By Paul Nicolaus
February 6, 2017 | When “The Greatest” passed away in 2016 at the age of 74, his words and actions left an indelible mark on the world. “Float like a butterfly, sting like a bee” isn’t fading away anytime soon, and the image of Muhammad Ali towering over Sonny Liston has seeped into our collective consciousness. Equally unforgettable, however, was his fight against Parkinson’s disease (PD).
Over the course of more than three decades, we watched as his toughest opponent yet stripped Ali of the physical prowess that earned him the title of three-time World Heavyweight Champion and the gift of gab that earned him the nickname “The Louisville Lip.” His quickness vanished, his speech quieted, the tremors set in. Along the way, the sports legend and cultural icon helped shine an international spotlight on a condition that plagues millions across the globe.
But as experts are discovering, the version experienced by Ali, who developed PD in his forties following thousands of blows to the head, could differ significantly from, say, a woman who suffers from it later in life. It was a mistake to assume that this is a single disease, Alberto Espay, director of the James J. and Joan A. Gardner Family Center for Parkinson’s Disease and Movement Disorders at the University of Cincinnati, told Diagnostics World News.
In a new study published in Nature Reviews Neurology (DOI:10.1038/nrneurol.2016.196), he and colleagues argue that it is a complex disorder encompassing various clinical, epidemiological, and genetic subtypes, and more attention should be paid to the symptomatic and pathological differences between patients. “What we have conceived as Parkinson’s really began as a construct when we had no genetic knowledge and no biomarker knowledge,” Espay said. “We only went by the symptoms and signs.”
PD became a label for those who demonstrated at least two of the following symptoms: tremor, slowness, stiffness, or impaired balance. Over time, the medical community continued to stick to this clinically based diagnosis with the assumption that at some point it would be shown to represent a homogeneous molecular biological entity.
Based on that assumption, new treatments were prescribed to everyone sharing that diagnosis. “And what has happened is that over the last three decades we have had over 20 drugs that at any given point in time were found to have amazing promise as disease-modifying interventions,” Espay explained, “only to be demonstrated to have no effect on patients when the clinical trials were done.”
The finger has been pointed in a number of directions. Clinical trial design has been blamed. So has ineffective recruitment. Maybe patients were brought on at a stage in their disease when the horse is out of the barn, so to speak, and there’s little that can be done to rein in the pathology. The animal models on which therapies have been developed have received criticism as well. Maybe these models aren’t able to transfer over to the complexities of the human condition.
“So all along, we’ve poked a lot of holes in just about every part of the process, but the only thing we’ve never poked holes in, at least until recently, is the disease itself—the beast that we call Parkinson’s,” Espay said. It has been described as a multi-headed beast, but PD has never been thought of as a collection of distinct animals, each with a unique molecular and biological construct that requires unique therapeutic targeting.
Learning from Cancer
Perhaps the best analogy for the field of neurodegenerative research is oncology. Up until the 70s, breast cancer was thought of as a single disease. Today, there are almost 20 subtypes (molecularly speaking) each with targeted treatment cocktails. Many cases previously considered incurable are now effectively treated because their condition is understood on a much more specific level.
One of the biggest challenges facing PD therapy is the need for the medical community to shift gears intellectually and face the condition with a whole new mindset. “What we’re going through is a bit of a tipping point in our definition of Parkinson’s,” said Espay. “I think the definition of Parkinson’s will ultimately become what breast cancer as a label is to oncologists.”
That label may not tell doctors a whole lot about the individuals standing in front of them, but it would be a first step in the process of understanding the genetic mutations, the molecular biology, and the tissues involved. “That’s the era of precision medicine in Parkinson’s as it can be envisioned,” Espay added, “and it can never come to us unless we break away from this very old concept that somehow Parkinson’s is so heterogeneous but is still the same disease.”
With this shift in perspective, it is possible to look back on the many failed drug attempts and realize that some may have been effective for very specific subtypes of PD. At the time, however, the treatments were given to everyone that carried the label as opposed to the patients most likely to respond.
“In a sense, it makes us very underdeveloped compared to oncology,” Espay said, “and we’re talking about fields that are mirror images of each other.” Cancer is a collection of different conditions that ultimately converge in processes within the cell, and so is neurodegeneration. There are abnormalities in cell function—proliferation in one, degeneration in the other. The same biological principles apply.
Drug trials have also failed because of a lack of biomarkers, which Espay refers to as the missing links in the search for better treatments. The Parkinson’s Progression Markers Initiative (PPMI), a global, 33-site trial sponsored by the Michael J. Fox Foundation, was undertaken with the goal of identifying one or more biomarkers of disease progression. As the site leader for Cincinnati’s portion of the study, Espay hoped the research would help identify the underlying aspects of the disease. But the PPMI study was designed with the idea that the definition of Parkinson’s disease was already known and understood.
The existing method of developing biomarkers is problematic and needs to be turned on its head. Traditionally, patients diagnosed with PD have been divided into subtypes, and their biological processes were then measured and analyzed. The real solution lies in carrying out the opposite process by measuring signals in an aging population that includes those with PD and other neurodegenerative conditions as well as those considered to be healthy agers. From there, looking at the signals of interest and tracing them back to individuals will help unlock secrets to this mysterious condition.
