BACKGROUND: Sialic acid-protein interactions are involved in regulating central nervous system immunity; therefore, derangements in sialylation could be involved in neurodegeneration. OBJECTIVES: We evaluate the differences in serum transferrin sialylation in prodromal and early-stage Parkinson's disease (PD), its relation to substantia nigra degeneration, and the risk of phenoconversion to manifest disease. METHODS: Sixty treatment-naive PD patients; 72 polysomnography-confirmed isolated rapid eye movement sleep behavior disorder (iRBD) patients, that is, patients with prodromal synucleinopathy; and 46 healthy volunteers aged ≥45 years and drinking ≤60 standard drinks per month were included. The proportion of serum low-sialylated, carbohydrate-deficient transferrin (CDT) isoforms was assessed using high-performance liquid chromatography, and the values were adjusted for alcohol intake (CDTadj ). Dopamine transporter single-photon emission computed tomography (DaT-SPECT) imaging was performed. In iRBD, phenoconversion risk of DaT-SPECT and CDTadj was evaluated using Cox regression adjusted for age and sex. RESULTS: Median CDTadj was lower in PD (1.1 [interquartile range: 1.0-1.3]%) compared to controls (1.2 [1.1-1.6]%) (P = 0.001). In iRBD, median CDTadj was lower in subjects with abnormal (1.1 [0.9-1.3]%) than normal (1.3 [1.2-1.6]%) DaT-SPECT (P = 0.005). After a median 44-month follow-up, 20% of iRBD patients progressed to a manifest disease. Although iRBD converters and nonconverters did not significantly differ in CDTadj levels (P = 0.189), low CDTadj increased the risk of phenoconversion with hazard ratio 3.2 (P = 0.045) but did not refine the phenoconversion risk associated with abnormal DaT-SPECT yielding hazard ratio 15.8 (P < 0.001). CONCLUSIONS: Decreased serum CDTadj is associated with substantia nigra degeneration in synucleinopathies. iRBD patients with low CDTadj are more likely to phenoconvert to manifest disease. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson Movement Disorder Society.

Department of Circuit Theory Faculty of Electrical Engineering Czech Technical University Prague Prague Czech Republic

Department of Medical Pharmacology Expert Center for Parkinson CHU Lille Lille Neuroscience and Cognition Inserm UMR S1172 LICEND NS Park Network University of Lille Lille France

Department of Neurology and Centre of Clinical Neuroscience 1st Faculty of Medicine Charles University and General University Hospital Prague Prague Czech Republic

Institute of Medical Biochemistry and Laboratory Diagnostics 1st Faculty of Medicine Charles University and General University Hospital Prague Prague Czech Republic

Institute of Nuclear Medicine 1st Faculty of Medicine Charles University and General University Hospital Prague Prague Czech Republic

Zobrazit více v PubMed

Siderowf A, Lang AE. Premotor Parkinson's disease: concepts and definitions. Mov Disord 2012;27(5):608–616. PubMed PMC

Claassen DO, Josephs KA, Ahlskog JE, Silber MH, Tippmann‐Peikert M, Boeve BF. REM sleep behavior disorder preceding other aspects of synucleinopathies by up to half a century. Neurology 2010;75(6):494–499. PubMed PMC

Ponsen MM, Stoffers D, Booij J, van Eck‐Smit BL, ECh W, Berendse HW. Idiopathic hyposmia as a preclinical sign of Parkinson's disease. Ann Neurol 2004;56(2):173–181. PubMed

Heinzel S, Berg D, Gasser T, Chen H, Yao C, Postuma RB, MDS Task Force on the Definition of Parkinson's Disease . Update of the MDS research criteria for prodromal Parkinson's disease. Mov Disord 2019;34(10):1464–1470. PubMed

Boeve BF, Silber MH, Saper CB, et al. Pathophysiology of REM sleep behaviour disorder and relevance to neurodegenerative disease. Brain 2007;130(Pt 11):2770–2788. PubMed

Miglis MG, Adler CH, Antelmi E, et al. Biomarkers of conversion to alpha‐synucleinopathy in isolated rapid‐eye‐movement sleep behaviour disorder. Lancet Neurol 2021;20(8):671–684. PubMed PMC

