Serum glial fibrillary acidic protein and neurofilament light chain as biomarkers of retinal neurodysfunction in early diabetic retinopathy: results of the EUROCONDOR study

Abcouwer SF, Gardner TW (2014) Diabetic retinopathy: loss of neuroretinal adaptation to the diabetic metabolic environment. Ann N Y Acad Sci 1311:174–190. https://doi.org/10.1111/nyas.12412 Simó R, Hernández C (2014) Neurodegeneration in the diabetic eye: new insights and therapeutic perspectives. Trends Endocrinol Metab 25:23–33. https://doi.org/10.1016/j.tem.2013.09.005 Simó R, Hernández C (2015) Novel approaches for treating diabetic retinopathy based on recent pathogenic evidence. Prog Retin Eye Res 48:160–180. https://doi.org/10.1016/j.preteyeres.2015.04.003 Stitt AW, Curtis TM, Chen M et al (2016) The progress in understanding and treatment of diabetic retinopathy. Prog Retin Eye Res 51:156–186. https://doi.org/10.1016/j.preteyeres.2015.08.001 Barber AJ, Lieth E, Khin SA, Antonetti DA, Buchanan AG, Gardner TW (1998) Neural apoptosis in the retina during experimental and human diabetes. Early onset and effect of insulin. J Clin Investig 102:783–791. https://doi.org/10.1172/JCI2425 Carrasco E, Hernández C, Miralles A, Huguet P, Farrés J, Simó R (2007) Lower somatostatin expression is an early event in diabetic retinopathy and is associated with retinal neurodegeneration. Diabetes Care 30:2902–2908. https://doi.org/10.2337/dc07-0332 Garcia-Ramírez M, Hernández C, Villarroel M et al (2009) Interphotoreceptor retinoid-binding protein (IRBP) is downregulated at early stages of diabetic retinopathy. Diabetologia 52:2633–2641. https://doi.org/10.1007/s00125-009-1548-8 Metea MR, Newmman EA (2007) Signalling within the neurovascular unit in the retina. Exp Physiol 92:635–640. https://doi.org/10.1113/expphysiol.2006.036376 Newman EA (2013) Functional hyperemia and mechanisms of neurovascular coupling in the retinal vasculature. J Cereb Blood Flow Metab 33:1685–1695. https://doi.org/10.1038/jcbfm.2013.145 Jackson GR, Barber AJ (2010) Visual dysfunction associated with diabetic retinopathy. Curr Diabetes Rep 10:380–384. https://doi.org/10.1007/s11892-010-0132-4 Wolff BE, Bearse MA, Schneck ME et al (2015) Color vision and neuroretinal function in diabetes. Doc Ophthalmol 130:131–139. https://doi.org/10.1007/s10633-014-9476-4 Trento M, Durando O, Lavecchia S et al (2017) Vision related quality of life in patients with type 2 diabetes in the EUROCONDOR trial. Endocrine 57:83–88. https://doi.org/10.1007/s12020-016-1097-0 Sun JK, Aiello LP, Abràmoff MD et al (2021) Updating the staging system for diabetic retinal disease. Ophthalmology 128:490–493. https://doi.org/10.1016/j.ophtha.2020.10.008 Scott IU, Jackson GR, Quillen DA et al (2014) Effect of doxycycline vs placebo on retinal function and diabetic retinopathy progression in patients with severe nonproliferative or non-high-risk proliferative diabetic retinopathy: a randomized clinical trial. JAMA Ophthalmol 132:535–543. https://doi.org/10.1001/jamaophthalmol.2014.93 Parisi V, Ziccardi L, Barbano L, Giorno P, Varano M, Parravano MC (2021) Citicoline and vitamin B12 eye drops in type 1 diabetes: results of a 36-month pilot study evaluating macular electrophysiological changes. Adv Ther 38:3924–3936. https://doi.org/10.1007/s12325-021-01771-1 Simó R, Hernández C, Porta M et al (2019) Effects of topically administered neuroprotective drugs in early stages of diabetic retinopathy: results of the EUROCONDOR clinical trial. Diabetes 68:457–463. https://doi.org/10.2337/db18-0682 Laverse E, Guo T, Zimmerman K et al (2020) Plasma glial fibrillary acidic protein and neurofilament light chain, but not tau, are biomarkers of sports-related mild traumatic brain injury. Brain Commun 2:fcaa137. https://doi.org/10.1093/braincomms/fcaa137 Ayrignac X, Le Bars E, Duflos C et al (2020) Serum GFAP in multiple sclerosis: