ORIGINALLY POSTED 11/12/15

On Nov. 12, 2015, I had the pleasure of interviewing Dr. Patrick Hof who the Regenstreif Professor and Vice Chair of Fishberg Department of Neuroscience at Icahn School of Medicine at Mount Sinai in New York. I wanted to ask Dr. Hof if his 1990’s paper on an autistic 24 year old female could have been the second case of female CTE. This paper stands as one of two papers written as of 2015, on the female brain and possible CTE. The punch drunk wife - is the other case.

Katherine: Hello, Dr. Hof, I really appreciate your time to talk about your case which I think might be one of two cases in published of CTE in women.

Dr. Hof: It's my pleasure.

Katherine: I wanted to ask to you more about the story behind your paper...

because I am producing the National Summit on Female Concussion and other TBIs on February 27, 2016, at Georgetown University School of Medicine. One of the topics I want discussed is any cases of CTE found in women's brains. From my research on the topic, there is only your study and one other paper which could possibly be CTE.

Dr. Hof: Yes, there is very little done in women. I wonder whether we will soon have some information coming from servicewomen from the military. That's something that in fact Dr. Dan Perl might be in a position to answer better than I can.

Katherine: I wrote to him, so I am hoping but I think that's incredibly important to include any female data from the military.

Dr. Hof: Yes, absolutely. Other than that, from the sports world, it's really all male-dominated. Incidental cases may exist, but they have not been reported necessarily. I wonder if the original pathology series from Corsellis of the 70s in UK had actually a few women in there, but I really don't know. My case was kind of a bizarre situation. This was a patient with a very severe form of regressive autism.

Katherine: Hers is a tragic story.

Dr. Hof: Yes. She had these absolutely terrible fits of self-injurious behavior for most of her life, to the point that she was blind due to corneal scratching, and her skull had deformities. At 24 years old, she had a few neurofibrillary tangles interestingly in the amygdala, which in CTE is one of the primary area for early accumulation of tau-positive lesions. We see these in athletes, principally football players, and we see that even in the brain of relatively young players who unfortunately died. The amygdala is always affected. It is an area that seemingly has an increased vulnerability to the early stages of the development of the disease.

Katherine: Was her autism something that could be seen in the structure of the brain? Were there other abnormalities in her brain, organically caused damage or any other another reason but the trauma for finding tau in her brain? Overall, was the only thing abnormal in her brain the tau accumulation?

Dr. Hof: Yes. Other than that, it was really not much to be seen in this case. Frequently in autism you don't see something in the brain that permits you to say, "Okay, this is a patient with autism."

Katherine: Autism is all functional? The brain’s internal wiring?

Dr. Hof: Yes, you really have to look at fine-grained details at the distribution of certain types of neurons and the presence of dysplasias - when neuronal dysplasia occur. There is otherwise nothing jumping at you. If you look at the brain of the patient, it does look generally normal. If you look at my Figure 1, it had a cavum septi. That is something that you see frequently as a marker of repeated brain trauma. You see that in boxers very frequently.

Katherine: Which would be a sign of being "punch drunk?"

Dr. Hof: Yes, it's part of the punch-drunk syndrome. For a 24 year old, at death her brain was small. This is possibly conditioned by the fact that she had such an intense intellectual delay and that the brain possibly never really developed. But if you look at the morphology of the brain, there is nothing jumping at you that says it is frankly abnormal, besides the cavum septi and small size.

Katherine: Is there a way to compare the damage in her brain to a boxer who died in his 40s?

Dr. Hof: There is. First, there is that clustering distribution of lesions. Her brain was very, very comparable to what we see in the brain of professional athletes. Lesions that frequently center around a penetrating large vessel, that is very, very comparable. Lesions frequently occurring in the upper layers of the cortex rather than the deeper layers, so a distribution of tangles that is different than what we see in other neurodegenerative disorders like Alzheimer's disease.

Katherine: So you can rule out Alzheimer's in her case?

