rapamycin led to stem cell regeneration. Considering some of the applications for stem cells, this is an amazing discovery that could have far reaching implications on the future of medicine. And that’s potentially just the tip of the iceberg. Because of the mTOR1 inhibition through rapamycin, it has been found that there is a decreased risk of cancer, since mTOR1 signaling can lead to cell proliferation. Tumor regression has also been observed to occur. It’s also been found that mTOR1 signalling sometimes leads to misfolded proteins. Using rapamycin, inhibiting mTOR1 led to greater autophagy and suppression of protein synthesis, which is important because this means that rapamycin can have neuroprotective effects in not just Alzheimers, but also Parkinson’s Disease and Huntington’s Disease.

One of the most interesting positive effects found from administration of rapamycin was its ability to increase the lifespan of rats that were treated with the drug. It does this through slowing down the aging process along with inhibiting metabolic or neoplastic diseases. This also potentially includes cancer, as regulating cell proliferation through the drug means that cancer cells can’t spread as rapidly, and cancer cells may also happen less in the first place.

Before we all start taking insulin, it’s important to remember however that one of the most consequential aspects of a drug’s effects and effectiveness is the dosage and how often its administration. With rapamycin, the appropriate ratios of both of these factors are still unknown as of yet, but research is being done to try decipher further how to access the perceived positive effects of the drug. It has been seen though that rapamycin doesn’t fully inhibit mTORC1 processes, and so a combination with another treatment would more effectively implement the positive effects of Rapamycin.

This being said, there are observed downsides, which shouldn’t ever be overlooked within any kind of drug treatment. Rapamycin has been sometimes seen to actually increase insulin resistance, but the mechanism for why this occurs is speculated to be known (inhibition of mTOR2). Other negative effects included increased hyperglycemia within type 2 diabetes mouse models, and the ability for tumors to start regrowing after treatment with rapamycin stopped.

To end on a positive note about rapamycin treatment, there are no known overdose deaths due, which could signify that the ability for researchers to manipulate administered dosage levels could be rather high. All in all, more research into the side-effects and anti-aging effects of rapamycin are needed, but some people even now think that rapamycin can be used as an effective anti-aging (or at least an anti-disease) drug with very few discovered side-effects.

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Knocking Out Concussions: What do Concussions Mean for Athletes?

Posted on October 27, 2020 by / 0 Comment

Imagine you are at a high school football game. The tension in the air is thick as the play is ran, and you see a player that is hit, who falls down to the ground with a thud and doesn’t get back up right away. Generally, a medic/trainer will run out to the field and complete an assessment of the player to make sure they’re physically okay and check for a possible concussion. The player gets back up, shakes it off, and keeps playing. Do you think about it anymore after that? Concussions, or mild traumatic brain injuries (mTBIs), don’t necessarily always have to be symptomatic concussions or knock out the person, but they can put someone at an elevated risk of future concussions and can result in long-term impairments.

What are Concussions?

When we think of concussions, we tend to think of a hard hit to the head, one that may make you dizzy or confused, maybe even knock you unconscious. There’s a lot more that goes on though during a concussion than most people realize, and it’s important to know what is going on during a concussion to recognize the signs of one. A concussion, or mTBI, occurs when there is a significant blow or hit to the head that causes the brain to bruise, and rebound off the other side of the skull; this rebounding is referred to as the contrecoup. This rattling of the brain can disrupt axons and rupture the blood vessels. After a concussion occurs, the person may experience a variety of symptoms. They may have any of the following: headaches, confusion, dizziness, memory loss, nausea, blurred vision, sensitivity to noise and light, sleeping disturbances, mood changes, especially irritability, and may display slurred speech. To read more on the types of symptoms, you can read here: https://www.mayoclinic.org/diseases-conditions/concussion/symptoms-causes/syc-20355594

A concussion does not always create these symptoms though. People can also undergo sub-concussive impacts, which are blows to the head that do not cause full concussions. These types of hits can be incredibly dangerous because the person who has been hit may think they are fine because they have no symptoms, but the impact is putting them at a very high risk of developing a full concussion.

