A new analysis of gene expression in blood samples suggests that specific biological signs of Parkinson’s disease are detectable years before physical symptoms appear. These molecular signatures, related to how cells repair DNA and handle stress, seem to fade once the disease is fully established. The findings were published in npj Parkinson’s Disease.

Parkinson’s disease is traditionally diagnosed only after significant brain damage has occurred, typically manifested by tremors, stiffness, and slowness of movement. Scientists have long sought ways to identify the condition during the “prodromal” phase. This phase represents a period when internal biological changes are happening, but the classic motor symptoms have not yet surfaced. Identifying the disease at this stage is a major goal for medical science because it offers a potential window for early intervention.

Danish Anwer, a doctoral student at the Department of Life Sciences at Chalmers University of Technology in Sweden, led a team to investigate whether these early internal changes could be tracked in the blood. The research team operated on the hypothesis that the body’s genetic instructions for repairing DNA might be overactive or dysregulated early in the disease process.

Dopamine-producing neurons in the brain are high-energy cells that naturally produce toxic byproducts during their activity. These byproducts can damage DNA, requiring a robust repair system to keep the cells healthy.

The researchers theorized that in the early stages of Parkinson’s, these repair systems might be working overtime to save the dying cells. If this activity could be detected in the blood, it would serve as an early warning system. To test this, they needed to look at how these biological processes change over time rather than just taking a single snapshot.

The research team utilized data from the Parkinson’s Progression Markers Initiative, a large-scale observational study that tracks the evolution of the disease. They analyzed blood samples collected over a period of up to three years. The study included 188 healthy individuals to serve as a control group.

In addition to the healthy controls, the study analyzed 393 patients who had already been diagnosed with established Parkinson’s disease. Crucially, the researchers also included 58 individuals in the prodromal phase. These are people who do not yet have the motor symptoms of Parkinson’s but exhibit early warning signs such as REM sleep behavior disorder or loss of smell.

The researchers used a technique called RNA sequencing to look at the activity levels of thousands of genes in these blood samples. While DNA is the instruction manual, RNA is the message that tells the cell what to do at any given moment. By sequencing the RNA, the team could see which genes were being turned on or off.

They specifically examined genes responsible for three key biological pathways. The first was mitochondrial DNA repair, which maintains the energy generators of the cell. The second was nuclear DNA repair, which protects the main genetic code. The third was the integrated stress response, a safety mechanism cells use to handle dangerous conditions.

To analyze this vast amount of data, the team employed machine learning algorithms known as logistic regression classifiers. These computer models were trained to distinguish between the different groups based on their gene expression profiles. The researchers assessed how accurately these models could identify a person as healthy, prodromal, or having established Parkinson’s based solely on their blood data.

The investigation revealed that gene activity related to DNA repair and stress responses could accurately distinguish prodromal individuals from healthy controls. The models achieved high accuracy in identifying those in the early, pre-symptomatic stages. The accuracy of these predictions tended to improve as the participants moved closer to the typical time of diagnosis.

In contrast, these same gene patterns could not effectively separate patients with established Parkinson’s disease from healthy people. This suggests that the molecular signals are strong and distinct during the early development of the disease but quiet down later. Once the disease is clinically apparent, the gene expression in the blood appears to return to a state similar to that of healthy individuals.

The researchers observed that gene expression in the prodromal group was highly variable at the beginning of the study. Over the course of two to three years, this variability decreased significantly. This pattern indicates that the body initially mounts a chaotic or intense effort to repair cellular damage. As the disease progresses, this protective response appears to burn out or fail.

This concept was further supported by the observation of non-linear patterns in gene activity. About half of the DNA repair genes did not simply increase or decrease in a straight line. Instead, they followed complex trajectories, rising and then falling, or vice versa. This suggests a dynamic and transient biological struggle occurring before the onset of motor symptoms.

The study highlighted specific genes that were particularly predictive of the prodromal state. These included ERCC6 and NEIL2, both of which are involved in fixing damage to DNA. ERCC6 is known to be important for repairing active genes and is linked to conditions involving premature aging. NEIL2 helps repair damage caused by oxidative stress, which is a known factor in the death of dopamine neurons.

Another notable gene identified was NTHL1. This gene showed high importance as a predictor early in the prodromal phase. However, its relevance declined sharply as time passed. This decline supports the theory that specific repair mechanisms are recruited early on but eventually become overwhelmed or inactivated as the neurodegeneration advances.

The team also compared these specific stress and repair genes against broader sets of genes usually associated with Parkinson’s disease. They found that the repair and stress response genes were superior at identifying the prodromal phase. This indicates that general Parkinson’s risk genes might be less useful for tracking the active disease process in its earliest stages compared to these specific repair pathways.

The inability of the models to distinguish established Parkinson’s from controls is a significant finding. It implies that by the time a patient sees a doctor for tremors, the systemic battle in the blood has largely subsided. This highlights a limited temporal window where blood tests based on these markers would be effective.

There are limitations to this research that should be considered when interpreting the results. Blood samples serve as a proxy and do not always perfectly reflect what is happening inside the brain. It is possible that the signals detected in the blood are distinct from the specific degeneration occurring in central nervous system cells. The changes in the blood might reflect a systemic response to the disease rather than the direct brain pathology.

Additionally, the sample size for the prodromal group was relatively small compared to the other groups. While the statistical methods used were robust, larger studies will be necessary to confirm these patterns. The researchers also noted that external factors like medication could influence gene expression in established patients, potentially masking some signals.

The researchers did not perform functional tests to see if the changes in RNA levels resulted in changes in actual protein levels or cellular function. Gene expression is only the first step in protein production. Future studies will need to bridge the gap between these genetic signals and the actual cellular machinery.

Despite these limitations, the study provides evidence that the prodromal phase of Parkinson’s is biologically distinct from the established phase. It suggests that the body fights the disease aggressively in the beginning. This insight could help in the design of clinical trials by allowing researchers to select patients who are in this active, early phase.

The research team aims to understand exactly how these early repair mechanisms work and why they eventually fail. Developing these findings into a practical blood test for clinical use will require further testing and regulatory approval. The scientists estimate that such a test could potentially begin trials in healthcare settings within five years.

The study, “Longitudinal assessment of DNA repair signature trajectory in prodromal versus established Parkinson’s disease,” was authored by Danish Anwer, Nicola Pietro Montaldo, Elva Maria Novoa-del-Toro, Diana Domanska, Hilde Loge Nilsen, and Annikka Polster.