CTE in a soccer player with no history of concussion

Football/Soccer/Scientist friends,

This is a landmark study (see Grinberg et al. (2016). It shows the confirmation of chronic traumatic encephalopathy (CTE) in the post-mortem brain of a soccer player WITHOUT any history of concussion. By the way, the player (though he isn't named) is almost certainly Hilderado Bellini - a legend of the game. Bellini won the world cup with Brazil and played for some of the premier Brazilian clubs of his time.

The no-history of concussion is important, b/c it supports the idea that subconcussive impacts in soccer may be sufficient to produce CTE. And, honestly, as an aficionado of the beautiful game, this is somewhat troubling.

Why is it troubling? Because for the longest time, I (and many) assumed that CTE would rear it's ugly head in the world of soccer, and while there have been some reports of possible CTE in soccer players (see Hales et al. (2014) , this is the first (to my knowledge) which highlights the history of no-concussion.

There are caveats to over-interpreting this study-

1. This gentleman was playing soccer in the 50s - a time where diagnosing concussions wasn't the norm. Therefore, it is entirely possible that he did experience concussions - but were never diagnosed.

2. This is one anecdotal report. It's possible that his CTE is independent of his history as a soccer player and that his CTE was consequential of some other genetic/environmental effect.

Why is this study relevant to soccer?
Subconcussive injuries are asymptomatic. Therefore, they pose a greater risk to athletes than concussions because they are impossible to diagnose. If the link between subconcussive injuries and soccer is confirmed, perhaps we need to have a serious discussion about heading.

Do we know for sure that heading leads to subconcussive injuries?
No, far from it. There's little evidence for it, except this one study that suggests that heading in amateur soccer players leads to abnormal white matter (the stuff that allows brain cells to send messages to each other) restructuring ( see Lipton et al. (2013)). But, this is far from confirmation of the above.

It is interesting to note that Bellini was a central defender - a position which involves the most heading in a game (I don't have data to support this, but, it would be fairly obvious to anyone that plays/watches soccer). Therefore, the repeated subconcussive injury issue is consistent with what we might expect.

As more and more soccer players donate their brains to science, I expect us to see an increase in CTE diagnosis. With the suicides of Robert Enke and Gary Speed - two well known, high profile, footballers, the interest in CTE was always going to rise.

I'm not sure what the long-term impact will be on soccer. But, we are at the beginning stages of raising awareness for what might be an insidious beast preying upon our beloved soccer-playing heroes.

Pubmed link: Link to original study

Day 3 - MicroRNA Monday

Usually Mondays are the worst. But, not today!! It's SFN!!!

There were quite a few microRNA posters I attended today. In case you might not know what they are, here's a quick synopsis of what microRNA are --

microRNA (miRNA) are short strands of RNA that modulate protein expression. To give you an analogy if proteins are lights in a room, miRNA are the dimmer switch. They don't turn the light on or off, but they help ensure that the light isn't too bright, or too dim. 

Here were the highlights of today's events ---

Morning session

1. Minano-Molina (C45) - Found that miR-92-3p, miR-181c-5p, miR-210-3p modulation in Alzheimer's transgenic mice.

2. Edler (C20) - Abeta and tau pathology increases with age in chimpanzees. Studies in primates are becoming rare - for ethical reasons. This study was done with primate brains donated by zoos and research institutions.

3. Bicca (C20) - TRPA1 levels in AD mice are changed - possibly via a response to oxidative stress.

4. DeVito (Z26) - This was my favorite poster of the day. 142-3p involvement in a mouse model of Multiple Sclerosis. They found that 142-3p knockout mice show reduced symptoms associated with the mouse model of MS. The target for this miRNA was the mRNA coding for GLAST (glutamate aspartate transporter). They also found that anti-miR-132 - administered via an osmotic mini pump) help reduce symptoms in the MS mouse. I enjoyed that their group covered the miRNA work from basic, in vitro predictions, all the way to in vivo administration of the miRNA. 

