Does Parkinson's Begin in the Gut?

Pauline Anderson

June 14, 2012

June 14, 2012 — Two new studies advance the theory that the α-synuclein (αSYN) protein found in the intestinal wall signals early Parkinson's disease (PD), possibly opening the door for PD screening through routine colonoscopy or sigmoidoscopy.

One of the studies showed a distinct αSYN pattern in patients with early PD who had undergone sigmoidoscopy with biopsy, but not in specimens from healthy controls or patients with inflammatory bowel disease (IBD).

A second paper demonstrated αSYN in patients with more advanced PD who had had a colon biopsy several years before developing symptoms, suggesting that such biopsies could serve as a biomarker for premotor PD.

Diagnosing PD early, when dopaminergic neurons are still surviving, could help in the quest to find a neuroprotective therapy that slows, stops, or even reverses the disease.

"We've been trying to slow the disease progression in PD, and have been doing research on this for 25 years, and haven't found anything yet," said lead author Kathleen M. Shannon, MD, a neurologist in the Movement Disorders and Parkinson's Center at Rush University Medical Center, Chicago, Illinois.

Dr. Kathleen M. Shannon

"Patients have already lost half of the dopamine-producing brain cells by the time they are diagnosable," Dr. Shannon told Medscape Medical News. "So we're hoping this kind of research will help to push that time line back so we can intervene earlier."

The papers, a research article and a brief report on 3 cases, were published in the May issue of Movement Disorders.

From Gut to Brain?

Alpha-SYN, deposited in cells of the brain, is considered a pathologic hallmark of PD. Previous literature suggested that the process might start in nerve cells in the walls of the intestine and then move to other nerve cells, eventually getting into the lower part of the brain stem, and then ascending from there.

"It doesn't show itself until it has reached the substantia nigra where the brain cells that produce dopamine are located," said Dr. Shannon. "Patients diagnosed with PD have probably been losing dopamine-producing cells in the brain for 5 or 6 years, and have been having protein changes in other cells lower in the brain stem and in the periphery for maybe a decade before that."

The first study included usable tissue samples from 9 of 10 patients with PD (7 men; median age, 59 years; median duration of disease, 1.5 years) with mild disability who had never been treated with levodopa or direct-acting dopamine agonists. These patients had undergone sigmoidoscopy to the distal sigmoid at around 20 cm from the anal verge. No sedation or colon cleansing was required for the procedure, which lasted 5 to 10 minutes and was well tolerated.

Researchers studied the samples with immunohistochemistry for αSYN and 3-nitrotyrosine (3-NT).

The study also included tissue samples for 2 control groups from a tissue repository at Rush University Medical Center: 24 healthy persons without a history of gastrointestinal (GI) or neurologic disease and 23 patients with IBD (Crohn's disease and ulcerative colitis).

In the patients with PD, there was staining for αSYN in the lamina propria of the colonic submucosa in a pattern suggesting nerve fibers. No sample from healthy persons or patients with IBD showed this pattern of staining.

Because the patients with IBD did not show this pattern, inflammatory processes probably don't entirely explain αSYN expression "Were αSYN expression simply a result of inflammatory processes, its expression would be expected in cases with IBD, which did not occur," the authors write.

Adequate samples from 7 of 8 patients with PD, 14 of 24 normal controls, 7 of 10 patients with Crohn's disease, and 9 of 13 patients with ulcerative colitis showed positive staining for 3-NT, a finding that supports an important role of oxidative stress in inducing αSYN expression in neuronal cell bodies. However, the fact that patients with IBD lacked αSYN expression in neuritis despite the presence of the oxidative stress marker suggests that a simple oxidative milieu is probably insufficient to induce αSYN expression in neuritis.

Because some families seems to be at increased risk, there is probably a genetic component, added Dr. Shannon.

The GI tract might be a portal of pathogen entry in at least some patients with PD. Such patients often report longstanding constipation, which begins before motor signs in nearly half of all patients with PD and predates motor signs by 12 to 18 years.

Postmortem studies of patients with incidental Lewy body pathology suggest that αSYN pathology may begin not only in tissues of the GI tract but also in salivary glands and the olfactory system. Studies have confirmed the presence of αSYN in skin and colon in living patients with PD.

Because the first study from Dr. Shannon and her colleagues found αSYN protein in patients with early PD, they wondered if it could be found in living patients even before symptoms surface.

