Researchers know that repeated blows to the head can precipitate a neurodegenerative tauopathy called chronic traumatic encephalopathy (CTE). Marked by memory loss, movement problems, and changes in mood such as depression and anger, this disorder is most prevalent in boxers, football and hockey players, and military service members exposed to blasts. CTE can be confirmed by autopsy, but clinicians have no reliable way to diagnose it during life. This hampers efforts to identify risk factors and run clinical trials. Now, the National Institute of Neurological Disorders and Stroke (NINDS) has awarded a $16 million grant for a multicenter longitudinal study of people at risk for CTE. By administering a battery of clinical and cognitive tests, as well as measuring numerous potential biomarkers, researchers hope to refine diagnostic criteria and develop validated biomarkers for the disorder that will eventually enable clinical trials.
Despite ample media attention for CTE, researchers still know little about the disorder, noted Robert Stern at Boston University School of Medicine, who leads the new study. “For example, we don’t know anything about the incidence or epidemiology. We don’t know why one person with a history of head injury gets it, and another doesn’t,” he told Alzforum. The NINDS study will address this question by examining genetic and environmental risk factors.
CTE first vaulted to the headlines about a decade ago, when Bennet Omalu and colleagues at the University of Pittsburgh diagnosed the disorder in several professional football players who died in middle age, often due to suicide (see Jan 2007 news; Jan 2009 news; Jun 2008 Webinar). Postmortem analyses by Ann McKee at Boston University and others have now defined the neuropathology, which is marked by spreading tau tangles and sometimes TDP-43 deposits, but little to no Aβ (see Nov 2012 news series; Bieniek et al., 2015; McKee et al., 2015).
Many groups are studying potential biomarkers, including researchers at Harvard University who were awarded a $100 million grant in 2013 from the NFL Players Association (see Feb 2013 news). Stern led the recently completed Diagnosing and Evaluating Traumatic Encephalopathy using Clinical Tests (DETECT) study, which compared biomarkers in 100 symptomatic former NFL players and 50 controls (see Nov 2012 news; Stamm et al., 2015). However, no large prospective study has been done to determine the diagnostic utility of potential biomarkers.
The NINDS study hopes to meet this need with its new seven-year study. Besides Stern, Jeffrey Cummings at the Cleveland Clinic Lou Ruvo Center for Brain Health in Las Vegas, Eric Reiman at Banner Alzheimer’s Institute in Phoenix, and Martha Shenton at Brigham and Women’s Hospital in Boston will co-lead the effort. The researchers will follow 120 former NFL players, 60 former college football players, and 60 controls between 45 and 74 years old. The football players will include people with and without symptoms associated with CTE. This will allow researchers to track the change in biomarkers as symptoms develop or worsen. All participants will come in for a baseline visit and a three-year follow-up. In addition, researchers will ask them to donate their brains after death, so that diagnoses can eventually be confirmed neuropathologically.
The participants will be given a battery of cognitive tests, mood assessments, and clinical measures of motor abilities, posture, and balance. The findings should help identify the most useful clinical diagnostic criteria, Stern said. He noted that they are using the same measures as many other large studies, for example the Uniform Data Set in use by the National Alzheimer’s Coordinating Center, to facilitate comparisons between cohorts. For diagnostic biomarkers, researchers are focusing on signals that reflect the underlying pathology of the disorder. They will assess tau tangles using tau PET imaging, as well as by measuring total and phosphorylated tau in CSF and blood. To distinguish CTE from Alzheimer’s disease, participants will also undergo amyloid PET scans and be evaluated for fluid Aβ levels.
In addition, researchers will measure a suite of other biomarkers that may shed light on disease progression. These will include plasma proteins such as neurofilament light chain and α-synuclein, as well as structural and functional MRI scans. The researchers will use some advanced MRI techniques, such as diffusion tensor imaging, to look for axon damage, and magnetic resonance spectroscopy to study inflammation and microglial activation. Some of these biomarkers previously have been found to correlate with CTE in small studies (see Jan 2013 news; Oct 2013 news; Mar 2014 news).
Finally, the study will collect data on each participant’s history of head injury to correlate this risk factor with clinical symptoms. Participants will donate DNA for genotyping. The researchers will genotype for ApoE, since ApoE4 has been associated with worse outcomes after head injury, as well as for genes linked to tauopathies in genome-wide association studies. “We’ll try to create a genetic risk score,” Stern said. He noted that this study will draw on recent progress made in the study of several other neurodegenerative disorders. “Now is the perfect time [for this study], because there have been so many wonderful advances in biomarker development,” he said.