Predictive Value of Combined Serological Indicators for Cognitive Dysfunction in Patients with Systemic Lupus Erythematosus
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Abstract
Cognitive dysfunction (CD) is a common neuropsychiatric manifestation of systemic lupus erythematosus (SLE), but its early identification lacks objective serological markers. This study aimed to explore the predictive value of combined serum interleukin-6 (IL-6), intercellular adhesion molecule-1 (ICAM-1), and neurofilament light chain (NfL) for CD in SLE patients.
A total of 108 SLE patients (January 2018–December 2019) and 50 healthy controls were enrolled. SLE patients were divided into CD group (MoCA score <26, n=49) and non-CD group (MoCA score ≥26, n=59). Serum IL-6, ICAM-1, and NfL levels were detected by ELISA. Logistic regression and ROC curve analyses were performed to evaluate risk factors and predictive efficacy.
Serum IL-6, ICAM-1, and NfL levels were significantly higher in SLE patients than in controls (p<0.05), and further elevated in the CD group. These three markers were independent risk factors for SLE-related CD. The AUC of combined detection (0.852) was significantly higher than individual markers (0.734, 0.712, 0.677).
Serum IL-6, ICAM-1, and NfL have certain predictive value for CD in SLE patients, and the combined detection of these three indicators offers higher predictive value.
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2. Valdés Cabrera D, El Tal T, Mohamed I, Arciniegas SE, Fevrier S, Ledochowski J, et al. Effects of systemic lupus erythematosus on the brain: a systematic review of structural MRI findings and their relationships with cognitive dysfunction. Lupus Sci Med. 2024;11(2):e001214.
3. Ameer MA, Chaudhry H, Mushtaq J, Khan OS, Babar M, Hashim T, et al. An Overview of Systemic Lupus Erythematosus (SLE) Pathogenesis, Classification, and Management. Cureus. 2022;14(10):e30330.
4. Raghunath S, Glikmann-Johnston Y, Golder V, Kandane-Rathnayake R, Morand EF, Stout JC, et al. Clinical associations of cognitive dysfunction in systemic lupus erythematosus. Lupus Sci Med. 2023;10(1):e000835.
5. Paez-Venegas N, Jordan-Estrada B, Chavarria-Avila E, Perez-Vazquez F, Gómez-Bañuelos E, Medina-Dávalos R, et al. The Montreal Cognitive Assessment Test: A Useful Tool in Screening of Cognitive Impairment in Patients With Systemic Lupus Erythematosus. J Clin Rheumatol. 2019;25(8):325-8.
6. Borba EA, Scoto Dias E, Tercziany Vanzin JH, Ferreira de Queiroz Junior N, Dos Santos TAF, Skare T, et al. Cognitive dysfunction in patients with systemic lupus erythematosus. A cross-sectional study in a Brazilian sample. Lupus. 2023;32(7):900-9.
7. Aamodt WW, Waligorska T, Shen J, Tropea TF, Siderowf A, Weintraub D, et al. Neurofilament Light Chain as a Biomarker for Cognitive Decline in Parkinson Disease. Mov Disord. 2021;36(12):2945-50.
8. Ooi SZY, Spencer RJ, Hodgson M, Mehta S, Phillips NL, Preest G, et al. Interleukin-6 as a prognostic biomarker of clinical outcomes after traumatic brain injury: a systematic review. Neurosurg Rev. 2022;45(5):3035-54.
9. Cai XY, Lu Y, Tang C, Lin XJ, Ye JH, Li WN, et al. [Effect of interleukin-6 promoter DNA methylation on the pathogenesis of systemic lupus erythematosus]. Zhonghua Yi Xue Za Zhi. 2017;97(19):1491-5.
10. Du X, Zhao D, Wang Y, Sun Z, Yu Q, Jiang H, et al. Low Serum Calcium Concentration in Patients With Systemic Lupus Erythematosus Accompanied by the Enhanced Peripheral Cellular Immunity. Front Immunol. 2022;13:901854.
11. Zhang X, Liu C, Yang J, Ren H, Zhang J, Chen S, et al. Potential biomarkers for diagnosis and assessment of disease activity in systemic lupus erythematosus. Int Immunopharmacol. 2022;111:109155.
