Thursday, May 17, 2012

Blast Wave Injury and Chronic Traumatic Encephalopathy: What's the Connection?

Fig. 3 (Goldstein et al., 2012). Single-blast exposure induces CTE-like neuropathology in wild-type C57BL/6 mice.


In a tour de force, a group of 35 Boston-area scientists1 (Goldstein et al., 2012) developed a mouse model of blast-related neurotrauma that resulted in pathological changes similar to chronic traumatic encephalopathy (CTE), a progressive neurodegenerative disease seen most often in athletes with repeated concussions. They also reported post-mortem neuropathological findings from the brains of war veterans and amateur football players who had sustained concussions and traumatic brain injuries (TBIs).

Diagnosis of CTE occurs after autopsy, because the brain tissue has to be stained for characteristic protein abnormalities which cannot be visualized in a living human. A defining pathological feature is tauopathy - abnormal accumulations of the tau protein seen in other dementias (e.g., Alzheimer's disease). Aggregations of hyperphosphorylated tau into neurofibrillary tangles (NFTs) are a defining feature, as in frontotemporal lobar degeneration and amyotrophic lateral sclerosis - yet CTE is distinct from both of these (McKee et al., 2009). CTE results in cognitive and behavioral changes including memory impairments, poor impulse control, alterations in mood, suicidal behavior, disorientation, and ultimately dementia.


Can Blast Waves Cause Chronic Traumatic Encephalopathy?

The major conclusion drawn from the human data in this study is that exposure to blasts from IEDs causes CTE (Goldstein et al., 2012). However, my contention is that the cause of tauopathies in these military veterans is unclear. Three of the four had histories of concussion from other events.


Much of what you've read about this paper in the media is wrong.

The worst offender by far was Business Insider:
Scientists Looked Inside The Brains Of Troops Killed By Bombs And Made This Shocking Discovery

Trauma from exposure to a single improvised explosive device (IED) blast can result in long-term brain impairment, according to new research.

The study, published today in the journal Science Translational Medicine, is the first to examine postmortem brains of U.S. military personnel who were exposed to a blast and/or a concussive injury.

It found evidence that a single blast from a typical IED can cause traumatic brain injury (TBI) and chronic traumatic encephalopathy (CTE).

Really?

1) None of the troops were killed by bombs -- they all died from other causes.

2) None of the troops had a single isolated blast exposure.

3) It is not the first study to examine postmortem brains of U.S. military personnel who were exposed to a blast and/or a concussive injury. That would be the paper by Omalu, Hammers, et al. (2011). I wrote about it here.2

4) The evidence that a single IED blast can cause TBI and CTE did not come from looking inside the brains of troops, it was obtained from a mouse model of neurotrauma.

Next, let's take a look at what the paper actually did.


Part 1 - Human CTE

The brain banks at the Center for the Study of Traumatic Encephalopathy and the Alzheimer's Disease Center at Boston University provided the brains of 12 human subjects:
  • 4 male military veterans (ages 22-45 yrs) with histories of explosive blast and/or concussive injury 1 to 6 years before death
  • 4 male athletes (ages 17-27 yrs) with histories of repetitive concussive injury, including 3 football players and a professional wrestler
  • 4 male controls (ages 18-24 yrs) with no known blast exposure, trauma history, or neurological disease
Case histories of the military veterans are presented below, to show that 3 of the 4 had concussions that were not due to explosive blast.
Case 1, a 45-year-old male U.S. military veteran with a single close-range IED blast exposure, experienced a state of disorientation without loss of consciousness that persisted for ~30 min after blast exposure. He subsequently developed headaches, irritability, difficulty sleeping and concentrating, and depression that continued until his death 2 years later from a ruptured basilar aneurysm. His medical history is notable for a remote history of concussion associated with a motor vehicle accident at age 8 years.

Case 2, a 34-year-old male U.S. military veteran without a history of previous concussive injury, sustained two separate IED blast exposures 1 and 6 years before death. Both episodes resulted in loss of consciousness of indeterminate duration. He subsequently developed depression, short-term memory loss, word-finding difficulties, decreased concentration and attention, sleep disturbances, and executive function impairments. His neuropsychiatric symptoms persisted until death from aspiration pneumonia after ingestion of prescription analgesics.

