Researchers float ‘brain-first, body-first’ model as Parkinson’s origin

Hypothesis suggests disease is 'fueled' by environmental toxins

Margarida Maia, PhD avatar

by Margarida Maia, PhD |

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Toxic substances that enter via the nose or gut give rise to toxic protein clumps that eventually cause Parkinson’s disease, researchers propose.

“In both the brain-first and body-first scenarios the [disease mechanism] arises in structures in the body closely connected to the outside world,” Ray Dorsey, MD, a professor at the University of Rochester Medical Center, said in a university press release. “This further reinforces the idea that Parkinson’s, the world’s fastest growing brain disease, may be fueled by toxicants and is therefore largely preventable.” Toxicants can include pesticides, dry cleaning chemicals, and air pollutants.

The hypothesis, “The Body, the Brain, the Environment, and Parkinson’s Disease,” was published in the Journal of Parkinson’s Disease.

In Parkinson’s, a protein called alpha-synuclein folds abnormally and clumps into so-called Lewy bodies, which are toxic to nerve cells. Lewy bodies can spread from one area of the brain to another, which may contribute to how fast symptoms progress.

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Brain-first, body-first explained

Scientist have debated the origin of Lewy bodies — whether they first form in the brain or the gut. Both the nose and gut have well-established connections to the brain.

In one hypothesis, called brain-first, chemicals are inhaled through the nose and rapidly travel to the brain via the nerves responsible for smell. This leads to faster disease progression.

According to this model, breathing in certain chemicals, like pesticides and industrial pollutants, might lead to Parkinson’s. For example, farmers exposed to the pesticide paraquat have a higher risk of developing the disease and progressing faster.

Industrial chemicals like trichloroethylene (TCE), which is in contaminated water and air despite being banned in some countries, can also increase the risk of Parkinson’s. Particulate matter, that is, tiny particles suspended in polluted air, has also been suggested as a cause of the disease.

In the body-first hypothesis, the chemicals are ingested and pass through the lining of the gut where Lewy bodies begin to form. These then spread to the brainstem via the vagus nerve, the body’s longest nerve, and travel to other body parts, leading first to nonmotor symptoms such as trouble sleeping and later to the motor symptoms that are the hallmark of the disease.

In this model, ingesting toxic substances that come into contact with the gut would lead to dementia with Lewy bodies, which may cause some motor symptoms, but has earlier changes in cognition than those in Parkinson’s.

Combining brain-first, body-first

A hypothesis proposed by Dorsey and researchers in the U.S. and Denmark combines the brain-first and body-first scenarios. Toxic substances entering the body via different routes could lead to different forms of the disease.

“In this hypothesis paper, we seek to connect body- and brain-first models of the disease to one of the likely causes of [Parkinson’s], environmental toxicants,” the researchers wrote.

“We propose that Parkinson’s is a systemic [whole-body] disease and that its initial roots likely begin in the nose and in the gut and are tied to environmental factors increasingly recognized as major contributors, if not causes, of the disease,” Dorsey said.

That both brain-first and body-first pathways contribute to Parkinson’s is supported by multiple hypotheses.

For example, differences in exposure to environmental factors, such as pesticides, could explain why the number of Parkinson’s cases varies between and within countries, and regions with more pesticide use should see more cases.

“These environmental toxicants are widespread and not everyone has Parkinson’s disease,” Dorsey said. “The timing, dose, and duration of exposure and interactions with genetic and other environmental factors are probably key to determining who ultimately develops Parkinson’s. In most instances, these exposures likely occurred years or decades before symptoms develop.”

Consistent with this hypothesis, regions that have reduced the use of harmful chemicals, improved air quality, and banned pesticides may see a decrease in the disease’s occurrence over time. Regions of Europe with stricter regulations have already reported slower increases in the number of cases. 

Regions with increased exposure to toxic substances, such as sub-Saharan Africa, where pesticide use has “nearly tripled” over the past 30 years, may see a rise in Parkinson’s. This is concerning due to the potential health risks posed by these substances, especially in farming communities.

Exposures and brain cell loss

Depending on the route of exposure to toxins, people with Parkinson’s may show different imaging patterns. For example, those who’ve been exposed by breathing toxic substances may show asymmetric loss of brain cells, whereas those exposed via the body-first pathway may show a symmetric pattern.

These patterns could be reproduced in animal models of Parkinson’s, where breathing in toxic substances may cause Lewy bodies to first build up in the nose and brain, and ingesting them would cause them to first accumulate in the gut’s lining and autonomic nervous system, that is, the network of nerves that control automatic bodily functions such as heart rate and blood pressure.

Animal models could also help understand how genetic factors interact with environmental factors to drive Parkinson’s. Understanding this link could help identify prevention strategies, and improve diagnosis and treatment.

“The proposed link, though, has limitations and leaves many questions unanswered, such as the role of the skin, the influence of the microbiome [the genetic makeup of all microbes living in the body], and the effects of ongoing exposures,” the researchers wrote. “Despite these limitations, the interaction of [external] factors with the nose and the gut may explain many of the mysteries of Parkinson’s disease and open the door toward the ultimate goal — prevention.”