From Bench to Bedside: Neurofilament Light Chain as a Biomarker in Ischemic Stroke

Abstract

Neurofilaments (NFs) are protein structures that form part of the neuronal cytoskeleton, providing structural support and facilitating axonal transport. Neurofilament light chain (NFL) has emerged as a promising biomarker for various neurological conditions, as it is released into the bloodstream following neuronal damage. The ability of NFL to differentiate between types of injury and enhance the accuracy of clinical prediction models makes it an asset in both clinical practice and research. Studies suggest that NFL can be employed to diagnose and monitor disease progression and aid in the prognosis of various neurological conditions, including ischemic stroke (IS). In IS, NFL serves as a predictor of severity, functional recovery, and the risk of complications. This review therefore synthesizes current preclinical and clinical studies on the use of NFL as a biomarker for prognosis, monitoring, and treatment in IS.

Keywords

Neurofilament / Ischemic stroke / Neurofilament light chain (NFL) / Biomarker

References

[1] Mathias K, Machado RS, Stork S, et al.. Blood-brain barrier permeability in the ischemic stroke: an update. Microvasc Res., 2024, 151 Article ID: 104621

[2] Mathias K, Machado RS, Stork S, et al.. Short-chain fatty acid on blood-brain barrier and glial function in ischemic stroke. Life Sci., 2024, 354 Article ID: 122979

[3] Mathias K, Machado RS, Cardoso T, et al.. Innate lymphoid cells in the brain: Focus on ischemic stroke. Microvasc Res., 2025, 157 Article ID: 104755

[4] Liu D, Chen J, Wang X, et al.. Serum neurofilament light chain as a predictive biomarker for ischemic stroke outcome: a systematic review and meta-analysis. J Stroke Cerebrovasc Dis., 2020, 29(6): Article ID: 104813

[5] Neurofilament light chain as a biomarker of ALS. Nat Rev Neurol. 2012;8:413.

[6] Wai CH, Jin J, Cyrklaff M, et al.. Neurofilament light chain plasma levels are associated with area of brain damage in experimental cerebral malaria. Sci Rep., 2022, 12(1): 10726

[7] Kim SH, Choi MK, Park NY, et al.. Serum neurofilament light chain levels as a biomarker of neuroaxonal injury and severity of oxaliplatin-induced peripheral neuropathy. Sci Rep., 2020, 10(1): 7995

[8] Friberg S, Lindblad C, Zeiler FA, et al.. Fluid biomarkers of chronic traumatic brain injury. Nat Rev Neurol., 2024, 20(11): 671-684

[9] Sechi, Mariotto S, McKeon A, et al. Serum neurofilament to magnetic resonance imaging lesion area ratio differentiates spinal cord infarction from acute myelitis. Stroke. 2021;52(2):645–654.

[10] Qu Y, Tan CC, Shen XN, et al.. Association of plasma neurofilament light with small vessel disease burden in nondemented elderly: a longitudinal study. Stroke., 2021, 52(3): 896-904

[11] Jing X, Wang L, Song M, et al.. Serum neurofilament light chain and inflammatory cytokines as biomarkers for early detection of mild cognitive impairment. Sci Rep., 2024, 14(1): 9072

[12] Barba L, Vollmuth C, Abu-Rumeileh S, et al.. Serum β-synuclein, neurofilament light chain and glial fibrillary acidic protein as prognostic biomarkers in moderate-to-severe acute ischemic stroke. Sci Rep., 2023, 13(1): 20941

[13] Holmegaard L, Jensen C, Pedersen A, et al.. Circulating levels of neurofilament light chain as a biomarker of infarct and white matter hyperintensity volumes after ischemic stroke. Sci Rep., 2024, 14(1): 16180

[14] Ahn JW, Hwang J, Lee M, et al.. Serum neurofilament light chain levels are correlated with the infarct volume in patients with acute ischemic stroke. Medicine., 2022, 101(39): Article ID: e30849

[15] Yuan A, Rao MV, Veeranna, et al. Neurofilaments and neurofilament proteins in health and disease. Cold Spring Harb Perspect Biol. 2017;9(4):a018309.