Dr. Hof: If you look at Panel F of the second figure in the paper of her brain, this is pretty typical of what we see in an NFL player. At the upper right, you can see the end of a sulcus, so it's really in the cortex, at the deep point of the sulcus. That's where these clusters, these nests of lesions occur the most, and they occur around a blood vessel or in the close vicinity of a blood vessel.

Katherine: Is that the place where she actually hit her head? Does it relate to where she hit her head or is it a chemical change that is happening in that part of the brain?

Dr. Hof: It's probably the result of mechanical stressors due to the head banging. She hit her head principally on the frontal part. She hit her skull and maybe sometimes in lateral movements, but mostly it was a frontal type of banging.

When you do that, it's like being repeatedly punched in boxing. The brain moves inside the skull and is displaced, and the blood vessels that vascularize the brain move differently than the brain tissue itself. A blood vessel can literally slice through part of the tissue. Then you have tissue damage. Then you have inflammation. Inflammation can induce all sorts of molecular cascades that then lead to the accumulation of abnormal proteins like tau.

We think this is part of what's happening. In this nest of lesions here we see the tangles and a few neurites. There is a lot of other things in there. There are microglial cells, the brain’s macrophages. There are astrocytes that are reacting to that entire abnormal local environment and secreting chemical factors. We do not have a clear idea of what they all are, but they can produce neurotoxic environment.

Katherine: It's a whole cascade of one chemical setting off another reaction. Each builds upon itself and creates a chain reaction?

Dr. Hof: Exactly.

Katherine: Let's say she only banged her head on the left side, so she bangs her head for ten years on the left side but not on the right side. Would you think that tau would only be on one side of the head or is it the brain is moving back and forth so it's the actual motion of the whole brain, so it would be evenly distributed?

Dr. Hof: It would probably be evenly distributed because it's really the motion of the brain in the skull that eventually matters.

Katherine: Right. That's the problem with all of these helmet pads that are being marketed to kids and parents. They keep talking about how if you pad the outside of the skull, it's going to keep the brain from moving.

Dr. Hof: That is absolutely untrue.

Katherine: You are the author of one of two papers I have found that have looked at females. How many other female brains have you looked at that didn't have CTE?

Dr. Hof: I have seen a couple of autistic patients, female, and they didn't have any head trauma or anything like this. Females with autism are rarer than boys, so we have very few brains post-mortem of girls with autism. Other than that, I have never had a chance to look a female adult with a brain trauma. It's rather rare to come across brains like that.

Katherine: The reason that you looked at her brain was because she had an extreme case of autism, so were you surprised to find tau lesions?

Dr. Hof: Absolutely. That was a big surprise that we actually found lesions in there. What happened is that we were looking at the pathology in brains of boxers at the time because we wanted to see whether the distribution of lesions would be comparable to that of Alzheimer's disease. It was known that there were tangles in there, but no one had actually looked at the distribution in the cerebral cortex because neuropathologists usually do not report the distribution of lesions with cell-specific or layer-specific details as part of their diagnostic assessment, which is based on the presence or absence of lesions, and their apparent local densities. It's however really important to know what neurons are affected in terms of what circuits would be affected.

Katherine: So it’s like the difference of looking at a satellite picture and just looking from above at the surface of earth, as opposed to the side view when you are looking at each layers of the Earth and can identify one particular layer as deeper than another?

Dr. Hof: Exactly. The outer layers of the cerebral cortex will project more to other parts of the cortex. The deeper layers will project more to structures that are below the cortex, the subcortical structures. It's a different type of connectivity, and it's a completely different type of function.

Katherine: Wow, that's so amazing.

Dr. Hof: In the case of Alzheimer's disease, the lesions are pretty much equally distributed across superficial and deep layers with a little bit more, in fact, in the deeper layers and with regional differences, as well. In many other neurodegenerative disorders, you have the inverse pattern with more lesions in the upper layers of the cortex.

We started to think really that this other type of dementia because boxing encephalopathy was known as dementia pugilistica, really involved different elements of the brain circuits from the ones that are affected in Alzheimer's disease. We started to look at boxers to see where the tangles would preferentially be, and we came across that very particular case and thought, "She was banging her head. Maybe she has tangles." Sure enough, we found them. They are more in the upper layer, which turned out 20 years later to be comparable to what we see in people with CTE. It's really fascinating.

