20 Nov 2012

When autopsies of football stars and wrestlers who had committed suicide touched off a storm of media coverage some years ago, the initial story was one of concussions putting athletes at risk for Alzheimer’s disease. Since then, however, the story has taken a sharp turn. Prompted by striking brain pathology in both contact sport athletes and military veterans, scientists are now defining a new disease. Called chronic traumatic encephalopathy (CTE), the underlying concept envisions a massive tauopathy that spreads from the site of impact throughout the brain during the months and years after hits to the head. In other words, a progressive disease that stands apart from the known manifestations of traumatic brain injury (TBI). On 30 September to 1 October 2012, at the first research conference dedicated exclusively to CTE, scientists promulgated the idea that, of the estimated 1.7 million people who sustain mild TBIs in the U.S. every year, an untold number do not recover, nor do they live with the chronic, stable impairment that is sometimes called post-concussion syndrome. Instead, they develop a discrete secondary tauopathy that worsens with age and eventually leads to dementia or parkinsonism if the person survives long enough. Emerging research hints that CTE may self-propagate from cell to cell, as do other tauopathies.

In this way, CTE would be a new neurodegenerative disease. CTE is distinct from Alzheimer’s, Parkinson’s, frontotemporal dementia (FTD), or amyotrophic lateral sclerosis (ALS), though individual cases can overlap with either of these. “CTE is a debilitating disease found in people with a history of repeated brain trauma,” Vice Admiral Regina Benjamin, the U.S. Surgeon General, told a unique gathering of scientists and advocates at the Cleveland Clinic Lou Ruvo Center for Brain Health in Las Vegas, Nevada. “CTE can start months or years after brain trauma has occurred, either in contact sports, military service, veterans, or perhaps even partner violence, shaken baby syndrome, motor vehicle accidents, and other circumstances of life in the U.S.,” the nation’s top physician said in Las Vegas.

The conference set as its goal the launch of a serious scientific effort to define CTE, develop a lifetime diagnosis, and hammer out a research agenda for this nascent field. Jeffrey Cummings of the Lou Ruvo center hosted the meeting, which was co-organized jointly by Charles Bernick at the center and Robert Stern of Boston University Medical School. Besides drawing the Surgeon General, the conference brought leading AD and FTD neurologists together with Stanley Prusiner of the University of California, San Francisco, a Nobel laureate for his work on transmissive proteopathies, and with Boston University’s Ann McKee, who has been the prime mover of CTE research to date. It convened experts in trauma biomechanics, neurodegenerative disease biomarkers, and tau-based drug development. Military physicians joined Holly Posner, a leader in suicide research at Columbia University in New York City, and Chris Nowinski, a charismatic wrestler-turned-advocate who raised national awareness, persuaded athletes to participate in research and donate their brains, and is now arguing against letting young boys play tackle football (see Part 6 of this series).

After summarizing what is known about CTE, the Las Vegas gathering exchanged the latest information from ongoing research projects on boxers, more recent neuropathology, and CTE transmission in mice (see Part 2, Part 3, and Part 4 of this series). Then they articulated current challenges. For example, how can researchers, and eventually doctors in community practice, distinguish TBI from CTE? On this, progression is the key difference, so much so that the name might eventually change. “It may eventually be 'chronic progressive encephalopathy.' That’s because there are many people who have a stable encephalopathy following trauma. They probably do not have a progressive tau disorder,” Cumming said.

The incidence and prevalence of CTE are unknown at this point, even though the military in particular is concerned it may be high. “I believe we have a very large population of people who may be at the beginning of what we are talking about here,” said Captain Paul Hammer, who directs the Defense Centers of Excellence for Psychological Health and Traumatic Brain Injury. The Department of Defense’s estimate of mild TBIs has risen steeply since 2005.

To obtain epidemiological data, scientists need to know for sure who is a case. They need a consistent diagnosis—ideally a clinical/cognitive one anchored to the underlying disease process by biomarkers—to delineate the progressive disorder from TBI. At the Lou Ruvo conference, Stern introduced draft consensus diagnostic criteria for CTE that were inspired by recent advances in Alzheimer’s (see Part 5). In that disease, a 25-year-old diagnosis was modernized to become more specific in capturing preclinical stages. This, in turn, impressed regulators and is now helping define inclusion criteria for therapeutic trials in predementia AD (e.g., see ARF CTAD story).

In CTE, the biomarker research necessary for similar advances is in its infancy, Stern said. CTE biomarker research can benefit indirectly from natural history studies being done in AD and FTD, but that is not enough. “We need a prospective study, like ADNI or DIAN, for CTE,” said McKee.

Another challenge for academic scientists is that most published research to date has come from athletes. “We want both the diagnostic criteria and the broader research framework to accommodate progressive tauopathy from military trauma, too,” Cummings said.

Mechanistic research needs to tease out how a person goes from an injury to a progressive disease, and why only some people do. Sudden hits to the head rotate and accelerate the brain in a way that is thought to stretch and tear axons, causing what is called diffuse axonal injury (Meythaler et al., 2001; Barkhoudarian et al., 2011). What genetic, environmental, and pathophysiological factors lead from this initial injury to a tauopathy that then spreads relentlessly through the brain? What role do age, inflammation, and glia play in this process? “We need models for that,” said Lee Goldstein of Boston University (see Part 4).

Once a diagnosis, preclinical biomarker trajectories, and a mechanistic rationale are in hand, the goal of preventing CTE in concussed people who show signs of developing progressive disease will be within reach. Tau-based therapies remain slow to come on line, but a few, notably the axonal stabilizer epothilone D, are wending their way through clinical trials. Its current Phase 1b trial in Alzheimer’s was inspired by the research of Kurt Brunden of the University of Pennsylvania, Philadelphia, who spoke at the Lou Ruvo meeting (see ARF related news story).