Lunch -

None. Not happy about it. Still.

Afternoon session

I presented my poster all afternoon. It was D25 - microRNA298 -  a dual regulator of proteins involved in Alzheimer's Disease.

SFN Banter

Met some people I have been interacting with on twitter. Remembered that I am incredibly socially awkward in large groups. Also, very jealous of those people who are able to walk up to strangers and engage them in conversation. You know - extroverts.

What did you enjoy about your Monday at SFN?

Day 2 of SFN - Crashing helmets on Stampede Sunday

Stampede Sunday, as I like to call it, was as packed as it is each year. 

There was lots of cool science to talk about and cool scientists to talk about it with. Here with the highlights ---

1. Hendrix (DD56) – Her aim was to raise awareness for her local “brain awareness day”. She was able to do by promoting via social media and designing flyers. She also talked about having visited Capitol Hill and talking to policy-makers about the changing funding climate. Basically, Ms. Hendrix is an advocate for both neuroscience and neuroscientists. We need more people like her. Follow her @RDHendrix.

2. Brager (DD38) – a fellow blogger, her poster showed that cryotherapy increases both the amount as well as the quality of sleep in athletes. Sleep remains an underappreciated area of neuroscience and I saw some other cool work looking at sleep disruption in rodent models. Brager’s work was particularly fascinating because it was in athletes; something many of us ex-athletes can appreciate. Basically - those ice baths are really, really important for recovery. And, if possible, a cryo chambers is even better. 

3. Whitesall (D31) – Working at the Allen Institute, Ms. Whitesall’s work looked at Default Mode Network (DMN) in the mouse brain. In recent years, the idea of the Default Mode – essentially, the baseline of your brain activity – has become apparent. It makes for both interesting science, as well as interesting science fiction. Whitesall’s work hypothesizes that the brain regions comprising the DMN may be one of the first to perturbed in Alzhiemer’s Disease. She will test whether this is true in an AD transgenic mouse line.

4. Kawarabayashi – Looking at tg mice models, they found that PrPc, Abeta mono and dimers, Fyn, NMDA, GSK3beta and pTau all localized in lipid rafts! This ties in both the possible involvement of lipid rafts in AD, as well as seemed to support the amyloid hypothesis.

5. Graham (C87) – Western diet in APP/PS1 mice increases A-beta load and TREM2 activation. TREM2 is the new baby in the AD field, and there will be a lot of work on it. And, as for western diet, STOP BEING SUCH FATTIES, YOU GUYS. And, by you, i mean, me.

6. Brkic (C86) – Omega-3-Fatty Acids have beneficial effects on brain of AD mice – by reducing amyloid plaque burden. There was recently a longitudinal study that determined that fish oil showed no benefit for cognition in AD patients. Brkic informed me that she thought that study was done with patients who has advanced AD, and therefore, an amelioration of symptoms would have been lost in the noise of progressed neurodegeneration. I agree with her. Most AD therapies should be looking at helping decelerate the pathology in mild cognitive impairment patients, in my opinion.

7. Colello (C91) – This was my favorite poster of the day. Their group decided to address the issue of the g-forces experienced by helmet to helmet collisions in football players. They posit doing so by placing repulsive magnets in the helmet of players. This would lead to the generation of a repulsive force that would reduce the g-forces. Their proof of concept suggests that they are able to reduce g-forces (measured by accelerometers) in a rig where they are essentially crashing two helmets together. This is fascinating work! And, a perfect example of how invention often come from people who cross disciplines.

Lunch

All the places close by were closed! Stampede Sunday is the worst. I ate a sandwich from a grocery store. It was awful.

Afternoon sesh

I spent the entire time presenting the boss-man's poster.

What were your highlights from today? My poster is tomorrow (Afternoon session, D25). Stop by and say hi!

