What Caused Muhammad Ali’s Parkinson’s Disease?

By Matthew Hutson

June 10, 2016

Boxing and pesticide exposure both elevate the risk of the disease, but we’ll likely never know whether one was to blame.

Muhammad Ali throws a punch as he poses for photographers on his arrival at the Uptown Theater in Washington, D.C., for the premiere of Ali on Dec. 17, 2001.

During Muhammad Ali’s boxing career, scores of people played armchair coach. He was Great because of his footwork, or because of his hand speed, they argued. Once both began to lose their fearsome grace, people stopped coaching and started diagnosing. He suffered Parkinson’s disease because of his boxing, the newly minted armchair neurologists said. Or, as his family has suggested, his disease was due to the exposure to pesticides he had experienced earlier in life. But the truth is that we may never know what caused his Parkinson’s—or that of the vast majority of those diagnosed. To argue otherwise is as speculative as asserting that Ali would surely have trounced a time-traveling Tyson.

Parkinson’s disease is a neurodegenerative disorder in which cells in a part of the brain that controls movement begin to die. As a result, patients slow down, lose coordination, and tremble. It is the second-most-common neurodegenerative disease, after Alzheimer’s, afflicting about 1 percent of the population older than 60 in developed countries.

A growing awareness of the perceived link between the head trauma associated with playing football and chronic traumatic encephalopathy, or CTE, a neurodegenerative disease leading to disorientation, depression, and dementia, makes a connection between Ali’s boxing and his Parkinson’s seem obvious. But the science is not so clear. 

Boxing may have influenced Ali’s disease, but the data are far from conclusive.

Mechanisms do exist through which traumatic brain injury, or TBI, might lead to Parkinson’s. Head trauma can increase inflammation, which plays a role in the disease. Trauma also disrupts mitochondria, cell parts necessary for energy production, and it releases glutamate, an excitatory neurotransmitter that increases energy demands; metabolic dysfunction can play a role in the development of Parkinson’s. Most important, head trauma can lead to a buildup in the brain of a protein called alpha-synuclein. Alpha-synuclein and other proteins clump together to form deposits called Lewy bodies in the substantia nigra, a part of the brain important for movement. Lewy bodies in the substantia nigra are the most prominent biological signature of Parkinson’s disease.

Clinical studies linking TBI to Parkinson’s disease, however, have been inconsistent. Some show an influence, and others don’t. A 2014 meta-analysis looked at 65 studies and considered only five of them sound. Of the five, only one showed a statistically significant correlation, and this may have resulted from “reverse causality.” That is, early-stage parkinsonian symptoms may have led to falls and head injuries, rather than vice versa. A more recent study compared patients who’d had a TBI to those who’d had fractures but no TBI (thus controlling for clumsiness) and found that people who’d had a TBI had a 44 percent greater risk of developing Parkinson’s. But many TBI studies simply compare people with one concussion to people with zero. What happens when you look at athletes who’ve spent their whole careers offering their heads as punching bags?

What’s now called CTE was once known as dementia pugilistica, or punch-drunk syndrome, for the boxers who suffered its ravages. But even the connection between this disease and boxing is ambiguous—only 20 percent of retired boxers show chronic traumatic brain injury. And while CTE shares some similarities with Parkinson’s, they are not identical. One study of 704 retired Thai boxers found a prevalence of Parkinson’s similar to that of general Asian populations. The data hinted at a higher rate for boxers with more than 100 professional fights under their belts, but the researchers didn’t have enough cases to calculate the rate precisely. Ali had 61 bouts. So boxing may have influenced Ali’s disease, but the data are far from conclusive.

Ali’s family offers another potential cause for his condition: pesticides. In a recent interview with the Los Angeles Times, for instance, Ali’s oldest daughter theorized, “I believe it might have been a combination of head trauma from boxing and pesticides. He was exposed to a lot of pesticides at the Deer Lake training camp [in Pennsylvania].” Blaming Parkinson’s on bug spray may seem like a reach, but the data on pesticides and other toxins are actually clearer than the data for head trauma.

The link from toxins to Parkinson’s was established in 1983 when several intravenous drug users injected the toxin MPTP (sold as “synthetic heroin”) and within days developed parkinsonian symptoms. MPTP was later shown to damage dopamine-producing cells in the substantia nigra, that brain area involved in movement. The effect of exposure to pesticides and other chemicals on one’s chances of developing Parkinson’s disease is usually calculated by comparing a large number of farmers and others who have worked with the substances to control subjects who have not but are otherwise similar. One such study found that exposure to the pesticide paraquat increased the risk of Parkinson’s by 150 percent, as did exposure to one called rotenone. Lab studies show that rotenone inhibits mitochondrial activity, and paraquat increases the production of highly reactive oxygen-carrying molecules. Both factors are deadly for dopaminergic cells in the substantia nigra. A more recent meta-analysis concluded that exposure to any of a variety of pesticides, herbicides, insecticides, or solvents increased one’s chances of developing Parkinson’s by 33 to 80 percent.

