Does Parkinson’s disease start in the gut or in the brain?

During most of the 20th century, Parkinson’s disease (PD) was thought to be brain disorder - more specifically, a dopamine deficiency disorder leading to the characteristic motor symptoms, which defines the disease. In this millennium, however, our understanding of PD has become much more refined. We know now that many people with Parkinson’s display a stereotypical distribution of brain pathology, suggesting that the initial pathology may have arisen in the nerves of the gut and nose.

Animal studies have shown that the prototypical PD pathology, i.e. assemblies of the protein alpha-synuclein, can spread from neuron to neuron. If such pathology is introduced into the gut, either by injecting it in the gut wall or by the animals directly ingesting these proteins, the pathology readily spreads to the brain and involves key structures also known to be affected in the human condition. Alpha-synuclein pathology has been found in the gut of PD patients many years before they became symptomatic. Also, nationwide registry studies have demonstrated that surgical cutting of the vagus nerve, i.e. the most important putative gut-to-brain spreading route, reduces the risk of PD by as much as 50%.

The case for a “gut-start” therefore seems strong. Nevertheless, not all available evidence seems to be in line with this hypothesis. First, when brains from PD patients are examined after death, not all cases have pathology in key brain structures along the predicted spreading route. Second, it is rare to find a case with alpha-synuclein pathology restricted to the gut without also having pathology in the brain. If it were the case that symptomatic PD was preceded by an extended phase, during which only the gut was sick, we would expect these “gut-only” cases to be much more common.

There are several explanations for why such cases may actually be rare and difficult to find. If the initial gut pathology is very localized, perhaps the size of a small coin, it would be exceedingly difficult to find. The human gastrointestinal tract is approximately 10 meters long, and has a very large surface area. Finding a coin in this extended tube may be like finding the proverbial needle in the haystack. Also, it may be the case that initial gut-pathology immediately spreads to the brain. Therefore, the available time window for detecting “gut-only” pathology may be very narrow. These important questions have not been resolved.

We have recently proposed an alternative hypothesis, which seems capable of reconciling these contrasting views (See the full review paper in Journal of Parkinson’s disease). In one type of PD, the pathology starts in the gut and subsequently invades the brain. In another type, the pathology starts in the brain but given enough time, it will spread to the gut and other peripheral organs. In other words, at late-stage disease all people with Parkinson’s are quite similar with pathology in both the brain and the peripheral nerves, but if examined early on, these two PD subtypes look radically different.

Now why is it important to understand where and when the first pathology arises? Much research is being carried out to understand how gut bacteria, gut infections, and a so called “leaky gut” might predispose a person to develop PD. Although this is a very important research field, it seems probable that such factors are mainly important to the “gut-first” subtype of PD. Eventually, we may be able to altogether prevent gut-first PD by manipulating the intestinal microbiome, which would be a tremendous break-through. However, if there is a “brain-first” type of PD, we may need a different therapeutic strategy to treat these cases. Importantly, it will be crucial to develop robust biomarkers that can tell such different PD subtypes apart, so that each person with Parkinson’s can benefit from an optimal, targeted therapy.

Per Borghammer, MD, PhD, DMSc presented at the 5th World Parkinson Congress in Kyoto, Japan. He is currently a senior consultant and Professor in the Department of Nuclear Medicine & PET at Aarhus University Hospital in Denmark.

Ideas and opinions expressed in this post reflect that of the authors solely. They do not reflect the opinions or positions of the World Parkinson Coalition®