12. Liu S, Liu ZC, Zhang MY, Wang SJ, Pan M, Ji P, et al. ICAM-1 mediated cell-cell adhesion exerts dual roles on human B cell differentiation and IgG production. iScience. 2023;26(12):108505.
13. Fan S, Wang K, Wang S, Chen X. Potential drug targets for systemic lupus erythematosus identified through Mendelian randomization analysis. Medicine (Baltimore). 2025;104(7):e41439.
14. Koch K, Tikly M. Spectrum of cutaneous lupus erythematosus in South Africans with systemic lupus erythematosus. Lupus. 2019;28(8):1021-6.
15. Hong Y, Zeng X, Zhu CW, Neugroschl J, Aloysi A, Sano M, et al. Evaluating the Beijing Version of Montreal Cognitive Assessment for Identification of Cognitive Impairment in Monolingual Chinese American Older Adults. J Geriatr Psychiatry Neurol. 2022;35(4):586-93.
16. Yu H, Qiu X, Zhang YQ, Deng Y, He MY, Zhao YT, et al. Abnormal amplitude of low frequency fluctuation and functional connectivity in non-neuropsychiatric systemic lupus erythematosus: a resting-state fMRI study. Neuroradiology. 2019;61(3):331-40.
17. Xu J, Yang C, Zeng S, Wang X, Yang P, Qin L. Disturbance of neuron-microglia crosstalk mediated by GRP78 in Neuropsychiatric systemic lupus erythematosus mice. J Neuroinflammation. 2023;20(1):150.
18. Zabala A, Salgueiro M, Sáez-Atxukarro O, Ballesteros J, Ruiz-Irastorza G, Segarra R. Cognitive Impairment in Patients With Neuropsychiatric and Non-neuropsychiatric Systemic Lupus Erythematosus: A Systematic Review and Meta-analysis. J Int Neuropsychol Soc. 2018;24(6):629-39.
19. Tay SH, Mak A. Anti-NR2A/B Antibodies and Other Major Molecular Mechanisms in the Pathogenesis of Cognitive Dysfunction in Systemic Lupus Erythematosus. Int J Mol Sci. 2015;16(5):10281-300.
20. Katz P, Julian L, Tonner MC, Yazdany J, Trupin L, Yelin E, et al. Physical activity, obesity, and cognitive impairment among women with systemic lupus erythematosus. Arthritis Care Res (Hoboken). 2012;64(4):502-10.
21. Butt BA, Farman S, Khan SE, Saeed MA, Ahmad NM. Cognitive dysfunction in patients with Systemic Lupus Erythematosus. Pak J Med Sci. 2017;33(1):59-64.
22. Trysberg E, Nylen K, Rosengren LE, Tarkowski A. Neuronal and astrocytic damage in systemic lupus erythematosus patients with central nervous system involvement. Arthritis Rheum. 2003;48(10):2881-7.
23. Balajková V, Prokopcová A, Elisak M, Mojžišová H, Pavelka K, Olejárová M. Elevated serum neurofilament light chain levels in patients with neuropsychiatric systemic lupus erythematosus: a cross-sectional study. Lupus Sci Med. 2025;12(1):e001309.
24. Faraci FM. Reactive oxygen species: influence on cerebral vascular tone. J Appl Physiol (1985). 2006;100(2):739-43.
25. Tian R, Wu B, Fu C, Guo K. Correction for: miR-137 prevents inflammatory response, oxidative stress, neuronal injury and cognitive impairment via blockade of Src-mediated MAPK signaling pathway in ischemic stroke. Aging (Albany NY). 2021;13(1):1565.
26. Suntoko B, Hadisaputro S, Kalim H, Hadi S, Saputra WA. Relationship Between Disease Activity, Levels of IFN-a, IL-4, IL-6, and Anti-NMDA to Cognitive Dysfunction (MoCA-INA Score) in Systemic Lupus Erythematosus (SLE) Patients with Cognitive Dysfunction. Acta Med Indones. 2023;55(3):307-14.
27. Yan Q, Liu J, Long X, Wu C, Lin D, Wu Y, et al. Tofacitinib therapy in systemic lupus erythematosus with arthritis: a retrospective study. Clin Rheumatol. 2024;43(10):3139-45.
