Per 叠辞谤驳丑补尘尘别谤鈥檚 鈥渁ha鈥� moment came nearly 20 years ago. The neuroscientist was reading a paper from researchers who were examining whether REM sleep behaviour disorder (RBD), a condition that causes people to act out their dreams and is often found in people who later develop 笔补谤办颈苍蝉辞苍鈥檚 disease, could be an early form of the neurological condition.
Rather than starting with the brain, however, the team instead looked for nerve cell loss in the heart. Though 笔补谤办颈苍蝉辞苍鈥檚 is historically associated with nerve cell depletion in the brain, it also affects neurons in the heart that manage autonomic functions such as heart rate and blood pressure. And, says , 鈥淚n all of these patients, the heart is invisible; it is gone.鈥�
Not literally, of course. But in these people, the neurons that produce the neurotransmitter norepinephrine, which helps control heart rate, were so depleted that their hearts didn鈥檛 show up on scans using radioactive tracers. This kind of neuron loss is associated with 笔补谤办颈苍蝉辞苍鈥檚, but at the time, none of the people had been diagnosed with the disease and their brain scans seemed normal.
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What struck Borghammer was that 笔补谤办颈苍蝉辞苍鈥檚 didn鈥檛 seem to follow the same trajectory in everyone it affected: RBD strongly predicts 笔补谤办颈苍蝉辞苍鈥檚, but .
鈥淚 realised that 笔补谤办颈苍蝉辞苍鈥檚 must be at least two types,鈥� says Borghammer 鈥� when neuron loss starts outside the brain, eventually working its way in, and when from the beginning. By 2019, Borghammer, at Aarhus University in Denmark, had gathered enough evidence to formally propose his .
Now, with 14 published studies and more on the way, the idea is starting to gather steam. And if Borghammer is right, reframing the disease as existing in two discrete forms could dramatically transform how we treat or even prevent it.
鈥淚 think that we are getting to the heart of what causes 笔补谤办颈苍蝉辞苍鈥檚 disease,鈥� says , a neurologist at the University of Pittsburgh in Pennsylvania. 鈥淭hat will be a huge home run.鈥�
Getting to grips with the causes of 笔补谤办颈苍蝉辞苍鈥檚 disease can鈥檛 come soon enough. Cases are skyrocketing, with a recent study estimating that by 2050, , more than double the nearly 12 million people with it in 2021. Some researchers are even calling it (see 鈥湵什拱炀辈圆醮遣遭�檚 on the rise鈥�, below). Meanwhile, the search for more effective treatments, not to mention a cure, has been littered with disappointments.
Losing dopamine
笔补谤办颈苍蝉辞苍鈥檚 symptoms 鈥� tremors, unstable gait, muscular rigidity 鈥� were documented . But it wasn鈥檛 until the 19th century that the condition became known as 笔补谤办颈苍蝉辞苍鈥檚, after London physician James Parkinson described six people鈥檚 鈥渋nvoluntary tremulous motion鈥� in his . 笔补谤办颈苍蝉辞苍鈥檚 was then rare, and it would take involved were identified.
We now know that 笔补谤办颈苍蝉辞苍鈥檚 is associated with the loss of nerve cells in parts of the brain that help control movement, such as the substantia nigra. Some of these neurons produce the neurotransmitter dopamine, and the reduction in dopamine disrupts the normal signalling pathways that control motor function, leading to the 鈥渢remulous motion鈥� Parkinson observed.
This neuronal die-off appears to be caused by the proliferation of a misfolded form of the protein alpha-synuclein. Alpha-synuclein is found throughout our bodies and plays a critical role in controlling the release of neurotransmitters, including dopamine, at synapses, the junctions between neurons where communication happens. But for proteins to function within cells correctly, they need to assume the right shape. When alpha-synuclein misfolds, it can form clumps called Lewy bodies inside neurons. The Lewy bodies slowly kill the neurons, whether by disrupting signalling, or accumulating in the mitochondria, inhibiting cells鈥� ability to produce energy.
