Aducanumab update

Recent work (Sevigny et al (2016)) has been making the rounds on social media. I have seen exaggerated headlines such as "New drug that halts mental decline.." and "A cure for Alzheimer's" making the rounds.

So, what's the dealio, yo? Have we done it? Have we cured Alzheimer's? Let's get into the facts here ---

1. What's this drug called?
Aducanumab - it's marketed by Biogen.

2. How does it work?
This is a drug that targets aggregated beta-amyloid. (Click here for my review on amyloid).

3. How is it different from other drugs that have been tried?
Well, for one, it isn't a "drug" per se. It is an antibody which targets the aggregated beta-amyloid.

4. What's an antibody?
An antibody is something all our immune systems generate to fight off infection. Think of it as your Superman to a Lex Luther. An antibody's role is to identify bad stuff, bind to it, and neutralize it's threat.

Up, up and antibodyyyyy (I'll show myself out)

5. Okay, so what did the study find?

The study found that in one year, patients who were given aducanumab showed less of the amyloid burden than placebo (not given the antibody). And, rather excitingly, this was a dose-dependent effect.

6. What's a dose-dependent effect?

It's a fancy way of saying, the greater the amount of aducanumab given, the better the patients seemed to do.

7. What did they measure?

They looked at amyloid in the brain as well as behavioral symptoms. Both improved dose-dependently with aducanumab.

8. Does this mean anyone suffering from Alzheimer's would benefit from this drug?

Not quite. The effects seemed most pronounced in those who were in early stages of AD?

9. Is this a cure for AD?

Too early to say. The sample size of this drug trial was small. Biogen is currently conducting Phase III drug trials (~1500 patients). Those results will become available in 2021. Also, important to note that the effect was in early stages of AD. 

10. Why the hesitation, bro?

We have been here before. other drugs showed promise in Phase I/II trials only to show no effect in larger trials. Also, don't call me bro, bro.

11. So what's the takeaway?

Very promising data. But, if someone tells you that "they found a cure for Alzheimer's", tell them that statement is still premature.

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

Hallucinations and delusions in Alzheimer's disease?

When most people think of psychosis -- hallucinations and delusions -- the image that comes to mind is of a person with schizophrenia.

In fact, modern research suggests that psychotic symptoms are prevalent in many disorders and even appear in non-clinical populations. Individuals with Alzheimer's disease have an unusually high rate of psychosis, with best estimates putting the figure at over 40%. 

With a prevalence rate that high, you'd think that psychosis would get more attention in the literature on Alzheimer's. When these two conditions appear together they tend to cause particular difficulties in functioning and contribute to unusually high levels of caregiver burden, even by the standards of this already challenging disorder. 

However, the phenomenon gets little attention when compared to other commonly co-occurring symptoms. A Google search for "Alzheimer's psychosis" currently yields 500k hits, whereas "Alzheimer's depression" gets nearly 100 times that number at 40 million. The academic literature shows a similarly extreme imbalance.

The neglect of Alzheimer's and psychosis in research and in the media has had consequences. The FDA has yet to recognize any approved drugs for the treatment of this condition, and unlike the copious amounts of lay information available to family members interested in helping their loved one's handle other complexities of alzheimer's such as agitation and depression, there are few resources available for public consumption that address psychosis. 

I wish I could end this post with "a few simple tips" for family members and loved ones of people suffering from Alzheimer's and psychosis. There is some information out there, including limited scholarly work. But the truth is that the field simply has not gotten that far. Moving forward, we owe it to our patients -- and to our field -- to take a harder look at psychosis in Alzheimer's and how to help people more effectively.

Artificial turf and soccer

Before I start writing out whether or not playing soccer on artificial turf (AT) leads to injury, I have to admit that this was a real learning experience for me. For years, I've been convinced that playing on turf leads to higher chances for injury. So much so, that I repeated that on at least three radio shows last summer, during the women's World Cup.

But, that's why I love science. It proves me wrong all the time, and reminds me about how little I really know. It's humbling, wondrous and informative.

Just like my recent blog post on heading and youth soccer, I will be linking to the abstract of various articles. If you would like access to a particular paper in it's entirety, tweet me at @AlzBlog101 and I would be happy to send it to you.

1. What is Artificial Turf (AT)?

It's a playing surface used for sports such as field hockey, soccer, american football, etc. AT is made of synthetic fibers that look like grass. However, for countries where maintenance of natural grass is problematic due to non-ideal temperatures, AT has proven to be an alternative.

2. How did the idea that AT leads to increase in soccer injuries start?

While there were probably anecdotal reports, the first study that examined this issue was Arnason et al. (1996) . They found that the propensity for injury increased on AT vs natural grass.

