Objective: To discover plasma biomarkers that differentiate people with dystonia from healthy controls (HC).
Background: Blood-based biomarkers for dystonia could address several unmet clinical needs: improving diagnostic accuracy in sporadic cases, stratifying patients by molecular mechanism, monitoring therapeutic response in early-phase clinical trials, and predicting penetrance in genetic forms. Studies across focal dystonia subtypes have identified biomarker candidates in whole plasma1. This study focuses on extracellular vesicles (EVs) isolated from plasma, which may provide a distinct window into cellular status.
Method: Plasma samples were collected from DYT-TOR1A dystonia, sporadic cervical dystonia (CD), and HC populations (13 DYT-TOR1A vs 27 HC; 49 CD vs 45 HC). The EV fraction was isolated and subjected to quantitative LC/MS/MS proteomic analysis, identifying 2,100 proteins. Biomarker candidates were identified based on uncorrected p-values, fold change magnitude, and ROC properties, then further prioritized for mechanistic relationships to integrated stress response (ISR) dysregulation via cross-species comparison with EV proteins dysregulated in a DYT-TOR1A mouse model and normalized by ISR-modulating compounds. Prioritized candidates were tested in ELISA-based assays.
Results: Proteomics identified 23 differentially expressed plasma EV proteins between DYT-TOR1A and HC, and 283 between CD and HC. Downstream analyses prioritized 17 proteins; two showed differentiating signal in both dystonia cohorts and three showed regulation by ISR-targeting compounds in preclinical models. Plasma EV biomarkers were largely non-overlapping with published whole-plasma results. ELISAs with suitable sensitivity for validation were identified.
Conclusion: These results suggest potential for peripherally based biomarkers of dystonia. A subset of candidates showed intersecting biology between monogenic DYT-TOR1A and sporadic CD. Future studies are needed to further validate and develop these candidates for clinical use and to establish whether preclinical ISR-modulator responsiveness translates to human subjects.
References: 1. Timsina J, Dinasarapu A, Kilic-Berkmen G, Budde J, Sung YJ, Klein AM, Cruchaga C, Jinnah HA. Blood-Based Proteomics for Adult-Onset Focal Dystonias. Ann Neurol. 2024 Jul;96(1):110-120. doi: 10.1002/ana.26929. Epub 2024 Apr 5. PMID: 38578115; PMCID: PMC11186717.
To cite this abstract in AMA style:
Z. Caffall, J. Jordan, A. Norain, L. Longyear, G. Aldykiewicz, T. Tran, A. Wagle-Shukla, N. Sharma, A. Nixon, E. Soderblom, N. Calakos. Plasma Extracellular Vesicle Protein Biomarker Discovery for Monogenic and Sporadic Dystonia [abstract]. Mov Disord. 2026; 41 (suppl 1). https://www.mdsabstracts.org/abstract/plasma-extracellular-vesicle-protein-biomarker-discovery-for-monogenic-and-sporadic-dystonia/. Accessed October 1, 2026.« Back to 2026 International Congress
MDS Abstracts - https://www.mdsabstracts.org/abstract/plasma-extracellular-vesicle-protein-biomarker-discovery-for-monogenic-and-sporadic-dystonia/