[16] Liem RKH. Neuronal intermediate filaments. Curr Opin Cell Biol., 1990, 2(1): 86-90

[17] Chang R, Kwak Y, Gebremichael Y. Structural properties of neurofilament sidearms: sequence-based modeling of neurofilament architecture. J Mol Biol., 2009, 391(3): 648-660

[18] Shaw G. Neurofilaments: abundant but mysterious neuronal structures. Bioessays., 1986, 4(4): 161-166

[19] Nixon RA, Shea TB. Dynamics of neuronal intermediate filaments: a developmental perspective. Cell Motil Cytoskeleton., 1992, 22(2): 81-91

[20] Khalil M, Pirpamer L, Hofer E, et al.. Serum neurofilament light levels in normal aging and their association with morphologic brain changes. Nat Commun., 2020, 11(1): 812

[21] Götze K, Vrillon A, Dumurgier J, et al.. Plasma neurofilament light chain as prognostic marker of cognitive decline in neurodegenerative diseases, a clinical setting study. Alzheimers Res Ther., 2024, 16(1): 231

[22] Pedersen CC, Ushakova A, Alves G, et al.. Serum neurofilament light at diagnosis: a prognostic indicator for accelerated disease progression in Parkinson’s Disease. NPJ Park Dis, 2024, 10: 162

[23] Caron NS, Byrne LM, Lemarié FL, et al.. Elevated plasma and CSF neurofilament light chain concentrations are stabilized in response to mutant huntingtin lowering in the brains of Huntington’s disease mice. Transl Neurodegener., 2024, 13(1): 50

[24] Malucchi S, Bava CI, Valentino P, et al.. In multiple sclerosis patients a single serum neurofilament light chain (sNFL) dosage is strongly associated with 12 months outcome: data from a real-life clinical setting. J Neurol., 2024, 271(12): 7494-7501

[25] Wellmann S, Geis T, Kuhle J, et al.. Neurofilament light chain as biomarker in encephalitis. J Clin Med., 2024, 13(18): 5416

[26] Spitz G, Hicks AJ, McDonald SJ, et al.. Plasma biomarkers in chronic single moderate-severe traumatic brain injury. Brain., 2024, 147(11): 3690-3701

[27] Gottiparthy A, Lam K, Kundu S, et al.. Neurofilament light chain in serum of cancer patients with acute neurological complications. CNS Oncol., 2024, 13(1): 2386233

[28] Lv X, Zhao Q, Liu Q, et al.. Serum fatty acid profiles and neurofilament light chain levels in the general population. J Nutr., 2024, 154(10): 3070-3078

[29] Pilotto A, Ashton NJ, Lupini A, et al.. Plasma NfL, GFAP, amyloid, and p-tau species as Prognostic biomarkers in Parkinson’s disease. J Neurol., 2024, 271(12): 7537-7546

[30] Eratne D, Kang MJY, Lewis C, et al.. Plasma and CSF neurofilament light chain distinguish neurodegenerative from primary psychiatric conditions in a clinical setting. Alzheimers Dement., 2024, 20(11): 7989-8001

[31] Breznik L, Daurer M, Rabl R, et al.. Motor deficits and brain pathology in the Parkinson’s disease mouse model hA53Ttg. Front Neurosci., 2024, 18: 1462041

[32] Ahmad S, Imtiaz MA, Mishra A, et al.. Genome-wide association study meta-analysis of neurofilament light (NfL) levels in blood reveals novel loci related to neurodegeneration. Commun Biol., 2024, 7(1): 1103

[33] Rabl M, Zullo L, Lewczuk P, et al. Plasma neurofilament light, glial fibrillary acid protein, and phosphorylated tau 181 as biomarkers for neuropsychiatric symptoms and related clinical disease progression. Res Sq. 2024:rs.3.rs–rs.4116836.

[34] Kim KY, Kim E, Lee JY, et al.. Impact of amyloid and cardiometabolic risk factors on prognostic capacity of plasma neurofilament light chain for neurodegeneration. Alzheimers Res Ther., 2024, 16(1): 202

[35] Casiraghi V, Milone I, Brusati A, et al.. Quantification of serum TDP-43 and neurofilament light chain in patients with amyotrophic lateral sclerosis stratified by UNC13A genotype. J Neurol Sci., 2024, 466 Article ID: 123210

[36] Zhang X, Wang H, Li L, et al.. Neurofilament light chain: a candidate biomarker of perioperative stroke. Front Aging Neurosci., 2022, 14 Article ID: 921809

[37] Becktel DA, Frye JB, Le EH, et al.. Discovering novel plasma biomarkers for ischemic stroke: Lipidomic and metabolomic analyses in an aged mouse model. J Lipid Res., 2024, 65(9): Article ID: 100614

[38] Mages B, Aleithe S, Altmann S, et al.. Impaired neurofilament integrity and neuronal morphology in different models of focal cerebral ischemia and human stroke tissue. Front Cell Neurosci., 2018, 12: 161

