The Science and Art of Neuropathology

Neuropathology is like looking at the last frame of a movie. You can deduce a lot from that frame — maybe the film was a western or a musical — but what you can't deduce is the arc of the story that culminated in that final frame.

See more videos with Dr. Lee Goldstein.

We recently published a paper in Science Translational Medicine with my colleagues at Boston University but also with a large multidisciplinary team. And I will say that that piece, having a large multidisciplinary team, has really been essential to making the findings that we've made. This includes electrophysiologists and neurobehavioral people at New York Medical College, blast physicists at Lawrence Livermore, University of Oxford colleagues over at Harvard in genetics, molecular biologists and engineers as well, blast physicists, translational neuroscientists. We really covered many of the fields, if not most of the fields that are required. And really it took a village to do this. So this work that I'm about to tell you about really is the work of a lot of different people. We really started with patients and with the pathology. And as a clinician scientist, I think that's where we always need to start. We should start and finish with the people that we're trying to help. So as a consequence of the Brain Bank and Ann McKee's work in neuropathology in athletic injury, several autopsies came to our attention that involved military veterans who had had blast exposure but also had had other concussive injuries as well. And as a consequence of this, we had really the first case series of human brains, postmortem brains, from military veterans who had been exposed to blast and/or concussive injury. Interestingly and importantly, these individuals had other symptoms and other clinical histories, so that's always the case with human pathology is we have to deduce from the cases that we have what's actually going on. So it's a small case series, but it's the first one and it had some very important points. 3 of the 4 individuals had post-traumatic stress disorder. All of them had been exposed to blast and/or concussive injury. 3 of the 4 had not just blast injury but had had either 1 or multiple other types of injuries. 2 of them, I believe, had multiple injuries over time, both before deployment and after deployment. And all 4, naturally, had passed away. When we examined those brains and we compared them to a set of the youngest amateur athletes studied to date, postmortem brains-- these were late teenagers, early adults, 17, 18-year-old, 21-year-old, and I think there was another one of similar age-- we saw evidence of chronic traumatic encephalopathy that was virtually indistinguishable between the groups. In fact, from a neuropathological standpoint, they were indistinguishable. So what we noticed was that we found early tau pathology in parts of the brain where in this relatively young age group one would never expect to see any tau, let alone this pathologic form of tau. We saw damage to axons, which are the long cables that connect neurons one to another-- very pronounced damage to these axons. And we saw accumulation of tau within those axons as well. We saw damage to blood vessels, primarily the smaller blood vessels, and we saw tau building up around these blood vessels in a very unusual pattern that is characteristic of this disease. And we saw the tau accumulation in parts of the brain where we would not typically see it in other neurodegenerative diseases-- that is, the frontal cortex. We see it in a pattern that's very unusual in the valleys where the folding of the brain goes into a valley formation. We see it at the base of those valleys, and it actually tells us something about the physics of what's going on. And we saw damage to the axons and, very importantly, the capillaries in the microvasculature. We call that microvasculopathy. And we knew that these individuals, all of them were impaired. They had a variety of neuropsychiatric complaints, they had disturbances in thinking, in learning, in memory, and they made the clinical teams that took care of them and their families aware of these problems. These were chronic problems, and they seemed to be associated with trauma. So that was the lead-off for this study. So first off, we established that there was chronic traumatic encephalopathy in the brains of military veterans as opposed to athletes. We showed that it was indistinguishable from what we found in the youngest amateur athletes to date. And then the question becomes, what is the relationship? What is causing the relationship between this neuropathology on the one hand and the trauma? And for that there's really only 1 way that we can get at that question. With the neuropathology, it's something akin to looking at the final frame of a movie and trying to figure out what the movie is about. What is the arc of that story? If you have the last frame of the movie, you can probably figure out if it's a Western, if it's a musical, maybe even figure out the setting in which it was done, if it's an old movie, new movie. You can deduce a lot about it. But what you cannot deduce from that final frame is the arc that brought you to that last frame. And that's the problem that we always have with neuropathology is we can't make that link. So here's where we have to do animal models, and that's exactly what we did. What we did is we built a model based on what we know that our military servicepeople were exposed to in the recent conflicts in Afghanistan and Iraq. These are not new problems. We saw this in World War I with the high explosives in the European theater. And in the intervening years we built bigger and better bombs, but they still do the damage that the smaller bombs do.
Posted on BrainLine February 28, 2013.

Produced by Brian King, Vicky Youcha, and Erica Queen, BrainLine.