1
"DISCOVERY"
The disease, respecting which the present inquiry is made, is of a nature highly afflictive ... whilst the unhappy sufferer has considered it as an evil, from the domination of which he had no prospect of escape.
-James Parkinson, An Essay on the Shaking Palsy, 1817
Every three years, people with Parkinson's gather for a Parkinson's world summit of sorts. Over four days, patients-desperate for a cure-rub shoulders with biomedical professionals who have devoted their lives to conquering this disease. In 2013, at the third such world congress, in Montreal, the major Parkinson's charities, such as the Michael J. Fox Foundation, the American Parkinson Disease Association, the National Parkinson Foundation, Parkinson's UK, the Cure Parkinson's Trust, and the Parkinson's Disease Foundation, are present in force. So are pretty much all of the world's leading Parkinson's researchers, eager to report on their latest efforts to understand and defeat this awful malady. And there are lots of patients-some like me, who so far have only mild symptoms, and others who move around with canes, walkers, or wheelchairs.
The opening ceremony is intensely moving. United by a common enemy, more than three thousand Parkinson's patients, caregivers, researchers, and clinicians from sixty-five countries come together in Montreal's giant Palais des Congrès. The audience is animated, frequently rising to give standing ovations for the inspiring speakers whose images are displayed on massive video screens. The mood is defiant. Speaker after speaker urges the congregation not to give up hope.
I find it energizing to see so many Parkies in one place. We are in fact a rather impressive group, which includes accomplished dancers, musicians, filmmakers, entrepreneurs, scientists, and even true-life heroes, like the former NASA astronaut Rich Clifford and the endurance athlete Alex Flynn. The fact that so many people here have achieved great success in their professional lives supports my belief that if we all work together with the scientists, we can beat this disease.
The star performer that first night is the Canadian celebrity Tim Hague Sr. A Parkinson's patient since 2011, Hague (together with his son, Tim Hague Jr.) has against all odds just won the reality show The Amazing Race Canada, where pairs of contestants race across the length and breadth of Canada. On September 16, 2013, Canadian viewers watched as Tim and his son beat out the competition in the first season of the show. The story of his extraordinary physical triumph serves as a potent reminder of the power of the human spirit.
Hague steps up to the microphone and addresses all the stakeholders. "Whether you're the researcher, the health-care professional, the family member, the friend, the person with Parkinson's, persevere ... our journey together may very well be a long one ... don't give up. You never know what is just around the next corner ... never lose hope ... persevere, this race as well can be won."
Over the next four days, the attendees show no sign of giving up. Researchers try not to dwell on bad news and sometimes play down the considerable difficulties of (and delays in) bringing scientific advances to the clinic. Scientists and patients alike freely use the "cure" word. Even though I know much of it is exuberance, for those four days I willingly buy into this conspiracy of hope. I too feel the sense of urgency. After all, Parkinson's is now my world-a world where it is crucial to believe tomorrow can be better than today.
As the dozens of scientific sessions show, the quest to defeat Parkinson's is a long, complicated war being fought on many fronts. Some researchers focus on understanding the disease in detail. This basic research-often carried out with test tubes and laboratory rodents-generates lots of ideas about potential weak spots, so-called targets where a drug or other intervention might just slow, stop, or reverse the progress of the disease. But only a few of these ideas get out of the lab and into clinical trials, where other researchers test the new agents to see if they're safe and effective. There are geneticists searching for clues in patients' genomes. There are epidemiologists looking for factors that appear to increase or decrease the likelihood of contracting the disease, from pesticides, which appear to increase the risk of Parkinson's, to coffee and smoking, which seem to be protective against getting it. There are clinicians focused on understanding the varied symptoms of patients, and there are neuropathologists who study the cellular damage to the body and brain after death. And more.
A social scientist observing all the delegates sporting their colorful badges would surmise that we all shared a brand. In our case, it's not a product like Coca-Cola or Nike but a commitment to defeat a disease named after a man who lived some two hundred years ago. The observer would wonder as I had about the man behind the brand. Who was James Parkinson, and how did he come to have a disease named after him? And what is it about this condition that so fascinates the world of science and medicine? This is where our story of Parkinson's really begins.