[39] Härtig W, Krueger M, Hofmann S, et al.. Up-regulation of neurofilament light chains is associated with diminished immunoreactivities for MAP2 and tau after ischemic stroke in rodents and in a human case. J Chem Neuroanat., 2016, 78: 140-148

[40] Mages B, Aleithe S, Blietz A, et al.. Simultaneous alterations of oligodendrocyte-specific CNP, astrocyte-specific AQP4 and neuronal NF-L demarcate ischemic tissue after experimental stroke in mice. Neurosci Lett., 2019, 711 Article ID: 134405

[41] Mages B, Fuhs T, Aleithe S, et al.. The cytoskeletal elements MAP2 and NF-L show substantial alterations in different stroke models while elevated serum levels highlight especially MAP2 as a sensitive biomarker in stroke patients. Mol Neurobiol., 2021, 58(8): 4051-4069

[42] Park HJ, Choi JH, Nam MH, et al.. Induced neurodifferentiation of hBM-MSCs through activation of the ERK/CREB pathway via pulsed electromagnetic fields and physical stimulation promotes neurogenesis in cerebral ischemic models. Int J Mol Sci., 2022, 23(3): 1177

[43] Wu J, Wu D, Liang Y, et al.. Plasma neurofilament light chain: a biomarker predicting severity in patients with acute ischemic stroke. Medicine., 2022, 101(26): Article ID: e29692

[44] Pedersen A, Stanne TM, Nilsson S, et al.. Circulating neurofilament light in ischemic stroke: temporal profile and outcome prediction. J Neurol., 2019, 266(11): 2796-2806

[45] De Marchis GM, Katan M, Barro C, et al.. Serum neurofilament light chain in patients with acute cerebrovascular events. Eur J Neurol., 2018, 25(3): 562-568

[46] Lanzone J, Zulueta A, Boscarino M, et al.. Spectral exponent assessment and neurofilament light chain: a comprehensive approach to describe recovery patterns in stroke. Front Neurol., 2024, 15: 1329044

[47] Chong JR, Hilal S, Ashton NJ, et al.. Brain atrophy and white matter hyperintensities are independently associated with plasma neurofilament light chain in an Asian cohort of cognitively impaired patients with concomitant cerebral small vessel disease. Alzheimers Dement (Amst)., 2023, 15(1): Article ID: e12396

[48] Vollmuth C, Fiessler C, Montellano FA, et al.. Incremental value of serum neurofilament light chain and glial fibrillary acidic protein as blood-based biomarkers for predicting functional outcome in severe acute ischemic stroke. Eur Stroke J., 2024, 9(3): 751-762

[49] Li J, Zhang P, Zhu Y, et al.. Serum neurofilament light chain levels are associated with early neurological deterioration in minor ischemic stroke. Front Neurol., 2023, 14: 1096358

[50] Aulin J, Sjölin K, Lindbäck J, et al.. Neurofilament light chain and risk of stroke in patients with atrial fibrillation. Circulation., 2024, 150(14): 1090-1100

[51] Korley FK, Goldstick J, Mastali M, et al.. Serum NfL (neurofilament light chain) levels and incident stroke in adults with diabetes mellitus. Stroke., 2019, 50(7): 1669-1675

[52] Amrein M, Meier S, Schäfer I, et al.. Serum neurofilament light chain in functionally relevant coronary artery disease and adverse cardiovascular outcomes. Biomarkers., 2023, 28(3): 341-351

[53] Zhao H, Mo M, Miao C, et al.. Association of serum biomarker neurofilament light concentration with post-stroke depression: a preliminary study. Gen Hosp Psychiatry., 2020, 64: 17-25

[54] Wang DZ, Guo FQ, Guo L, et al.. Serum neurofilament light predicts 6-month mental health outcomes in a cohort of patients with acute ischemic stroke. Front Psychiatry., 2021, 12 Article ID: 764656

[55] Wang JH, Huang J, Guo FQ, et al.. Circulating neurofilament light predicts cognitive decline in patients with post-stroke subjective cognitive impairment. Front Aging Neurosci., 2021, 13 Article ID: 665981

[56] Wang Z, Wang R, Li Y, et al.. Plasma neurofilament light chain as a predictive biomarker for post-stroke cognitive impairment: a prospective cohort study. Front Aging Neurosci., 2021, 13 Article ID: 631738