3. Were the Arnason results replicated by other studies?

No. There have been many studies that suggest that there is no difference between injury risk of AT vs natural grass. These can be found here --- Ekstrand et al. (2006), Steffen et al. (2007), Fuller et al. (2007), Aoki et al. (2010), Bjorneboe et al. (2010), Kristenson et al. (2013) .

In essence, almost all studies suggest that the risk for injury does not increase for athletes playing on artificial turf. It's important to note that the studies cited above cover the gamut from NCAA soccer players to professional footballers - both male and female. So, there isn't a bias in terms of the level that the game is being played.

Here's something even more surprising. There have been studies that suggest that playing on artificial grass may be linked to LOWER injury rates than natural grass. Those can be found here --- Ekstrand et al. (2006), Soligard et al. (2012), Williams et al. (2013), Almutawa et al. (2014), Meyers (2013).

4. Okay, so playing soccer on AT is better than on natural grass?

Not so fast. You see, the articles cited above look at injuries as a whole. It's still possible that there are differences in particular injuries. A good analogy is that the articles above are looking at the injury issue at a whole-forest level. Whereas, in order to understand the risk for specific injuries, we have to go down to the tree-level.

5. Have there been studies that look at specific injuries in terms of artificial turf?

Yes.

6. What did they find?

The big one is that AT seems to be bad news bears for your ankle! Ekstrand et al. (2006), Steffen et al. (2007), Ekstrand et al. (2011) all found that playing on AT leads to an increase in ankle injuries in soccer players. For the sake of completion, it is important to note that Soligard et al. (2012) found the opposite - a reduction in ankle injury in soccer players playing on AT.

Hagglund et al. (2011) found that there was no difference between AT and natural grass surface for risk of patellar tendinitis (that's a fancy way of saying pain caused by inflammation in the knee).

Ekstrand et al. (2011) found that male soccer players were less likely to have a quad injury when playing on AT vs natural grass.

7. Woah! Getting too much. Summarize this for me.

Essentially, there is no increase in overall risk for injuries when playing on artificial turf vs natural grass; in fact, some studies suggest that it may be better overall than grass. However, there's general consensus that playing on AT may be a risk factor for ankle injuries, in particular. So, watch those ankles, friends!

8. So why does this myth about AT persist?

There are some general reasons - such as the naturalistic fallacy - where people believe that just because something is natural, it is automatically better than something synthetic or artificially manufactured.

Another reason is that we tend to extrapolate results from other sports into soccer. A perfect example of this is comparing football injuries to soccer. Both can be played on AT and therefore, when we see a study that suggests that injury X is increased in football, we assume incidence of injury X is also increased in soccer.

However, the sports are drastically difference and this assumption isn't necessarily true. For example, Balazs (2015) performed an examination of the literature, and found that playing on AT results in an increased risk for anterior-cruciate ligament (ACL) injuries in american football, but not soccer players. Therefore we should be careful to not over-interpret data seen in other sports played on AT.



So, lesson learned from my perspective - always fact-check everything. Especially things that I "know" are true.

Heading in youth soccer: what the science says

Recently, the United States Soccer Federation (USSF) released a report advising the elimination of heading in soccer for kids under the age of 10. And recommends that full-contact heading not be allowed till athletes get to 16 years of age.

Now, while everyone is on board with the idea that player safety is very important, particularly that of children and young adults, there has been much debate over whether the guidelines would benefit athletes and soccer in the long-term.

Let me start by saying that I believe that concussions in soccer are a serious, serious, serious, serious, serious, serious, serious concern. Is that serious enough? I believe that concussions are currently being managed incorrectly by the Football Associations and FIFA. And that things need to change rapidly so that our soccer players can live a healthy life after they retire. However, today, we will be focusing on the topic of concussions in youth soccer players.

While one can have a myriad of personal opinions on this topic, and certainly, I do, too (I'll discuss those later), the majority of this post will look at what the scientific literature says re: Heading in youth soccer. I understand that many do not have access to the articles I'm citing here, so I will link to the abstract (which is available to all), and if you are interested in a particular article, tweet at me, and I'll send it to you.

1. Can heading the ball lead to concussions in high school players?

Yes. It isn't the most common form of concussive injury in youth soccer players, but, it is certainly possible (Cornstock et al, 2015 ). However, what this study does not look at  is HOW those ball-to-head related concussions were procured. That is a key caveat to this study.

There is another study that suggests that zero concussions were produced by heading the ball correctly, and all were a result of the ball striking an unprepared player at close distance (Boden, 1998) .

2. Can heading the ball lead to concussions in youth soccer players?

Doesn't seem like it. Here's a key excerpt from a book chapter  ---

"Dr. Kirkendall . . . calculated the impact of a soccer ball on the head of youths of various sizes, based on the likely speed of the ball, and concluded that the force of impact is well below the force that is thought to be necessary to cause a concussion in heading a soccer ball." --- Dr. Donald Kirkendall, Causes of head injuries in soccer .