The tangles of tau - breaking down highways

In a stereotypical brain from an Alzheimer's patient, there is the presence of amyloid plaque and tau tangles. We have already covered amyloid deposits in a previous post. Today, we will be discussing this tau thing. What is it? And, what the heck does it have to do with Alzheimer's Disease?

What is the link between Alzheimer's Disease and tau protein?

Post-mortem brains from Alzheimer's patients often have tau tangles (also called neurofibrillary tangles. The pictures below shows a magnified version of what these tangles look like (tau tangles are on the right, amyloid deposits on the left).

Image taken from bigthink.com

What are tau tangles aka neurofibrillary tangles?

These tangles are composed of a bunch of abnormal tau protein stuck together.

What is tau? why does it clump together during Alzheimer's Disease?

In order to answer this question, I think we should first go over what microtubules are. Microtubules allow the transport of materials across the neurons.

Here is an analogy - if your neuron is a city, then microtubules are the roads. You see, your neuron is constantly making stuff that it needs to send to different parts of the cell. One way to do that would be to simply make something and let it diffuse through the cell. But, this would not be very efficient. Therefore, the cell sets up it's own roadways in order to keep delivery organized and efficient.

Here's the really neat thing. These roadways are entirely dynamic! If the cell is done sending one protein to one part of the cell, it can send workers to that road and break down that roadway.

From Nature Reviews

And this is where tau becomes important. You see, what tau does, it helps the workers know whether or not to break a highway down. Sort of like a beacon to say - this road needs to stay!

Microtubules - the roadway of cells. (Image taken from absoluterights.com)

What happens to tau in AD?

Tau gets hyperphosphorylated in AD.

Wait, stop using big words, you showoff. What does that 'phosphorylation' mean?

Phosphorylation occurs when a phosphate group is thrown onto a protein.

Every protein in every cell of your body is under tight control. This is because, evolution has ensured that every protein can be made, destroyed or made to disappear as the cell needs it. Phosphorylation is one of these regulatory processes. By throwing a phosphate group onto a protein, you can change what that protein is doing.

Okay, what does phosphorylation do to tau?

Well, here's the weird thing about tau, it can exist in three forms---

1. Unphosphorylated - this is the form we have been talking about - when this form is present, the cell knows that that roadway needs to stay.

2. Phosphorylated - This is the green signal for the roadway to be taken apart. Let me reiterate, that this is normal. This phosphorylation-unphosphorylation allows the dynamic rearrangement of the roads in the cell.

3. Hyperphosphorylated - This is bad news bears. This is when the tau starts to misbehave and clumps together.

Okay, this is getting too sciency again. What are you even talking about?

Here's the gist so far - Tau is important to maintain normal function in the cell. During Alzheimer's this protein gets too many phosphate groups put on it. This makes the cell lose a bunch of it's roadways for no good reason.

And, what's worse is that all that hyperphosphorylated tau starts to clump together and form those aforementioned tau tangles.

What do these tau tangles do that's so bad?

Just like the amyloid plaque story, this isn't so cut and dry. Many believe that these deposits lead downstream to neuronal death. And, as we've discussed earlier, neuronal death is a key component of the cognitive issues in Alzheimer's Disease.

Is there a link between this tau stuff and the a-beta stuff?

Yes, there have been many studies that show that a-beta can actually lead to tau hyperphosphorylation (the bad version of tau). There are also a small number of studies, that are studying whether the converse is true - that tau can affect a-beta production.

Can we reduce this hyperphosphorylation?

There have been attempts to target the things that regulate the phosphorylation of tau. These have had limited to no success.

Okay, I'm bored. Summarize this.

Okay, here goes. Tau itself is not bad. The neuron needs it. But, for reasons that remain unclear, tau converts to a form (hyperphosphorylated). And this form arguably leads to cell death. And that, in turn leads to the tau tangles we observe in the brains of Alzheimer's patients.