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There are no portraits or engravings of James Parkinson,* just a commemorative stone tablet in St. Leonard's church, Shoreditch, the East London parish where he was born, lived, and died. His home has long since been demolished. If you go to Shoreditch, you'll see that a simple plaque adorns the building that now stands at 1 Hoxton Square, the address where he ran his medical practice. The son of a physician, Parkinson studied Latin, Greek, natural philosophy, medicine, surgery, drawing, and shorthand; the latter he considered essential for taking medical histories. His published writings reveal the eclectic interests of an Enlightenment intellectual. In addition to producing medical discourses on mental illness, gout, hernia, and appendicitis, he dabbled in chemistry, paleontology, and political activism-writing pamphlets under the nom de plume Old Hubert.
Parkinson seems to have been a curious and compassionate man. He would almost certainly be unknown today, however, but for one thing: a small monograph he published in 1817 about a new disease he called the shaking palsy. A careful observer, he'd noticed the syndrome during his regular walks around the streets of East London. From time to time, he came across people who moved differently from the crowd, and when he saw them, he'd approach them for an interview to find out more. One day, for example, he encountered a sixty-two-year-old man who had worked as an attendant in a magistrate's court. His body, observed Parkinson, was "much bowed and shaken. He walked almost entirely on the fore part of his feet, and would have fallen every step if he had not been supported by his stick." The attendant told Parkinson that he was resigned to "the incurable nature of his complaint." Based on just six cases, only two of which he examined fully, Parkinson came up with a description of what he suggested might be a new disease.
An Essay on the Shaking Palsy is a beautiful piece of medical literature, one that people with Parkinson's everywhere will recognize captures much of what they go through-including tremor, poverty of movement (also called bradykinesia), and postural instability. "Walking," Parkinson wrote, "becomes a task which cannot be performed without considerable attention. The legs are not raised to that height, or with that promptitude which the will directs, so that the utmost care is necessary to prevent frequent falls."
Despite its brilliance, few physicians noticed Parkinson's essay. As a consequence, nineteenth-century individuals struck down with the condition were left to figure out matters on their own. One of the most moving stories that I have come across is that of the Prussian linguist, diplomat, and educational reformer Wilhelm von Humboldt (1767-1835). Ignorant of Parkinson's essay, Humboldt documented his own parkinsonian decline in a series of wrenching letters to a friend, Charlotte Diede. He noted his stooped posture, complained of "an intolerable slowness and clumsiness" when unbuttoning clothes, and reported that his handwriting was shrinking (what's now called micrographia). In a poignant passage written on November 4, 1833, he laments, "Every line starts, with best intentions, in large letters only to end, with ill success, in barely legible small ones. If my life hadn't taught me patience and self-control, this would seem to me insupportable." Not understanding that he had a neurodegenerative disease, Humboldt interpreted his symptoms as accelerated aging following the death of his wife. After seven years of Parkinson's symptoms, Humboldt died of pneumonia.
Humboldt joins a list of intellectuals in history who suffered with the symptoms of Parkinson's disease before the infirmity had been recognized and named. Another was the seventeenth-century English philosopher Thomas Hobbes. John Aubrey wrote in his Brief Lives that Hobbes "had the shaking palsy in his hands; which began in France before the year 1650, and has grown upon him by degrees, ever since, so that he has not been able to write very legibly since 1665 or 1666, as I find by some of his letters to me."
