Parkinson's disease is traditionally understood as a neurodegenerative disease that starts in the brain. While that might be true in some cases, growing evidence suggests this disorder is actually two diseases, with one variant that starts in the gut.
In a new brain imaging study, researchers found that in some people with Parkinson's, damage to the nervous system begins in the intestinal nervous system and then travels to the brain.
In other patients, the disease appears to emerge in the brain first.
"Until now, many people have viewed the disease as relatively homogeneous and defined it based on the classical movement disorders," says neuroscientist Per Borghammer from Aarhus University in Denmark.
"But at the same time, we've been puzzled about why there was such a big difference between patient symptoms. With this new knowledge, the different symptoms make more sense, and this is also the perspective in which future research should be viewed."
While the new study is small in size – including only 37 individuals with Parkinson's or considered at risk, all between the ages of 50 and 85 – the researchers say their cohort is large enough to demonstrate highly significant differences using advanced imaging techniques like PET and MRI imaging.
In the study, a significant number of the participants also had a REM sleep disorder closely tied to the disease, and the team found that this particular issue, which results in people acting out their dreams, tended to signal a body-first progression of Parkinson's.
The researchers suspect this is probably because the disease's pathology is first travelling from the gut to a part of the brain closely tied to REM sleep, before progressing to the substantia nigra, which is where brain-first Parkinson's tends to originate.
The study used REM sleep disorder as a way to determine who could be at risk of developing Parkinson's later, hypothesising it could be a sign of the neurodegeneration to come. Brain scans and other assessments on body health and nerve function created profiles that clearly spelled out two different biological signals.
This implies that there may be, in fact, two variants of the disease, each of which starts in different parts of the body and then progress in slightly different ways.
The authors call the two different manifestations body-first Parkinson's and brain-first Parkinson's.
"Previous studies have indicated that there could be more than one type of Parkinson's, but this has not been demonstrated clearly until this study, which was specifically designed to clarify this question," says Borghammer.
"We now have knowledge that offers hope for better and more targeted treatment of people who are affected by Parkinson's disease in the future."
The gut was first tied to Parkinson's disease nearly two centuries ago. Today, constipation is acknowledged as one of the most common symptoms of the condition, and yet it was only in 2003, after closely studying cadavers, that neuroanatomist Heiko Braak proposed a gut origin for Parkinson's.
Since then, further studies have produced mixed opinions. While some animal studies suggest there is a passage for gut-to-brain spreading of Parkinson's biomarkers, autopsy studies on humans suggest these represent only a minority of cases.
In one study of over 600 cadavers, researchers did not find a single case of 'gut-only' Parkinson's. All were found to originate in the brain.
But that doesn't mean the gut's nervous system, known as the enteric nervous system, isn't involved. The gastrointestinal tract is huge, and some researchers argue it would take many hundreds of microscopic slides to rule out localised gut pathology "with any degree of confidence".
Finding evidence of gut-first cases that progress in a similar way has proved difficult, but the new study suggests there might be a middle ground among the mixed results.
The authors predict from current trajectories that all patients, regardless of how their Parkinson's may have started, will eventually develop severe damage to their sympathetic nervous system.
This means both variants end up looking very similar - whether it's the dopamine system in their brains that begins degenerating first, or their peripheral nervous system.
Knowing about these two variants could help us identify the preliminary stages of Parkinson's much earlier - at least for the body-first variant.
"The next step is to examine whether, for example, body-first Parkinson's disease can be treated by treating the intestines with faeces transplantation or in other ways that affect the microbiome," says Borghammer.
If this body-origin of Parkinson's really does exist, then we might be able to stop the disease before it progresses to the brain. Once it's in our heads, it's much harder to control.
Unfortunately, by the time symptoms from the brain-first variant begin to show, the cognitive degeneration is already quite far along. By then, Borghammer says they have already lost more than half their dopamine system, which means slowing the disease will be much more difficult.
The study was published in Brain.