Katherine: Would you say she definitely had CTE?

Dr. Hof: Yes, I think she did have CTE. That's completely compatible with the diagnosis.

Katherine: Right. Could you republish the paper as a case of CTE?

Dr. Hof: I don't know that I can republish it, but I can certainly feature it and say that in fact, this case is a CTE case in a young adult with autism due to self-injury behavior.

Katherine: I just think it's so important. In February 2015, I asked Dr. Bennett Omalu if he had ever seen CTE in a female and he hadn't, but he knew of your case. I couldn't find your paper because I kept looking for the key word, CTE. Two weeks ago, I asked Dr. Ann McKee if she knew of the paper and she sent me a copy of two papers. The other paper has "punch drunk” in the title.

Dr. Hof: Yes. The only term in my keywords is head trauma.

Katherine: Had you read the 1989 study "Dementia in a Punch-Drunk Wife," in the Lancet?

Dr. Hof: I had read it, but at the time I was actually working on the paper.

Katherine: The author of that papers is Dr. G. W. Roberts. Do you know of anybody who has seen, wrote about anything about female CTE, other than these two papers?

Dr. Hof: I don't think there has been anything else, quite frankly.

Katherine: Don't you think it tragic so few female brain have been examined?

Dr. Hof: It certainly points to a lack of knowledge in a rapidly growing field and something that should be addressed.

Katherine: I'm so grateful for you to actually have put this on the map. Are you interested in presenting about it?

Dr. Hof: Yes, sure. It's something we can do.

Katherine: I would love to have you present this case and include the paper in the summary of the conference to build a database of gender/sex related concussion and TBI cases. In my research of females athletes' experience of concussion, 39% of the female athletes felt they showed signs of cognitive change and 25% of behavioral change. The long term effects of concussion seem to be of concern to them. The average number of concussions that these women had was eight.

Dr. Hof: Yes, but there is no reason it should be different from what the male athletes are exposed to. There is something as women's rugby, and that cannot be good.

Katherine: That's the problem because the girls are getting so many concussions. They love the sport, but they are getting so many concussions that they are not able to play through high school. It's really important to me to encourage women playing sports, but what I am pushing for is a different protocol for women. Should women after a concussion, if the average man returned to sport in 8 days, maybe the average woman returned to play 16?

I think we need a protocol based on gender. The best test case I have is Tim Kelly. He's the athletic trainer for West Point. He finds his female cadets take twice as long as his male cadets to come back to sports. If you think about a West Point cadet, that's the top level U.S. Army, totally conditioned soldier. You can't say those female cadets want the attention of taking twice as long to recover as the males, right?

Dr. Hof: Yes.

Katherine: Now Dr. Bennett Omalu's off-the-cuff hypothesis as we were talking at a conference in California was that he took a guess that we might find less CTE in women. He wondered, "Maybe female brains take longer to heal because they heal more efficiently?"

Dr. Hof: That needs to be established by an in-depth study. It can be only a prospective clinical study at this point. A population of athletes has to be enrolled in that, and eventually these people will have to be followed by brain imaging with MR and PET.

Katherine: I have pledged my brain to … (updated in 2021) LE-TBI Project at the Mount Sinai Brain Bank. I've had double digits concussions. I have been trying different social media campaigns to encourage women to signup to donate their brains after they die. Any woman who participated in my survey two years ago had the option of requesting more info about brain donation. I really want create a national campaign for women to donate their brains upon their death.

Dr. Hof: Yes, absolutely. The brain donation is a fundamentally important part of the whole thing. We are doing this in the context of autism and really trying to do a massive outreach at the national level currently to encourage families when there is a death to consider brain donation.

Katherine: Do you find that people are squeamish about it? I feel like people are so good about donor organs like eyes, but when you start talking about brain, there's something about the brain that I think makes people hesitate.

Dr. Hof: There is. There are a number of issues. First of all, brain donation is not like organ donation because organ donation you see almost an immediate benefit for someone else. You can give a liver and someone is going to be a lot better after, so there is something almost rewarding in that process based on that.