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The disease that James Parkinson noticed would gain widespread recognition thanks to the nineteenth-century French physician Jean-Martin Charcot, the second major figure in the history of this disease. In his day, Charcot, a short, stocky figure with a striking resemblance to Napoleon, was a medical celebrity. According to the neuroscientist and historian Christopher Goetz, people came from all over the world to watch Charcot's clinical lectures at the Salpêtrière Hospital in Paris. Housing five thousand patients, three thousand of whom had neurological conditions, the Salpêtrière was a neurologist's paradise. Whereas James Parkinson had informally looked at just six cases with one common syndrome, Charcot methodically analyzed hundreds of patients with a wide range of odd disorders. He soon discovered several neurologically distinct entities-including multiple sclerosis, amyotrophic lateral sclerosis, Charcot-Marie-Tooth disease (a peripheral nervous system disorder involving loss of touch sensation), and the shaking palsy.
James Parkinson's 1817 essay was hardly known in France. But sometime in the 1860s, Charcot obtained a copy and immediately realized its importance. By carefully observing his own patients at the Salpêtrière, he codified (more precisely than Parkinson) the disease's four common symptoms-tremor, rigidity, slowness or poverty of movement, and postural instability-and added two more, which Parkinson had missed: small handwriting (the micrographia that von Humboldt had noticed) and facial masking (hypomimia), in which the patient's facial expression is lost or diminished because of altered muscle tone.
The perceptive Charcot-whose students included Sigmund Freud and William James-noticed that not all patients had tremor (about one in five patients lacked this symptom). Charcot argued that given this fact, calling the condition the shaking palsy was misleading. He proposed instead the label "Parkinson's disease." And it stuck.
By the 1880s, thanks to his extensive clinical research at the Salpêtrière, Charcot had essentially completed the clinical picture of Parkinson's disease, at least when it came to the motor symptoms. He would have had little difficulty distinguishing those of us at the Palais des Congrès in Montreal who had Parkinson's from those who didn't. And in addition to becoming an expert at diagnosing the condition, he started treating patients' symptoms, like tremor, with plant-based formulations that he came up with by trial and error. He prescribed hyoscyamine-an extract of jimsonweed-in pill form rolled into bits of white bread. Other medicines were derived from belladonna (deadly nightshade).
Charcot developed other intriguing therapies. Having observed that the symptoms of Parkinson's patients appeared to improve after long rides in carriages, in trains, and even on horseback, he speculated that the vibrations might be therapeutic. So Charcot developed an electrically powered "shaking chair," or fauteuil trépidant. One of his students, Gilles de la Tourette, refined this concept into a portable shaking helmet that vibrated the brain. His therapeutic vibration concept was recently tested in a controlled trial using commercially available massage chairs. Patients were assigned to one of two groups: one cohort had daily sessions in a vibrating chair for one month; the other had the same number of sessions in the same chair but with the vibration switched off. Both groups were exposed to relaxing natural sounds, such as ocean waves. The researchers concluded that what Charcot observed was largely a placebo effect, in which perceived benefit had more to do with the patient's and the clinician's wishful expectations of improvement than the vibrational therapy. (And it turns out that the placebo effect, which I'll discuss in chapters 8 and 16, plays an important role in Parkinson's disease.)
We can thank Jean-Martin Charcot, then, for clinically defining, naming, and even attempting to treat the disease that had brought me to Montreal that week in 2013. In reality, however, in Charcot's day, Parkinson's was not yet a disease in the true sense of the word but merely a cluster of symptoms or, in medical parlance, a "syndrome." Before a syndrome can be classified as a true disease, physicians need to possess at least one of two additional pieces of knowledge: how the malady started or how it ends. Knowing a syndrome's cause is the clearest sign you have a real disease-as occurred when scientists discovered that the human immunodeficiency virus (HIV) caused acquired immunodeficiency syndrome (AIDS). If a cause is unknown, then physicians and scientists hunt for specific pathological changes in the patient's tissues, which, in the case of the brain, are usually detected in a postmortem examination after the patient dies.
In the 1880s, scientists had little idea what caused parkinsonism, but pathologists routinely dissected patients' brains looking for signs of damage to various tissues. Charcot, originally trained as a pathologist, taught the "anatomo-clinical" method, which sought to connect the clinical features of a disease like Parkinson's to anatomical changes or "lesions" in the brain.