Even in U14's soccer, there is likely not enough ball velocity to cause concussion (Hanlon and Bir, 2012) .

A meta-analysis (looking at various studies between athletes 10-24) suggested heading the ball was unlikely to cause injuries (Pickett et al., 2005).

Essentially, those kids do not kick the ball hard enough to cause the G-forces (acceleration forces) to result in concussive injuries.

3. What about subconcussive injuries from heading?

In order to answer this, a quick primer on subconcussive injuries: It is an emerging area of research that suggests that repeated impact to the brain can result in brain damage, even though concussion hasn't occurred. The problem with studying subconcussive injuries is - how do you tell if someone has one? Neuroscience tackles this in a couple of ways. Firstly, we have identified certain biomarkers (biological red flags) to suggest if someone is exhibiting hallmarks of disease. The second technique is to look at behavioral tests that suggest whether someone is cognitively impaired. The assumption being, in both cases, if subconcussive injuries have occurred, there will be a biological (biomarker) and/or behavioral (neurocognitive) change.

Coming back to the original question. Most literature suggests that heading the ball does NOT lead to changes in biomarkers/neurocognition. These can be found here --- Kontos et al. (2011), Stephens et al. (2005), Kaminski et al. (2007), Broglio et al. (2004), Guskiewicz et al. (2002) and others.

But, this study, does suggest that a cognitive change may occur - Zhang et al. (2013) . I have to state a caveat - this Zhang study is poor. The effect size (how different the soccer-playing and non-soccer-playing groups were from each other) is very small. For my science friends - they set a non-one sided gaussian t-test alpha of 0.1, which is an immediate red flag. For my non-science friends - I think the effect they observe is not worth believing.

4. Okay, that's a lot of words. What's the gist?

Currently, a preponderance of the literature does not support the idea that heading the ball leads to subconcussive injuries in youth (kids - high school) soccer players.

5. Is that a definitive no then?

Not quite. You see, the work surround subconcussive injuries is nascent. And, as such, has caveats. For example, some of the behavioral tests and biomarker tests need further validation. Therefore, it is theoretically possible that subconcussive injuries ARE occurring, but our tests aren't well enough designed to detect them... just yet.

6. What about the report of the kid who almost died after heading the ball?

That's a real report. That happened a few years ago, and no one has contradicted the young man's claim that his subdural hematoma (potentially fatal bleed in the brain) was the result of a single header (Lutfi et al., 2009). My concern is that the report says he headed the goalkick with the "front" of his head. I am not sure if this means with his forehead (which would be the correct way to head the ball), or with the top of the head (incorrect, and unfortunately seen in young soccer players who haven't practiced heading).

7. What about player to player contact?

Yes, this often is the culprit for concussions. Most of the articles I've linked to above suggests the same. These injuries can be a result of two players going for a header, or accidental contact with one player's knee, while the other is on the ground, etc. There are a myriad of ways that player to player contact can result in head injury and concussion.

Head to head injury is a serious concern

Okay, now we are going away from the realm of scientific literature into my own opinion (using the literature I've read as a basis, of course)

8. So, what's the solution?

In my opinion, there should be a serious punishment for serious player to player contact. In the last 3-4 years, the concept of "out of control" tackling has come into play.

You see, while I was growing up, the definition of a good tackle was "getting the ball". If a player got the ball before he made contact with the player, it was deemed a good tackle - regardless of whether this involved excessive force or injury to the opposing player. However, now, even if a player wins the ball, if he comes in with excessive force, tackles from behind or uses two-feet, the referee usually punishes the tackler with a red card (FIFA, law 12) . Why? Because all of those conditions are optimal for causing injury.

Similarly, excessive force, using elbows, out of control contact with an opposing player's head (knee-head, for example) should be deemed dangerous play, and therefore a red card. This would result in players being careful of so-called 50-50 balls, and wary of using their elbows as leverage.

9. But, what about heading itself?

I respect people's opinion who think "well, removing heading in youth players won't hurt". But, in my opinion, having young kids learn how to head the ball early would lead to developing the appropriate neck muscles needed (Gutierrez et al., 2014) to prevent head injury in the future. If heading the ball isn't being introduced to them until they are 14, this may lead to an INCREASE in the number of concussions. Because, by the time they're 14, they are kicking the ball much harder, and have yet to learn the basics of heading.

Incorrect way to head the ball. (Image via http://hubpages.com/sports/Soccer-Head-Injuries-in-Children-Brain-Damage-from-Heading)

10. To summarize:

1. Preponderance of scientific literature does not support the idea that heading can lead to concussions or subconcussive injuries in soccer players.
2. More work needs to be done.
3. In order to minimize concussion, new rules regarding player contact need to be made.

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!