Katherine: Wow, I never thought of that.

Dr. Hof: The brain, you are going first of all to open the skull of the dead relative and take that stuff out which is then going to float in a jar full of chemicals prior to being dissected. It has a gigantic ick factor, and people are squeamish about it. In fact, brain donation and organ donation, from the point of view of consent, are completely separate processes.

Katherine: Yes, this is a problem.

Dr. Hof: People don't realize this and may think the brain donation is just part of organ donation but it is different. The brain is dead. The organs we maintain and put in a living person. It's a very, very different concept.

Katherine: Dr. Bennett Omalu told me he is studying right now suicides in young men and traumatic brain injury. He said he can look at brains if they've been embalmed up to two or three years.

Dr. Hof: Yes. You can do a limited amount of things, but from the pathological point of view, it's sufficient. For more sophisticated studies that gets really, really limited. For the type of thing that we would really do today you would take part of a brain frozen, part of a brain fixed to study the type of cellular microscopy and use the frozen to study genetics and gene expression patterns in the tissue, even at the single cell level resolution, really to crack down the molecular mechanisms of the pathology. That's where human brain donation becomes fundamentally important because that's not going to be necessarily modeled so accurately in a laboratory animal.

Katherine: Yes, and study both male and female brains. I know from the animal models that most of the people that I've talked to that it's only male rats used in the animal model studies.

Dr. Hof: That's right, and increasingly, the NIH now is requiring that investigators include female and male in any study. It is logistically difficult because depending what parameters you are measuring, these parameters can be influenced by the hormonal cycle of the female, and that throws out your results. Controlling for these changes is very, very difficult to do.

Katherine: Do you know what the timing of the cycle of a mouse is?

Dr. Hof: It goes over a few days.

Katherine: I was actually thinking it was 32 days like humans. That was my mistake there.

Dr. Hof: No, they cycle very, very fast. They are constantly in a reproductive mode. If you are working with monkeys, it's a lot easier because it's much similar to humans. Still, depending what you do, you have to know exactly what part of the cycle you are and you have to account for hormonal levels all the time.

Katherine: Wow, that's amazing. Is there anything about your study that you would change about your paper if you wrote now with what's come out about CTE?

Dr. Hof: Well, I would certainly change the title a little bit. CTE would be in the title. That's one thing. We would have much more sophisticated tools to study a brain like this in terms of immunohistochemical reagents that would tell us a lot more about pathological forms of protein from what was available in 1990.

Katherine: Her brain is gone now, right?

Dr. Hof: No, it's still in Geneva. It's still there. It's still part of the collection. It has been cut. There are sections around. There are still blocks of it.

Katherine: Could you use modern tools on a brain that has been preserved since 1990?

Dr. Hof: To an extent. Not everything is going to work because that's tissue that has been sitting in fixative now for a very extensive period of time, nearly 30 years. A lot of the proteins you are looking at would not be easy to detect any longer, even with antigen retrieval techniques. It gets very difficult. If I could start completely fresh, I would freeze half of the brain and fix half of the brain, and I would make sure to distribute the tissues to the best possible people to do things like whole genome sequencing on the brain material, single cell transcriptomics. There is a lot you can do. In the fixed hemisphere, I would probably take that hemisphere, put it first in a very high-field magnet, and get a structural MR and diffusion tensor imaging.

Katherine: Yes. Diffusion tensor images are so cool.

Dr. Hof: We would do all this now, but at the time, of course, none of that was available. This is really sort of a museum case, essentially.

Katherine: Even if I were to raise money to bring the brain to you, it's not worth it to look at her brain again?

Dr. Hof: We could try to do a few things, and I have full access to that brain. I'm from Geneva originally, so I have maintained contact with my friends in psychiatry and pathology there for all these years. We still work together.

Katherine: That's great. I was going to offer to go get her brain for you.

Dr. Hof: Except that I cannot take it out of the country.

Katherine: We need to get you to Geneva in front of the brain. I think that's really important to do. Maybe we could suggest that and maybe do some fundraising or something around that to try to see?

