Further Evidence Parkinson's May Start in the Gut  

April 27, 2017

Further evidence supporting the idea that Parkinson's disease (PD) may start in the peripheral nerves in the gut and spread to the central nervous system through the vagus nerve via prion-like mechanisms, known as the Braak hypothesis, comes from a new study showing a lower risk for PD in individuals who have undergone vagotomy.

The study, published online April 26 in Neurology, was led by researchers from the Karolinska Institutet, Stockholm, Sweden.

"This is an observational study and our findings are preliminary, so it does not prove the Braak hypothesis. But it does provide additional suggestive evidence for the idea that Parkinson's may start in the gut and travel to the brain," senior author, Karin Wirdefeldt, MD, Karolinska Institutet, Stockholm, Sweden, commented to Medscape Medical News.

"We need more studies to understand the process underlying the transport of the pathology between cells," she added. "Our results are very interesting from a scientific perspective, but they won't affect clinical practice at present — they should be regarded as a small piece of the puzzle in the understanding of the cause of Parkinson's disease."   

In the paper, the researchers explain that the Braak hypothesis has been supported by recent studies that found pathologic features characteristic of PD:  Lewy body and α-synuclein deposition in the gut of individuals with prodromal PD, and the observation of cell-to-cell transmission of α-synuclein in both grafted neurons in patients with PD and in transplanted neurons in a transgenic mouse model of the disease.

To look further at this potential mechanism, they conducted a matched-cohort study using data from nationwide Swedish patient registers comparing 9430 patients who had undergone vagotomy — a treatment that used to be a treatment for gastric ulcers — identified between 1970 and 2010 with 377,200 reference individuals from the general population individually matched to vagotomy patients by sex and year of birth.

Participants were followed up from the date of vagotomy until PD diagnosis, death, emigration out of Sweden, or the end of 2010, whichever occurred first. A total of 4930 cases of incident PD were identified during 7.3 million person-years of follow-up, with 61.8 cases per 100,000 person-years among vagotomized patients compared with 67.5 per 100,000 person-years among reference individuals.

After adjustment for country of birth, chronic obstructive pulmonary disease, diabetes mellitus, vascular diseases, rheumatologic disease, osteoarthritis, and comorbidity index, results showed that overall, vagotomy was not associated with PD risk (hazard ratio [HR], 0.96; 95% confidence interval [CI], 0.78 - 1.17).

However, there was a suggestion of lower risk among patients with truncal vagotomy (HR, 0.78; 95% CI, 0.55 - 1.09), which became significant when only those who had truncal vagotomy at least 5 years before PD diagnosis were considered (HR, 0.59; 95% CI, 0.37 - 0.93).

Selective vagotomy was not related to PD risk in any analyses.

The researchers suggest their results could be explained by the fact that truncal vagotomy denervates multiple organs in the gut while selective vagotomy eliminates innervation to the stomach alone, so that "synucleinopathy initiated at other gastrointestinal sites may still find its way to the vagus nerve and then to the brainstem."

Noting that a previous Danish study has shown largely consistent findings, the investigators say the two studies together offer "preliminary support that truncal vagotomy may decrease the risk of Parkinson's disease" and provide "preliminary and indirect support for the Braak and prion-like hypotheses for Parkinson's disease prodromal development." 

Commenting on the study for Medscape Medical News, James Beck, PhD, chief scientific officer, Parkinson's Foundation, said, "This is a relatively modest effect, and an epidemiology study such as this one cannot show cause and effect, but these results are a further indication that there seems to be a connection between the gut and the brain in Parkinson's disease."

The Braak hypothesis that PD may start in the gut "has completely upended thinking in this field, and this study lends support to this idea," Dr Beck said. "Obviously there needs to be much more study to try and understand the mechanism, and we should definitely not be thinking about recommending vagotomy as strategy to treat or prevent Parkinson's at this stage."

Dr Wirdefeldt said she didn't think vagotomy would ever be a realistic intervention for the prevention of PD, even if the Braak hypothesis were proven.

"There may be many other easier ways to prevent transmission to the brain, such as specific diets or medications, but a lot more research is needed before we start thinking about that." 

In an accompanying editorial published in Neurology, Per Borghammer, MD, Aarhus University Hospital, Denmark, and Clement Hamani, MD, Toronto Western Hospital, Ontario, Canada, note that early involvement of the gastrointestinal tract is supported by evidence that a substantial fraction of patients with PD develop constipation years or even decades before motor symptoms. In addition, α-synuclein inclusions may be found in gastrointestinal nerve endings up to 20 years before diagnosis.

"The current study provides an independent dataset suggesting that truncal vagotomy may be protective in Parkinson's disease," they say. "Therefore, the time has come to seriously consider the implications of these findings."

They also point out that further studies are needed to elucidate the spatial temporal spreading patterns of pathologic α-synuclein propagation, and improved methods to define and detect pathologic α-synuclein inclusions in peripheral organs are also required.

The editorialists agree with Dr Wirdefeldt and Dr Beck that there is insufficient knowledge to propose vagotomy as a putative treatment for PD. But they suggest that the effects of vagotomy could perhaps be studied in patients with mutations in the leucine-rich repeat kinase-2 gene (LRRK2), which dramatically increases the risk for neurodegenerative parkinsonism. They note, though, that it is largely unknown whether α-synuclein aggregates are present in gastrointestinal nerve endings of these patients.

They add that although vagotomy will likely never become a widespread treatment for PD, strategies to prevent α-synuclein misfolding in the gastrointestinal tract may be proposed because nerve terminals are reachable by oral therapeutic interventions.

The study was funded by the Swedish Research Council for Health, Working Life and Welfare, the Parkinson Research Foundation in Sweden, and the Karolinska Institutet–National Institutes of Health Doctoral Partnership Program. The study authors have disclosed no relevant financial relationships. Disclosures for the editorialists are available with the online version of the editorial.

Neurology. Published online April 26, 2017.  Full text, Editorial

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