Exploratory mediation analysis of associations between serum biomarkers of neuronal injury, astrocyte reactivity, neuroinflammation, and neurotrophic support and fatigue in Parkinson's disease
DOI:
https://doi.org/10.15584/ejcem.2026.3.2Keywords:
fibro-fatigue, mediation study, neuronal damage biomarkers, Parkinson’s disease, Wnt pathway biomarkersAbstract
Introduction and aim. Fatigue is a debilitating non-motor symptom in Parkinson's disease (PD). This exploratory cross-sectional mediation analysis investigated whether specific serum biomarkers mediate the relationship between PD and fatigue severity.
Material and methods. Ninety PD patients and 45 matched controls were enrolled in the study. Fatigue was assessed using the Fibro-Fatigue scale (FF). Serum levels of ten biomarkers (neuron‑specific enolase (NSE), glial fibrillary acidic protein (GFAP), brain-derived neurotrophic factor (BDNF), β-amyloid-42, α-synuclein, ubiquitin carboxy‑terminal hydrolase L1 (UCHL1), high‑mobility group box 1 (HMGB1), R‑spondin 1 (RSPO1), Dickkopf‑1 (DKK1), and sclerostin) were quantified by enzyme-linked immunosorbent assay. Mediation analysis (PROCESS Macro, Version 4.2, Model 4) tested whether these biomarkers mediated the relationship between PD status and FF score.
Results. The overall model predicting FF scores was highly significant (F(26,108)=54.08, p<0.001, R²=0.929). Mediation analysis revealed significant indirect effects from PD status to fatigue via GFAP, HMGB1, BDNF, and NSE. Moderation analysis indicated that the biomarker fatigue relationship was significantly modified by PD status only for HMGB1 and BDNF. For GFAP and NSE, the interactions were non‑significant. Bootstrapped analyses confirmed significant indirect effects of PD on fatigue through elevated levels of NSE (effect=1.743), HMGB1 (effect=1.207), GFAP (effect=1.101), and BDNF (effect=0.921).
Conclusion. PD-related fatigue is significantly mediated by neuroinflammation (HMGB1), astroglial activation (GFAP), neuronal injury (NSE), and a paradoxical BDNF response. Disease‑specific moderation was confirmed only for HMGB1 and BDNF.
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References
Mhyre TR, Boyd JT, Hamill RW, Maguire-Zeiss KA. Parkinson's disease. Subcell Biochem. 2012;65:389-455. doi:10.1007/978-94-007-5416-4_16
Tong J. The pathogenesis and treatment of Parkinson's disease. Theoretical and Natural Science. 2024;47:15-19. doi:10.54254/2753-8818/47/2024PJ0101
Tarakad A. Motor features of Parkinson's disease. Neurol Clin. 2025;43(2):279-289. doi:10.1016/j.ncl.2024.12.007
Heo JY, Nam MH, Yoon HH, et al. Aberrant tonic inhibition of dopaminergic neuronal activity causes motor symptoms in animal models of Parkinson's disease. Curr Biol. 2020;30(2):276-291.e279. doi:10.1016/j.cub.2019.11.079
Peña-Zelayeta L, Delgado-Minjares KM, Villegas-Rojas MM, et al. Redefining non-motor symptoms in Parkinson's disease. J Pers Med. 2025;15(5):172. doi:10.3390/jpm15050172
Müller B, Assmus J, Herlofson K, Larsen JP, Tysnes OB. Importance of motor vs. non-motor symptoms for health-related quality of life in early Parkinson's disease. Parkinsonism Relat Disord. 2013;19(11):1027-1032. doi:10.1016/j.parkreldis.2013.07.010
Siciliano M, Trojano L, Santangelo G, De Micco R, Tedeschi G, Tessitore A. Fatigue in Parkinson's disease: a systematic review and meta-analysis. Mov Disord. 2018;33(11):1712-1723. doi:10.1002/mds.27461
