Epigenetic study reveals potential for earlier diagnosis in Parkinson’s disease

Parkinson’s disease, a neurodegenerative disorder, largely affects movement and causes irreversible neuronal damage. It may start with a tremor or it may be manifested in a speech problem; however, by the time symptoms are evident, it is too late to halt the course of the disease. 

Parkinson's originates from the loss of neurons releasing dopamine. Because these neurons control coordination in movement, their loss results in a multitude of movement-related deficiencies.

Although there is medication to treat the symptoms of Parkinson's, there is no known cure. To mediate this problem and propose more effective therapeutic strategies, an earlier diagnosis is key.

“One of the biggest issues with neurodegenerative diseases like Parkinson’s disease or Alzheimer’s disease is that diagnosis is mostly clinically based, and it comes late in the disease — the brain is already degenerated, and it is extremely difficult to restore brain function at that stage,” said Travis Dunckley, an assistant research professor at the ASU-Banner Neurodegenerative Disease Research Center and the School of Life Sciences.

Dunckley teamed up with other universities including UCSD, Texas A&M and Harvard University and research institutes such as TGen to study the epigenetic changes in Parkinson's patients over time, specifically alterations in DNA methylation patterns over the course of the disease. If researchers were to obtain a better understanding of the DNA methylome in Parkinson's patients, they could potentially diagnose the disease earlier.

Currently, the disease is identified through clinical symptoms related to physical movement.

“When physicians treat PD patients, it is usually too late to change the trajectory of the disease. I am interested in early diagnostics to try to identify people prone to the disease before they get it,” Dunckley added. “Using this approach, you could put patients at risk for PD on certain therapies before symptoms arise.”

Parkinson's is governed both by genetic factors and environmental factors, making epigenetics an apt area of study.

“It’s about 60% environmental — it’s much less genetic than many other neurodegenerative diseases,” Dunckley said. “It’s made of up of environmental interactions with the genome. One of the major ways that the environment acts with the genome is through epigenetics.”

DNA methylation, one form of epigenetic alteration of genes, is a process during which methyl groups are added to DNA. These methyl groups can change the activity of the DNA without changing its sequence. However, in the context of Parkinson's disease, it can be difficult to conclude that changes in DNA methylation are solely correlated to disease progression.

“It is hard to link them without confounding variables in that there are a lot of environmental factors,” Dunckley said. “It’s difficult to say whether epigenetic changes are based on disease, environmental factors or a combination of disease and environmental factors.”

In this study, the largest longitudinal epigenetic study in Parkinson's disease to date, 189 patients’ methylomes were studied and compared to that of 191 control subjects. Two years later, their methylomes were compared once again.

The project identified distinct methylation patterns in Parkinson's patients relative to control patients and identified specific sites at which methylation changed longitudinally. The study also found differences in methylation patterns for those subjected to anti-Parkinson’s drugs (dopamine replacement drugs) versus those who received no treatment. The researchers found that DNA methylation changed more for those patients without treatment, further exacerbating the link between epigenetics and Parkinson's progression.

“The main findings are that one, the epigenome does change as the disease progresses. The second finding is that the PD medications themselves alter the epigenome,” Dunckley added. 

If researchers can identify changes in methylation that are characteristic of Parkinson's disease, they can diagnose earlier, allowing for more effective therapeutic strategies before there is irreversible damage. The methylation signatures are therefore promising candidates for biomarkers useful in early detection. 

To expand the scope of the project, Dunckley and his counterparts are repeating the same study but with a longer range of time and with a new subset of patients. 

“The next study we are doing is a replication and extension of this one to validate the findings and extend the observation period to five years,” Dunckley said. “We are also including patients that are very early in PD progression, patients who have symptoms that are highly predictive of future PD. The ultimate goal is to identify changes in these earliest stages of disease that can be predictive of future PD onset.”

Further exploration of epigenetic changes like DNA methylation promise to expand the understanding of this enigmatic disease and hopefully point the way to effective treatments.