Origins of Parkinson's may lie in the gut. Researchers hope to prove it.
The first detailed description of Parkinson's disease, published in 1817 by British physician James Parkinson, is a harrowing read. Based on his observation of six cases, Parkinson found that a patient starts by experiencing a slight sense of weakness and some bothersome trembling in one of their hands.
The condition slowly worsens to the point where tremors become more frequent. Simple actions such as walking and eating become challenging to the point where assistance is needed. After several years, the patient loses all voluntary muscle control and requires around-the-clock care.
It has been more than 200 years since Parkinson's essay on the "shaking palsy," as he called it. Yet, the disease now bearing his name still has no cure, and why some people get it and others don't remains a mystery.
"No one really knows what causes Parkinson's disease, other than about 10 to 20 percent is genetic," said Ted M. Dawson, a professor of neurology at Johns Hopkins University School of Medicine. "Right now, the only therapies we have are symptomatic. We don't have anything that slows the progression."
Researchers such as Dawson have been searching for clues, and in the last two decades, a growing body of evidence points to an unexpected origin for Parkinson's disease: the gut.
What is known as the "gut-first" - as opposed to "brain-first" - hypothesis states that Parkinson's begins as abnormal proteins in the nerves of the gastrointestinal tract. While normal proteins fold into a specific three-dimensional shape, misfolded proteins fail to achieve this form.
Misfolded proteins, found excessively in the post-mortem brains of patients with Parkinson's as well as Alzheimer's, accumulate into large, toxic clumps that disrupt nerve cell function.
"According to the hypothesis, the inciting agent - this misfolded protein - starts in the nerves of the gut wall and ascends to the brain, causing those pathological changes that lead to Parkinson's," said Pankaj J. Pasricha, gastroenterologist and chair of internal medicine at the Mayo Clinic. "If we can prove that the disease is progressing from the gut to the brain, then we can start thinking about early prevention."
The link between Parkinson's, traditionally considered a brain disorder, and the gastrointestinal tract is not new. Constipation is considered a risk factor for Parkinson's and one of the most prevalent non-motor symptoms, affecting up to two-thirds of all patients. Even Parkinson, in his long-ago essay, wrote that the patient's bowels often "demand stimulating medicines of very considerable power."
A meta-analysis of four population studies found that patients with inflammatory bowel disease (IBD), which includes Crohn's disease and ulcerative colitis, have a 46 percent greater likelihood of developing Parkinson's. The seemingly unrelated conditions even share a common genetic mutation. One of the studies also showed that individuals with IBD who received drugs to reduce their gut inflammation had a 78 percent lower incidence of Parkinson's disease compared with those who did not.
In August, Pasricha and his colleagues demonstrated that four gastrointestinal issues in particular - constipation, dysphagia (difficulty swallowing), gastroparesis (delayed stomach emptying) and irritable bowel syndrome without diarrhea - increase the risk of being diagnosed with Parkinson's. The results, published in the journal Gut, analyzed medical record data from 24,624 patients.
"Symptoms of Parkinson's related to the gut," such as constipation and dysphagia, "can present years before more typical signs like tremor, stiffness and difficulty walking," said Nabila Dahodwala, director of the Parkinson Foundation Center of Excellence at the University of Pennsylvania. "Some people think that means you actually have the disease much earlier - and if that's the case, we need to rethink how we define Parkinson's."
Regardless of which hypothesis is correct, Dahodwala recommends that everyone - not just those at risk for Parkinson's - should engage in behaviors known to benefit cognitive health, including regular exercise and healthy eating patterns such as the Mediterranean diet, which emphasizes, among other things, grains, vegetables and nuts, and limits red meats and sweets.
The gut-first hypothesis was proposed by German anatomist Heiko Braak in 2003. He performed autopsies, staining for a misfolded neuronal protein named alpha-synuclein, a known hallmark of Parkinson's disease. Even today, a diagnosis is typically confirmed by searching for alpha-synuclein pathology in the post-mortem brain.
Patients with severe disease - motor symptoms such as tremor and stiffness, along with dementia - had misfolded alpha-synuclein throughout the brain. Those with very early signs of Parkinson's had the protein only in the lower brainstem. Others whose disease fell somewhere in between, who had some motor symptoms but no dementia, had abnormal alpha-synuclein throughout the brainstem and midbrain, but not the outermost cerebral cortex.
The findings led Braak to develop a hypothesis of how Parkinson's progresses, infiltrating the brain from the inside out.
Misfolded proteins can sometimes trigger neighboring proteins to fold abnormally, as seen in prion disorders such as Creutzfeldt-Jakob disease in humans or bovine spongiform encephalopathy (commonly known as mad cow disease) in cattle. The "misfoldedness" propagates from cell to cell like an infection.
How does it get to the brainstem, though? The bottom of the brainstem can be traced via a nerve superhighway to the digestive system, so Braak decided to look there. Interestingly, he found clumps of alpha-synuclein in the stomach wall of all five Parkinson's patients, but none of the five controls.
"When it was first proposed, the Braak hypothesis was quite controversial," Dawson said. "But since then, the field has just exploded with all this evidence supporting that, in a group of patients with Parkinson's, the disease may start in the gut."
A number of autopsy studies have confirmed Braak's results, the largest of which included 46 Parkinson's patients and 340 controls. Aggregations of alpha-synuclein in the lower esophagus were observed in 41 out of 46 patients compared with zero controls.
A 2016 study analyzed tissue samples from the gastrointestinal tract of 39 people who were later diagnosed with Parkinson's disease. Twenty-two had alpha-synuclein pathology present in their gut samples, as much as 20 years before their actual diagnosis.
And in 2019, Dawson and his colleagues demonstrated that, at least in mice, misfolded alpha-synuclein can indeed travel from the gut to the brain. They injected the abnormal protein into the stomach and small intestine of healthy mice and, after one month, noticed it building up at the bottom of the brainstem. It then continued to spread throughout the midbrain and cortex, mirroring what Braak saw in his autopsy subjects.
At 10 months, clumps of alpha-synuclein riddled the entire brain. The mice showed telltale signs of Parkinson's, including motor symptoms and cognitive decline. Severing the nerve that serves as a pathway between the gut and the brain, called the vagus nerve, completely protected the mice against these effects. A 2015 study looking at humans who had their vagus nerve cut as a treatment for peptic ulcer also showed a reduced risk of Parkinson's.
"But how does this pathological alpha-synuclein form in the gut in first place? Is the microbiome involved? Or is it exposure to toxins? There are still a lot of questions," Pasricha said.
Braak originally thought that some kind of pathogen such as a virus could possibly trigger a cascade of misfolding. For example, the human equivalent of mad cow disease spreads by eating meat infected with a misfolded protein called a prion. Other experts suspect Parkinson's begins with an imbalance in the normal gut microbiome.
Either way, solving the long-standing mystery of how most cases of Parkinson's begin - because at least 85 percent of cases are sporadic and not genetic - opens the door for early detection and treatment.
"If you look at what's going on in Alzheimer's with antibody therapies, patients do better with earlier treatment," Dawson said. "With Parkinson's, as therapies come online that slow the progression, the earlier you treat, the more effective they're likely to be as well."
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