A team of Boston scientists has published a study suggesting that patients with chronic traumatic encephalopathy (CTE) may be at greater risk of motor neuron disease (MND). The report, published online Aug. 11 in the Journal of Neuropathology and Experimental Neurology, is now being hotly debated as neurologists field calls from worried head injury patients and patients with amyotrophic lateral sclerosis (ALS) who wonder whether their motor neuron disease was triggered by repeated injuries to the head.
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The study has also generated much attention in the lay press after the lead investigator, Ann C. McKee, MD, director of the neuropathology laboratory for the New England Veterans Administration Medical Center, was quoted in an Aug. 18 article in The New York Times questioning whether Lou Gehrig had the classic sporadic case of ALS.
“Here he is, the face of this disease,” Dr. McKee said in the New York Times article, “and he may have had a different disease as a result of his athletic experience.” But the Journal of Neuropathology and Experimental Neurology paper itself made no such claims about the famed first baseman.
In an interview with Neurology Today, Dr. McKee said that Lou Gehrig might have suffered six or seven major concussions during his career. Such blows to the head are not as common in baseball as they are in football or boxing.
“It is clearly a possibility that the head trauma he suffered may have contributed to his motor neuron disease,” Dr. McKee said. Lou Gehrig did not have any of the features of CTE, which looks more like the memory loss and cognitive decline that has come to define dementia pugilistica. “It makes you wonder, “ she said. “If trauma can trigger an ALS-like syndrome it gives us an opportunity to look at nerve cells early in the disease. It is very exciting.”
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Dr. McKee and her colleagues have been in the thick of the research on sports-related traumatic encephalopathy, particularly among former NFL players. The Boston scientists had access to postmortem brain and spinal cord tissue samples from 12 professional athletes with CTE. Three of the 12 athletes also had been diagnosed with ALS.
The investigators studied the pathology in the tissue and compared it to an equal number of patients who died with sporadic ALS and others who had no signs of a neurological disorder at death. The three athletes with CTE and MND — the study authors did not refer to it as ALS — had an abundant accumulation of tau and TAR DNA- binding protein 43 (TDP-43) in their brains and spinal cord, which they say sets them apart from the sporadic ALS patients who did not have tau deposits and have different patterns of TDP-43 accumulation.
The authors believe that the “shared presence of two aggregated phosphorylated proteins associated with neurodegeneration in the great majority of cases argues against the coincidental occurrence of CTE and sporadic ALS, suggesting instead that a common stimulus provokes the pathological accumulation of both proteins.”
“This pattern is unique and has not been found before,” Dr. McKee added. She said that the finding helps explain the mysterious cluster of MND among professional athletes — three cases of ALS among the San Francisco 49ers and another cluster of cases among Italian soccer players.
“It is too early to be sure,” Dr. McKee said. “It suggests a history of repetitive head or neck trauma may trigger this unique disease.”
John Q. Trojanowski, MD, PhD, co-director of the Center for Neurodegenerative Disease Research and director of the Institute on Aging and an endowed professor of geriatric medicine and gerontology at University of Pennsylvania, said that the study does break new ground in describing a new protein involved in CTE. TDP-43 is increased in the brains of these athletes with traumatic brain encephalopathy, said Dr. Trojanowski, who was not involved with the paper. It has already been associated with ALS.
“We are all trying to better understand how common this is and what types of trauma this pathology is associated with,” said Andrew Budson, MD, deputy chief of staff at the VA Boston Health System and professor of neurology at Boston University.
But ALS experts say that the small numbers in the study make it difficult to draw the conclusions that this is a new condition or that CTE can increase the risk for ALS. “The researchers are drawing inferences that may not be true,” said Carmel Armon, MD, professor of neurology at Tufts University School of Medicine and chief of the Division of Neurology at Baystate Medical Center. That ALS and CTE both involve an accumulation of TDP-43 does not mean that one leads to another, he said.
“The principal TDP-43 data do not permit making a distinction between the two possibilities — that the two conditions occurred coincidentally in some patients, or that one is linked to the other, because the findings when CTE and ALS occur together are largely the sum of what would be seen in each condition separately.”
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Dr. Armon noted that an additional limitation of the study is that an autopsy allows scientists to see the end stage of the disease, and probably does not provide the best understanding of what is happening in the early stages of a chronic neurodegenerative disease.
The Boston investigators reported that TDP-43 immunopathological changes are far more extensive than seen in typical ALS, said Hiroshi Mitsumoto, MD, medical director of the Eleanor and Lou Gehrig MD/ALS Research Center and professor of neurology at the Neurological Institute of Columbia University Medical Center and the New York Presbyterian Hospital. But tau pathology is not seen in sporadic ALS, he said. “We cannot exclude the possibility that this is a coincidence of CTE and ALS.”
“A primary problem with the study was that cases were selected based on a history of head trauma with or without a recent diagnosis of ALS,” said Lucie Bruijn, PhD, chief scientist for the ALS Association. “Given this means of ascertainment, it is not at all surprising that cases with a diagnosis of ALS and head trauma showed neuropathological changes indicative of both ALS and head trauma. To confirm any conclusions about the relationship between head trauma and ALS will require additional research involving a much larger population.”
“We clearly need more clinical research, extensive studies in patients with ALS and trauma,” Dr. Mitsumoto agreed. “A prospective epidemiological investigation must be carried out to see if major trauma or repeated head trauma are associated with motor neuron disease.”
Robert G. Miller, MD, program director of the Forbes Norris MDA/ALS Research Center at the California Pacific Medical Center, said that it is possible that many roads can converge on ALS. If trauma does increase the risk for ALS it would not be a new disease but one more possible trigger.
“The scientists have posed an interesting hypothesis but they have by no means proven a relationship between CTE and ALS,” said Dr. Miller. “There is no indication that head trauma selectively damages the motor neurons. It is just wrong to imply that people with ALS might have CTE based on this small unconvincing study.”
WHAT ABOUT LOU GEHRIG?
Dr. Armon said that he has fielded queries from his patients about whether concussions or other brain trauma could cause ALS. Also, many of his colleagues have raised concern about the interpretation that Lou Gehrig may not have had ALS. “Such an interpretation is not in keeping with the data” of this study,” he said. “There will have to be a major effort to set the scientific record straight. Nothing in the paper shakes my belief that Lou Gehrig had ALS.”
ALS doctors fielding calls agree. “I remain concerned about this paper and the confusion it will inevitably stir in my patients,” said Leo McCluskey, MD, associate professor of neurology at the University of Pennsylvania. “They are taking this way too far.”
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ARTICLE IN BRIEF
A new paper suggesting an association between chronic traumatic encephalopathy and motor neuron disease is the subject for debate among ALS and movement disorders experts.
McKee AC, Gavett BE, Stern RA, et al. TDP-43 proteinopathy and motor neuron disease in chronic traumatic encephalopathy. J Neuro-pathol Exp Neurol 2010; E-pub 2010 Aug. 11.
©2010 American Academy of Neurology