The hallmark presence of Lewy bodies in the pathway related to sense of smell and in the gut years before a Parkinson’s diagnosis, as well as the potential cumulative impact of different triggers, may help researchers understand the environmental factors that contribute to the development of the disease, according to a review study.

The study, “The Search for Environmental Causes of Parkinson’s Disease: Moving Forward,” appeared in the Journal of Parkinson’s Disease.

Environmental factors contribute at least partially to late-onset sporadic Parkinson’s disease. Because neurodegenerative changes are too advanced to be stopped or reversed by the time a diagnosis is reached, understanding modifiable risk factors that can help to identify the disease and allow for an early intervention may lead to more successful treatment of Parkinson’s, the neurological disease with the fastest-growing prevalence.

“The greatest risk factors for [Parkinson’s] are likely environmental and not genetic,” Honglei Chen, MD, PhD, from Michigan State University, and Beate Ritz, MD, PhD, from the University of California Los Angeles, said in a press release. “Yet we know relatively little about environmental causes or triggers. Identifying these and defining ways to reduce their impact will be great research challenges for the coming two decades.”

Environmental factors may trigger Parkinson’s or modify its progression during the prodromal (early) stage, in which early symptoms or signs are present, but clinical diagnosis is not yet possible. Among the reported factors, smoking, coffee, exercise, plasma urate, and use of ibuprofen have been linked to a lower risk of Parkinson’s, while pesticide exposure and traumatic brain injury have been associated with a greater risk.

Apart from two pesticides known as rotenone and paraquat, researchers have had difficulties in providing evidence that other risk factors can cause the disease. Reverse causation — meaning that Parkinson’s changes lifestyle and behavior before a clinical diagnosis rather than the other way around — has been proposed as an explanation for the link between these environmental triggers and Parkinson’s in its early stages.

“This prodromal stage is of major interest for prevention efforts,” the researchers said in the release, adding that the discovery of Lewy bodies — protein aggregates mainly composed of alpha-synuclein that are characteristic of Parkinson’s — in the olfactory pathway and the digestive tract made targeting factors that enter the body via the nose or gut “even more important.”

The Braak hypothesis presents a potential explanation for environmental contributions in Parkinson’s prodromal development. It suggests that Lewy pathology starts in the brain’s olfactory bulb — an area of the brain involved in the sense of smell — or in enteric (gut) nerves (nerve cells that control the function of the gastrointestinal tract) years, if not decades, before reaching the substantia nigra — an area of the brain key in the control of movement that shows progressive loss of dopamine-producing neurons in Parkinson’s disease.

Findings such as a reduced sense of smell and constipation years before a Parkinson’s diagnosis have supported the Braak hypothesis. Pesticides and other environmental toxins such as air pollutants, of which there is growing evidence of harmful effects on cognitive function, organic solvents, and meats cooked at high temperatures may lead to Parkinson’s through these pathways, although a proinflammatory gut microbiome — the community of bacteria, viruses and fungi that lives in the gut — has also been proposed as a potential starting point. Certain genetic factors may also interact with these environmental causes to boost the risk for the disease.

Besides the Braak hypothesis, the scientists also discussed reported epigenetic differences — alterations in gene function but not in the DNA sequence itself — in the blood and saliva of people with Parkinson’s as well as the importance of lifelong exposure to environmental triggers.

The exposome, which refers to all environmental exposures over a lifetime, suggests that multiple environmental stimuli combine to increase the risk of Parkinson’s. This has been shown with traumatic brain injury and paraquat exposure, and with smoking combined with factors such as caffeine intake and physical activity.

“We are at an exciting moment to unveil environmental contributions to [Parkinson’s] development and progression by taking a life-course approach, and utilizing novel tools to assess environmental exposures,” the researchers said.

While they caution that the long duration of the prodromal stage complicates understanding the extent to which environmental factors contribute to Parkinson’s, the investigators “nevertheless believe it will be possible to assess long-term exposures through large-scale environmental monitoring and by using novel biomarkers that reflect the exposome.”

Both the Braak hypothesis and the exposome concept provide “a theoretical framework for scientists to design future studies to decipher the environmental causes of [Parkinson’s] and develop early interventions to halt the progression to the characteristic motor dysfunction in [Parkinson’s],” they concluded.