So based on these population studies, neurotoxins (and potentially head trauma) can dramatically increase one’s risks of developing Parkinson’s, possibly even doubling them. That sounds like a pretty clear causal pathway for Ali, if indeed Ali was exposed to pesticides. But remember, only 1 percent of us will develop Parkinson’s. Double 1 percent is still only 2 percent. In the vast majority of cases, exposure to toxins, trauma, or both will not cause Parkinson’s.

If we can’t blame environmental factors, can we blame genes? There’s a genetic component to Parkinson’s, in at least some cases. Only 10 to 15 percent of sufferers have a family history of the disease, suggesting that any genetic role is weak. And in only 5 to 10 percent of cases do patients have mutations in single genes known to cause Parkinson’s. But Ali was diagnosed at 42, a young age, suggesting the influence of genes. His parents and grandparents were never diagnosed, but that doesn’t mean they never had the disease, according to James Beck, a neuroscientist and the vice president for scientific affairs at the Parkinson’s Disease Foundation. “People in underrepresented populations, like African Americans or Hispanics, are not necessarily seeking out the care that they need,” he says, “and there may even be a cultural belief that the slow movements or the shakiness is age-related.” (Beck notes that seeing a specialist may extend the life of a man with Parkinson’s by seven years and offers an 800-number people can call for information and resources on the disease: 1-800-457-6676.)

One of the current difficulties of diagnosing both Parkinson’s and CTE is that they can only be confirmed in death, by dissecting the brain. It remains unclear what Ali’s family plans to do with his brain, but even such an autopsy wouldn’t clarify the cause of his Parkinson’s. “Even if pesticide residues are found, a causal nexus cannot be drawn,” Félix Carvalho, a toxicologist at the University of Porto, in Portugal, says. According to Raquel Gardner, a behavioral neurologist at the University of California–San Francisco who studies neurodegenerative disorders, an autopsy would only determine whether Ali’s symptoms derived from Parkinson’s (identifiable by Lewy bodies in the substantia nigra) or CTE (identifiable by abnormal deposits of a protein called tau). If an autopsy shows signs of CTE and not Parkinson’s, it is more likely that trauma caused his symptoms, she says, but if it shows signs of Parkinson’s and not CTE, it would be hard to say what caused the disease.

Trying to find a root cause for Ali’s suffering is likely futile, short of a genetic analysis pointing to one of a few key mutations. “In most cases,” Gardner says, “the cause of [Parkinson’s disease] remains a mystery. There is mounting evidence, however, for both an independent and synergistic role of genetics and environmental exposures, such as TBI or pesticides, in the development of PD in some cases.” Like many diseases, Parkinson’s is complex, the result of many factors interacting. According to one paper on its genetics, “the etiology of PD is multifactorial, which probably results from an elaborate interplay of mostly unknown factors: several genes, modifying effects by susceptibility alleles, environmental exposures and gene-environment interactions (e.g., influence of environmental agents on gene expression), and their direct impact on the developing and aging brain.”

What’s more, Beck says, “It may be that we find that Parkinson’s disease is not just one disease, in the sense that there’s many causes and many treatments.” According to a paper on risk factors for Parkinson’s, “It seems likely that Parkinson’s disease is not a single disease but a number of phenotypically similar illnesses.”

Humans love to find causes for things. And they especially love explaining human cognition and behavior in terms of neuroscience. The theory that O.J. Simpson’s alleged killing spree was due to CTE, for example, has been posited by experts and media alike, Slate included. While that makes for a tidy story, it misrepresents the science. Similarly, pegging Ali’s disease to brain injury may intensify conversations about whether we should be pitting men and their fists against each other for national entertainment. But the research is much less clear about the actual line of causation—between Ali’s disease and boxing, and between football and CTE. Instead, we should take this as a moment to assess what we know, what we don’t know, and what we need to find out.

Until we have more information, anything else is just shadowboxing, throwing punches at an imaginary opponent.

http://www.slate.com/articles/health_and_science/medical_examiner/2016/06/what_caused_muhammad_ali_s_parkinson_s_disease_it_s_nearly_impossible_to.html