Article In Brief
PET imaging showed elevated levels of tau, but not amyloid-beta, in brain areas implicated in chronic traumatic encephalopathy (CTE) in former NFL players. The imaging offers insights into the pathophysiology of CTE but is not ready for clinical use, the investigators said.
Using an experimental PET scan radioligand, flortaucipir, researchers identified higher phosphorylated tau levels in more than two dozen former NFL players with cognitive and neuropsychiatric symptoms compared with age-matched controls without symptoms and with no history of traumatic brain injury (TBI).
The tau deposits were found in the same areas where pathologists have identified tau related to chronic traumatic encephalopathy (CTE), the study, published in the April 10 online edition of The New England Journal of Medicine, found.
The findings suggest that scientists can measure tau deposits in living people suspected of having CTE, but for now they said the scans are not ready to be used to diagnose CTE in individual patients.
“The test is an important advance towards our progress in developing a diagnostic biomarker for CTE,” the lead study scientist Robert Stern, PhD, professor of neurology, neurosurgery and anatomy and neurobiology at Boston University (BU) School of Medicine told Neurology Today. “We need to refine how we analyze the tau data to be better able to detect elevations on an individual level. We are not there yet. This experimental PET scan ligand is not ready for use in the clinic.”
But the findings do move the field towards a deeper understanding of CTE—how it develops and progresses, he said. Pathology studies show the brains of people with CTE is riddled with tau but there is little or no amyloid neuritic plaque deposition, Dr. Stern said. It also is not known how common CTE is or what the specific risk factors are for this neurodegenerative disease.
“As far as we know, CTE has a cause: exposure to repeated hits to the head,” added Dr. Stern. “The findings from this study bring us one important step closer to being able to diagnose CTE during life. There are now biomarkers to help diagnose Alzheimer's disease and we need similar biomarkers for CTE.”
BU scientists collaborated on this study with other dementia experts from Mayo Clinic Arizona, the Banner Alzheimer's Institute, Arizona State University and Brigham and Women's Hospital. Avid Radiopharmaceuticals, makers of the tau ligand, donated the tracer and helped fund the study. Several Avid scientists were co-authors of the study.
Study Methodology, Findings
To get a better understanding of CTE, the researchers felt it was important to use PET tracers that bind to both amyloid and tau. They recruited 26 former NFL players with a range of cognitive, behavioral and mood problems, and 31 men with no history of TBI. The men in both groups were between 40- and 69-years-old. Each of the study participants was administered tests to identify cognitive, behavioral, and mood problems. The researchers also had histories of how long the football players spent on the field. The former NFL study recruits were primarily line backers, linemen, and defensive end players. These players suffer the most blows to the head compared with quarterbacks and kickers.
The rate of depression was high, about 80 percent, among former NFL players. And on a common test of memory, 35 percent of the former players had problems on the delayed recall on a verbal list learning task.
The investigators found significantly higher tau PET levels in the former NFL players as a group compared with the controls. It was impossible to see individual differences in the two groups because the signal was small and the location of the signal was too variable. The tau deposits were primarily in the bilateral superior frontal lobes, the bilateral medial temporal lobes, and the left parietal lobe.
The researchers were able to correlate the higher uptake levels with the years of play time on the field, however. “The more they played, across all levels, from elementary school to the pros—the more tau deposition they had,” said Dr. Stern.
There were no significant differences on the amyloid PET scans–one person among the former NFL players and one in the controls—had mildly elevated amyloid-beta levels. Dr. Stern said that this was not surprising because they knew amyloid deposition was not part of the CTE pathological process. And this finding was important to demonstrate what they were seeing in living people was consistent with what they found in autopsy studies.
“We need to refine how we analyze the tau data to be better able to detect elevations on an individual level. We are not there yet. This experimental PET scan ligand is not ready for use in the clinic.”
—DR. ROBERT STERN
Interestingly, the scientists could not find a relationship between the amount of tau in the brains of former NFL players and the clinical symptoms. “Just because there is tau deposition doesn't mean that there is neurodegeneration yet,” explained Dr. Stern. “It's also possible that our sample was too small to show an association.”
Dr. Stern pointed out the public and many clinicians believe that CTE is synonymous with Alzheimer's, but it is not. For one thing, both amyloid and tau are critical to a diagnosis of AD, he said, and in CTE, tau is the culprit. The tau deposits in CTE are uniquely found around small blood vessels, typically at the depths of the cortical sulci, he explained.
