When a new disease emerges, clinicians grapple early on with how to diagnose it. This is true for chronic traumatic encephalopathy (CTE), the degenerative tauopathy that develops in some people after they receive a blow to the head in the course of contact sports or military service. Researchers do not know how common the disease is. They do not have biomarkers for it. There are no treatment trials for it. “At the very base of asking any of these questions is, Who is a case? That is why we need to advance consensus diagnostic criteria,” said Jeffrey Cummings, who hosted a recent conference on CTE at the Cleveland Clinic Lou Ruvo Center for Brain Health in Las Vegas, Nevada.
At this meeting, Robert Stern of Boston University for the first time presented a draft version of research-based criteria to any kind of public forum. The time has come to focus the field’s attention on consensus criteria, because the pathology of CTE by now is fairly clear and physicians are beginning to diagnose the condition during a patient’s lifetime, but they are doing so each in their own way. CTE at present is tricky to diagnose, Stern said. “We must differentiate it from Alzheimer’s, from frontotemporal dementia, and from chronic stress. We need to diagnose and then follow people with CTE, both to study progression and to try to protect them from suicide, which is a big problem in this population.” Moreover, purely clinical, phenotypic diagnoses are often inaccurate; objective tests should be built into it.
Stern recounted how recent progress in the Alzheimer’s field has inspired his group’s attempt to get off the starting blocks. In AD, criteria dating back to 1984 used clinical and paper-and-pencil psychometric tests to diagnose dementia. A definitive diagnosis had to await autopsy, much like CTE today. In AD, this has given way to a much more accurate lifetime diagnosis. The formal change began five years ago with a biomarker-driven diagnosis for research purposes (Dubois et al., 2007), which in turn spurred the development of new diagnostic criteria for earlier-stage disease by other leading groups as well (see Alzforum Webinar). There has been debate about the attendant terminology in this shift, and different groups have accepted biomarkers to a differing degree, but in essence, Alzheimer’s disease has moved to being diagnosed during a person’s lifetime at early stages, before the person shows the overt dementia that is increasingly viewed as the disease’s endstage. Years of convergent findings on brain imaging and cerebrospinal fluid protein measurements from natural history cohorts in Europe, the U.S., Australia, and Japan now anchor this change. Knowing the trajectory of biomarker change in the years before people develop symptoms is transforming clinical trials in AD toward preclinical treatment that aims to delay the clinical presentation (see CTAD 2012 Alzforum series). By learning from AD, CTE research can advance toward similar trials more quickly, Stern said.
To create diagnostic criteria for CTE, Stern and colleagues first reviewed the world literature, then interviewed the families and studied the medical records of the 68 CTE cases Ann McKee has analyzed recently (see Part 3 of this series). They used information on the 40 of these 68 who had "pure" CTE without motor neuron disease or other major confounds, and whose last brain trauma dated back at least five years to eliminate the immediate effects of concussion. These 40 had died at ages 22 to 98 at CTE stages 1 through 4 of suicide, drug overdose, dementia, or other medical conditions. The primary symptoms loved ones reported fell into four groups. Cognitive problems centered on memory, executive function, and dementia, as in AD. Behavioral problems included a short fuse, aggression/violence, and substance abuse, not the inappropriate touching and public behavior that is typical of frontotemporal dementia. Mood problems included apathy—a known symptom of certain FTDs—but also sadness, suicidality, hopelessness, and irritability. Motor disturbances included falls, disturbed gait, poor balance, and parkinsonism. Behavioral and motor symptoms tend to precede cognitive ones, and the number of symptoms grew as people advanced to stage 4.
Candidate biomarkers for CTE exist. Besides elevated CSF tau with normal CSF Aβ, they include a handful of MRI modalities, a biochemical metabolite signature by magnetic resonance spectroscopy (MRS), and amyloid PET to rule out AD. Tau PET ligands for CTE are much anticipated. EEG as measured by BrainScope, a handheld tool used by the military, has also shown promise. However, none is fully studied for inclusion in a CTE consensus diagnosis.
