TDP-43 and Tau Entangle Athletes’ Nerves in Rare Motor Neuron Disease

Getting hit in the head might not just ring your bell—in rare cases, it may predispose athletes in contact sports to motor neuron disease, according to a paper posted online August 11 by the Journal of Neuropathology & Experimental Neurology. Researchers from Boston University’s Center for the Study of Traumatic Encephalopathy report on three cases—two former football players and one former boxer—who suffered multiple head injuries as sportsmen and were later diagnosed with amyotrophic lateral sclerosis. Upon autopsy, the scientists discovered each had unusual pathology, comprising the TDP-43 one expects from ALS, as well as tau tangles uncommon in the disease.

“One can get a disorder that looks, for all the world, like ALS—but really is related to head trauma,” said study co-author Daniel Perl of the Mount Sinai School of Medicine in New York City. The results could explain why both athletes and war veterans, who are more likely to sustain head injury than the general population, also have unusually high rates of ALS (Belli et al., 2005; Weisskopf et al., 2005).

The New York Times trumpeted the study as evidence that baseball player Lou Gehrig, who suffered many concussions during his career, might not have had typical ALS, which is often referred to in the U.S. as “Lou Gehrig’s disease.” This un-testable implication has worried some neurologists, who suggest that some people with ALS would be sorry to lose kinship with the baseball legend. “It is perfectly appropriate to still call ALS Lou Gehrig’s disease,” said Leo McCluskey of the University of Pennsylvania in Philadelphia.

Scientists led by Ann McKee and Robert Stern at Boston University have already shown that head injury can lead to Alzheimer-like symptoms, producing enough data to help persuade the National Football League to fund research and run public-safety announcements about the risks of concussions (see ARF related news story and ARF Live Discussion). The Center for the Study of Traumatic Encephalopathy, a joint venture between Boston University and the Sports Legacy Institute, maintains a registry of athletes, professional and amateur, who have pledged to donate their brains upon death. Researchers at the center have defined a condition called chronic traumatic encephalopathy, or CTE, a progressive tauopathy associated with dementia and parkinsonism (McKee et al., 2009). Repeated head trauma also ramps up amyloid-β deposition and hampers cognition in mice (Uryu et al., 2002).

Previous epidemiological studies have suggested that head injuries could be relevant to ALS as well. In one study, researchers reported that multiple head injuries tripled the risk of ALS (Chen et al., 2007). The current work, led by McKee, is the first to offer pathological data. The study authors report on 12 cases of CTE. “Three of them had died of ALS, and that seemed excessive,” Perl said. They examined brain and spinal cord tissue for evidence of neurodegenerative disease. In 10 CTE brains, the researchers observed TDP-43 proteinopathy, accumulations of a protein commonly linked to ALS and frontotemporal lobar degeneration (see ARF related news story on Neumann et al., 2006), in addition to the tau tangles of CTE. The three men who suffered ALS-like disease also showed this TDP-43-and-tau pathology in the spinal cord. In contrast, 12 control cases, who had sporadic ALS, had the typical TDP-43 proteinopathy, but not tau pathology. A dozen healthy controls evinced no TDP-43 pathology and very few tau tangles.

“There is no study like this on TDP-43,” wrote John Trojanowski of the University of Pennsylvania in an e-mail to ARF. “The novel aspect of this paper is that it links TDP-43 pathology to traumatic brain injury.” The results lend support to the idea that TDP-43 is a common factor in most kinds of ALS, Trojanowski wrote. CTE-linked ALS, in fact, looks most like another rare form of TDP-43-and-tau ALS clustering on the island of Guam (Geser et al., 2008). However, Perl noted, people in Guam do not experience high rates of head trauma.

“Those of us in the field of ALS have always been intrigued about the relationship of trauma to ALS,” said neurologist Richard Lewis of Wayne State University in Detroit, Michigan. Lewis is also a spokesperson for the American Academy of Neurology. People often show their first neurodegenerative symptoms after an accident, he noted. The current study is “intriguing,” but “preliminary,” he said, pointing out that there were only three cases available for study and the authors made qualitative, but not quantitative, judgments of pathology.

Scientists have few explanations, thus far, as to how head injury could lead to neurodegenerative disease. Perhaps, Trojanowski speculated, inflammation at the injury site could lead to downstream damage. Another possibility researchers raised is that an athlete with a predisposition to neurodegeneration—from a mutation or other causes—might have the disease course speed up after repeated traumas.

Whether Lou Gehrig’s disease is the result of head injury, genetic mutations, or causes unknown does not matter much in the clinic. At this point, McCluskey said, disease origin makes little difference to therapy; all comers have the same, unfortunately limited, treatment options. “ALS is a syndrome,” Lewis added. “There are multiple ways that people can get ALS.” And Lewis also noted that the current data do not suggest it’s time to pull the kids out of football practice; these cases are “incredibly unusual,” he said. “It’s not like everyone has to stop doing contact sports.”

