Chronic Traumatic Encephalopathy: 2 Distinct Presentations?

Pauline Anderson

August 22, 2013

Chronic traumatic encephalopathy (CTE), a neurodegenerative disease marked by widespread accumulation of hyperphosphorylated tau, could have 2 distinct initial clinical presentations: one with behavior or mood changes, typically at a relatively young age, and the other with cognitive symptoms, a new study suggests.

The study is an important step toward diagnosing CTE while patients are still alive instead of relying on neuropathologic descriptions, as is currently the case, said lead author Robert A. Stern, PhD, professor, neurology and neurosurgery, Center for the Study of Traumatic Encephalopathy, and director, BU Alzheimer's Disease Center Clinical Core, Boston University School of Medicine, Massachusetts.

"That's the main reason I did this study," he said. "We need to start somewhere, and the starting point is to come up with adequate and accurate clinical diagnostic criteria to describe what...CTE looks like during life."

Among the next steps is to develop objective biomarkers for CTE, he said.

The study was published online August 21 in Neurology.

Outstanding Questions

Scientists have learned a great deal about the neuropathology of CTE just in the past few years, said Dr. Stern. For example, CTE is now known to be distinct from other neuropathological conditions in the distribution of the abnormal tau protein in the brain. All confirmed cases of CTE, including athletes involved in contact sports and military personnel, have had repeated brain trauma (RBT), but many questions still remain. Because not all people with a history of RBT develop CTE, what roles do genetics or other risk factors play? Also, why do some people get the disorder while others do not? How prevalent is it, and how can it best be prevented or treated?

For this study, researchers analyzed the brains of 36 participants in the Boston University Center for the Study of Traumatic Encephalopathy brain bank. All were male athletes, many of them professionals, including football players, hockey players, wrestlers, and boxers. All had a history of RBT and, on autopsy, showed no brain problems other than CTE, said Dr. Stern.

Military personnel, some of whom have a history of contact sports as well as traumatic brain injury while on duty, were specifically excluded from the study to avoid "clouding the picture" and to leave the "cleanest" sample possible, said Dr. Stern.

Researchers conducted postmortem interviews with next of kin to retrospectively learn what the participants were like during their life and the clinical issues they faced.

Using neuropathologic evidence, researchers categorized the cases on the 4-stage scale of CTE, from least severe (I) to most severe (IV). They also grouped the participants according to whether they had initial difficulties with cognitive functioning, such as episodic memory impairment and executive dysfunction (n = 11), or initial behavior symptoms or mood changes (n = 22).

The behavior/mood group, which was more likely than the cognitive group to display behaviors such as impulsivity and physical and verbal violence, developed symptoms earlier in life. Other studies have shown that athletes and others sustaining RBT have alterations in the white matter in their brain, but it is unclear whether behavior and mood changes are part of the CTE process or a consequence of RBT unrelated to the actual disease, said Dr. Stern

Dementia Diagnosis

Ten patients were diagnosed with dementia, all of whom had stage IV CTE. Of the 10 participants, 7 exhibited cognitive symptoms initially, 2 had mood symptoms initially, and 1 initially presented with behavioral changes.

The mean age of symptom onset for this dementia group was 57.7 years, and the mean age of dementia diagnosis was 72.6 years.

"What that tells me is that the clinical presentation of CTE can, on the surface, be hard to differentiate from the clinical presentation of Alzheimer's disease," said Dr. Stern. "If one does not look at the behavior and mood symptoms, if one does not look at the history of RBT, and just considers that this person has memory problems and is over 65, one may misdiagnose that person with [Alzheimer's disease] as opposed to CTE."

But physicians should be careful about jumping to the conclusion that someone with memory problems has CTE just because they have played sports, said Jeffrey Kutcher, MD, a sports neurologist and associate professor, neurology, University of Michigan, Ann Arbor, and member of the American Academy of Neurology, when approached for comment by Medscape Medical News.

"It's being treated as a diagnosis of exposure: If you played football or if you played hockey, you must have CTE," said Dr. Kutcher. "Time and time again, I see patients who have been labeled as having CTE, but after I see them and do a comprehensive neurological evaluation and uncover the layers of things that can cause their symptoms, lo and beyond, when treated appropriately, they're better."