Galbiati A, Verga L, Giora E, Zucconi M, Ferini‐Strambi L. The risk of neurodegeneration in REM sleep behavior disorder: a systematic review and meta‐analysis of longitudinal studies. Sleep Med Rev 2019;43:37–46. PubMed

Postuma RB, Iranzo A, Hu M, et al. Risk and predictors of dementia and parkinsonism in idiopathic REM sleep behaviour disorder: a multicentre study. Brain 2019;142(3):744–759. PubMed PMC

Arnaldi D, Chincarini A, Hu MT, et al. Dopaminergic imaging and clinical predictors for phenoconversion of REM sleep behaviour disorder. Brain 2021;144(1):278–287. PubMed PMC

Moreau C, Duce JA, Rascol O, et al. Iron as a therapeutic target for Parkinson's disease. Mov Disord 2018;33(4):568–574. PubMed

Mahoney‐Sanchez L, Bouchaoui H, Ayton S, Devos D, Duce JA, Devedjian J‐C. Ferroptosis and its potential role in the physiopathology of Parkinson's disease. Prog Neurobiol 2021;196:101890 PubMed

Hopes L et al. Magnetic resonance imaging features of the nigrostriatal system: biomarkers of Parkinson's disease stages? PLoS One 2016;11(4):e0147947 PubMed PMC

Jimenez‐Jimenez FJ, Alonso‐Navarro H, García‐Martín E, Agúndez JAG. Biological fluid levels of iron and iron‐related proteins in Parkinson's disease: review and meta‐analysis. Eur J Neurol 2021;28(3):1041–1055. PubMed

Ayton S, Lei P, Mclean C, Bush AI, Finkelstein DI. Transferrin protects against parkinsonian neurotoxicity and is deficient in Parkinson's substantia nigra. Signal Transduct Target Ther 2016;1:16015 PubMed PMC

Ezquerra M, Campdelacreu J, Muñoz E, Tolosa E. Association study of the G258S transferrin gene polymorphism and Parkinson's disease in the Spanish population. J Neurol 2005;252(10):1269–1270. PubMed

Mastroberardino PG, Hoffman EK, Horowitz MP, et al. A novel transferrin/TfR2‐mediated mitochondrial iron transport system is disrupted in Parkinson's disease. Neurobiol Dis 2009;34(3):417–431. PubMed PMC

Rhodes SL, Buchanan DD, Ahmed I, et al. Pooled analysis of iron‐related genes in Parkinson's disease: association with transferrin. Neurobiol Dis 2014;62:172–178. PubMed PMC

van Eijk HG, van Noort WL, Dubelaar ML, van der Heul C. The microheterogeneity of human transferrins in biological fluids. Clin Chim Acta 1983;132(2):167–171. PubMed

Stibler H, Kjellin KG. Isoelectric focusing and electrophoresis of the CSF proteins in tremor of different origins. J Neurol Sci 1976;30(2–3):269–285. PubMed

Stibler H, Borg S. Glycoprotein glycosyltransferase activities in serum in alcohol‐abusing patients and healthy controls. Scand J Clin Lab Invest 1991;51(1):43–51. PubMed

Stibler H, Borg S. Evidence of a reduced sialic acid content in serum transferrin in male alcoholics. Alcohol Clin Exp Res 1981;5(4):545–549. PubMed

Stibler H, Borg S, Allgulander C. Clinical significance of abnormal heterogeneity of transferrin in relation to alcohol consumption. Acta Med Scand 1979;206(4):275–281. PubMed

Sharpe PC. Biochemical detection and monitoring of alcohol abuse and abstinence. Ann Clin Biochem 2001;38(Pt 6):652–664. PubMed

Russell AC, Šimurina M, Garcia MT, et al. The N‐glycosylation of immunoglobulin G as a novel biomarker of Parkinson's disease. Glycobiology 2017;27(5):501–510. PubMed

van Kamp GJ, Mulder K, Kuiper M, Wolters EC. Changed transferrin sialylation in Parkinson's disease. Clin Chim Acta 1995;235(2):159–167. PubMed

Dusek P, Bezdicek O, Brozová H. Clinical characteristics of newly diagnosed Parkinson's disease patients included in the longitudinal BIO‐PD study. Cesk Slov Neurol Neurochir 2020;83(116):633–639.