In a typical postmortem dissection at the Salpêtrière, a pathologist peeled back the face, cut open the top of the skull, and removed the brain (quite similar to how a postmortem dissection would be performed today). But thereafter, all he had to guide him was the gross appearance of the brain's "white" and "gray" matter. The upper portion of the brain-the cerebral hemispheres-looks a bit like the cap of a mushroom, and the rest of the brain resembles its stem. The mushroom cap is split by a deep canyon (dividing the left and right hemispheres) and covered by a wrinkled outer layer of gray matter called the "cortex" (the Latin word for "bark"). Underneath the cortex is largely white matter punctuated with islands of gray matter. When Charcot's pathologists sawed into the brain horizontally (slicing from the top to the bottom) or coronally (going from the back to the front), they observed different brain structures, which earlier anatomists had assigned Latin names-ventricles (bellies), corpus callosum (tough body), corpus striatum (striped body), globus pallidus (pale globe), thalamus (inner chamber), and substantia nigra (black stuff). This last structure was so named because its cells contained the pigment melanin, making them dark.
The anatomo-clinical method depended on finding differences between the brains of healthy and sick individuals. Because most impoverished Salpêtrière patients were wards of the state, autopsies were commonplace, so Charcot and his colleagues had numerous opportunities to find odd lesions in deceased patients' brains that might explain the neurological symptoms they suffered in life. One day in 1893 (the same year that Charcot died), two of Charcot's students, Paul Blocq and Georges Marinesco, got a lucky break. They admitted to the Salpêtrière a thirty-eight-year-old patient with a parkinsonian tremor and rigidity on the left side of his body. The patient subsequently died of pulmonary complications and was autopsied. The postmortem turned up a hazelnut-sized lump in the right side of his midbrain, very close to the substantia nigra. Blocq and Marinesco's discovery inspired Édouard Brissaud, Charcot's successor at the Salpêtrière, to hypothesize that the substantia nigra-the site of the black stuff-was the key pathological source of Parkinson's disease.
Was this a meaningful finding or just coincidence? For twenty-five years, no one bothered to systematically investigate the matter. Then, in 1919, Constantin Tretiakoff, a Russian graduate student working in Paris, offered convincing proof that the black stuff was indeed associated with Parkinson's disease. His dissertation examined fifty-four autopsied brains, nine of which had Parkinson's. Tretiakoff found that all the genuinely parkinsonian brains showed extensive damage to the substantia nigra, whereas none of the healthy controls did. As Figure 5 shows, the difference between normal and parkinsonian brains could scarcely have been clearer: the diseased brains had simply lost their black stuff.
Tretiakoff also noticed something else. Some of the brain cells of deceased Parkinson's patients contained small spherical structures. They were roughly the size of a red blood cell and were surrounded by a clear halo. Tretiakoff named them "corps de Lewy," or "Lewy bodies," to acknowledge their discoverer, Frederick Lewy, a German pathologist working in Dr. Alois Alzheimer's Munich laboratory.
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Pathologists and neurologists would in time come to accept that Lewy bodies were the defining hallmark of genuine Parkinson's disease. Neurologists might diagnose parkinsonism in life. But only after pathologists found Lewy bodies in a patient's damaged substantia nigra after death would they be sure that he truly had Parkinson's disease.
While scientists still had no idea of what caused Parkinson's, it could now fairly be called a disease rather than a syndrome. By the 1950s, more than 130 years after James Parkinson's essay, scientists-especially Charcot, Tretiakoff, and Lewy-had established the commonly known features of the Parkinson's brand. This brand framed the disease as a "movement disorder," mostly found in the elderly, and resulting from damage to a very small region of the brain-the substantia nigra.
So far, little had been found to effectively treat the condition, but that was about to change, thanks to the efforts of a group of brilliant Swedish and Austrian researchers. They proved that it wasn't only the black stuff that vanished when neurons died in Parkinson's patients. Something else disappeared as well-a brain chemical called dopamine.
Copyright © 2015 by Jon Palfreman
