The Brain of a Fighter

Muhammad Ali was laid low by a disease that is turning out to be many different diseases.

Cassius Clay examined by Samuel Swetnick before a fight with Billy Daniels, hovering, May 12, 1962 (AP)

“I know for a fact that he does not have Parkinson's disease,” the physician Martin Ecker decreed from Columbia Presbyterian Medical Center in September of 1984, where Muhammad Ali was hospitalized. “He’s not in any danger.”

The doctor—also a business partner of the fighter—was apparently convinced that the reason Ali had been shuffling as he walked, slowing and tripping over slurred words, was “a past viral infection or heavy-metal toxicity.” That same year, though, Ali would be formally diagnosed with Parkinson’s disease, the early stages of what the world would witness in bloom when Ali carried the Olympic torch in 1996, raising it over his head with slow, robotic movement, looking upon the stadium without expression.

This is the classic presentation of what is today called Parkinson’s, currently defined as one disease, the second most common degenerative brain disorder. It has long been understood to emanate from a region at the core of the brain that is less than half a centimeter wide, known as the substantia nigra, Latin for “black substance” (the most descriptive thing that could be said of the area of strangely pigmented cells in the 19th century).

This black substance—which we now know to be black because of melanin, the pigment that colors and tans our skin in various degrees—is a normal part of every brain. The area is home to much neural communication, specifically by way of the signaling chemical dopamine, which is released by a neuron to float across a synapse and activate the next neuron in turn. The signal cascades into fluid motion of the muscles of the body.

Even at the time that Ali was diagnosed with Parkinson’s, it was known that the disease meant that these neurons mysteriously lose their ability to produce dopamine (and, therefore, to communicate with one another). A person becomes rigid. These symptoms can be lessened—as Ali’s were in 1984, and for decades after—by taking a synthetic form of dopamine. This intuitive treatment has proven helpful, though it tends to make a person too mobile, creating tics and involuntary jerks that many people misunderstand to be part of the disease itself. When Ali lit the flame, it was not the disease that made his hands quake, but the treatment.

While loading people with dopamine has helped many, it has also created a false sense that everyone who has “Parkinson’s disease” is the same, when it is now proving to fundamentally differ between people at a microscopic level. As James Beck, vice president of Scientific Affairs at the Parkinson’s Disease Foundation, put it, “All these diseases have different causes, but a similar phenotype. That is, essentially, that they respond well to [synthetic dopamine].”

In this way, what we today call Parkinson’s disease might be likened to the common cold (which is caused by many different viruses). Beck likens Parkinson’s to high cholesterol—something that can be caused by many different things, affecting people young and old, in all states of health. Just because the findings look the same in the doctor’s office, that is, doesn’t mean the people have the same disease. Some neurologists have lately taken to calling Parkinson’s disease “Parkinson’s disease syndrome”—syndrome being defined as a constellation of symptoms that tend to come along with one another, by whatever cause.

For decades there has been a tendency to blame Ali’s fate on his profession. There are correlations between sustaining head trauma and developing Parkinson’s disease (just as there are correlations with living in rural areas and, oddly, not smoking). There’s also something instinctive to believing that it was the mechanical force of being pummeled by large men that caused Ali's disease. In The New Yorker this week, editor and Ali biographer David Remnick recalls visiting Ali and his wife Lonnie at their farm in Michigan: “He was suffering from Parkinson’s, and it was hard to believe that the accumulation of punishment (from Frazier, from Earnie Shavers, Ken Norton, Larry Holmes, from a lifetime of beatings) had not been at least partially responsible for his condition.” (As ever, Ali “refused any note of regret,” watching an old film of a fight with Liston and calling himself “sooo pretty!”)

“The only thing ordinary about the boxing career of Muhammad Ali,” Remnick writes, “was that he stayed too long and ended up damaged.”

The fighter himself, not known for admissions to being less than superlative, said as much in 1984: “I’ve been in the boxing ring for 30 years, and I’ve taken a lot of punches, so there is a great possibility something could be wrong.”

* * *

Though she was not a celebrated pugilist, my grandmother was diagnosed with Parkinson’s disease in the 1990s. Among her first reactions was to venture to the medical library at Mayo Clinic to learn more—ideally all—of what was known of the disease. Not long after, I received a distended manilla envelope in the mail, full of clippings and excerpts that she had photocopied from textbooks, journals, and newspapers. She had underlined every segment that suggested that the disease was not hereditary. It was perfectly keeping with her character to be diagnosed with a terminal illness and first think to console her family.

