By Diagnostics World Staff
February 5, 2026 | Parkinson’s disease affects over 10 million people worldwide, and the number is expected to double by 2050. No cure or established early-stage detection method for the disease has been found yet. Patients do not receive a diagnosis until motor symptoms begin to appear, which is when about 50-80% of brain cells are damaged or gone.
Before motor symptoms begin showing up, patients often undergo a prodromal phase that has subtle non-motor symptoms, such as REM sleep behavior disorder, olfactory loss, constipation, depression, and anxiety. A team of researchers from Chalmers University of Technology, Sweden and Oslo University Hospital, Norway hypothesized that this is a “window of opportunity” to identify early signs of Parkinson’s disease, as well as novel treatment targets—and they were correct. The team has found that biomarkers of DNA repair dysfunction and integrated stress response (ISR) expressions in the blood signal prodromal Parkinson’s disease (npj Parkinson’s Disease, DOI: 10.1038/s41531-025-01194-7).
DNA damage and DNA repair problems are emerging as key mechanisms in the development of Parkinson’s disease. Increasing evidence indicates that DNA damage builds up in neurons and may contribute to the onset and progression of the disease. Dopaminergic neurons are metabolically active and exposed to high levels of reactive oxygen species generated during dopamine metabolism and mitochondrial activity (npj Parkinson’s Disease, DOI: 10.1038/s41531-025-01194-7). In Parkinson’s, defects in mitochondrial function and mitophagy increase DNA damage. Over time, the damage will exceed the cell’s ability to repair DNA, resulting in hazardous single-strand and double-strand breaks.
Using longitudinal transcriptomics from healthy and early onset individuals and patients with established Parkinson’s and applying machine learning, the researchers analyzed data taken from the Parkinson’s Progression Markers Initiative (PPMI) across three participant groups (healthy individuals, prodromal PD, and idiopathic PD) at four different time points: baseline, after 12 months, after 24 months, and after 36 months. At the baseline level, the cohort had 188 healthy individuals (35.4% were female), 58 prodromal PD individuals (20.6% female), and 393 established PD patients (34.5% female).
They analyzed five gene sets: mitochondrial DNA damage repair, general DNA damage repair, the integrated stress response, core PD-related genes, and PD-associated genes. To evaluate the different activities of each biological process, the team used logistic regression for classification analysis. Logistic regression is a supervised learning method that estimates the likelihood that a sample belongs to a particular group and works well with high-dimensional gene expression data.
To examine for possible sex-related differences, the team analyzed separately for male and female subjects. However, these showed similar or lower accuracy than the combined analysis, likely because of the small subgroup sizes. As such, only the pooled results were reported, and detecting sex-specific effects was limited.
The results showed that DNA repair and ISR expressions are disrupted before clinical symptoms of Parkinson’s appear, which aligned with previous studies’ findings. The team identified distinct patterns of DNA repair and ISR gene activity during the prodromal phase. Using classification analyses of blood transcriptomic data, they found that these gene sets could reliably distinguish prodromal PD individuals from healthy controls and those with established PD. Conversely, these signatures were not present in healthy individuals or patients with established Parkinson’s, which suggest that DNA repair and ISR signals occur during early stages.
“This means that we have found an important window of opportunity in which the disease can be detected before motor symptoms caused by nerve damage in the brain appear,” says Annikka Polster, assistant professor at the Department of Life Sciences at Chalmers University and study lead, in a press release.
One limitation of the study is that whole blood gene expression only partly reflects gene expression in the brain, so the blood samples provide an incomplete view of brain-related processes. It limits how the findings can be linked to disease mechanisms in the central nervous system (CNS). However, because prodromal PD involves systemic changes affecting multiple organs, important molecular alterations may also occur outside the brain, meaning there is value to studying blood and other tissues alongside the CNS.
Gene expressions were also probably influenced by immune status, medications, or other existing health conditions. Specifically, those with established PD may have been taking medication that could have skewed gene expression and reduced the classification accuracy. The study also did not capture all relevant biological changes. There was no stratification of the established PD group by medication, disease severity, or comorbidities because this would have led to very small subgroup sizes.
Though whole blood gene expression offers a limited view of brain-related processes, blood-based analyses can help identify potential biomarkers that can then be tested in more informative samples, such as cerebrospinal fluid, neuroimaging, and nasal swabs. Combining these tissue-measuring techniques with multi-omics approaches and brain-wide mitochondrial mapping techniques may help link peripheral signals to central neurodegenerative processes.
A Breakthrough for Early Diagnosis
The study confirmed that biomarkers of DNA repair dysfunction and ISR pathways occur early in Parkinson’s disease and can be reliably captured in blood. Furthermore, these longitudinal gene expression changes indicate that DNA repair disruptions shift over time as individuals move from the prodromal phase to established PD. This discovery provides the opportunity for early diagnosis.
Future studies are encouraged to examine larger, more diverse cohorts and use in vitro and in vivo models of Parkinson’s to explore the biological mechanisms. Integrating multi-omics approaches, such as proteomics, metabolomics, and epigenomics, could enhance understanding of DNA repair dysfunction and ISR pathways in prodromal PD. Further research must also be done to explore interventions that target early compensatory mechanisms.