28. Weickert T, Cai H, O’Donnell M, Balzan R, Wells R, Liu D, et al. O1.5. Icam-1 Is Increased in Brain and Peripheral Levels of Soluble Icam-1 is Related to Cognitive Deficits In Schizophrenia. Schizophr Bull. 2018;44(Suppl 1):S73-4.
29. Lauvsnes MB, Zetterberg H, Blennow K, Kvaløy JT, Tjensvoll AB, Maroni S, et al. Correction to: Neurofilament light in plasma is a potential biomarker of central nervous system involvement in systemic lupus erythematosus. J Neurol. 2024;271(5):2926-7.
30. Kammeyer R, Chapman K, Furniss A, Hsieh E, Fuhlbrigge R, Ogbu EA, et al. Blood-based biomarkers of neuronal and glial injury in active major neuropsychiatric systemic lupus erythematosus. Lupus. 2024;33(10):1116-29.
31. Ahmadzade A, Simani L, Roozbeh M, Farsad F, Sheibani M, Negaresh O, et al. Correlation between neurofilament, HMGB1, MMP9, ds DNA blood levels and cognitive impairment in patients with neuropsychiatric systemic lupus erythematosus. Caspian J Intern Med. 2024;15(1):58-65.
32. Zervides KA, Janelidze S, Nystedt J, Gullstrand B, Nilsson P, Sundgren PC, et al. Plasma and cerebrospinal fluid neurofilament light concentrations reflect neuronal damage in systemic lupus Erythematosus. BMC Neurol. 2022;22(1):467.
33. Yi S, Wang L, Wang H, Ho MS, Zhang S. Pathogenesis of α-Synuclein in Parkinson's Disease: From a Neuron-Glia Crosstalk Perspective. Int J Mol Sci. 2022;23(23):14753.
34. Macher S, Zrzavy T, Höftberger R, Altmann P, Pataraia E, Zimprich F, et al. Longitudinal measurement of cerebrospinal fluid neurofilament light in anti-N-methyl-D-aspartate receptor encephalitis. Eur J Neurol. 2021;28(4):1401-5.
35. Benkert P, Meier S, Schaedelin S, Manouchehrinia A, Yaldizli Ö, Maceski A, et al. Serum neurofilament light chain for individual prognostication of disease activity in people with multiple sclerosis: a retrospective modelling and validation study. Lancet Neurol. 2022;21(3):246-57.
36. Karantali E, Kazis D, Chatzikonstantinou S, Petridis F, Mavroudis I. The role of neurofilament light chain in frontotemporal dementia: a meta-analysis. Aging Clin Exp Res. 2021;33(4):869-81.
37. Yuan A, Rao MV, Veeranna, Nixon RA. Neurofilaments and Neurofilament Proteins in Health and Disease. Cold Spring Harb Perspect Biol. 2017;9(4):a018309.
2. Valdés Cabrera D, El Tal T, Mohamed I, Arciniegas SE, Fevrier S, Ledochowski J, et al. Effects of systemic lupus erythematosus on the brain: a systematic review of structural MRI findings and their relationships with cognitive dysfunction. Lupus Sci Med. 2024;11(2):e001214.
3. Ameer MA, Chaudhry H, Mushtaq J, Khan OS, Babar M, Hashim T, et al. An Overview of Systemic Lupus Erythematosus (SLE) Pathogenesis, Classification, and Management. Cureus. 2022;14(10):e30330.
4. Raghunath S, Glikmann-Johnston Y, Golder V, Kandane-Rathnayake R, Morand EF, Stout JC, et al. Clinical associations of cognitive dysfunction in systemic lupus erythematosus. Lupus Sci Med. 2023;10(1):e000835.
5. Paez-Venegas N, Jordan-Estrada B, Chavarria-Avila E, Perez-Vazquez F, Gómez-Bañuelos E, Medina-Dávalos R, et al. The Montreal Cognitive Assessment Test: A Useful Tool in Screening of Cognitive Impairment in Patients With Systemic Lupus Erythematosus. J Clin Rheumatol. 2019;25(8):325-8.
