Decreased cerebrospinal fluid TNFRSF8 (sCD30) confirmed as a biomarker of Huntington’s disease progression
Journal of Neurology, 2026
Grétarsdóttir H., Cunningham J., Rasmusson A., Burman J., Kultima K., Paucar M., Svenningsson P., Constantinescu R., Niemelä V.
| Disease area | Application area | Sample type | Products |
|---|---|---|---|
Neurology | Pathophysiology Patient Stratification | CSF |  Olink Explore 3072/384 |
Abstract
Background
In Huntington’s disease (HD), clinical heterogeneity in age at onset and disease progression poses demands on precision medicine approaches. Biofluid biomarkers are needed to monitor disease progression, but may also provide insights into pathogenic mechanisms and support the development of disease-modifying therapies (DMTs).
Objective
To identify dysregulated cerebrospinal fluid (CSF) proteins in HTT gene expansion carriers (HDGECs), and to evaluate their relationship with disease progression.
Method
CSF was collected from a discovery and a validation cohort, both comprising HDGECs and neurologically unaffected controls (HCs). A total of 734 proteins were quantified using a high-sensitive Proximity Extension Assay (PEA) (Olink Neuro Explore panel 1 and 2). Protein association with disease progression was evaluated using the composite Unified HD Rating Scale (cUHDRS). Disease stage was classified according to the HD Integrated Staging System (HD-ISS).
Results
In total, samples included HDGECs ( n =61), HCs ( n =54), and longitudinal HDGEC samples ( n =21). Sixteen proteins were nominally dysregulated in HDGECs vs. HCs. Most pronounced was a twofold decrease of TNFRSF8 (sCD30) in HDGECs, and longitudinally declining levels were found. TNFRSF8 correlated significantly with cUHDRS, after adjustment for age, sex, and CAG. Levels of TNFRSF8 were similarly reduced in the validation cohort, and correlated with Total Functional Capacity (TFC).
Conclusion
TNFRSF8 recently emerged as a biomarker of neuroimmune dysfunction in HD. The results indicate and confirm that it is highly dysregulated in HDGECs and also tracks clinical disease progression. This pathway may be a promising potential target for DMTs.