Case 3, a 22-year-old male U.S. military veteran with a single close-range IED blast exposure 2 years before death. He did not lose consciousness, but reported headache, dizziness, and fatigue that persisted for 24 hours after the blast. He subsequently developed daily headaches, memory loss, depression, and decreased attention and concentration. ... He was diagnosed with PTSD 3 months before death from an intracerebral hemorrhage. His past history included 2 years of high school football and multiple concussions from fist fights.

Case 4, a 28-year-old male U.S. military veteran with two combat deployments, was diagnosed with PTSD after his first deployment 3 years before death. His history was notable for multiple concussions as a civilian and in combat, but he was never exposed to blast. ... He died from a self-inflicted gunshot wound 2 years after his last concussion.
In brief, Case 1 had a concussion in a car accident as a child, Case 3 had multiple concussions from football and fist fights, and Case 4 had major concussions at 12 yrs (bicycle accident with loss of consciousness and amnesia), 17 yrs (football injury with no loss of consciousness), 25 yrs (altered mental status during military deployment), and 26 yrs (accident with loss of consciousness and amnesia).

Case 4 had no history of blast exposure at all, so his results are not even related to the title of the paper. Only Case 2 had blast exposures with no other cause of concussion. And here we don't know the duration of unconsciousness, so it's difficult to know the severity of the TBIs.


Part 2 - Mouse CTE

In addition to reporting the post-mortem pathology, the authors developed an animal model of blast injury. The paper was truly a collaborative effort, as it involved physics, engineering, immunology, neuropathology, immunohistochemistry, neuroanatomy, electron microscopy, behavioral neurobiology, electrophysiology, and biochemistry. I'm surprised there weren't more than 35 authors. You'd certainly need a small army of bloggers to adequately describe all the experiments, so I'll merely outline some of the methods and results in the Appendix at the end of this post.

The take home message is that CTE-like pathology, cellular dysfunction, and impairments in learning and memory were observed within 2 weeks of a single blast exposure. Two weeks.


What does it all mean for veterans and athletes with brain injury?

We don't know the full implications yet. Many questions remain.

1) Do such dramatic changes really occur within 2 weeks of a single blast wave or concussive injury in humans? Most individuals (up to 90%) with a single concussion recover fully within 3 months (Bigler, 2008).

2) Would the mice continue to get worse if followed over a longer time interval? CTE is a degenerative disease, yet most individuals with concussions improve over time.

3) Is the damage dose-dependent? How many hits do you need for cognitive and behavioral changes to occur? Two of the athletes had such severe injuries that they died shortly after the last concussion.

4) Are some people more susceptible to developing CTE? One might guess that's the case, or else there would be hundreds of thousands of former athletes with very severe cognitive and psychiatric issues.

5) Studies have shown there are risk genes, such as polymorphisms of apolipoprotein E (APOE), that influence outcomes after head injury (Teasdale et al., 1997; Omalu, Bailes et al., 2011). It would be nice to have a more complete picture of the cases reported here.

6) I believe none of the CTE pathology is evident from in vivo MRI scans of various sorts. That's why diagnosis is done at autopsy. However, it might be time to explore the use of 18F-FDDNP (Shin et al., 2011; Small et al., 2012), a molecular imaging probe that labels tau and NFTs, in PET studies of living persons considered at risk for CTE.


Footnotes

1 ...with 26 separate sources of funding.

2 This case also involved multiple concussions from football and auto accidents in addition to blasts. Omalu et al. linked the pathology to PTSD rather than concussion. I argued there was Little Evidence for a Direct Link between PTSD and Chronic Traumatic Encephalopathy.



References

Bigler ED. (2008). Neuropsychology and clinical neuroscience of persistent post-concussive syndrome. J Int Neuropsychol Soc. 14:1-22.