Screening Colonoscopy

Accordingly, the second study, also published in Movement Disorders, included 3 patients with PD who had undergone screening colonoscopy with biopsy or polyp removal 2 to 5 years before their first motor symptom. It also included colonic specimens from 23 healthy controls and brain bank specimens that contained Lewy bodies and neuritis.

Biopsies of colon tissue from all patients with PD showed intense staining for αSYN. In contrast, healthy controls did not display specific αSYN staining in the colon.

"We were able to demonstrate the protein in all 3 of the PD patients, which is exciting because it's the first time that anyone has ever been able to demonstrate that αSYN protein was present in a living patient before the first symptom," said Dr. Shannon. Generally, patients don't seek medical care until they have a symptom.

The results suggest that it may eventually be possible to use colonic tissue biopsy to predict who will develop motor PD. Tissue could be obtained at the time of a screening colonoscopy, a procedure routinely carried out for colon cancer surveillance beginning at age 50 years.

Identifying PD before patients have significant brain cell loss could change the whole thrust of treatment, said Dr. Shannon.

"If this turns out to be an important finding, then it might change what our targets are for neuroprotection," she said. "For example, let's say you could identify who would get PD 20 years in advance, before they had significant brain cell loss. Maybe you could up-regulate their immune system to target that protein, and eliminate it from the system so it doesn't get to the brain."

The next step for the research team is to study a group of patients who present with what could be early signs of PD — things like constipation, loss of sense of smell, excessive daytime sleepiness, depression, and anxiety, said Dr. Shannon. "We want to look at that enriched population and see if we can demonstrate who has the protein and what happens to them."

This research provides a good lesson in how neurologic diseases can involve areas outside the nervous system, said Dr. Shannon. "We have to recognize that our diseases have footprints that go on for a long time, before we're able to diagnose them. We also need to start listening to patients telling us about constipation and anxiety. These are important clues and should make us look at other things, not to gloss over them because they don't fit in with our idea of what the disease is."

Dr. Shannon noted that when she was in medical school, PD was considered a disease of the substantia nigra and dopaminergic cells only. "There was never any talk of anything other than that, any other part of the brain that might be affected, any other part of the body that might be affected."

A Work in Progress

Reached for a comment, Peter A. LeWitt, MD, professor of neurology, Wayne State University School of Medicine, director, Parkinson's Disease and Movement Disorders Program, West Bloomfield, Michigan, and a member of the Movement Disorder Society, said that biomarkers are important — if there's a need to diagnose the disorder early.

"The hope is that biomarkers will be an integral part of future therapeutics, but in the current situation, if we have an earlier marker for PD you could say, so what; you have bad news earlier."

The research is still fairly preliminary, said Dr. LeWitt. In the current study, for example, there were only 3 examples where αSYN was demonstrated to be a premotor feature, and in the earlier cases, "there was some variability in the intensity of finding," he said.

"It would seem that it looks promising but unproven. It's good research, but I don't think it's a test yet; it's a work in progress."

The idea that neural degeneration in PD does not begin in the substantia nigra and that motor symptoms are a phase in a multiphase disease process is not new, said Dr. LeWitt. He pointed to research by Heiko Braak, MD, clinical professor of anatomy, Goethe University in Frankfurt, Germany, that shows that early stages of the condition center on the nucleus of the vagus nerve, which sends vagrant connections to the GI tract.

"The idea that it began in the GI tract, in the nervous system there, or that it might even be promoted by something happening in the diet that is toxic or gets the process going, is largely derived from Dr. Brakk's work. That work also shows that changes in the brain where this nerve arises, the lower part of the brain, are years earlier than the changes in the dopamine system that we associate with the symptoms."

Dr. LeWitt also noted that a biomarker is not just a diagnostic tool, but a mechanistic clue. An important recent finding is that the αSYN protein seems to be transmitted from one cell to another, a mechanism that occurs with prion diseases. "This isn't a prion disease, but it's starting to sound a little like one," said Dr. LeWitt.

He agreed that the GI tract might prove an ideal therapeutic target. "Beyond just diagnostically, this might be where you cure PD if you had something that inhibits the formation of the protein or blocks the protein or binds the protein," said Dr. LeWitt.

The studies were supported in part by a research grant from Mr. and Mrs. Larry Field and by the Parkinson Disease Foundation. The authors and commenters have disclosed no relevant financial relationships.

Move Dis. 2012;27:709-715, 716-719. Abstract Abstract

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