Inside the Brain

Now that we know what is occurring symptomatically during a full concussion, what is happening in the pathophysiology of the brain to result in these impairments? When a mTBI occurs, a neurometabolic cascade occurs. In the initial stages of the cascade, an ionic flux and depolarization occurs, which triggers excitatory neurotransmitters like glutamate to be released. There are ATP-ionic pumps within the membrane that are overstimulated due to this and creates an increase in ADP, an efflux of potassium, hyperglycolysis, and an influx of calcium. This creates an imbalance, or energy crisis. The imbalance ultimately leads to damage of axonal integrity, mitochondrial dysfunction, and altered neurotransmission. It’s also important to note the role of inflammation after a mTBI. Microglia are activated after a blow to the head, stimulating upregulation of cytokine, and ultimately activating inflammatory genes. Inflammation can result in severe headaches, or even rupturing blood vessels in the brain. Due to these pathophysiology changes that occur from a mTBI, long-term structural changes can occur within the brain and result in atrophy.

Looking Forward

Researching concussions has become a hotspot in the neuroscience community due to the prevalence it has in the sport world. Many athletes in contact sports like football, boxing, or hockey experience multiple concussions within their life and can suffer from long-term, symptomatic impairments that affect their everyday life. There are many athletes who have received so many hits to the head, especially boxers, that are at an elevated risk of developing chronic traumatic encephalopathy (CTE), which is a progressive neurodegenerative disease. CTE develops after years of repetitive symptomatic concussions and sub-concussive impacts and tends to cause severe memory loss, confusion, impulsivity, depression, and aggression. It’s important to be researching concussions to possible prevent CTE or multiple concussions from occurring. Young athletes are especially vulnerable to this due to the brain’s development, which means at a younger age there are more unmyelinated axons that are vulnerable to injury. With so many young people participating in sports and being placed at a higher risk of developing a concussion, society needs to look at different preventative measures that can be put into place to try and fully prevent mTBIs, or curb the progression to CTE.

References:

https://www.pearson.com/us/higher-education/product/Carlson-Physiology-of-Behavior-12th-Edition/9780134080918.html

https://www.bu.edu/cte/about/frequently-asked-questions/#:~:text=Chronic%20Traumatic%20Encephalopathy%20(CTE)%20is,that%20do%20not%20cause%20symptoms.

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The Joy of Winter Football Games

Posted on October 27, 2020 by / 0 Comment

The snap-crunch of football pads & helmets colliding pulled my attention up from wrapping yet another blanket around myself as I watched my younger brother’s third high school football game of the COVID-modified season while sitting in cold, snow-covered, and socially distanced bleachers with about 30 other player family members. It was 19 degrees Fahrenheit. I was sitting on an inflatable camping sleeping pad with my mom as 22 high school students ran around the field in front of us, each student using the exercise as a somewhat futile attempt to stay warm while endeavoring valiantly to score more points than the other team. Yet, as these athletes gave all of their attention to the game, my mind as a scientist and concerned sibling was drawn to one of the physical perils of competitive varsity football: concussions. As my brother is the star first-string outside linebacker and running back of his team, he ends up involved in tackles on either the receiving or performing side of things on nearly every play.

Concussions are an insidiously common type of mild traumatic brain injury (mTBI) that occurs when the brain rapidly moves within the skull as the head is subjected to rapid acceleration and deceleration. For example – during a football tackle. While advances in protective technology for athletes helps reduce risk, the risk is never zero. This injury can result in both immediate symptoms – pain, ‘seeing stars,’ confusion, headaches – and symptoms lasting weeks – headaches, confusion, and inability to focus. This begs the question, what is happening on a fundamental biochemical level to cause these symptoms?