Arenas E, Saltó C, Villaescusa C. WNT signaling in midbrain dopaminergic neuron development and cell replacement therapies for Parkinson’s disease. Springer Plus. 2015;4(1):L49. doi:10.1186/2193-1801-4-S1-L49
Dai TL, Zhang C, Peng F, et al. Depletion of canonical Wnt signaling components has a neuroprotective effect on midbrain dopaminergic neurons in an MPTP-induced mouse model of Parkinson's disease. Exp Ther Med. 2014;8(2):384-390. doi:10.3892/etm.2014.1745
Vallée A, Vallée JN, Lecarpentier Y. Potential role of cannabidiol in Parkinson's disease by targeting the WNT/β-catenin pathway, oxidative stress and inflammation. Aging. 2021;13(7):10796-10813. doi:10.18632/aging.202951
Marchetti B, Tirolo C, L'Episcopo F, et al. Parkinson's disease, aging and adult neurogenesis: Wnt/β-catenin signalling as the key to unlock the mystery of endogenous brain repair. Aging cell. 2020;19(3):e13101. doi:10.1111/acel.13101
Jacobs BM, Belete D, Bestwick J, et al. Parkinson's disease determinants, prediction and gene-environment interactions in the UK Biobank. J Neurol Neurosurg Psychiatry. 2020;91(10):1046-1054. doi:10.1136/jnnp-2020-323646
Huang Y, Liu L, Liu A. Dickkopf-1: Current knowledge and related diseases. Life Sci. 2018;209:249-254. doi:10.1016/j.lfs.2018.08.019
Drake MT, Khosla S. Hormonal and systemic regulation of sclerostin. Bone. 2017;96:8-17. doi:10.1016/j.bone.2016.12.004
Angelopoulou E, Piperi C, Papavassiliou AG. High-mobility group box 1 in Parkinson's disease: from pathogenesis to therapeutic approaches. J Neurochem. 2018;146(3):211-218. doi:10.1111/jnc.14450
Liang K, Li X, Guo Q, et al. Structural changes in the retina and serum HMGB1 levels are associated with decreased cognitive function in patients with Parkinson's disease. Neurobiol Dis. 2024;190:106379. doi:10.1016/j.nbd.2023.106379
Anand AA, Khan M, V M, Kar D. The molecular basis of Wnt/β-Catenin signaling pathways in neurodegenerative diseases. Int J Cell Biol. 2023;2023:9296092. doi:10.1155/2023/9296092
Das S, Ramteke H. A Comprehensive review of the role of biomarkers in early diagnosis of Parkinson's disease. Cureus. 2024;16(2):e54337. doi:10.7759/cureus.54337
Soni R, Mathur K, Shah J. An update on new-age potential biomarkers for Parkinson's disease. Ageing Res Rev. 2024;94:102208. doi:10.1016/j.arr.2024.102208
Han Y, Wang Y, Zou X, Guo H. The serum proteomic profile in patients with migraine. Front Mol Neurosci. 2025;18:1460403. doi:10.3389/fnmol.2025.1460403
Al-Hakeim HK, Khudhair HN, Ranaei-Siadat SO, et al. Affective and chronic fatigue symptoms are associated with serum neuronal damage markers in Parkinson's disease. Sci Rep. 2025;15(1):20647. doi:10.1038/s41598-025-07735-7
Wolf D, Ayon-Olivas M, Sendtner M. BDNF-Regulated modulation of striatal circuits and implications for Parkinson's disease and dystonia. Biomedicines. 2024;12(8). doi:10.3390/biomedicines12081761
Ali NH, Al-Kuraishy HM, Al-Gareeb AI, et al. BDNF/TrkB activators in Parkinson's disease: a new therapeutic strategy. J Cell Mol Med. 2024;28(10):e18368. doi:10.1111/jcmm.18368
Lin J, Ou R, Li C, et al. Plasma glial fibrillary acidic protein as a biomarker of disease progression in Parkinson's disease: a prospective cohort study. BMC Med. 2023;21(1):420. doi:10.1186/s12916-023-03120-1
Liddelow SA, Barres BA. Reactive astrocytes: production, function, and therapeutic potential. Immunity. 2017;46(6):957-967. doi:10.1016/j.immuni.2017.06.006
