Parkinson's May Spread From Gut to Brain via Vagus Nerve

Megan Brooks

August 06, 2015

A large Danish epidemiologic study supports the theory that Parkinson's disease (PD) may begin in the gastrointestinal tract and spread through the vagus nerve to the brain. Researchers found that patients who have had the entire vagus nerve severed were less apt to develop PD.

"Their risk was halved after 20 years," Elisabeth Svensson, PhD, from the Department of Clinical Epidemiology, Aarhus University in Denmark, said in a statement.

"However, patients who had only had a small part of the vagus nerve severed were not protected. This also fits the hypothesis that the disease process is strongly dependent on a fully or partially intact vagus nerve to be able to reach and affect the brain," Dr Svensson noted.

This study is an "important piece of the puzzle" in terms of the causes of PD, she told Medscape Medical News.

The study was published online July 17 in Annals of Neurology.

Gut-Brain Connection in PD

In the past, vagotomy was commonly performed for peptic ulcer, the researchers note in their paper. The two most common procedures were full truncal vagotomy, in which both vagal trunks were severed, and superselective vagotomy, in which only the nerves supplying the fundus and body of the stomach were resected.

Using prospectively collected Danish registry data, the researchers investigated the risk for PD in 5339 patients who had truncal and 5870 who had superselective vagotomy, in relation to 66,711 and 60,500 matched population controls, respectively.

A direct comparison of the two vagotomy groups showed that patients who had truncal vagotomy had a lower risk for PD than did those having the superselective procedure, after adjustment for age and sex (adjusted hazard ratio [HR], 0.85; 95% confidence interval [CI], 0.56 - 1.27). After a follow-up period of over 20 years after the date of surgery, the age- and sex-adjusted HR was 0.58 (95% CI, 0.28 - 1.20), the researchers report.

The risk for PD was also lower after truncal vagotomy when compared with the general population. The overall adjusted HR was 0.84 (95% CI, 0.63 - 1.14). After more than 20 years' follow-up, the adjusted HR was 0.53 (95% CI, 0.28 - 0.99).

The risk for PD in patients who had superselective vagotomy was similar to that in population controls overall (HR, 1.09; 95% CI, 0.84 - 1.43) and after 20 years (HR, 1.16; 95% CI, 0.80 - 1.70).

These findings, say the researchers, "suggest that having an intact vagus nerve increases the risk of developing PD. The finding is in accord with a primary pathological process being initiated in the gastrointestinal mucosa, which then uses the vagus as a major entry point into the brain."

They say strengths of the study include the large sample size and nationwide population-based design with long-term follow-up, reducing the potential for selection bias. They note, however, that the statistical precision of their risk estimates was "limited" and they encourage independent verification of their observations.

Important Contribution

Christopher H. Hawkes, MD, FRCP, professor of neurology, Barts and the London School of Medicine & Dentistry, United Kingdom, who reviewed the findings for Medscape Medical News, called them "very interesting."

He noted that while the article is "awash with adjustments, nonsignificant results and unfamiliar statistical methods," the conclusion is "plausible, particularly the 35-year cumulative PD incidence curve that shows a clear diverging separation of the total vagotomy group compared to the general population. The beneficial effect size of surgery is difficult to quantify but likely to be small, eg, not more than a 1% lower risk for those who had truncal vagotomy."

Dr Hawkes said the findings "support the original proposal by Braak et al. who suggested that a neuropathogen, present in the gastric mucosa, traveled up vagal afferent fibers, resulting in Lewy-related pathology in the dorsal motor nucleus of the vagus and glossopharyngeal nerves. Also supported is the concept of a prolonged prodrome, given that the cumulative curve is divergent even after 35 years."

"Overall, this is an important contribution to our understanding of PD that reinforces the concept of a transmissible neurotropic agent," Dr Hawkes concluded.

The study was funded by the Program for Clinical Research Infrastructure established by the Lundbeck and Novo Nordisk Foundations, the Aarhus University Research Foundation, and the Danish Parkinson Foundation. The authors and Dr Hawkes have disclosed no relevant financial relationships.

Ann Neurol. Published online July 17, 2015. Abstract


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