Inside the brain

Once the initial impact causing the concussion occurs, a cascade of events altering the chemical balance in the brain takes place. First, instead of the typical highly regulated signaling expected in a normal functioning brain, nonspecific depolarization and initiation of axon potentials occur. This causes the release of excitatory neurotransmitters to be widely released throughout the brain at a scale not seen under normal circumstances. This leads to the efflux of potassium ions from the brain and severe ion imbalance, leading to extremely high activity of ATPase, an enzyme responsible for maintaining ion balance in neurons. Since ATPase is powered by ATP, the brain enters an energy crisis trying to restore the ion balance and burns through stored glucose reserves to meet the need. When glucose runs out, the brain switches to other sources of energy which causes lactate to accumulate in the brain. At the same time, the physical injury to neurons results in Calcium entry into the cells. While the ATPase will help rebalance the Calcium entry eventually, in the short-term Calcium entry results in sequestration in the mitochondria. This Calcium imbalance both impairs the mitochondria’s ability to be the “powerhouse of the cell” by interfering with ATP production, further contributing to the brain’s energy crisis, but too much Calcium activates calpain proteins which then initiate apoptosis, or programmed cell death, which results in the dying back of neurons in concussed areas.

Image source: Giza, C. C., & Hovda, D. A. (2001). The Neurometabolic Cascade of Concussion. Journal of Athletic Training, 36(3), 228–235.

Additionally, scientists are building on this understanding of what happens in concussion by looking at what small chemical messengers that modulate inflammatory responses called cytokines do to change inflammation states in response to injury. After the injury, glial cells called microglia and astrocytes become activated and produce Glial Fibrillary Acidic Protein (GFAP, a biomarker of brain injury) and both pro- and anti-inflammatory cytokines. Due to the existence of both pro- and anti-inflammatory cytokines, teasing apart the differences in how these factors change inflammatory responses is pretty challenging. Interleukin 1 beta (IL-1b) offers an excellent case study in the challenges and opportunities presented by cytokine study.

IL-1b expression patterns after injury show a gradual rise in expression levels, with expression levels directly correlating with the severity of the injury. Interestingly, IL-1b causes the release of ciliary neurotrophic factor (CTNF) and nerve growth factor (NGF), two hormones associated with recovery from concussion. However, IL-1b also stimulates the release of high levels of other inflammation-causing cytokines such as tumor necrosis factor-alpha (TNF-a), which results in toxic inflammation. Therefore, some suggest that interrupting IL-1b after it stimulates growth factor release but before it can stimulate pro-inflammatory cascades may be an effective therapeutic target. Cytokines are incredibly important in regulating neuroinflammation and have both anti- and pro-inflammatory properties, therefore, parsing apart the exact cytokines associated with triggering hyperinflammatory cascades and interrupting their signaling cascades could serve as a therapeutic target in the treatment of concussion.

Clearly, a pharmacologic intervention for concussion treatment is still years away from becoming a reality for athletes. Currently, the best ‘treatment’ for concussions is prevention through educating players, coaches, and parents of all sports on methods that minimize risks of getting a concussion such as proper tackling and running technique, as expertly demonstrated by my brother in his game. While my brother’s team narrowly lost on Friday night, no player got a concussion. So, while not as immediately satisfying as a win, I take solace in the knowledge that through coaching and mentorship, everyone walked away safely.

Uncategorized

Concussions and Tau: The Danger You Might Not See

Posted on October 27, 2020 by / 0 Comment

Well, this began as a foray into concussions and the damage that is caused behind the scenes. Now as an athlete myself, I understand the danger of concussions and know that proper handling of any type of brain injury is vital to the continued function of that brain as we know it. That’s why the direction my research took me began to scare me. As I looked more into the effects sub-concussive impacts, I began to see more ties and connections to various terminal diseases. At this point in time, to nobody’s surprise, I found CTE as a linked disease associated with this repeated trauma. But what I had not expected was that even “non-traumatic” contacts led to a connection to Alzheimer’s. Alzheimer’s is typically characterized by tau accumulations (which can lead to Neurofibrillary tangles) and β Amyloid plaques.