6. Borba EA, Scoto Dias E, Tercziany Vanzin JH, Ferreira de Queiroz Junior N, Dos Santos TAF, Skare T, et al. Cognitive dysfunction in patients with systemic lupus erythematosus. A cross-sectional study in a Brazilian sample. Lupus. 2023;32(7):900-9.
7. Aamodt WW, Waligorska T, Shen J, Tropea TF, Siderowf A, Weintraub D, et al. Neurofilament Light Chain as a Biomarker for Cognitive Decline in Parkinson Disease. Mov Disord. 2021;36(12):2945-50.
8. Ooi SZY, Spencer RJ, Hodgson M, Mehta S, Phillips NL, Preest G, et al. Interleukin-6 as a prognostic biomarker of clinical outcomes after traumatic brain injury: a systematic review. Neurosurg Rev. 2022;45(5):3035-54.
9. Cai XY, Lu Y, Tang C, Lin XJ, Ye JH, Li WN, et al. [Effect of interleukin-6 promoter DNA methylation on the pathogenesis of systemic lupus erythematosus]. Zhonghua Yi Xue Za Zhi. 2017;97(19):1491-5.
10. Du X, Zhao D, Wang Y, Sun Z, Yu Q, Jiang H, et al. Low Serum Calcium Concentration in Patients With Systemic Lupus Erythematosus Accompanied by the Enhanced Peripheral Cellular Immunity. Front Immunol. 2022;13:901854.
11. Zhang X, Liu C, Yang J, Ren H, Zhang J, Chen S, et al. Potential biomarkers for diagnosis and assessment of disease activity in systemic lupus erythematosus. Int Immunopharmacol. 2022;111:109155.
12. Liu S, Liu ZC, Zhang MY, Wang SJ, Pan M, Ji P, et al. ICAM-1 mediated cell-cell adhesion exerts dual roles on human B cell differentiation and IgG production. iScience. 2023;26(12):108505.
13. Fan S, Wang K, Wang S, Chen X. Potential drug targets for systemic lupus erythematosus identified through Mendelian randomization analysis. Medicine (Baltimore). 2025;104(7):e41439.
14. Koch K, Tikly M. Spectrum of cutaneous lupus erythematosus in South Africans with systemic lupus erythematosus. Lupus. 2019;28(8):1021-6.
15. Hong Y, Zeng X, Zhu CW, Neugroschl J, Aloysi A, Sano M, et al. Evaluating the Beijing Version of Montreal Cognitive Assessment for Identification of Cognitive Impairment in Monolingual Chinese American Older Adults. J Geriatr Psychiatry Neurol. 2022;35(4):586-93.
16. Yu H, Qiu X, Zhang YQ, Deng Y, He MY, Zhao YT, et al. Abnormal amplitude of low frequency fluctuation and functional connectivity in non-neuropsychiatric systemic lupus erythematosus: a resting-state fMRI study. Neuroradiology. 2019;61(3):331-40.
17. Xu J, Yang C, Zeng S, Wang X, Yang P, Qin L. Disturbance of neuron-microglia crosstalk mediated by GRP78 in Neuropsychiatric systemic lupus erythematosus mice. J Neuroinflammation. 2023;20(1):150.
18. Zabala A, Salgueiro M, Sáez-Atxukarro O, Ballesteros J, Ruiz-Irastorza G, Segarra R. Cognitive Impairment in Patients With Neuropsychiatric and Non-neuropsychiatric Systemic Lupus Erythematosus: A Systematic Review and Meta-analysis. J Int Neuropsychol Soc. 2018;24(6):629-39.
19. Tay SH, Mak A. Anti-NR2A/B Antibodies and Other Major Molecular Mechanisms in the Pathogenesis of Cognitive Dysfunction in Systemic Lupus Erythematosus. Int J Mol Sci. 2015;16(5):10281-300.
20. Katz P, Julian L, Tonner MC, Yazdany J, Trupin L, Yelin E, et al. Physical activity, obesity, and cognitive impairment among women with systemic lupus erythematosus. Arthritis Care Res (Hoboken). 2012;64(4):502-10.
