New research appears to confirm that positron emission tomography (PET) imaging using the [F-18] FDDNP tracer can identify the distinctive brain tau pathology of chronic traumatic encephalopathy (CTE) in a living person.
The neuropathological findings during a brain autopsy of a retired National Football League (NFL) player confirmed the “fingerprint” signature of CTE uncovered by a previous in vivo [F-18] FDDNP-PET scan.
Dr Bennet Omalu
“This is showing us that FDDNP is doing what we believe it should be doing, so this is a very major milestone,” lead author, Bennet Omalu, MD, Department of Medical Pathology and Laboratory Medicine, School of Medicine, University of California, Davis, told Medscape Medical News
“It’s encouraging us to now take this up to the next level — a phase 3 clinical trial.”
Dr Omalu hopes the results of such a trial will eventually lead to FDDNP-PET being used to diagnose CTE and to differentiate that condition from other dementia types of dementias.
The paper was published online November 10 in Neurosurgery.
Distinctive Signature
[F-18]FDDNP (-(1-{6-[(2-[F-18]fluoroethyl)(methyl)amino]-2-naphthyl}ethylideine)malononitrile) is a molecular imaging probe that binds to both amyloid and tau proteins, which can then be picked up by PET scanning. FDDNP-PET is thought to be the only method of imaging tau tangles in living humans.
Prior research showed that CTE exhibits a distinctive neuropathological signature with differential and selective topographic vulnerability of brain regions. Some of these vulnerable brain regions may include the midbrain, pons, limbic structures, parasagittal, and periventricular regions of the brain.
“These are the sagittal and parasagittal regions of the brain that appear to bear the maximal shearing, angular–rotational acceleration–deceleration forces in traumatic brain injuries and in American football players,” the authors write.
The pathology progression of CTE involves neuronal circuits that are consistent with clinical symptoms. Hallmark CTE symptoms include mood and behavioral symptoms in younger patients and cognitive deficits, and eventually dementia, in older patients at advanced stages of CTE, the investigators note.
Fred McNeill at Minnesota Vikings training camp, Aug. 19, 1975. AP
The patient in the study was an African American man. Although unnamed in the paper, Dr Omalu confirmed to Medscape Medical News that he was NFL football player Fred McNeill, who played in the league for 22 years, including 12 years as a linebacker for the Minnesota Vikings. He died in 2015.
McNeill was 59 years old at the time of his [F-18] FDDNP-PET scan. The scan identified tau pathology as well as amyloid pathology in certain brain regions. It also identified regions of the brain with only tau pathology, or predominant tau pathology, such as the midbrain and amygdala.
Motor Deficits
Two years after his scan, McNeill’s wife noticed his progressive motor deficits, including inability to button his shirts, zip his pants, or tie his shoes, and then to feed himself. She reported that he developed muscle twitching in his arms and decreased muscle mass in his shoulders and arms.
About 17 months before death, he was diagnosed with motor neuron disease/amyotrophic lateral sclerosis in addition to his pre-existing clinical and presumptive diagnosis of CTE.
During his final months, he was admitted to a nursing home with dehydration, failure to thrive, progressive dysphagia, incontinence, progressive neck and limb weakness, and slurred speech. He died at age 61.
The patient’s brain was donated and harvested within 48 hours of death. Researchers compared proteinopathies in the brain to documented topographic distribution of the PET brain imaging findings.
They obtained correlations between the PET distribution volume ratios and tau, amyloid, and TDP-43 (TAR DNA-binding protein 43) deposit densities. TDP-43 is a protein found in common subtypes of frontotemporal dementia and amyotrophic lateral sclerosis.
The results showed that the tau regional findings and densities obtained from PET imaging were highly correlated with the postmortem autopsy findings (Spearman rank-order correlation coefficient [rs] = 0.592; P = .0202). The highest relative distribution volumes were in the parasagittal and paraventricular regions of the brain and the brain stem.
The researchers found no statistical correlation with amyloid deposition (rs = −0.481; P = .0695) or with the presence of TDP-43 (rs = 0.433; P = .1066).
These findings, said Dr Omalu, suggest that FDDNP can differentiate CTE from Alzheimer’s disease and other dementias.
The new findings indicate that [F-18] FDDNP-PET brain imaging may be a useful in vivo radiologic tool for the clinical assessment and diagnosis of traumatic encephalopathy syndromes, including chronic traumatic myeloencephalopathy, which affects the spinal cord as well as the brain, and CTE post-traumatic stress disorder, as well as CTE, the authors note.
A potential limitation of this new research was the 52-month lag between the brain imaging and brain autopsy.
“Since CTE is a progressive disease, further progression of neuropathological substrates should have existed over this period,” the authors write.
This is particularly evident in this case, when the patient was diagnosed with motor neuron disease 2 years after the PET scan and experienced advancing symptoms until death, they add.
However, said Dr Omalu, “we factored that into our statistical analysis.”
Clinical Trial Planned, but Funding Needed
Dr Omalu and colleagues have been consulting with the US Food and Drug Administration regarding a clinical trial that would test the hypothesis that FDDNP can identify CTE changes in the brains of living people and can differentiate CTE from other dementias. The clinical trial would last 2 to 3 years, he said.
“Everything is in place to go,” said Dr Omalu. “The only thing holding us back is funding.”
Although Dr Omalu is enthusiastic about the new confirmatory findings, his excitement “is very toned down.”
“My excitement will be real when somebody, or some organization, gives me $5 million to do this study,” he said.
Dr Omalu predicted that once that funding is secured and the trial gets under way, a commercial test for CTE could be available within 5 years.
Another study author, Julian Bailes, MD, Department of Neurosurgery, North Shore University Health System and University of Chicago Pritzker School of Medicine in Illinois, told Medscape Medical News that such a test would be extremely useful.
“It could be used to longitudinally follow patients to measure how much tau protein deposits they have and, if there is ever a treatment, to monitor their progress.”
Although CTE to date is “a bit of an orphan disease,” this new research “may spur others” to look at potential treatments, said Dr. Bailes.
Speculating on such potential treatment approaches, Dr Bailes said they might include psychiatric interventions, brain antioxidants, and perhaps Alzheimer’s disease drugs already available.
Or, he added, a commercial test could be used as a preventive tool. “Individuals who are actively participating in sports or in the military could be scanned and we could get them out of harms way” if necessary.
Dr Omalu and Dr Bailes are members of TauMark LLC, a limited liability company that owns the licensing rights to [F-18] FDDNP-PET technology. Funding was received from the National Institutes of Health, the Toulmin Foundation, Sheridan Lorenz, and Robert and Marion Wilson. No company provided research funding for this study. Dr Omalu and Dr Bailes are directors of Brain Injury Research Institute, Inc (BIRI), a charitable/research company that performs brain autopsies and analysis including CTE diagnosis. No director has received any compensation from BIRI for any work performed or otherwise.
Neurosurgery. Published online November 10, 2017. Abstract
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