The first thorough account of Parkinson’s disease was written by British physician James Parkinson and published in 1817. Parkinson’s disease discovered, based on his observation of six cases, that a patient initially feels a mild sense of weakness and some annoying tremor in one of their hands.
Tremors gradually increase in frequency as the disease deteriorates. Simple tasks like walking and eating become difficult to the point that help is required. After a number of years, the patient is completely unable to control their muscles and needs round-the-clock care.
More than 200 years have passed since Parkinson wrote his essay on the “shaking palsy,” as he referred to it. However, the illness that bears his name still has no known treatment, and it is still unclear why some people contract it while others do not.
Ted M. Dawson, a professor of neurology at Johns Hopkins University School of Medicine, stated that “no one really knows what causes Parkinson’s disease, other than the fact that 10 to 20 percent is genetic.” “At the moment, our sole treatments are symptomatic. Nothing we have can stop the progression.
In the past two decades, a rising body of evidence has pointed to an unexpected genesis for Parkinson’s disease: the gut. Researchers like Dawson have been looking for signs.
Parkinson’s disease is thought to start as aberrant proteins in the nerves of the gastrointestinal system, according to the “gut-first” concept, as opposed to the “brain-first” theory. Misfolded proteins are unable to reach the precise three-dimensional shape that normal proteins fold into.
Misfolded proteins build up into enormous, poisonous clumps that impair nerve cell function and are frequently observed in the post-mortem brains of Parkinson’s and Alzheimer’s patients.
Pankaj J. Pasricha, MD, gastroenterologist and chair of internal medicine at the Mayo Clinic, explained that the inciting agent, this misfolded protein, starts in the nerves of the gut wall and ascends to the brain, creating the degenerative changes that lead to Parkinson’s. “We can start considering early prevention if we can show that the disease is moving from the gut to the brain.”
Parkinson’s, which is typically seen as a brain condition, has long been linked to the digestive system. Up to two-thirds of all patients have constipation, which is one of the most common non-motor symptoms and is thought to be a risk factor for Parkinson’s disease. Even Parkinson acknowledged in a long-ago essay that patients’ bowels frequently “demand stimulating medicines of very considerable power.”
Patients with inflammatory bowel disease (IBD), which includes Crohn’s disease and ulcerative colitis, had a 46 percent higher risk of acquiring Parkinson’s, according to a meta-analysis of four population studies. Even though they seem unrelated, the diseases have a similar genetic mutation. According to one of the research, people with IBD who took medications to treat their gut inflammation had a 78% lower risk of Parkinson’s disease than those who did not.
In August, Pasricha and his coworkers showed that four specific gastrointestinal problems – constipation, dysphagia (difficulty swallowing), gastroparesis (slow stomach emptying), and irritable bowel syndrome without diarrhoea – raise the likelihood of receiving a Parkinson’s diagnosis. Results from an analysis of 24,624 patients’ medical records were published in the journal Gut.
Constipation and dysphagia are examples of gut-related Parkinson’s symptoms that might appear years before more conventional symptoms like tremor, stiffness, and walking difficulties, according to Nabila Dahodwala, head of the Parkinson Foundation Centre 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 theory is true, Dahodwala advises everyone – not just those at risk for Parkinson’s – to practise behaviours that are known to improve cognitive health. These include regular exercise and healthy eating habits like the Mediterranean diet, which places an emphasis on foods like grains, vegetables, and nuts while limiting red meat and sweets.
German anatomist Heiko Braak put forth the gut-first theory in 2003. He conducted autopsy and stained the brains for the misfolded protein alpha-synuclein, a known indicator of Parkinson’s disease. Even today, the post-mortem brain is frequently examined for alpha-synuclein pathology in order to confirm a diagnosis.
Patients with advanced disease, including dementia and motor symptoms including tremor and stiffness, showed misfolded alpha-synuclein throughout the brain. Only the lower brainstem of those with very early Parkinson’s symptoms had the protein. Altered levels of alpha-synuclein were found throughout the brainstem and midbrain but not in the outermost cerebral cortex in those individuals with diseases that fell somewhere in between, who had some motor symptoms but no dementia.
Braak came up with a theory about how Parkinson’s disease proceeds by invading the brain from the inside out as a result of the findings.
As demonstrated in prion diseases like Creutzfeldt-Jakob disease in humans or bovine spongiform encephalopathy (commonly known as mad cow disease) in cattle, misfolded proteins can occasionally cause nearby proteins to fold incorrectly. Like an illness, the “misfoldedness” spreads from cell to cell.
But how does it enter the brainstem? Braak chose to study at the bottom of the brainstem because a nerve superhighway connects it to the digestive system. It’s interesting to note that, in contrast to the five controls, all five Parkinson’s patients had aggregates of alpha-synuclein in their stomach walls.
The Braak hypothesis was very debatable when it was initially put forth, according to Dawson. But since then, the science has just blossomed with information suggesting that the disease may begin in the gut in a subset of Parkinson’s patients.
The largest autopsy study, which had 46 Parkinson’s patients and 340 controls, validated Braak’s findings. 41 out of 46 patients had alpha-synuclein aggregations in the lower oesophagus, compared to 0 controls.
Tissue samples from the gastrointestinal tracts of 39 individuals who later received Parkinson’s disease diagnoses were examined in a 2016 study. Twenty-two individuals had disease associated with alpha-synuclein in their gut samples up to 20 years before to their official diagnosis.
And in 2019, Dawson and his associates provided evidence that misfolded alpha-synuclein can definitely go from the gut to the brain, at least in mice. They gave healthy mice stomach and small intestine injections of the unusual protein, and after a month they found it accumulating near the base of the brainstem. Following that, it kept spreading throughout the cortex and midbrain, replicating what Braak had observed in his autopsy cases.
The entire brain was covered in alpha-synuclein aggregates at the age of 10 months. The mice displayed movement symptoms and cognitive deterioration, two hallmarks of Parkinson’s disease. The mice were totally protected from these effects by cutting the vagus nerve, a nerve that acts as a conduit between the gut and the brain. A 2015 study of people who had their vagus nerve cut as a peptic ulcer treatment revealed a lower incidence of Parkinson’s disease.
But first, how does this abnormal alpha-synuclein start to form in the gut? Does the microbiome have a role? Or is it toxic exposure? Many questions remain, according to Pasricha.
Braak’s first hypothesis was that a pathogen, such as a virus, might be able to start a chain reaction of misfolding. For instance, the human form of mad cow disease is spread by consuming meat that has been exposed to a prion, a protein that has misfolded. Others believe that an imbalance in the typical gut microbiota is where Parkinson’s disease starts.
Because at least 85% of Parkinson’s cases are random and not inherited, finding the answer to the long-standing riddle of how most cases start will allow 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,” said Dawson. The earlier you start treatment for Parkinson’s, the more effective it’s likely to be as new treatments emerge that delay the disease’s course.