Researchers have identified changes in blood-based gene expression that may signal the risk of developing Parkinson’s disease years before clinical diagnosis. The study, published in npj Parkinson’s Disease, focused on DNA repair and integrated stress response (ISR) genes in healthy individuals, people with prodromal Parkinson’s disease (PD), and those with established PD.
Parkinson’s disease is a progressive disorder that typically manifests motor symptoms only after significant neurodegeneration has occurred. Before these symptoms appear, patients often experience a prodromal phase marked by non-motor signs such as loss of smell, anxiety, depression, constipation, and sleep disturbances.
The research team analyzed peripheral blood transcriptomic data from 188 healthy controls, 58 individuals with prodromal PD, and 393 patients with established PD from the Parkinson’s Progression Marker Initiative cohort. They found that differences in gene expression between groups increased as the disease progressed. While there were no significant differences between healthy and prodromal groups at baseline, extensive differences emerged when comparing healthy individuals to those with established PD.
The study evaluated whether patterns of ISR and DNA repair gene expression could distinguish between healthy controls and PD patients using machine-learning models across multiple time points. At baseline and during follow-up visits up to 36 months, classification accuracy for distinguishing established PD from healthy controls ranged from 50% to 64%. However, the ability to differentiate prodromal PD from healthy individuals improved over time for certain gene sets—particularly mitochondrial DNA repair genes—with accuracy peaking at 89% after three years.
Variability in gene expression was highest at baseline among prodromal participants but became more uniform as the disease advanced. According to the authors: "This pattern represents a transient, potentially adaptive transcriptional response that diminishes as PD advances." The researchers also noted high classification accuracy when distinguishing between prodromal and established PD groups.
When assessing known PD-related genes alongside ISR and DNA repair pathways, these specific gene sets did not reliably separate healthy people from those with established PD but did help distinguish healthy controls from prodromal cases. Classification performance was strongest shortly after baseline but declined at later visits.
Feature importance analysis highlighted several genes—such as ERCC6, PRIMPOL, NTHL1, and NEIL2—as key predictors of prodromal Parkinson’s disease status.
The authors concluded: "The results illuminate distinct molecular changes that occur before clinical diagnosis of PD, revealing candidate molecular signatures that may help inform earlier-stage disease stratification." They cautioned that blood-based signals are indirect measures of brain pathology; immune system activity might influence observed patterns; not all prodromal cases will progress to clinical Parkinson’s; and transcript-level changes do not always correspond to protein function. Further research is needed to validate these findings in larger populations and explore their diagnostic potential.