In other words, the future lies in moving away from what we’ve long considered to be the definition of Parkinson’s, and investment into this true biomarker development would provide the tools needed for precision medicine. “It’s very difficult and, as you might imagine, very expensive to get there because it requires a very, very large population,” Espay said. “It also requires a study design that is unbiased.”
The first success will probably only apply to 1% or 2% of those who have what we currently refer to as Parkinson’s disease, he acknowledged, but that’s how success has looked in other fields. Look at cystic fibrosis, for example. The only drug approved for this disorder was initially considered a failure. However, a variety of different biomarkers were later collected, and researchers looked back at the individuals who experienced remarkable improvement.
From there, another trial was conducted using a smaller population who shared that same mutation, and the result was positive. The subtype only accounts for 4% of all cystic fibrosis patients, but it’s still a success story, Espay argued, because we would otherwise have a 0% success rate, and the drug would have been declared dead. There will be another drug that will come along under the same principle of precision medicine that will apply to the next 2% or 3% of these people, and that’s how we chew away at a syndrome.
Mind-Gut Connection
Other research is revealing that one of the most promising avenues of research could stem from the relationship between PD and the gut microbiome. In the last several years, several studies have suggested that the gut flora may play a role in PD development. Researchers at the California Institute of Technology, for example, have discovered that changes in the composition of gut bacterial populations contribute to, and could even cause, the deterioration of motor skills.
Caltech microbiology professor Sarkis Mazmanian and his team transplanted gut bacteria from PD patients and healthy humans into PD mouse models. These mice produce excessive amounts of alpha-synuclein (αSyn), a protein believed to play a significant role in the progression of the disease, and researchers wanted to explore how changes in the gut microbiome affected them. The study, published in Cell (DOI: http://dx.doi.org/10.1016/j.cell.2016.11.018), suggests a fundamental relationship between bacteria in the gut and the disease processes involved in PD.
Everyone is familiar with the notion that the brain is the center of our nervous system, but what people are often less familiar with is the fact that there are also significant numbers of neurons in other parts of the body, explained Ron Pfeiffer, a professor of neurology at Oregon Health & Science University who specializes in Parkinson’s disease and other movement disorders. The gut, in particular, is a hotbed. The system of neurons running from the esophagus through the anus takes direction from the brain, but it also affects processes in the mind, so there is a two-way connection between the central and peripheral nervous systems.
The intriguing thing about PD and gastrointestinal (GI) dysfunction, Pfeiffer pointed out, is that this mind-gut connection has been known since James Parkinson described the disease that bears his name all the way back in 1817. “He clearly described difficulty swallowing,” he said. “He described constipation. He actually went so far as to describe the two aspects of constipation and Parkinson’s disease that we know about today—the decreased frequency that’s due to slow transit of material through the colon and difficulty with the act of defecation itself.”
Yet there was virtually nothing written about GI issues and PD after 1817 Only in the last 25 years has a growing body of literature confirmed the notion, including work by Heiko Braak, a German neuropathologist whose work suggested that, contrary to the assumption that PD is exclusively a brain disease, it may actually progress from the gut to the brain.
The work of Mazmanian’s team and other related studies could wind up leading to dramatic changes in how treatment is approached. Parkinson’s patients have typically taken drugs to control their physical symptoms, which worsen over time, but the blood-brain barrier that stops most small and large molecules from entering the brain has been a major impediment to the development of neurotherapeutic drugs. If PD is, in fact, caused by changes in the microbiome in addition to brain alterations, it may be possible to intervene by delivering drugs to the gut, which is a much simpler feat.
“There are many things that can be done about the microbiota,” said Robert Friedland, a clinical and research neurologist at the University of Louisville School of Medicine, whose research, published in Nature (DOI:10.1038/srep34477) has also demonstrated the importance of these bacteria. “It’s very hard to influence chemistry or genetics in the brain, but the bacteria are quite amenable to manipulation through diet and other means.” Bacteria and other organisms inside the gut are completely dependent on what we eat, so these populations can be altered through changes in diet as well as prebiotics or probiotics.
Moving forward, Mazmanian intends to focus on identifying the specific bacteria that may play a role in PD and believes that future findings could lead to safer and more effective therapeutic approaches. Replacing the gut microbiome, rather than using drugs, is yet another potential avenue of treatment that could be pursued. Pfeiffer indicated that fecal transplantation has been explored as a potential treatment for disease, including PD. The idea behind this approach is that if abnormal changes in the gut microbiome can lead to disease, then changing that microbiome might delay progression or improve symptoms.
Importantly, this research exploring the implications of the gut microbiome potentially extends beyond Parkinson’s, Friedland pointed out, because of the similarities that exist among PD, Alzheimer’s disease, and amyotrophic lateral sclerosis (ALS). “We have no effective treatments for ALS or Alzheimer’s disease. We have very effective treatments for Parkinson’s disease, but we can’t stop the progression,” Friedland said. “The existing therapeutic approaches have all been failing for the past 20 years.”
There is a need to be open to new perspectives on the causes and mechanisms of neurodegeneration, Friedland noted, and the body of research exploring the intestinal bacteria offers promise. It will be interesting to see how our understanding of the illness changes over the next decade, Pfeiffer added. As we look ahead, it is equally fascinating to travel back two centuries to James Parkinson and his hunch that the disease begins in the belly. His gut feeling could very well turn out to be right.
Paul Nicolaus is a freelance writer specializing in health and medicine. Learn more at www.nicolauswriting.com.