Postuma RB, Berg D, Stern M, et al. MDS clinical diagnostic criteria for Parkinson's disease. Mov Disord 2015;30(12):1591–1601. PubMed

American Academy of Sleep Medicine. International Classification of Sleep Disorders. 3rd ed. Darien, IL: American Academy of Sleep Medicine; 2014. PubMed

Arndt T. Carbohydrate‐deficient transferrin as a marker of chronic alcohol abuse: a critical review of preanalysis, analysis, and interpretation. Clin Chem 2001;47(1):13–27. PubMed

Goetz CG, Fahn S, Martinez‐Martin P, et al. Movement Disorder 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. PubMed

Nasreddine ZS, Phillips NA, Bédirian V, et al. The Montreal cognitive assessment, MoCA: a brief screening tool for mild cognitive impairment. J Am Geriatr Soc 2005;53(4):695–699. PubMed

Doty RL, Shaman P, Dann M. Development of the University of Pennsylvania Smell Identification Test: a standardized microencapsulated test of olfactory function. Physiol Behav 1984;32(3):489–502. PubMed

Kaiserova M, Opavsky J, Maertin JJ, et al. Czech version of the autonomic scale for outcomes in Parkinson's disease (SCOPA‐AUT) – questionnaire to assess the presence and severity of autonomic dysfunction in patients with Parkinson's disease. Cesk Slov Neurol Neurochir 2014;77(1):96–99.

Visser M, Marinus J, Stiggelbout AM, Van Hilten J. Assessment of autonomic dysfunction in Parkinson's disease: the SCOPA‐AUT. Mov Disord 2004;19(11):1306–1312. PubMed

McKeith IG, Dickson DW, Lowe J, et al. Diagnosis and management of dementia with Lewy bodies: fourth consensus report of the DLB consortium. Neurology 2017;89(1):88–100. PubMed PMC

Darcourt J, Booij J, Tatsch K, et al. EANM procedure guidelines for brain neurotransmission SPECT using (123)I‐labelled dopamine transporter ligands, version 2. Eur J Nucl Med Mol Imaging 2010;37(2):443–450. PubMed

Dusek P, Veronika LLI, Bezdicek O, et al. Relations of non‐motor symptoms and dopamine transporter binding in REM sleep behavior disorder. Sci Rep 2019;9(1):15463 PubMed PMC

Calvini P, Rodriguez G, Inguglia F, Mignone A, Guerra UP, Nobili F. The basal ganglia matching tools package for striatal uptake semi‐quantification: description and validation. Eur J Nucl Med Mol Imaging 2007;34(8):1240–1253. PubMed

Laguna A, Xicoy H, Tolosa E, et al. Serum metabolic biomarkers for synucleinopathy conversion in isolated REM sleep behavior disorder. NPJ Parkinsons Dis 2021;7(1):40 PubMed PMC

Davids M, Kane MS, He M, et al. Disruption of Golgi morphology and altered protein glycosylation in PLA2G6‐associated neurodegeneration. J Med Genet 2016;53(3):180–189. PubMed PMC

Klaus C, Liao H, Allendorf DH, Brown GC, Neumann H. Sialylation acts as a checkpoint for innate immune responses in the central nervous system. Glia 2020;69(7):1619–1636. PubMed

Schwarz F, Pearce OMT, Wang X, et al. Siglec receptors impact mammalian lifespan by modulating oxidative stress. Elife 2015;4:e06184. 10.7554/eLife.06184.001 PubMed DOI PMC

Linnartz‐Gerlach B, Bodea L‐G, Klaus C, et al. TREM2 triggers microglial density and age‐related neuronal loss. Glia 2019;67(3):539–550. PubMed PMC

Mount MP, Lira A, Grimes D, et al. Involvement of interferon‐gamma in microglial‐mediated loss of dopaminergic neurons. J Neurosci 2007;27(12):3328–3337. PubMed PMC