Postuma RB, Poewe W, Litvan I, et al. Validation of the MDS clinical diagnostic criteria for Parkinson's disease. Mov Disord. 2018;33(10):1601-1608. doi:10.1002/mds.27362
Al-Hakeim HK, Al-Rammahi DA, Al-Dujaili AH. IL-6, IL-18, sIL-2R, and TNFα proinflammatory markers in depression and schizophrenia patients who are free of overt inflammation. J Affect Disord. 2015;182:106-114. doi:10.1016/j.jad.2015.04.044
Goetz CG, Tilley BC, Shaftman SR, et al. Movement isorder society-sponsored revision of the unified Parkinson's disease rating scale (MDS-UPDRS): scale presentation and clinimetric testing results. Mov Disord. 2008;23(15):2129-2170. doi:10.1002/mds.22340
Hoehn MM, Yahr MD. Parkinsonism: onset, progression and mortality. Neurology. 1967;17(5):427-442. doi:10.1212/wnl.17.5.427
Zachrisson O, Regland B, Jahreskog M, Kron M, Gottfries CG. A rating scale for fibromyalgia and chronic fatigue syndrome (the FibroFatigue scale). J Psychosom Res. 2002;52(6):501-509. doi:10.1016/s0022-3999(01)00315-4
Gogishvili D, Honey MIJ, Verberk IMW, et al. The GFAP proteoform puzzle: how to advance GFAP as a fluid biomarker in neurological diseases. J Neurochem. 2025;169(1):e16226. doi:10.1111/jnc.16226
Godeiro Coelho LM, Teixeira FJP, Koru-Sengul T, et al. Predictive value of nervous cell injury biomarkers in moderate-to-severe traumatic brain injury: a network meta-analysis. Neurology. 2025;105(5):e213997. doi:10.1212/wnl.0000000000213997
Tang Y, Han L, Li S, et al. Plasma GFAP in Parkinson's disease with cognitive impairment and its potential to predict conversion to dementia. NPJ Parkinsons Dis. 2023;9(1):23. doi:10.1038/s41531-023-00447-7
Su W, Chen HB, Li SH, Wu DY. Correlational study of the serum levels of the glial fibrillary acidic protein and neurofilament proteins in Parkinson's disease patients. Clin Neurol Neurosurg. 2012;114(4):372-375. doi:10.1016/j.clineuro.2011.11.002
Gao HM, Zhou H, Zhang F, Wilson BC, Kam W, Hong JS. HMGB1 acts on microglia Mac1 to mediate chronic neuroinflammation that drives progressive neurodegeneration. J Neurosci. 2011;31(3):1081-1092. doi:10.1523/jneurosci.3732-10.2011
Li J, Wu N, Xiao Y, Xia Y. High mobility group box 1 and its post-translational modifications: Molecular mechanisms underlying neurodegenerative disease pathogenesis. Neural Regen Res. 2025. doi:10.4103/nrr.Nrr-d-25-01091
Razali K, Mohamed WMY. High-mobility group box 1 (HMGB1) protein in Parkinson's disease research: a 10-year bibliometric analysis. J Integr Neurosci. 2023;22(4):87. doi:10.31083/j.jin2204087
Goyal A, Agrawal A, Dubey N, Verma A. High mobility group box 1 protein: a plausible therapeutic molecular target in Parkinson's disease. Curr Pharm Biotechnol. 2024;25(8):937-943. doi:10.2174/1389201025666230905092218
Palasz E, Wysocka A, Gasiorowska A, Chalimoniuk M, Niewiadomski W, Niewiadomska G. BDNF as a promising therapeutic agent in Parkinson's disease. Int J Mol Sci. 2020;21(3). doi:10.3390/ijms21031170
Rochester L, Galna B, Lord S, et al. Decrease in Aβ42 predicts dopa-resistant gait progression in early Parkinson disease. Neurology. 2017;88(16):1501-1511. doi:10.1212/wnl.0000000000003840
Butterfield DA, Perluigi M, Sultana R. Oxidative stress in Alzheimer's disease brain: new insights from redox proteomics. Eur J Pharmacol. 2006;545(1):39-50. doi:10.1016/j.ejphar.2006.06.026
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