Dr. Hof: Yes. I can just ask my colleagues to look at her brain.

Katherine: Oh, could you?

Dr. Hof: Yes. I would have to initiate it. I would just tell them, "Let's look at a few more markers in that brain and see if it works."

Katherine: Could you?

Dr. Hof: I can easily do it.

Katherine: Do we know her first name or did you guys have a nickname for her?

Dr. Hof: I must have something like this in my past archive. I would have to dig it out.

Katherine: I wanted to give her back her name. it’s really important to link a person’s name to the CTE as in the case of Mike Webster or Junior Seau. I would love to know her name to make her more tangible and real to people.

Dr. Hof: Yes. If her family can be reached and would give their consent to release her name.

Katherine: She was from Switzerland?

Dr. Hof: Yes.

Katherine: I wonder what her family thinks now. It would be interesting to talk to a family member to see if they connect that it was CTE.

Dr. Hof: They probably don't. We have no contact with the family. We didn't have contact at the time I even wrote the study.

Katherine: If the brain was studied today, the family would have been interviewed, right?

Dr. Hof: Absolutely. This case really comes from another time.

Katherine: It's so odd because 1990 doesn't seem that long ago.

Dr. Hof: No, but things have changed.

Katherine: Right. I really, really appreciate your time, and I think it's just absolutely fascinating. If there is anything that I can do to raise some money, to whatever, I would love to help you look at this brain again.

Dr. Hof: Sure. I think this case, quite frankly, is very informative as an early observation of something interesting that turned out to be exactly what we see in athletes and people with repeated traumatic brain injury. We have to move forward from that type of case and really work on the population we can reach and on which we can have potentially an actual impact.

Katherine: Right, and I think it will be in domestic violence. I think domestic violence cases will be the football equivalent for women.

Dr. Hof: There certainly is that issue. That goes back to the Roberts case, incidentally. And with all the girls who are involved in high contact sports nowadays, some prevention has to be done and education has to be done.

There are some very interesting numbers in there in your research you sent me on student concussions in the Norwalk Schools.

Katherine: Concerning the high number of females?

Dr. Hof: Yes. I would have never suspected that it would be the case.

Katherine: My research shows a large number of the female concussions are non-sport, occurring at home. I don't think it's the case that girls are just more honest about reporting concussions.

Dr. Hof: Yes. That's interesting. Are the causes of non-sport concussions documented? There is good evidence?

Katherine: These are all concussions of students seen by the school nurses. The school nurse first receives a letter from the doctor diagnosing a concussion in a student and then she records the concussion by age, gender, and details about how the concussion occurred. I'm hoping this year to understand more what's going on with the girls. There is one fundamental difference between boys and girls’ education about concussions. Boys in general play video games, and the soccer, FIFA16, Football and hockey game all have concussion as part of a component of the game. If your player gets a concussion, they are out for the rest of the game. Girls don't have an equivalent education reminder unless they play these male-oriented video games.

Dr. Hof: That's interesting because soccer is very, very popular with girls in this country. They don't play these video games?

Katherine: I wonder now how many girls are coming online with FIFA16 and now playing with the female teams? We hope to gather better data this year to find out what the girls are doing when they get concussed.

Dr. Hof: Yes. These data are very interesting and should be somewhat published somewhere, somehow.

Katherine: There is also an issue that if a high school has an athletic trainer, how often does the athletic trainer cover the boys' football game, not the girls' sports like volleyball? In my study it showed of the 130 boys who played football between the two teams there were nine concussions, and of the 30 girls that played volleyball there were four. They are concussing to twice the rate and don't have the same access to the trainers. Then there is the issue of cheerleading, which isn't a sport in most parts of the country so most cheerleaders aren't even followed by the athletic trainers.

So, Dr. Hof, I really, really appreciate your time. It was absolutely fascinating to talk to you. If anything develops with re-examining Lucy's brain, or if you come across another female, please let me know?

Dr. Hof: Okay, absolutely.

Katherine: Thank you so much.

Dr. Hof: Great talking to you.

Katherine: Great talking to you.