To skip a lot of nuance, a concussion occurs when axonal damage is inflicted. This axonal damage leads to what is called a “Neurometabolic Cascade”, which causes axons and their function to go haywire. One such issue begins with ion flux in a neuron, and results in the spreading of a depression-like state. There is the beginning of an energy imbalance, and ultimately causes mitochondrial dysfunction, and metabolism changes that are associated with losses in the ability to learn. Of course, these are important, and concussions are typically very closely monitored. What is often overlooked however, is the sub-concussive impacts. These sub-concussive hits will not damage axons, however they will damage the even more fragile microtubules, which in turn releases bits of it’s structural protein, tau. For the most part this tau is soluble, but where the problems occur is under certain situations, the tau can be phosphorylated, and form clumps which are now insoluble. As most could probably guess, this is most commonly seen in boxers. Shocker! However newer research is seeing the changes in tau levels in college athletes as well, and have seen a correlation between tau levels and the return to play time! At 6 hours after the injury, or the SRC (Sports Related Concussion), if an athlete’s plasma tau levels were above the threshold, it was consistent with a >10 day Return To Play protocol, whereas those who were under the threshold had an RTP of 3-5 days. While the biomarkers are monitored it is important to note that the RTP is still symptom based.

Where I am conflicted, is in my belief that this is a good thing for athletes. It is great we are seeing biomarkers, especially those which can be found in blood plasma and gathered relatively un-invasively. But that biomarker we are seeing we know is due to some sort of damage to the brain. Damage that releases a protein we can link directly to Alzheimer’s as well as CTE. While this may lead to an improvement in treatment, it is by no means a method of prevention.

Health

The Hidden Hinderance of Bilingualism

Posted on October 27, 2020 by / 0 Comment

As communities continue to be more and more diverse in their populations, the number of languages present increases as well. As bilingualism becomes more common in households across the world, the benefits of such a skill of knowing more than one language has come into question.

There is a theory, typically called the “critical period hypothesis” that states that children have an easier time learning and better benefit from learning a second language in comparison to adults. This theory follows the stereotypical generalization that the left brain is the “logical and analytical” side of the brain, whereas the right brain is considered to be “emotional and creative.” Though this has been disproven and is no longer a well-held theory in psychology and neuroscience, you still see it from time to time in generalizable situations.

For example, the “critical period hypothesis” states that children get more out of learning a second language because their brains are still developing, and synaptic plasticity is at a high. This is believed to allow children to learn the language on both sides of the brain and gain an emotional component to the language, where adults are believed to lean more towards a “left-brain” understanding of the language.

This learning of a second language tends to be localized to the dorsolateral prefrontal cortex which is also highly involved in executive functioning, such as working memory and flexible thinking. The learning of a second language is believed to strengthen executive function, and in turn be a neuroprotective factor of neurogenerative diseases, such as Alzheimer’s and dementia.

Though the idea of teaching a child a second language seems like a simple “YES” answer, there is a secret hinderance that has come into the light of research. With 1.4 million individuals experiencing a mild traumatic brain injury (mTBI) on a yearly basis with most occurring in the prefrontal cortex or temporal lobes, it definitely raises the question if bilingualism still shows similar neuroprotective factors.

According to Raitu et al. (2017), a bilingual brain is just as susceptible to the impaired executive function and cognition as any monolingual brain. Even if the neurons are strengthened by the bilingual brain they still undergo immense strain following an mTBI. This strain comes from the calcium influx, axonal injury, altered neurotransmission, and vulnerability to second injury from an energy metabolism crisis. Specifically, axonal injury and altered neurotransmission is believed to be at the root of impaired cognition and executive function following an mTBI.

Besides being just as susceptible to executive function deficits, bilinguals are also at an increase risk of language control deficits following a mTBI. One theory states that following a mTBI, languages return in a disproportionate manner with the one most frequently used at time of impact returns faster. Monolinguals sustaining one mTBI have not been mentioned to experience such a deficit.

This language control deficit coming from axonal injury raises a concern from the lack of myelination seen in younger children. Myelination offers a “cushion” to the axon, and a decreased volume of myelin on any neuronal axon can significantly impact the results of an mTBI.

To put it all together, if a child learns a second language during the critical period of development, it can significantly benefit them in the long run. However, they are at an increased risk of executive function and language control deficits after sustaining an mTBI, or concussion, due to lack of myelination on axons in their developing brain. This can impact the recovery time and “Return to Play/Learn”. This is not meant to discourage bilingualism, but to show how important it is to take head injuries seriously in children with their developing brain.

Photo Sourced From: https://mosaicscience.com/bilingual-brains/