What causes alpha-synuclein to misfold is , but the irregular proteins seem to then spread the disease from cell to cell. 鈥淥ne of the mechanisms that cells have to defend themselves against bad proteins is to get rid of it by kicking it out of the cell with exosomes 鈥� a small balloon of bad material,鈥� says Borghammer. 鈥淎nd then the neighbour is stupid enough to import it, and then you have kick-started the process in the next cell.鈥�
Where 笔补谤办颈苍蝉辞苍鈥檚 starts
Trying to understand why and how alpha-synuclein goes wrong, researchers began to search for the places in the body where the misfolding could originate. In the 1990s, neuroanatomist at Goethe University Frankfurt in Germany observed that the proliferation of the Lewy body clumps resembled 鈥渁 falling row of dominoes鈥�. This led him to suspect that the disease might originate outside the central nervous system and somehow find its way in. In 2003, Braak proposed that in a network of nerve cells within the gut called the enteric nervous system and initiate the corruption of alpha-synuclein. Neurons in the vagus nerve, a conduit that connects the gut and brain, would then carry the misfolded protein to the vulnerable brain regions.
Braak鈥檚 hypothesis has gained ground in the years since. However, critics note that it doesn鈥檛 describe the development of 笔补谤办颈苍蝉辞苍鈥檚 in all cases. In a small but pivotal , Borghammer, Aarhus University PhD student and their colleagues assessed 37 people with 笔补谤办颈苍蝉辞苍鈥檚, of whom 13 also had RBD, as well as 22 people with only RBD. The team showed that, on average, people with RBD had more neuron loss in the heart and gut than those with only 笔补谤办颈苍蝉辞苍鈥檚, hinting that the disease originated there before making its way to the brain.
But crucially, the team also found that those without RBD 鈥渓ose the dopamine system first but have more normal hearts and guts鈥�, says Borghammer, implying that for them, the disease started in the brain.
Borghammer realised that, though Braak might have been correct in thinking that neuronal degradation starts 鈥渂ody-first鈥� in some people with 笔补谤办颈苍蝉辞苍鈥檚, that didn鈥檛 describe everyone. There are other people for whom the dopamine-producing structures in the brain are affected from the start, 鈥渂rain-first鈥�. 鈥淚t is completely two separate categories with no overlap,鈥� says Borghammer.
Brain-first, body-first
叠辞谤驳丑补尘尘别谤鈥檚 offered yet more evidence that the disease followed at least two trajectories: some people had misfolded alpha-synuclein only in the centre of their brain, supporting the brain-first idea, but for others, it was found only at the bottom of the brainstem, as if it had just reached the brain from somewhere else. 鈥淲hen you鈥檝e got several hundred brains [showing this], it starts to get pretty convincing,鈥� says , a neurologist at University College London.
叠辞谤驳丑补尘尘别谤鈥檚 team isn鈥檛 alone in pursuing this idea. Married neurologists and at Johns Hopkins University in Maryland have tested the body-first theory by . 鈥淚t just seemed like a reasonable experiment to do, to formally test the hypothesis,鈥� says Ted Dawson.
One month later, the misfolded protein was in the mice鈥檚 brains, killing off their dopamine-producing neurons and inducing the onset of symptoms such as movement difficulties and loss of smell. 鈥淭hey got the whole spectrum of disease,鈥� says Valina Dawson.
Crucially, this didn鈥檛 occur for mice that had their vagus nerve cut shortly after the injections. 鈥淚 think that the data is very persuasive,鈥� says , who researches 笔补谤办颈苍蝉辞苍鈥檚 genetic pathways at the University of Dundee, UK.