The study authors hope to pursue their understanding of CTE-ALS in animal models. Even if injury-based ALS is different from the most common sporadic form, the mechanisms are likely related, Perl said. “One will teach us about the other.”—Amber Dance

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References

News Citations

  1. NFL Does About Face on Head Injury, Funds Researchers
  2. New Ubiquitinated Inclusion Body Protein Identified

Webinar Citations

  1. Sports Concussions, Dementia, and APOE Genotyping: What Can Scientists Tell the Public? What’s Up for Research?

Paper Citations

  1. Belli S, Vanacore N. Proportionate mortality of Italian soccer players: is amyotrophic lateral sclerosis an occupational disease?. Eur J Epidemiol. 2005;20(3):237-42. PubMed.
  2. Weisskopf MG, O'Reilly EJ, McCullough ML, Calle EE, Thun MJ, Cudkowicz M, Ascherio A. Prospective study of military service and mortality from ALS. Neurology. 2005 Jan 11;64(1):32-7. PubMed.
  3. McKee AC, Cantu RC, Nowinski CJ, Hedley-Whyte ET, Gavett BE, Budson AE, Santini VE, Lee HS, Kubilus CA, Stern RA. Chronic traumatic encephalopathy in athletes: progressive tauopathy after repetitive head injury. J Neuropathol Exp Neurol. 2009 Jul;68(7):709-35. PubMed.
  4. Uryu K, Laurer H, McIntosh T, Praticò D, Martinez D, Leight S, Lee VM, Trojanowski JQ. Repetitive mild brain trauma accelerates Abeta deposition, lipid peroxidation, and cognitive impairment in a transgenic mouse model of Alzheimer amyloidosis. J Neurosci. 2002 Jan 15;22(2):446-54. PubMed.
  5. Chen H, Richard M, Sandler DP, Umbach DM, Kamel F. Head injury and amyotrophic lateral sclerosis. Am J Epidemiol. 2007 Oct 1;166(7):810-6. PubMed.
  6. Neumann M, Sampathu DM, Kwong LK, Truax AC, Micsenyi MC, Chou TT, Bruce J, Schuck T, Grossman M, Clark CM, McCluskey LF, Miller BL, Masliah E, Mackenzie IR, Feldman H, Feiden W, Kretzschmar HA, Trojanowski JQ, Lee VM. Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Science. 2006 Oct 6;314(5796):130-3. PubMed.
  7. Geser F, Winton MJ, Kwong LK, Xu Y, Xie SX, Igaz LM, Garruto RM, Perl DP, Galasko D, Lee VM, Trojanowski JQ. Pathological TDP-43 in parkinsonism-dementia complex and amyotrophic lateral sclerosis of Guam. Acta Neuropathol. 2008 Jan;115(1):133-45. PubMed.

External Citations

  1. The New York Times
  2. Center for the Study of Traumatic Encephalopathy
  3. Sports Legacy Institute

Further Reading

Papers

  1. King A, Sweeney F, Bodi I, Troakes C, Maekawa S, Al-Sarraj S. Abnormal TDP-43 expression is identified in the neocortex in cases of dementia pugilistica, but is mainly confined to the limbic system when identified in high and moderate stages of Alzheimer's disease. Neuropathology. 2010 Aug;30(4):408-19. PubMed.
  2. Horner RD, Kamins KG, Feussner JR, Grambow SC, Hoff-Lindquist J, Harati Y, Mitsumoto H, Pascuzzi R, Spencer PS, Tim R, Howard D, Smith TC, Ryan MA, Coffman CJ, Kasarskis EJ. Occurrence of amyotrophic lateral sclerosis among Gulf War veterans. Neurology. 2003 Sep 23;61(6):742-9. PubMed.
  3. Yoshiyama Y, Uryu K, Higuchi M, Longhi L, Hoover R, Fujimoto S, McIntosh T, Lee VM, Trojanowski JQ. Enhanced neurofibrillary tangle formation, cerebral atrophy, and cognitive deficits induced by repetitive mild brain injury in a transgenic tauopathy mouse model. J Neurotrauma. 2005 Oct;22(10):1134-41. PubMed.
  4. Schmidt ML, Zhukareva V, Newell KL, Lee VM, Trojanowski JQ. Tau isoform profile and phosphorylation state in dementia pugilistica recapitulate Alzheimer's disease. Acta Neuropathol. 2001 May;101(5):518-24. PubMed.
  5. Schmidt S, Kwee LC, Allen KD, Oddone EZ. Association of ALS with head injury, cigarette smoking and APOE genotypes. J Neurol Sci. 2010 Apr 15;291(1-2):22-9. PubMed.

Primary Papers

  1. McKee AC, Gavett BE, Stern RA, Nowinski CJ, Cantu RC, Kowall NW, Perl DP, Hedley-Whyte ET, Price B, Sullivan C, Morin P, Lee HS, Kubilus CA, Daneshvar DH, Wulff M, Budson AE. TDP-43 proteinopathy and motor neuron disease in chronic traumatic encephalopathy. J Neuropathol Exp Neurol. 2010 Sep;69(9):918-29. PubMed.

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