Plasma-derived protein and imaging biomarkers distinguish disease severity in oculopharyngeal muscular dystrophy

被引:0
|
作者
Smith, Ian C. [1 ,2 ]
Sampaio, Marcos L. [2 ,3 ,4 ,5 ]
Melkus, Gerd [2 ,4 ,5 ,6 ]
Meier-Ross, Kaitlynn [3 ]
Chakraborty, Shaoni [7 ]
Stotts, Cameron [8 ,9 ,10 ]
Bourque, Pierre R. [2 ,3 ,11 ]
Lochmuller, Hanns [1 ,2 ,3 ,11 ,12 ]
Brais, Bernard [13 ]
Ayoub, Othmane [14 ]
Perkins, Theodore J. [1 ,2 ,8 ]
Khacho, Mireille [2 ,8 ,15 ]
Warman-Chardon, Jodi [1 ,2 ,3 ,11 ,12 ]
机构
[1] Ottawa Hosp Res Inst, Ottawa, ON, Canada
[2] Univ Ottawa, Eric Poulin Ctr Neuromuscular Dis, Ottawa, ON, Canada
[3] Univ Ottawa, Fac Med, Ottawa, ON, Canada
[4] Ottawa Hosp, Dept Med Imaging, Ottawa, ON, Canada
[5] Univ Ottawa, Dept Radiol Radiat Oncol & Med Phys, Ottawa, ON, Canada
[6] Carleton Univ, Dept Phys, Ottawa, ON, Canada
[7] Univ Ottawa, Fac Sci, Ottawa, ON, Canada
[8] Univ Ottawa, Dept Biochem Microbiol & Immunol, Ottawa, ON, Canada
[9] Univ Ottawa Heart Inst, CAPITAL Res Grp, Ottawa, ON, Canada
[10] Univ Ottawa Heart Inst, Vasc Biol & Expt Med Lab, Ottawa, ON, Canada
[11] Univ Ottawa, Ottawa Hosp, Dept Med, Ottawa, ON, Canada
[12] Childrens Hosp, Eastern Ontario Res Inst, Ottawa, ON, Canada
[13] McGill Univ, Montreal Neurol Inst & Hosp, Montreal, PQ, Canada
[14] Univ Ottawa, Fac Engn, Sch Elect Engn & Comp Sci, Ottawa, ON, Canada
[15] Univ Ottawa, Ottawa Inst Syst Biol, Ottawa, ON, Canada
关键词
proteomics; muscle MRI; muscular dystrophy; biomarker discovery; accelerated aging; skeletal muscle; GCG EXPANSIONS; DISCOVERY; MASS; FAMILIES;
D O I
10.1177/22143602241304990
中图分类号
R74 [神经病学与精神病学];
学科分类号
摘要
Background: Oculopharyngeal muscular dystrophy (OPMD) is a rare, late-onset, slowly progressive neuromuscular disorder characterized by ptosis, dysphagia, and proximal limb weakness. Emerging clinical trials require rapidly accessible and sensitive biomarkers to evaluate OPMD disease progression and potential response to future treatments.Objective: This cross-sectional study was designed to identify candidate circulating protein and imaging biomarkers of OPMD severity for future use in clinical trials.Methods: Twenty-five individuals with OPMD (age 63.3 +/- 10.5 years; GCN copy number of 13 in PABPN1) were assessed using the 7k SOMAScan assay to profile the plasma proteome, and MRI to quantify replacement of muscle by fat. OPMD severity was first categorized using the clinical presence/absence of limb weakness, and protein signals were considered distinguishing if they differed by more than 30% between subgroups and had statistically significant P-values after correcting for multiple comparisons. Distinguishing proteins were contrasted with age-matched controls (n = 10). OPMD severity was also treated as a continuous variable using fat fraction of the soleus muscle, and proteins were considered distinguishing if the slope of relationship between protein signal and soleus fat fraction differed significantly from zero after correcting for multiple comparisons. Pathway analyses were conducted using Metascape and the Database for Annotation, Visualization, and Integrated Discovery webtools.Results: Eighteen plasma proteins distinguished OPMD on both indicators of severity. Pathway analyses identified skeletal muscle tissue, phagocytosis/engulfment, and extracellular matrix organization as enriched ontology clusters in OPMD with limb weakness. The most distinguishing plasma protein signals (ACTN2, MYOM2, CA3, APOBEC2, MYL3, and PDLIM3) were over 200% higher in OPMD with limb weakness than OPMD without limb weakness as well as controls, and correlated strongly with percent of fatty replacement of soleus (r = 0.89 +/- 0.04).Conclusions: The candidate biomarkers identified contribute to the ongoing search for sensitive and accessible biomarkers of OPMD progression, prognosis, and monitoring.
引用
收藏
页码:244 / 259
页数:16
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