The first dominant genetic linkage to Parkinson’s disease was not reported until 1996. Another came in 2002. And this week, reporting in Nature Genetics, researchers announced discovery of a third gene that seems to reliably cause Parkinson’s disease. (As defined in its most classic form, including hallmark microscopic changes in brain tissue known as Lewy bodies)

At Northwestern University, neuroscientists Teepu Siddique and Han-Xiang Deng have been searching for decades for hereditary causes of the disease. In 1996, they began studying a Canadian family wherein 15 members had the disease. Siddique and Deng analyzed the genomes of 65 members of the family, and compared people with Parkinson’s to those without. They found a consistent difference in a region of DNA at the tip of chromosome 20, and spent years trying to figure out what specific gene was the culprit. As technology advanced in the last five years, they were able to sequence the genomes of these patients. That led them to find more than 90,000 variants, which they sorted until they found one gene that seems invariably linked to the disease: TMEM230.

The gene hadn’t been described before, so Deng and Siddique had to find out what it does. It turned out to encode a protein that packages dopamine within neurons, forming the membrane around what's called a synaptic vesicle that stores the chemicals that nerve cells use to communicate with one another.

These little packets were the impetus for the 2013 Nobel Prize in Physiology. Chemicals manufactured inside brain cells have to be delivered to the brink of the cell and released, and this must happen with precise timing and accuracy. The key is the vesicles, membrane-bound bubbles, that haul the chemicals to the edge of the cell, where they burst and release the load.

Deng and Siddique believe that the key mechanism behind many cases of Parkinson's is a problem with trafficking of these vesicles—and not just for cases with this mutation, as all three of the known genes are concentrated on synaptic vesicles. And their gene encodes a protein that forms the membrane of those vesicles. “We think these mutations may slow down the movement of vesicles,” Siddique said—and, thus, slow down the communication of brain cells.

“We think this is a new player in the game,” he continued. “Because the vesicles formed by this gene are present in other neurons besides the substantia nigra, it has a potential to explain the various effects of Parkinson’s disease as it progresses from being a sleep disorder to a motor disorder to a disorder of higher functioning.”

This particular mutated gene is rare—Deng and Siddique have found it in several families in China and North America—as are the others known to cause Parkinson’s. The Northwestern team has found no one who carries the mutation and does not develop the disease in old age. Still, it will account for relatively few cases of the disease overall. The importance of the discovery is evidence that this specific set of symptoms is due to malfunctioning dopamine vesicles.

“Theoretically, we can improve that vesicle movement,” Deng told me, emphasizing the practical relevance of the discovery. And, indeed, a small molecule called NAB2 that promotes dopamine trafficking has recently been shown to reverse dysfunction in isolated neurons sampled from some patients with Parkinson’s disease.

“Understanding this gene, and how it can lead to diseases, can help all kinds of people who may not have this particular mutation,” Beck concurred.

And understanding the disease at this level—as one of the slight malfunctioning of one type of vesicle in a tiny part of the brain—it becomes less intuitive that the disease is the product of being punched in the head. Repetitive trauma certainly does damage brains, most often in a global way, as in the traumatic encephalopathy that plagues the NFL. A CT scan of Ali’s in 1983 showed evidence of this: Ali’s brain was slightly shrunken, and the fluid-filled ventricles enlarged. His physician at UCLA at the time, called it “dementia pugilistica.” (A circular appraisal, Latin for the dementia that happens as a result of being hit in the head.)

“It's been known for a long time that boxers are disposed to dementia pugilistica,” Siddique told me this week. “I don't know Ali's clinical state, but I don't believe he was demented. He had Parkinson's disease, and some people think it's because of head trauma. As a neurogenetecist, I'm prejudiced to say that people have a certain proclivity that resides at the genetic level which predisposes them to environmental insults—whether they be pesticides, well water, living in rural areas, or trauma, possibly.”

The National Parkinson's Foundation does list head trauma to be a possible factor in Parkinson's, along with some insecticides and herbicides. The organization cites an adage to capitulate the limits of our understanding: “Genes load the gun, and environment pulls the trigger.”

The same could be said of most things in life.

Many more genetic linkages will likely be discovered in coming years, affecting many points in the process by which dopamine is released from nerve cells. Inside this man who was an icon of power, it may simply have been the case that these tiny vesicles couldn't make it to the surface. Multiple different problems might have been responsible for that. His symptoms may also have been caused by another, totally different process within his nerves that impaired his dopamine system. Some mutations linked to Parkinson’s disease (without Lewy bodies) affect the function of mitochondria. Other patients with the same symptoms have impairments in recycling of vesicles, but not in transport or mitochondrial function. A vaccine is being tested in Austria that would target a protein called alpha synuclein, which binds to vesicles and impairs them (and some researchers believe may be infectious). To treat these conditions the same way, as we do now, is like treating a headache and a sprained ankle the same way, with Tylenol.

One day, these causes of Parkinson's disease (syndrome) stand to be understood as different diseases, treated differently. The name Parkinson’s disease may well be forgotten long before the name Muhammad Ali.