Vawter MP, Dillon‐Carter O, Tourtellotte WW, Carvey P, Freed WJ. TGFbeta1 and TGFbeta2 concentrations are elevated in Parkinson's disease in ventricular cerebrospinal fluid. Exp Neurol 1996;142(2):313–322. PubMed

Lecours C, Bordeleau M, Cantin L, Parent M, Paolo TD, Tremblay M‐È. Microglial implication in Parkinson's disease: loss of beneficial physiological roles or gain of inflammatory functions? Front Cell Neurosci 2018;12:282 PubMed PMC

Bohm S, Schwab I, Lux A, Nimmerjahn F. The role of sialic acid as a modulator of the anti‐inflammatory activity of IgG. Semin Immunopathol 2012;34(3):443–453. PubMed

Annunziata I, Patterson A, Helton D, et al. Lysosomal NEU1 deficiency affects amyloid precursor protein levels and amyloid‐beta secretion via deregulated lysosomal exocytosis. Nat Commun 2013;4:2734 PubMed PMC

Nakagawa K, Kitazume S, Oka R, et al. Sialylation enhances the secretion of neurotoxic amyloid‐beta peptides. J Neurochem 2006;96(4):924–933. PubMed

van Rensburg SJ, Potocnik FC, De Villiers JN, Kotze MJ, Taljaard JJ. Earlier age of onset of Alzheimer's disease in patients with both the transferrin C2 and apolipoprotein E‐epsilon 4 alleles. Ann N Y Acad Sci 2000;903:200–203. PubMed

van Rensburg SJ, Berman PA, Potocnik FC, Taljaard JJ. Glycosylation of transferrin in Alzheimer's disease and alcohol‐induced dementia. Metab Brain Dis 2000;15(4):243–247. PubMed

van Rensburg SJ, Berman P, Potocnik F, MacGregor P, Hon D, de Villiers N. 5‐ and 6‐glycosylation of transferrin in patients with Alzheimer's disease. Metab Brain Dis 2004;19(1–2):89–96. PubMed

Pietrobono S, Stecca B. Aberrant sialylation in cancer: biomarker and potential target for therapeutic intervention? Cancers (Basel) 2021;13(9). 10.3390/cancers13092014 PubMed DOI PMC

Dong X, Mondello S, Kobeissy F, Talih F, Ferri R, Mechref Y. LC‐MS/MS glycomics of idiopathic rapid eye movement sleep behavior disorder. Electrophoresis 2018;39(24):3096–3103. PubMed PMC

Mondello S, Kobeissy F, Mechref Y, et al. Novel biomarker signatures for idiopathic REM sleep behavior disorder: a proteomic and system biology approach. Neurology 2018;91(18):e1710–e1715. PubMed

de Jong G, van Noort WL, Feelders RA, de Jeu‐Jaspars CM, van Eijk HG. Adaptation of transferrin protein and glycan synthesis. Clin Chim Acta 1992;212(1–2):27–45. PubMed

Fleming M, Mundt M. Carbohydrate‐deficient transferrin: validity of a new alcohol biomarker in a sample of patients with diabetes and hypertension. J Am Board Fam Pract 2004;17(4):247–255. PubMed

Peters S, Gallo V, Vineis P, et al. Alcohol consumption and risk of Parkinson's disease: data from a large prospective European cohort. Mov Disord 2020;35(7):1258–1263. PubMed PMC

Iranzo A, Santamaría J, Valldeoriola F, Serradell M, Salamero M, Gaig C, et al. Dopamine transporter imaging deficit predicts early transition to synucleinopathy in idiopathic rapid eye movement sleep behavior disorder. Ann Neurol 2017;82(3):419–428. PubMed

Arnaldi D, Mattioli P, Famà F, et al. Stratification tools for disease‐modifying trials in prodromal Synucleinopathy. Mov Disord 2021;37(1):52–61. PubMed PMC

Leitner DF, Connor JR. Functional roles of transferrin in the brain. Biochim Biophys Acta 2012;1820(3):393–402. PubMed