Trauma, TDP‐43, and amyotrophic lateral sclerosis

Widespread publicity surrounding a recently published article, entitled “TDP-43 Proteinopathy and Motor Neuron Disease in Chronic Traumatic Encephalopathy,”1 has engendered much consternation from our amyotrophic lateral sclerosis (ALS) patients because media interviews of the authors suggest “…brain trauma can mimic Lou Gehrig's disease”—New York Times, August 18, 2010, and “Maybe Lou Gehrig Didn't Die of Lou Gehrig's Disease”—Time magazine, August 17, 2010. Both statements are lacking in scientific validation. The published study1 reported on 12 patients with pathological changes of “chronic traumatic encephalopathy (CTE),” 3 of whom had pathological changes of ALS, and claims “…that repetitive head trauma experienced in collision sports might be associated with the development of a motor neuron disease.” The report was entirely pathological and lacked much clinical information. What was unique about the pathology in these 3 patients is that two aggregated proteins were noted in spinal cord motor neurons: TDP-43 and tau. TDP-43–positive inclusions have been described previously in many different diseases, including almost all cases of ALS, while tau is also present in many different disorders. The latter is more commonly associated with dementia, but it is far less commonly noted in motor neurons. Aggregated tau is also the pathological hallmark of frontotemporal dementia (FTD), and many familial forms of FTD overlap with ALS. Based on the findings of both TDP-43 and tau in motor neurons of these 3 patients, the authors conclude that the head trauma and chronic traumatic encephalopathy led to the “ALS-like” picture. A more likely explanation is that the patients with clinical evidence of CTE had CTE, whereas patients with clinical evidence of ALS had ALS. Thus, their 3 patients with CTE and ALS most likely had two different diseases, namely, CTE and ALS. In fact, one of the ALS patients was reported to have a “sibling with probable ALS,” suggesting a familial form of the disease. Selective ascertainment of subjects who had both head trauma and a clinical diagnosis of ALS obviously preclude determination by this study of any causal relation between these two conditions. ALS is diagnosed clinically by the demonstration of symptoms and signs of progressive and relatively selective deterioration of the nerves that control voluntary movement. An expanding list of genetic mutations causes ALS in a minority of patients, but most cases likely result from interaction of genetic and environmental triggers or risk factors, possibly including prior head trauma. These potentially disparate causes may underlie the notable clinical heterogeneity in ALS: the degree of upper and lower motor neuron clinical features differs between patients; the sites of onset can involve limb or speech function; there is a wide range in age of onset and rate of progression; and the degree of cognitive impairment in problem-solving and executive function varies widely. At autopsy, the hallmark of ALS is loss of motor neurons in the brain and spinal cord. Neuropathological investigations may allow future subcategorization of ALS, but at present the diagnosis of ALS is established by patients meeting the well-defined clinical criteria rather than identification of any stereotypical pathological findings. An additional complexity of the recent article arose when one of the authors, during media interviews, suggested naming the “new” condition in the 3 ALS patients “chronic traumatic encephalomyopathy,” or CTEM, even though no clinical or pathological evidence of muscle disease was reported. The 3 reported cases are too few and too highly selected to prove that CTE can lead to ALS. Clearly, both CTE and ALS occur separately in most patients; even if they share pathophysiological mechanisms in some individuals, there is no evidence that one condition causes the other. Professional athletes who succumb to ALS are particularly dramatic and heart-wrenching patients, and a link between ALS and trauma, especially with sports injuries, has been inconclusively sought for decades. Epidemiological studies are still trying to settle the matter. Dr. Lorene Nelson, a renowned neuroepidemiologist at Stanford University, recently commented that “…early case–control studies with weak study design features identified physical trauma and skeletal fractures as possible risk factors for ALS. However, one of the pioneers in neuroepidemiology, Dr. Len Kurland, wrote an article in 1992 saying that there was no strong epidemiological evidence of an association. This statement still holds today” (personal communication). In fact, the only studies that have demonstrated a significant association between head injury and ALS are retrospective (case–control) investigations that relied on patient and control subject recall of head injuries; these studies are very susceptible to recall bias. In contrast, records-based studies that did not rely on subject self-report did not find any association between head injury and ALS (risk ratios ranging from 0.8 to 1.05). Thus, the totality of evidence does not support the concept that a single head injury or repeated head injuries will lead to an increased risk of ALS. Dr. Nelson and colleagues conducted a rigorous population-based study of ALS in western Washington State that used methods to avoid recall bias, and they did not find an association of ALS with previous fractures, head injuries, or hospitalizations.2 However, a slightly higher number of fractures was observed in ALS patients compared with controls during the few years preceding ALS diagnosis. This was interpreted as showing that subclinical weakness can increase the risk of falls and fractures early in ALS. This finding has been substantiated by a recent cohort study conducted by scientists in Britain who linked 36 years of hospitalization data (with documentation of head injury) with ALS mortality data.3 They found that the risk of ALS was only elevated in the first year after head injury, and a similar transiently increased risk of ALS was observed after the occurrence of an arm or a leg injury that required hospitalization. The investigators interpreted these findings as providing evidence that head injury (and limb injury) was most likely to be a “consequence of incipient ALS” that caused an increased tendency to fall. What is most disconcerting to our ALS patients is the implication that they may have been misdiagnosed. With the extensive media coverage, our patients have been calling, concerned about whether they really have ALS, or something called CTEM. They also want our input as to whether Lou Gehrig really had ALS, especially as the coauthors suggest that Lou Gehrig may have suffered from CTEM rather than ALS. Gehrig was definitively diagnosed with ALS by all the clinical criteria we have noted. What caused his ALS is as unclear today as it was in his time. He clearly had multiple sports injuries, but at no time did he manifest evidence of the cognitive dysfunction characteristic of chronic traumatic encephalopathy. Whether head trauma may have played a role in Gehrig's development of ALS can never be verified, but it is a complete disservice to his place in history as an icon for ALS to suggest that his disease was not ALS. Further studies on the role of TDP-43 and tau as potential therapeutic targets are warranted as are studies of the role of trauma in ALS. In the absence of scientific evidence indicating that CTE causes “an ALS-like syndrome,” we must be sensitive to the plight of patients and families who currently confront the ravages of ALS.