For a start, Stern leads a cohort study called Diagnosing and Evaluating Traumatic Encephalopathy using Clinical Tests, aka DETECT. This interdisciplinary study is the first CTE program funded by the National Institutes of Health. It measures side by side a range of biomarkers in 100 symptomatic former NFL players who played positions that tend to take severe hits to the head most often, and compares their data to those of 50 former Olympians in sports not prone to concussions. All participants come to Boston for two packed days of assessments, clinical and neuropsychological tests, and a blood draw to analyze genetic risk factors. “We have been very successful in recruitment and expect to get this done quickly,” Stern said. The study started in the fall of 2011 and is a collaboration between BU, Les Shaw at the University of Pennsylvania for CSF analysis, outside academic consultants on head trauma and suicide, and Brigham and Women’s Hospital in Boston for brain imaging.
In Las Vegas, Martha Shenton of Brigham and Women’s, who leads DETECT's imaging component, noted that a pilot study on five concussed former athletes confirmed some of the findings reported in the literature, seen by Ann McKee (see Part 3), and also seen in Charles Bernick’s study of boxers and cage fighters (see Part 2). These include holes in the septum pellucidum membrane, a shrunken cortex, a thinned corpus callosum, and fiber damage revealed by a new imaging modality called tractography.
What about milder hits to the head? Do they cause changes that brain imaging can pick up? In the November 13 Journal of the American Medical Association, Shenton published results of a DTI study comparing the integrity of the white matter in 12 elite German soccer players, whose frequent heading exposes them to sub-concussive blows, to that in 11 elite swimmers. Working with colleagues at the Ludwig-Maximilians-Universität in Munich, Germany, Shenton’s group found greater radial diffusivity in many brain areas, and greater axial diffusivity in the corpus callosum. Only visible with advanced DTI—not on regular MRI—these kinds of subtle changes do, however, suggest possible demyelination, the authors write (Koerte et al., 2012).
Back to DETECT. Even if this larger study finds clear differences in the biomarker signature between the full cohort of football players and the controls, they will not constitute proof that those changes are due to CTE. “From a cross-sectional measurement, we cannot distinguish if we are seeing changes from the repetitive brain trauma that might be chronic, or evidence of a new, progressive disease,” Stern said. For that, a prospective natural history study that yields progression slopes will be necessary.
With current knowledge in mind, Stern took a first stab at research diagnostic criteria. They stipulate a minimum age, a history of brain trauma exposure, and definition of the identity and progressive nature of symptoms. Borrowing from Alzheimer’s, Stern proposes five diagnostic categories—preclinical CTE, possible early-stage CTE, probable early-stage CTE, possible CTE dementia, and probable CTE dementia—and lists biomarker and symptom combinations for each. This first draft is currently incorporating feedback from other CTE researchers, and will then be published, Stern said. At that point, the CTE diagnosis may be close to where the Alzheimer’s field was in 2007, when biomarker research criteria were published and awaiting validation. “Our criteria are a ways off from being ready for clinical use,” Stern said.
Before that happens, the draft’s framework will also need to expand to include military trauma so that soldiers can be diagnosed with the final diagnostic criteria as well, Cummings said. Most of the work to date has come from athletes.—Gabrielle Strobel.
- CTAD: Turning the Ship Around Toward Early Trials
- CTE: Trauma Triggers Tauopathy Progression
- Boxing: Study of Human Model for CTE Enters Second Round
- Meet the New Progressive Tauopathy: CTE in Athletes, Soldiers
- Do Tau "Prions" Lead the Way From Concussions to Progression?
- CTE Advocates Pivot Toward Preventing Concussions in Kids
- Dubois B, Feldman HH, Jacova C, Dekosky ST, Barberger-Gateau P, Cummings J, Delacourte A, Galasko D, Gauthier S, Jicha G, Meguro K, O'brien J, Pasquier F, Robert P, Rossor M, Salloway S, Stern Y, Visser PJ, Scheltens P. Research criteria for the diagnosis of Alzheimer's disease: revising the NINCDS-ADRDA criteria. Lancet Neurol. 2007 Aug;6(8):734-46. PubMed.
- Koerte IK, Ertl-Wagner B, Reiser M, Zafonte R, Shenton ME. White matter integrity in the brains of professional soccer players without a symptomatic concussion. JAMA. 2012 Nov 14;308(18):1859-61. PubMed.