Such research cannot ethically be done in humans, but scientists can study people who had their vagus nerve cut as a last-resort treatment for peptic ulcer disease. In one study, those who had the nerve cut at the junction between the oesophagus and the stomach 鈥� the 鈥渢runk鈥� of the nerve tree that communicates with digestive organs 鈥� were than people in the general population who hadn鈥檛 had the procedure. In a separate study, Borghammer and his team uncovered more evidence for a gut connection. They analysed gut tissue samples taken from 57 people up to 20 years before they were diagnosed with 笔补谤办颈苍蝉辞苍鈥檚 disease and found , at significantly higher levels than in people who never developed the disease.
Though much of the research focus in body-first 笔补谤办颈苍蝉辞苍鈥檚 has been on the gut, some scientists have gone looking for and found misfolded alpha-synuclein in other places in the bodies of people who don鈥檛 have neuron loss in the brain, including the and the nasal cavity. 鈥淚 think that it is plausible that an initiating event in a 笔补谤办颈苍蝉辞苍鈥檚 disease cascade can occur in the periphery and then move centrally,鈥� says , a neurologist at Queen Mary University of London.
Different types, different symptoms
The two subtypes also align with how differently the condition can manifest in people. 鈥淲e are confronted with a very broad spectrum of what we call 笔补谤办颈苍蝉辞苍鈥檚 disease that can be very differentially expressed in different patients,鈥� says , a neurologist at Helsinki University Hospital in Finland.
For example, people with signs of body-first 笔补谤办颈苍蝉辞苍鈥檚 鈥� exhibiting misfolded alpha-synuclein in peripheral tissues outside of the brain 鈥� are more likely to experience disruption to autonomic systems. In such people, RBD, unexplained drops in blood pressure, and can occur years before their movement is affected. 鈥淲hen you see them in the street, you wouldn鈥檛 know that this is a sick person,鈥� says Borghammer. 鈥淎nd in 70 per cent of these cases, when you do a dopamine scan, it is normal, [but] sooner or later it becomes abnormal.鈥�
For brain-first 笔补谤办颈苍蝉辞苍鈥檚 disease, movement-related symptoms dominate from the start. 鈥淭hese are the people who are more likely to have tremor,鈥� says at the University of Plymouth, UK.
New paths to treatment
Knowing that 笔补谤办颈苍蝉辞苍鈥檚 might actually be two different types of disease can offer new pathways to treating it. 鈥淭he point is: why the hell is there a brain-[first] and body-first type?鈥� says Borghammer. 鈥淚f there are some differences 鈥� molecular differences, genetic differences, cellular differences 鈥� these might constitute treatment targets, but we have no idea, because nobody has studied 笔补谤办颈苍蝉辞苍鈥檚 disease in this framework.鈥�
At the moment, says Borghammer, only a handful of medical centres around the world have the scanning equipment needed to differentiate between body-first or brain-first forms of the disease. However, future studies could divide trial participants into these two groups, so drugs are tested on those who have the best shot of benefiting from them. This could be particularly important when targeting the gut microbiome, which can be dramatically altered in people with 笔补谤办颈苍蝉辞苍鈥檚 disease.
Several teams are already working on this. In a study published in 2020, neurologist at the University of Alabama at Birmingham examined the gut microbiomes of 490 people with 笔补谤办颈苍蝉辞苍鈥檚 and 234 people without the condition. She found that 30 per cent of the species of gut microorganisms in people with 笔补谤办颈苍蝉辞苍鈥檚 were , compared with those without the condition. One species that was elevated was Escherichia coli; some kinds of E. coli have been found to induce alpha-synuclein misfolding in the gut. Some bacteria can also stimulate inflammation, which could damage dopamine-producing neurons in the gut, says Scheperjans.
But these findings throw up the age-old dilemma of correlation versus causation. Is the gut microbiome intrinsically different in people who will go on to develop 笔补谤办颈苍蝉辞苍鈥檚 or do symptoms such as constipation lead to changes? To investigate this question, a team led by microbiologist at the California Institute of Technology transplanted faecal samples from people with 笔补谤办颈苍蝉辞苍鈥檚 disease into germ-free mice bred to overexpress the normal alpha-synuclein protein, seeding the rodents with bacteria from the patients鈥� guts. Within six weeks, the mice , including being unable to perform mouse-specific motor function tests as well as before. 鈥淭hat is a nice step in the direction of causation,鈥� says Carroll.