correlation with disease type and MRI markers of disease severity. Sci Rep 10:10923. https://doi.org/10.1038/s41598-020-67934-2 Schindler P, Grittner U, Oechtering J et al (2021) Serum GFAP and NfL as disease severity and prognostic biomarkers in patients with aquaporin-4 antibody-positive neuromyelitis optica spectrum disorder. J Neuroinflammation 18:105. https://doi.org/10.1186/s12974-021-02138-7 Santos AR, Ribeiro L, Bandello F et al (2017) Functional and structural findings of neurodegeneration in early stages of diabetic retinopathy: cross-sectional analyses of baseline data of the EUROCONDOR project. Diabetes 66:2503–2510. https://doi.org/10.2337/db16-1453 Marmor MF, Fulton AB, Holder GE et al (2009) ISCEV standard for fullfield clinical electroretinography (2008 update). Doc Ophthalmol 118:69–77. https://doi.org/10.1007/s10633-008-9155-4 Lakhani E, Wright T, Abdolell M, Westall C (2010) Multifocal ERG defects associated with insufficient long-term glycemic control in adolescents with type 1 diabetes. Invest Ophthalmol Vis Sci 51:5297–5303. https://doi.org/10.1167/iovs.10-5200 Bronson-Castain KW, Bearse MA Jr, Neuville J et al (2009) Adolescents with type 2 diabetes: early indications of focal retinal neuropathy, retinal thinning, and venular dilation. Retina 29:618–662. https://doi.org/10.1097/IAE.0b013e31819a988b Simão S, Costa MÂ, Sun JK, Cunha-Vaz J, Simó R, European Consortium for the Early Treatment of Diabetic Retinopathy (EUROCONDOR) (2017) Development of a normative database for multifocal electroretinography in the context of a multicenter clinical trial. Ophthalmic Res 57:07–117. https://doi.org/10.1159/000450958 Hernández C, Porta M, Bandello F et al (2020) The usefulness of serum biomarkers in the early stages of diabetic retinopathy: results of the EUROCONDOR clinical trial. J Clin Med 9:1233. https://doi.org/10.3390/jcm9041233 Zetterberg H, Blennow K (2016) Fluid biomarkers for mild traumatic brain injury and related conditions. Nat Rev Neurol 12:563–574. https://doi.org/10.1038/nrneurol.2016.127 Lei J, Gao G, Feng J et al (2015) Glial fibrillary acidic protein as a biomarker in severe traumatic brain injury patients: a prospective cohort study. Crit Care 19:362–362. https://doi.org/10.1186/s13054-015-1081-8 Puspitasari V, Gunawan PY, Wiradarma HD, Hartoyo V (2019) Glial fibrillary acidic protein serum level as a predictor of clinical outcome in ischemic stroke. Open Access Maced J Med Sci 7:1471–1474. https://doi.org/10.1186/s13054-015-1081-8 Chmielewska N, Szyndler J, Makowska K, Wojtyna D, Maciejak P, Płaźnik A (2018) Looking for novel, brain-derived, peripheral biomarkers of neurological disorders. Neurol Neurochir Pol 52:318–325. https://doi.org/10.1016/j.pjnns.2018.02.002 Abdelhak A, Foschi M, Abu-Rumeileh S et al (2022) Blood GFAP as an emerging biomarker in brain and spinal cord disorders. Nat Rev Neurol 18:158–172. https://doi.org/10.1038/s41582-021-00616-3 Traub J, Otto M, Sell R et al (2022) Serum glial fibrillary acidic protein indicates memory impairment in patients with chronic heart failure. ESC Heart Fail 9:2626–2634. https://doi.org/10.1002/ehf2.13986 Ebenau JL, Pelkmans W, Verberk IMW et al (2022) Association of CSF, plasma, and imaging markers of neurodegeneration with clinical progression in people with subjective cognitive decline. Neurology 98:e1315–e1326. https://doi.org/10.1212/WNL.0000000000200035 Mizutani M, Gerhardinger C, Lorenzi M (1998) Müller cell changes in human diabetic retinopathy. Diabetes 47:445–449. https://doi.org/10.2337/diabetes.47.3.445 Bringmann A, Wiedemann P (2012) Müller glial cells in retinal disease. Ophthalmologica 227:1–19. https://doi.org/10.1159/000328979 Yuan A, Rao MV, Veeranna Nixon RA (2017) Neurofilaments and neurofilament proteins in health and disease. Cold Spring Harb Perspect Biol 9:a018309. https://doi.org/10.1101/cshperspect.a018309 