Imagine being told that you have this disorder which has no treatment, and ends only one way. Dr. Jeffrey Kutcher

This unwarranted CTE label can have tremendous negative consequences, said Dr. Kutcher. "Imagine being told that you have this disorder which has no treatment, and ends only one way." It can contribute to depression, anxiety, and making sudden life decisions, such as quitting a job, and can increase the risk for suicide, he said.

"We need to understand that we are doing damage by making these diagnoses. It's not just that we're getting the diagnosis incorrect, it's that we are affecting people's lives significantly by getting it wrong," said Dr. Kutcher.

Dr. Stern shares this concern. "Just because someone has a history of playing football or hockey doesn't mean that any of their problems are necessarily due to CTE," he said.

That is why accurate clinical diagnostic criteria, along with objective biomarkers, are so important, he said. He and his research colleagues are conducting a large prospective study funded by the National Institutes of Health to develop such biomarkers.

APOE Genotyping

The current study also involved APOE genotyping from DNA extracted from the participants. The researchers found that there were significantly more E4 homozygotes in the sample than expected in a normal age-matched population. This effect was largely driven by the cognition group: 2 of the 11 subjects in this group and 1 of 22 participants in the behavior/mood group were homozygous for the E4 allele.

E4 homozygosity only occurs in 1% to 3% of the general population but in 10% of patients with Alzheimer's disease. The APOE E4 variant is the strongest known genetic risk factor for sporadic Alzheimer's disease.

According to the authors, future research should examine what aspects of RBT exposure (eg, types, severity, frequency, initial age, and duration of trauma) are associated with CTE, as well as what lifestyle variables such as diet, exercise, and steroid use are associated with the disease initiation and variability.

The findings should be viewed with some caution, as the study did not include a comparison group of former athletes without CTE. In addition, families participating in the study may have been more likely to witness more severe symptoms than those not participating, which could have affected the results.

The results of this study run counter to those of a study published in the August issue of the Journal of the International Neuropsychological Society that questioned the validity of the CTE. Asked to comment on those findings, Dr. Stern said it reflects a lack of understanding of the neuropathology of this disorder.

That previous study, by researchers led by Christopher Randolph, PhD, a neuropsychologist and clinical professor of neurology from Loyola University Medical Center in Maywood, Illinois, surveyed 513 former NFL players older than 50 years. They found a rate of mild cognitive impairment similar to late life cognitive impairment in the general population, but the authors did not examine these participants with measures that would distinguish Alzheimer's disease from CTE; for example, measures of executive function or behavior or mood, said Dr. Stern.

"What they're saying is that if you don't see a distinction on clinical presentation, then therefore there can't possibly be a distinct disease," he said. That is like saying that if people present with wheezing and coughing, there is no such thing as lung cancer because the coughing and wheezing look just like asthma, he added.

The authors also refer to CTE as a concept or hypothesis when, in fact, it is a very clearly accepted neuropathic condition, said Dr. Stern. "Saying that the symptoms are no different from normal aging shows absolutely no understanding of the neuropathology of neurodegenerative disease. It's a distinction in distribution and types of the abnormal proteins, not just whether it exists of not."

The study authors also refer to mild cognitive impairment as a disease when it is a clinical presentation, not a disease, he added.

The study was supported by the National Institutes of Health, the Department of Veterans Affairs, the National Operating Committee on Standards for Athletic Equipment, the Sports Legacy Institute, the National Football League, and the Andlinger Foundation. Dr. Stern has received National Institutes of Health grants and support from the Alzheimer's Association, the Andlinger Foundation, the National Operating Committee on Standards for Athletic Equipment, Janssen Alzheimer's Immunotherapy, Pfizer, and Medivation. He has been a paid consultant to Janssen Alzheimer's Immunotherapy, Outcome Science, and Elan Pharmaceuticals and has been a paid Expert Advisor to Eli Lilly. He receives royalties from Psychological Assessment Resources for the publication of neuropsychological tests.

Neurology. Published online August 21, 2013. Abstract


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