Where in the body does Parkinson’s disease begin?

“How Parkinson’s progresses over time is a critical question in the field of PD research. This review provides a timely overview of where the research addressing this issue currently is, as well as asking some key unanswered questions. And this is an important area for the Parkinson’s research community as there are major ongoing clinical trial programmes targeting the toxic form of alpha-synuclein. Therapies that are attempting to remove the toxic form of alpha synuclein have now reached the all important phase II stage, which tests whether the treatment actually works. A better understanding of the role of alpha synuclein in the progression of Parkinson’s would greatly help those clinical trial efforts”

Since neurons are not only present in the brain, but across the whole body, including the lining of the gut, researchers have been trying to map the presence of alpha-synuclein in people with Parkinson’s to understand the way in which it spreads as the condition starts and progresses. If we can trace its very earliest origins, then we may be able to stop its spread. So where does Parkinson’s really start?

First, the ways in which major neuronal pathways are interconnected in the brain, but also connect the brain to different parts of the body and organs such as the gut and heart would theoretically allow for this pattern of a-synuclein spread. Beyond the theory, preclinical studies have also shown that alpha-synuclein injected into the gut can be found a week later in the brainstem. In people with Parkinson’s, alpha-synuclein can be found in a number of organs including the gut, skin and heart, as well as the brain. If the dual-hit hypothesis is correct then there should be some cases in which alpha-synuclein, in addition to being found in the key brain regions, should be found in the olfactory bulb, and others in which it is only found in the gut (in the periphery). Unfortunately, different groups report inconsistent results in this respect. Some of the difficulties in this research which is performed at autopsy include inconsistencies in the actual methods used to identify alpha-synuclein, and future multi-centre studies will aim to standardize these methods to answer this question definitively.

One of the most important and fascinating sources of support for the possibility that in some people Parkinson’s may start in the gut originates in studying the effects of surgically severing or cutting the vagus nerve which supplies the gut. Prior to the use of antibiotics for the treatment of peptic ulcers, surgery was often performed to cut the vagus nerve. When individuals who had undergone this vagotomy were followed up decades later, two independent studies found this led to a lower risk for Parkinson’s, but a third group reanalyzed some of these data and did not replicate this result. Again, methodological differences confounded the issue. Other intriguing findings include the relatively higher risk for Parkinson’s seen after surgery for appendicitis and antibiotics for peptic ulcers, which could point to a different effect altogether – that of inflammation in the gut which may be triggering the abnormal folding of alpha-synuclein in the first instance.

Link between inflammatory bowel disease and Parkinson’s

Hawkes, CH, Del Tredici, K, Braak, H. (2007). Parkinson’s disease: a dual-hit hypothesis. Neuropathol Appl Neurobiol, 33(6): 599-614.