Yuan A, Rao MV, Sasaki T, Chen Y, Kumar A, Veeranna Liem RKH, Eyer J, Peterson AC, Julien JP, Nixon RA (2006) Alpha-internexin is structurally and functionally associated with the neurofilament triplet proteins in the mature CNS. J Neurosci 26:10006–10019. https://doi.org/10.1523/JNEUROSCI.2580-06.2006 Yuan A, Sasaki T, Kumar A, Peterhoff CM, Rao MV, Liem RK, Julien JP, Nixon RA (2012) Peripherin is a subunit of peripheral nerve neurofilaments: implications for differential vulnerability of CNS and peripheral nervous system axons. J Neurosci 32:8501–8508. https://doi.org/10.1523/JNEUROSCI.1081-12 Yuan A, Nixon RA (2021) Neurofilament proteins as biomarkers to monitor neurological diseases and the efficacy of therapies. Front Neurosci 15:689938. https://doi.org/10.3389/fnins.2021.689938 Lin CH, Li CH, Yang KC et al (2019) Blood NfL: a biomarker for disease severity and progression in Parkinson disease. Neurology 93:e1104–e1111. https://doi.org/10.1212/WNL.0000000000008088 Blennow K (2017) A review of fluid biomarkers for Alzheimer’s disease: moving from CSF to blood. Neurol Ther 6:15–24. https://doi.org/10.1007/s40120-017-0073-9 Williams T, Zetterberg H, Chataway J (2020) Neurofilaments in progressive multiple sclerosis: a systematic review. J Neurol 268:3212–3222. https://doi.org/10.1007/s00415-020-09917-x Moseby-Knappe M, Mattsson N, Nielsen N et al (2019) Serum neurofilament light chain for prognosis of outcome after cardiac arrest. JAMA Neurol 76:64–71. https://doi.org/10.1001/jamaneurol.2018.3223 Shahim P, Politis A, van der Merwe A, Moore B, Chou YY, Pham DL, Butman JA, Diaz-Arrastia R, Gill JM, Brody DL, Zetterberg H, Blennow K, Chan L (2020) Neurofilament light as a biomarker in traumatic brain injury. Neurology 95:e610–e622. https://doi.org/10.1212/WNL.0000000000009983 Fohner AE, Bartz TM, Tracy RP et al (2022) Association of serum neurofilament light chain concentration and mri findings in older adults: the cardiovascular health study. Neurology 98:e903–e911. https://doi.org/10.1212/WNL.0000000000013229 Sundstrom JM, Hernández C, Weber SR et al (2018) Proteomic analysis of early diabetic retinopathy reveals mediators of neurodegenerative brain diseases. Invest Ophthalmol Vis Sci 59:2264–2274. https://doi.org/10.1167/iovs.17-23678 Verberk IMW, Laarhuis MB, van den Bosch KA et al (2021) Serum markers glial fibrillary acidic protein and neurofilament light for prognosis and monitoring in cognitively normal older people: a prospective memory clinic-based cohort study. Lancet Healthy Longev 2:e87–e95. https://doi.org/10.1016/S2666-7568(20)30061-1 Lin TY, Vitkova V, Asseyer S et al (2021) Increased serum neurofilament light and thin ganglion cell-inner plexiform layer are additive risk factors for disease activity in early multiple sclerosis. Neurol Neuroimmunol Neuroinflamm 8:1051. https://doi.org/10.1212/NXI.0000000000001051 Khalil M, Teunissen CE, Otto M et al (2018) Neurofilaments as biomarkers in neurological disorders. Nat Rev Neurol 14:577–589. https://doi.org/10.1038/s41582-018-0058-z Notturno F, Capasso M, DeLauretis A, Carpo M, Uncini A (2009) Glial fibrillary acidic protein as a marker of axonal damage in chronic neuropathies. Muscle Nerve 40:50–54. https://doi.org/10.1002/mus.21323 Cui M, Cheng C, Zhang L (2022) High-throughput proteomics: a methodological mini-review. Lab Invest 3:1–12. https://doi.org/10.1038/s41374-022-00830-7 van Lierop ZYGJ, Verberk IMW, van Uffelen KWJ et al (2022) Pre-analytical stability of serum biomarkers for neurological disease: neurofilament-light, glial fibrillary acidic protein and contactin-1. Clin Chem Lab Med 60:842–850. https://doi.org/10.1515/cclm-2022-0007 Mattsson-Carlgren N, Palmqvist S, Blennow K, Hansson O (2020) Increasing the reproducibility of fluid biomarker studies in neurodegenerative studies. Nat Commun 11:6252. https://doi.org/10.1038/s41467-020-19957-6