A March 21 study by other researchers in the journal, Nature, showed that the tau species found in AD and CTE, though very similar, had specific molecular differences, Dr. Stern noted. Also, there is growing evidence that there is a large vascular impact in the CTE pathology. The white matter damage could be the result of the vascular impact but the white matter damage could also be due to direct effects of the repeated blows to the head. (The BU group is now studying the relationship between cerebrovascular changes and CTE pathology and the clinical presentation).
“These findings suggest that the symptoms that we see in these former athletes is not attributable to Alzheimer's disease,” added Eric Reiman, MD, executive director of the Banner Alzheimer's Institute in Phoenix and a senior author of the NEJM paper. “It is important to study athletes with and without concussion to figure out what other factors put people at risk.”
He said that it is possible that there will be better tau ligands. There are different tau species involved with various neurodegenerative diseases and it may be that the ligand they used is not sensitive to all tau species.
“Even if we see these changes in groups, we still don't know whether this test will have prognostic value, and whether the tau depositions are related to eventual cognitive decline “ Dr. Reiman added.
The NIH-funded, multisite DIAGNOSE CTE research project will hopefully help answer some of the open questions about how CTE takes hold in the brain, Drs. Stern and Reiman agreed. The study has been recruiting former football players with more variability in their histories and symptoms: 240 former NFL players and former college football players who have no symptoms will be compared with those with dementia, and controls who never played contact sports and who are asymptomatic. The study is being conducted at four different research centers, and testing includes three days of testing, comprising a medical history, neurological exam, MRIs, collection of blood and saliva, lumbar puncture, amyloid PET, tau PET, and neurocognitive testing and questionnaires on mood and behavior. The scientists are almost done collecting the baseline data. The men in the study will be re-tested three years later.
“The [current] study is truly novel and interesting from a scientific point of view because it shows that the tau ligand was elevated in this group of men who had repeated concussive and sub-concussive blows and that there was a correlation with their years of playing time,” said David S. Knopman, MD, FAAN, professor of neurology at Mayo Clinic in Rochester, MN. “But it is really important to emphasize that the findings apply to a group and the investigators could not tell on an individual level who was a former football player and who was a control. This is quite different from the situation in Alzheimer's disease where tau PET imaging often demonstrates dramatic changes on individual scans.”
Dr. Knopman had no access to this study data but he is an advisor to the ongoing DIAGNOSE study.
“...it is really important to emphasize that the findings apply to a group and the investigators could not tell on an individual level who was a former football player and who was a control. This is quite different from the situation in Alzheimer's disease where tau PET imaging often demonstrates dramatic changes on individual scans.”
—DR. DAVID S. KNOPMAN
“To be able to image presumed pathology in real time and in living people is so much more insightful than relying on autopsy material,” he added. The DIAGNOSE study will include diffusion tensor imaging [DTI] scans, which provide a measure of white matter integrity. “If it turned out that DTI results did correlate with cognitive and behavioral changes and tau did not, it would point to a white matter disease as the basis for the cognitive and behavioral changes. This would be very important information. We know that white matter damage can result from head trauma.”
“We have similar data,” said Gil Rabinovici, MD, the Edward Fein & Pearl Landrith distinguished professor in the departments of neurology, radiology and biomedical imaging at University of California, San Francisco. “We see some football players with a subtle tau PET signal, and it is well below what we see in Alzheimer's patients.
“Their findings show that we may be able to detect CTE in living patients with PET and begin to understand how prevalent it is and how much head trauma does one need and whether there are factors that can shape risk and resilience. Until we have people imaged during life and then come to autopsy we really won't know how well these tau tracers work at detecting tau pathology.”
“There is a big overlap between the former football players and controls. The low tau signal makes it impossible to make a differential diagnosis on an individual,” added Michael W. Weiner, MD, professor of neurology, radiology, medicine and psychiatry at UCSF and principal investigator of the Alzheimer's Disease Neuroimaging Initiative. “It would be like looking at the height of men and women and saying that someone is male just because he is tall. There is not enough information. My concern is that people will now think that we can diagnose CTE. That is not what these scientists are saying. That would definitely be wrong.”
Dr. Stern has received consultant fees from Biogen as a member of the Advance Medical Education International Working Group and from Ely Lilly as a member of the Executive Committee for AZD3293 Alzheimer's disease studies; he has received royalties from Psychological Assessment Resources, Inc. for published neuropsychological tests. Dr. Weiner has received compensation from Ely Lilly as part of their global AD board. Dr. Rabinovici reported receiving grants from the American College of Radiology, the Alzheimer's Association, Avid Radiopharmaceuticals Inc., GE Healthcare, Life Molecular Imaging, and Eli Lilly. He has received personal fees from Eisai, Piramal Imaging, Merck, and Genentech. Dr. Knopman reported no competing interests.