That raised the tantalising idea that the reverse procedure 鈥� transplanting healthy bacteria into the guts of people with 笔补谤办颈苍蝉辞苍鈥檚 鈥� could treat symptoms. The prospect has shown promise in animal studies and in at least one 2024 human trial that found on motor symptoms in people with early-stage 笔补谤办颈苍蝉辞苍鈥檚.
Other research, however, has shown mixed results. In July 2024, Scheperjans and his colleagues gave 45 people with mild to moderate 笔补谤办颈苍蝉辞苍鈥檚 either . Six months later, there was no difference in movement-related symptoms between the two groups. However, those who had a transplant went on to need a lower dose of levodopa, a drug that helps replace the lost dopamine, than those in the placebo group. The transplant may have improved their body鈥檚 ability to use levodopa, so they required a smaller dose even if their symptoms progressed as much as those who had a placebo, says Scheperjans.
Researchers aren鈥檛 yet done investigating the link between the gut microbiome and 笔补谤办颈苍蝉辞苍鈥檚 symptoms: , as well as a trial testing the antibiotic rifaximin鈥檚 effects on symptoms via its action on the gut microbiome. And though the July 2024 trial wasn鈥檛 quite the bullseye researchers might have hoped for, it could nevertheless lend further support to the idea that 笔补谤办颈苍蝉辞苍鈥檚 exists in two types. Because the trial didn鈥檛 separate participants into subtypes, it鈥檚 unclear whether the treatment could be beneficial solely for individuals whose 笔补谤办颈苍蝉辞苍鈥檚 originates in the gut, for example. 鈥淚t could be that there are some mechanisms that we try to attack with new treatments, [but] they only work for one subtype,鈥� says Horsager, who was not involved in the trial.
And that, say researchers, is an incredibly important step in the direction of more effective treatment. 鈥淲e need to be able to give tailored treatments to subgroups of patients that really benefit from them,鈥� says Borghammer. 鈥淗ow do we get there? We get there by subtyping.鈥�
But more than that, says Horsager, 鈥淚t has revolutionised our understanding of the disease, if it is correct. We have to start thinking about the disease in whole new way.鈥�
Parkinson's on the rise
Parkinson's is the . The question is: why? Initial rises in disease rates were attributed to increased life expectancy 鈥� diagnoses generally and "as more people get old, there'll be more people with Parkinson's", says at the University of Dundee, UK. But that can't be the whole answer. Rates of Parkinson's are rising faster than would be expected even if people are living longer, says at Helsinki University Hospital in Finland.
Many point the finger at pesticides, which have been the subject of dozens of Parkinson's-related studies over the past 40 years. They enter cells and damage mitochondria, which provide cells with energy, says Alessi. "You get to that level where the body can't compensate anymore and you start getting symptoms." Much of this research is observational and cannot prove cause and effect, but the sheer volume of evidence makes the idea increasingly convincing. "It is very robust, very consistent across studies," says at Queen Mary University of London. Studies of agricultural workers also show that greater pesticide exposure is linked to greater likelihood of diagnosis. "If you sprayed more [pesticides] and were protected less, that seemed to increase your risk even more," says at Oregon Health & Science University.
Air pollution is also increasingly under scrutiny. Traffic exhaust fumes release particles known as PM2.5. These measure just 2.5 micrometres across and contain even smaller particles that can cross the blood-brain barrier, the membrane that keeps harmful substances in the blood out of the brain, triggering inflammation that may damage dopamine-producing neurons. , people who had the greatest PM2.5 exposure, determined by their home address, were 23 per cent more likely to have a Parkinson's diagnosis than those with the lowest exposure. However, the 鈥� defining PM2.5 exposure is difficult, as is quantifying an individual's exposure over their lifetime.