Let me know what you guys think. Did anything still seem confusing? Please reach out to me at @AlzBlog101 or @NipunChopra7 .

What is Alzheimer's Disease - defining some key terms

Everyone has heard of Alzheimer's Disease. Whether it is because someone you know has suffered from it, have read about it, or are trying to impress a lady with your knowledge of The Notebook (Admit it, gentlemen, we only pretend to enjoy that movie).

But, what exactly is this disorder? We will cover the diagnoses and underlying pathology in future posts. Today, we will focus on a definition of the disease, along with explaining a few key terms that are integral to all future posts.

So, let's get to those key terms. Now, all of you fall under two categories here -- 

1. If you are a neuroscientist, or have taken graduate level biology, most of this might seem redundant to you. But, I would appreciate you reading through this any way, to help critique my explanations and analogies. 

2. If you have always wondered what these terms meant, I hope I can shine a light on their meaning.

Neuron - These are cells in the brain. They are responsible for all your emotions and your memories.  Depending on where in the brain they are located (there are different brain regions responsible for different functions) or what type of neuron is present (there are different types), they contribute to why you think - "Ryan Gosling", every time you hear the word "dreamy". Or, you scrunch your nose, every time someone brings up yogurt (seriously guys, yogurt is disgusting). Neurons are the minions that facilitate everything you consider to be a feeling or a memory. 

In a certain part of the brain, called the Hippocampus, there are neurons that allow for the formation of new memories. During Alzheimer's Disease, this is one of the first regions to be affected. What does it mean to be affected? The neurons in this brain region die. Why is this relevant? Because, unlike cells in other parts of our body, neurons do not divide. Therefore, once a neuron dies, there will not be another one to replace it. And the relevance to memory? Well, theoretically, if you've lost a neuron relevant to a memory, you've lost that memory, or the ability to make a new memory. 

If the brain is an engine, and different areas of the brain represent different engine parts, neurons are the nuts and bolts that enable everything to work. 

Receptor - A gateway for communicating with neurons. Think of the cell as a fortress. A receptor is the draw bridge which allows communication with the fortress. Either by allowing a visitor in, or by relaying the messages of the visitor to the people inside the fortress.

Dementia - This is a loose term that is often misinterpreted. Dementia refers to a state in which normal brain function is impaired. Memory loss (as seen in Alzheimer's) is a subtype of dementia. Alzheimer's Disease represents the most common form of dementia in the adult population.

Memory - What is a memory? The ability to recall something. How are memories made? Well, we have a pretty good idea of the mechanism and brain regions involved. Where are memories stored? We know certain brain regions are important for making memories vs storing memories. Where is the memory of the lyrics to Taylor Swift's album stored? We could figure out the general area by hooking you up to a fancy machine, but here the pictures gets hairy. Suffice to say, memory formation/retrieval/consolidation/storage remain one of the key areas of research in neuroscience. What we do know is that Alzheimer's Disease involves impairment of memory processes.

Neurodegeneration - a process during which neurons progressively continue to die. Much like the progressive collapse of well-set dominoes, once this process starts, neurons continue to die over time, and there is very little (currently) we can do about it. What starts neurodegeneration in Alzheimer's Disease (Or, using our analogy, what pushes the very first domino?) ? We will visit this controversial question in future posts.

So, what is Alzheimer's Disease?

This disease, first characterized by Alois Alzheimer (hence the name) is a disorder in which neurons in key brain regions die. This results in the initial symptoms of memory loss and eventual death. Interestingly, patients of Alzheimer's Disease do not die of the disorder, per se, but it is usually the diseases associated with Alzheimer's (Pneumonia, for example) which is the direct cause of death. 

Alzheimer's Disease is an incredibly prevalent form of dementia in the elderly. And, as our sanitation, medication and standard-of-living continue to improve, the number of people suffering from it is only expected to increase. 

Please let me know if there are specific areas you would like for me to cover. You can reach out to me on twitter at @NipunChopra7.