[57] Jiang L, Wang Z, Wang R, et al.. Plasma neurofilament light chain is associated with cognitive impairment after posterior circulation stroke. Evid Based Complement Alternat Med., 2022, 2022: 2466982

[58] Peng Y, Li Q, Qin L, et al.. Combination of serum neurofilament light chain levels and MRI markers to predict cognitive function in ischemic stroke. Neurorehabil Neural Repair., 2021, 35(3): 247-255

[59] Sanchez JD, Martirosian RA, Mun KT, et al.. Temporal patterning of neurofilament light as a blood-based biomarker for stroke: a systematic review and meta-analysis. Front Neurol., 2022, 13 Article ID: 841898

[60] Pujol-Calderón F, Portelius E, Zetterberg H, et al.. Neurofilament changes in serum and cerebrospinal fluid after acute ischemic stroke. Neurosci Lett., 2019, 698: 58-63

[61] Gattringer T, Pinter D, Enzinger C, et al.. Serum neurofilament light is sensitive to active cerebral small vessel disease. Neurology., 2017, 89(20): 2108-2114

[62] Chen CH, Chu HJ, Hwang YT, et al.. Plasma neurofilament light chain level predicts outcomes in stroke patients receiving endovascular thrombectomy. J Neuroinflammation., 2021, 18(1): 195

[63] Zhou FY, Chen DW, Li HY, et al.. The association of serum neurofilament light chain and acute ischaemic stroke is influenced by effective revascularization. Dis Markers., 2022, 2022: 5236080

[64] Correia M, Silva I, Gabriel D, et al.. Early plasma biomarker dynamic profiles are associated with acute ischemic stroke outcomes. Eur J Neurol., 2022, 29(6): 1630-1642

[65] Gendron TF, Badi MK, Heckman MG, et al. Plasma neurofilament light predicts mortality in patients with stroke. Sci Transl Med. 2020;12(569):eaay1913.

[66] Uphaus T, Bittner S, Gröschel S, et al.. NfL (neurofilament light chain) levels as a predictive marker for long-term outcome after ischemic stroke. Stroke., 2019, 50(11): 3077-3084

[67] Heshmatollah A, Fani L, Koudstaal PJ, et al.. Plasma β-amyloid, total-tau, and neurofilament light chain levels and the risk of stroke: a prospective population-based study. Neurology., 2022, 98(17): e1729-e1737

[68] Xu C, Yi T, Qing T, et al.. Serum neurofilament light chain: a predictive marker for outcomes following mild-to-moderate ischemic stroke. Front Neurol., 2024, 15: 1398826

[69] Ferrari F, Rossi D, Ricciardi A, et al.. Quantification and prospective evaluation of serum NfL and GFAP as blood-derived biomarkers of outcome in acute ischemic stroke patients. J Cereb Blood Flow Metab., 2023, 43(9): 1601-1611

[70] Dhana A, DeCarli C, Aggarwal NT, et al.. Serum neurofilament light chain, brain infarcts, and the risk of stroke: a prospective population-based cohort study. Eur J Epidemiol., 2023, 38(4): 427-434

[71] Rattanawong W, Ongphichetmetha T, Hemachudha T, et al.. Neurofilament light is associated with clinical outcome and hemorrhagic transformation in moderate to severe ischemic stroke. J Cent Nerv Syst Dis., 2023, 15: 11795735221147212

[72] Nielsen HH, Soares CB, Høgedal SS, et al.. Acute neurofilament light chain plasma levels correlate with stroke severity and clinical outcome in ischemic stroke patients. Front Neurol., 2020, 11: 448

[73] Onatsu J, Vanninen R, Jäkälä P, et al.. Serum neurofilament light chain concentration correlates with infarct volume but not prognosis in acute ischemic stroke. J Stroke Cerebrovasc Dis., 2019, 28(8): 2242-2249

[74] Tiedt S, Duering M, Barro C, et al. Serum neurofilament light. A biomarker of neuroaxonal injury after ischemic stroke. Neurology. 2018;91(14):e1338–e1347.

[75] Traenka C, Disanto G, Seiffge DJ, et al.. Serum neurofilament light chain levels are associated with clinical characteristics and outcome in patients with cervical artery dissection. Cerebrovasc Dis., 2015, 40(5–6): 222-227

[76] Singh P, Yan J, Hull R, et al.. Levels of phosphorylated axonal neurofilament subunit H (pNfH) are increased in acute ischemic stroke. J Neurol Sci., 2011, 304(1–2): 117-121

Funding

Universidade Do Extremo Sul Catarinense

RIGHTS & PERMISSIONS

The Author(s)