Dr. Jian-Hong Zhu (X: @jz84_zhu) is a full professor and head of the Center for Research at Wenzhou Medical University’s School of Public Health, and Drs. Jian-Yong Wang, an associate chief physician, and Xiong Zhang, a chief physician and professor, work in the Department of Neurology in the Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University. Their team is committed to advancing the understanding of Parkinson’s disease, with a particular focus on developing diagnostic tools for its early detection.
Imagine being able to detect Parkinson’s disease (PD) years before tremors, stiffness, or slowness become obvious. This is no small challenge: early PD is notoriously tricky to diagnose. Symptoms can be subtle, mimic other conditions, or be dismissed as “just getting older.” Misdiagnosis and delayed diagnosis are common, which means opportunities for timely treatment and better patient outcomes are often missed. Our team set out to see if a single blood sample could provide the clues we need — not by looking at genes themselves, but at their epigenetic “decorations”, specifically a chemical mark called 5-hydroxymethylcytosine (5hmC). Think of 5hmC as tiny “sticky notes” on your DNA — little markers telling the cell which instructions to read and which to skip, without changing the genetic code itself.
Why 5hmC?
Epigenetics has had its share of hype over the last decade, but its transition from a research curiosity to a clinical tool has been slow. Still, there is good reason to believe it could revolutionize the approach to neurological diseases like PD. Patterns of 5hmC are known to change in response to disease, and if these patterns are detectable in the blood, they could serve as biomarkers — easy-to-measure signatures of disease presence and stage. To find them, we used a high-precision mapping technique called APOBEC-coupled epigenetic sequencing (ACE-seq). Simply put, this allows us to measure 5hmC changes with exquisite detail, down to individual DNA letters.
Two phases, one goal
We took a two-phase approach: 1) Discovery Phase: we recruited five newly diagnosed, PD patients with drug-naivety and their spouses as controls (using spouses helped minimise lifestyle-related differences). We analysed their entire blood hydroxymethylome — the complete set of 5hmC marks across the genome — at single-base resolution. From this deep dive, we identified differentially hydroxymethylated regions (DhmRs) — stretches of DNA where PD patients consistently showed different 5hmC patterns from controls. 2) Validation Phase: we then tested these candidate regions in a larger group of 78 PD patients, including 47 with early PD, and 82 control subjects. This time, we zeroed in on specific differentially hydroxymethylated cytosines (DhmCs) within those regions — a more fine-grained approach.
The numbers that matter
While DhmRs provided only modest diagnostic accuracy, DhmCs led to a striking improvement, particularly for the detection of early PD (Hoehn & Yahr stage ≤2). The refined nine-site DhmC panel (plus age) achieved an Area Under the Curve (AUC) of 0.923 in both training and validation datasets. For context, an AUC of 1 means perfect accuracy, and anything above 0.9 is considered excellent. Sensitivity, specificity, and precision were all above 80%. The panel could even differentiate early from late PD and was moderately correlated with standard clinical measures like the Movement Disorder Society-Unified Parkinson’s Disease Rating Scale (MDS-UPDRS), meaning that the test doesn’t just “spot differences”: it captures meaningful aspects of disease severity.
Why this matters for practice
Early PD diagnosis remains a substantial unmet need. The earlier we can confirm a diagnosis, the sooner we can start symptomatic treatments optimised to maintain quality of life, enrol patients in clinical trials for disease-modifying therapies, and offer targeted lifestyle and supporting interventions. A blood-based test is especially appealing because it’s minimally invasive (just a quick blood sample), relatively low-cost, and easy to integrate into routine care, even in primary care settings.
What’s next?
We plan to explore whether similar approaches could detect PD even earlier — perhaps in people at high risk but without symptoms. If so, we may be moving towards a future where a quick blood draw could flag PD before irreversible brain changes take hold. We could also consider further development of a model to distinguish PD subtypes, which could pave the way for more personalised treatment strategies. Imagine being able to tailor therapies based on a patient’s molecular profile, not just their symptoms.
For now, our study adds fresh evidence that the blood can tell us far more about brain health than we once thought. If 5hmC episignatures live up to their potential, a simple blood test could become one of the most powerful tools in the fight against PD.