Goldstein, L., Fisher, A., Tagge, C., Zhang, X., Velisek, L., Sullivan, J., Upreti, C., Kracht, J., Ericsson, M., Wojnarowicz, M., Goletiani, C., Maglakelidze, G., Casey, N., Moncaster, J., Minaeva, O., Moir, R., Nowinski, C., Stern, R., Cantu, R., Geiling, J., Blusztajn, J., Wolozin, B., Ikezu, T., Stein, T., Budson, A., Kowall, N., Chargin, D., Sharon, A., Saman, S., Hall, G., Moss, W., Cleveland, R., Tanzi, R., Stanton, P., & McKee, A. (2012). Chronic Traumatic Encephalopathy in Blast-Exposed Military Veterans and a Blast Neurotrauma Mouse Model. Science Translational Medicine, 4 (134), 134-134 DOI: 10.1126/scitranslmed.3003716

McKee AC, Cantu RC, Nowinski CJ, Hedley-Whyte ET, Gavett BE, Budson AE, Santini VE, Lee HS, Kubilus CA, Stern RA. (2009). Chronic traumatic encephalopathy in athletes: progressive tauopathy after repetitive head injury. J Neuropathol Exp Neurol. 68:709-35.

Omalu B, Bailes J, Hamilton RL, Kamboh MI, Hammers J, Case M, Fitzsimmons R. (2011). Emerging histomorphologic phenotypes of chronic traumatic encephalopathy in American athletes. Neurosurgery 69:173-83; discussion 183.

Omalu B, Hammers JL, Bailes J, Hamilton RL, Kamboh MI, Webster G, & Fitzsimmons RP (2011). Chronic traumatic encephalopathy in an Iraqi war veteran with posttraumatic stress disorder who committed suicide. Neurosurgical focus 31 (5): E3.

Shin J, Kepe V, Barrio JR, Small GW. (2011). The merits of FDDNP-PET imaging in Alzheimer's disease. J Alzheimers Dis. 26 Suppl 3:135-45.

Small GW, Siddarth P, Kepe V, Ercoli LM, Burggren AC, Bookheimer SY, Miller KJ, Kim J, Lavretsky H, Huang SC, Barrio JR. ( 2012). Prediction of cognitive decline by positron emission tomography of brain amyloid and tau. Arch Neurol. 69:215-22.

Teasdale GM, Nicoll JA, Murray G, Fiddes M. (1997). Association of apolipoprotein E polymorphism with outcome after head injury. Lancet 350:1069-71.


Appendix


Part 1 - Human CTE

Athletes

Case 5, a 17-year-old male high school football player who died from second impact syndrome 2 weeks after concussion
Case 6, an 18-year-old high school football and rugby player with a history of 3-4 previous concussions, one requiring hospitalization, who died 10 days after last concussion
Case 7, a 21-year-old male college football player, who played as a lineman and linebacker but had never been diagnosed with a concussion during 13 seasons of play beginning at age 9, and who died from suicide
Case 8, a 27-year-old male professional wrestler who experienced more than 9 concussions during his 10-year professional wrestling career who died from an overdose of OxyContin

Controls

Case 9, an 18-year-old male who died suddenly from a ruptured basilar aneurysm
Case 10, a 19-year-old male who died from a cardiac arrhythmia
Case 11, a 21-year-old male who died from suicide
Case 12, a 24-year-old male who died from suicide



Fig. 1 (modified from Goldstein et al., 2012). CTE neuropathology in postmortem brains from military veterans with blast exposure and/or concussive injury and young athletes with repetitive concussive injury.