While researchers focus on mechanisms and drug discovery, advocates such as Nowinski have shifted their attention toward protecting children from sports concussions to prevent future cases (see Part 6 of this series). Both sports and military medicine specialists are developing mobile device applications for coaches and field doctors to better detect concussions where they happen. For example, Jay Alberts of the Department of Biomedical Engineering at the Cleveland Clinic’s home base in Ohio is field-testing a new iPad 2 app in 56 regional high schools. The app measures reaction time, postural stability, and balance errors by the side of the field. It integrates this information with the player’s electronic medical records to render a return-to-play decision during the game. For the military, Hammer mentioned an mTBI Pocket Guide that provides clinical guidance for physicians in theater or far-flung medical stations via their mobile phones. The Surgeon General talked about a National Prevention Strategy instituted by the Obama administration, as well as a central data repository on TBI research which the NIH is building together with the Department of Defense.

The made-for-headlines narrative appeal of youthful star athletes and warriors risking their minds has created an unusual situation. Media attention on CTE has far outpaced the available science. In most areas of science, researchers make progress in relative obscurity before the general media develops an interest. Here, the opposite has happened. The dramatic neuropathology of early cases, football players shooting themselves in the heart to preserve their brains for research, the National Football League’s gradual turnaround, the hardship of veterans struggling to reintegrate at home—all this has fed an appetite for CTE coverage beyond even the nation’s newspapers and ESPN. The television entertainment industry in the past year featured CTE in segments on the TV shows Harry’s Law, Law & Order, The Good Wife, House, and CSI, said Stern.

“We are at such a beginning stage with the science of CTE that it is the outline of the major problems which is now emerging and is allowing us to develop a work agenda. The importance of the conference was to bring the interested parties together so they could identify the low-hanging fruit,” said Cummings.

The Lou Ruvo Center for Brain Health is uniquely positioned to harness the twin powers of celebrity and notoriety for serious research purposes. Las Vegas is the capital of boxing, CTE’s archetypal sport. The star architect Frank Gehry designed the institute’s building with money raised by Keep Memory Alive, a fundraising organization endowed by wealthy philanthropist Larry Ruvo in memory of his father Lou, who suffered from Alzheimer’s. The building is iconic, with a meeting space that flaunts 199 windows, no two of them alike and each fitted with its own motor to shade against the desert sun. The atrium features a 24-foot work by the contemporary American painter James Rosenquist, who reportedly lost family members to Alzheimer’s. Called Brain Space, the painting was commissioned by casino hotel magnate Steve Wynn. The center’s clinic staff trained at the Four Seasons Las Vegas to impart an atmosphere of hospitality—not hospital—when patients and their caregivers come for medical appointments.

Helping to pay off the building and fund the research done inside, Keep Memory Alive hosts events such as its annual Power of Love gala. Last February’s gala celebrated the 70th birthday of Muhammad Ali (see Time U.S. article; Celebrity Net Worth video). The former boxer is said to suffer from parkinsonism, possibly CTE. Stevie Wonder sang "Happy Birthday to Ali" at midnight, President Obama recorded a video greeting, and the night’s 2,000 glamorous guests raised $11 million. Next year’s gala will fete Quincy Jones’ 80th birthday and feature Oprah Winfrey, Cummings said.

The Lou Ruvo Center has started up 27 clinical trials in Alzheimer’s, Parkinson’s, ALS, multiple sclerosis, and Huntington’s, as well as a natural history study of boxers and cage fighters (see Part 2 of this series). “For our patients, we think participating in research is how they can solve their own disease and the disease that afflicts their family. For us, we think science matters more when it generates diagnoses and treatments. It matters less when we only write grants and publish papers,” Cummings said.—Gabrielle Strobel.

This is Part 1 of a six-part series. See also Part 2, Part 3, Part 4, Part 5, Part 6. Read a PDF of the entire series.

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References

News Citations

1. CTE Advocates Pivot Toward Preventing Concussions in Kids 28 Nov 2012
2. Boxing: Study of Human Model for CTE Enters Second Round 21 Nov 2012
3. CTE: Trauma Triggers Tauopathy Progression 23 Nov 2012
4. Do Tau "Prions" Lead the Way From Concussions to Progression? 26 Nov 2012
5. CTE Needs Consensus on Lifetime Diagnosis 27 Nov 2012
6. CTAD: Regulatory Science Gains Prominence in AD Research 9 Nov 2012
7. Paper Alert: Microtubule Stabilizer Improves Tauopathy in Mice 16 Mar 2012

Paper Citations

1. Meythaler JM, Peduzzi JD, Eleftheriou E, Novack TA. Current concepts: diffuse axonal injury-associated traumatic brain injury. Arch Phys Med Rehabil. 2001 Oct;82(10):1461-71. PubMed.
2. Barkhoudarian G, Hovda DA, Giza CC. The molecular pathophysiology of concussive brain injury. Clin Sports Med. 2011 Jan;30(1):33-48, vii-iii. PubMed.

Other Citations

1. Read a PDF of the entire series.

External Citations

1. estimate of mild TBIs
2. Phase 1b trial
3. mTBI Pocket Guide
4. central data repository
5. 24-foot work
6. Time U.S. article
7. Celebrity Net Worth video

Further Reading

News

1. CTAD: Regulatory Science Gains Prominence in AD Research 9 Nov 2012
2. Paper Alert: Microtubule Stabilizer Improves Tauopathy in Mice 16 Mar 2012