Part 2 - Mouse CTE

Developed a blast neurotrauma model (using a compressed gas blast tube) to investigate the mechanistic linkage between blast exposure, CTE neuropathology, and neurobehavioral sequelae
  • Measured intracranial pressure dynamics and head kinematics during real or sham blasts

Assessed subsequent CTE-linked neuropathology, ultrastructural pathology, and phosphorylated tau proteinopathy

  • Examined brains 2 weeks after single blast or sham
  • Gross examination was unremarkable, but immunohistochemical analysis revealed marked neuropathology in the blasted brains, which included:
  1. reactive astrocytosis throughout the cortex, hippocampus, brainstem, etc.
  2. enhanced phosphorylated tau CP-13 immunoreactivity in superficial cortical layers
  3. hippocampal CA1 neurons intensely Tau-46–immunoreactive with evidence of frank neurodegeneration in hippocampal CA1 and CA3 subfields and dentate gyrus
  4. activated perivascular microglia throughout the brain, especially in the cerebellum

Examined ultrastructural pathology using electron microscopy



Confirmed the presence of phosphorylated tau proteinopathy using immunoblot analysis of tissue homogenates prepared from mouse brains 2 weeks after single-blast or sham-blast

  • Immunoblot analysis revealed a significant blast-related elevation of various phosphorylated tau protein epitopes


Found persistent functional impairments in hippocampal neurophysiology
  • Slowed axonal conduction
  • Deficient long-term potentiation (LTP) of activity-dependent synaptic transmission (a candidate mechanism of memory storage)

Single-blast exposure induced long-term behavioral deficits
  • Acquisition and long-term retention of hippocampal-dependent spatial learning and memory was impaired
  • These deficits were prevented by head immobilization during blast exposure

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4 Comments:

At May 18, 2012 6:24 AM, Blogger TheCellularScale said...

Impressive paper. Business Insider is ridiculous, I mean put a little effort in people.
I would have liked to see 'reward learning' (along with spatial learning) tested in these model mice because of its link to depression.

 
At May 20, 2012 7:36 AM, Blogger Lee Goldstein, M.D., Ph.D. said...

Very thorough and thoughtful commentary. As is frequently the case in science, new studies often raise more questions than answers. Unquestionably, a lot more research is needed to address the many questions raised by our work. Further clarification may come from examination of: (1) new cases in which blast exposure and trauma histories allow better ascertainment of associative linkage, and (2) new results from laboratory studies that address critical and still unanswered questions regarding mechanistic causality. You have identified a number of inherent methodological confounds that complicate interpretation of the available clinical cases--these are few in number and limited by confounds as you correctly note in your piece. Such are some of the many inherent methodological limitations of neuropathological correlational analysis--and precisely the reason we undertook the laboratory research also presented in our report. In this respect, our study is somewhat unusual in combining these two approaches, but we strongly believe that the importance of our clinical findings necessitated rigorous experimental investigation to establish mechanistic causality. Some of the questions raised by our study cannot be rigorously addressed otherwise. While the scientific community and lay public continue to metabolize the findings (and limitations) of our study, we trust that our work provides important new information relevant to ongoing discussion on this subject, and additionally, stimulates further research to address the many unanswered questions that remain. Thank you for taking the time to carefully read and consider what our report actually reports. Your distillation is timely and helpful. Keep up the good work! Lee Goldstein, M.D., Ph.D., Boston University School of Medicine, College of Engineering, and Alzheimer's Disease Center

 
At May 20, 2012 1:39 PM, Blogger The Neurocritic said...

Dr. Goldstein - Thank you for taking the time to comment on this post. Your study was certainly a massive undertaking, and very unusual in its interdisciplinary scale. I know that by necessity, the neuropathological cases are limited to the unfortunate few that come to autopsy. As more evidence accumulates, the risk factors for developing CTE, and the extent of pathology after a single blast (vs. multiple blasts and repetitive head injury), will become clearer. The importance of having a model for the mechanisms that produce CTE-like pathology, and for the factors that may be protective, can't be overemphasized.

 
At June 07, 2012 1:25 PM, Anonymous Doehrman Chamberlain said...

We agree with Dr. Goldstein that this is an extremely thorough analysis of the study, and we applaud the many factors that you have taken into consideration. As both your comments and Dr. Goldstein’s address, additional research will need to be performed in order to gain a fuller understanding of the implications for veterans and athletes with TBIs. While this post addresses many of the questions that still remain about brain injuries, we believe the study provides an important starting point to help develop ways to prevent CTE.

 

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