21. Butt BA, Farman S, Khan SE, Saeed MA, Ahmad NM. Cognitive dysfunction in patients with Systemic Lupus Erythematosus. Pak J Med Sci. 2017;33(1):59-64.
22. Trysberg E, Nylen K, Rosengren LE, Tarkowski A. Neuronal and astrocytic damage in systemic lupus erythematosus patients with central nervous system involvement. Arthritis Rheum. 2003;48(10):2881-7.
23. Balajková V, Prokopcová A, Elisak M, Mojžišová H, Pavelka K, Olejárová M. Elevated serum neurofilament light chain levels in patients with neuropsychiatric systemic lupus erythematosus: a cross-sectional study. Lupus Sci Med. 2025;12(1):e001309.
24. Faraci FM. Reactive oxygen species: influence on cerebral vascular tone. J Appl Physiol (1985). 2006;100(2):739-43.
25. Tian R, Wu B, Fu C, Guo K. Correction for: miR-137 prevents inflammatory response, oxidative stress, neuronal injury and cognitive impairment via blockade of Src-mediated MAPK signaling pathway in ischemic stroke. Aging (Albany NY). 2021;13(1):1565.
26. Suntoko B, Hadisaputro S, Kalim H, Hadi S, Saputra WA. Relationship Between Disease Activity, Levels of IFN-a, IL-4, IL-6, and Anti-NMDA to Cognitive Dysfunction (MoCA-INA Score) in Systemic Lupus Erythematosus (SLE) Patients with Cognitive Dysfunction. Acta Med Indones. 2023;55(3):307-14.
27. Yan Q, Liu J, Long X, Wu C, Lin D, Wu Y, et al. Tofacitinib therapy in systemic lupus erythematosus with arthritis: a retrospective study. Clin Rheumatol. 2024;43(10):3139-45.
28. Weickert T, Cai H, O’Donnell M, Balzan R, Wells R, Liu D, et al. O1.5. Icam-1 Is Increased in Brain and Peripheral Levels of Soluble Icam-1 is Related to Cognitive Deficits In Schizophrenia. Schizophr Bull. 2018;44(Suppl 1):S73-4.
29. Lauvsnes MB, Zetterberg H, Blennow K, Kvaløy JT, Tjensvoll AB, Maroni S, et al. Correction to: Neurofilament light in plasma is a potential biomarker of central nervous system involvement in systemic lupus erythematosus. J Neurol. 2024;271(5):2926-7.
30. Kammeyer R, Chapman K, Furniss A, Hsieh E, Fuhlbrigge R, Ogbu EA, et al. Blood-based biomarkers of neuronal and glial injury in active major neuropsychiatric systemic lupus erythematosus. Lupus. 2024;33(10):1116-29.
31. Ahmadzade A, Simani L, Roozbeh M, Farsad F, Sheibani M, Negaresh O, et al. Correlation between neurofilament, HMGB1, MMP9, ds DNA blood levels and cognitive impairment in patients with neuropsychiatric systemic lupus erythematosus. Caspian J Intern Med. 2024;15(1):58-65.
32. Zervides KA, Janelidze S, Nystedt J, Gullstrand B, Nilsson P, Sundgren PC, et al. Plasma and cerebrospinal fluid neurofilament light concentrations reflect neuronal damage in systemic lupus Erythematosus. BMC Neurol. 2022;22(1):467.
33. Yi S, Wang L, Wang H, Ho MS, Zhang S. Pathogenesis of α-Synuclein in Parkinson's Disease: From a Neuron-Glia Crosstalk Perspective. Int J Mol Sci. 2022;23(23):14753.
34. Macher S, Zrzavy T, Höftberger R, Altmann P, Pataraia E, Zimprich F, et al. Longitudinal measurement of cerebrospinal fluid neurofilament light in anti-N-methyl-D-aspartate receptor encephalitis. Eur J Neurol. 2021;28(4):1401-5.
35. Benkert P, Meier S, Schaedelin S, Manouchehrinia A, Yaldizli Ö, Maceski A, et al. Serum neurofilament light chain for individual prognostication of disease activity in people with multiple sclerosis: a retrospective modelling and validation study. Lancet Neurol. 2022;21(3):246-57.
36. Karantali E, Kazis D, Chatzikonstantinou S, Petridis F, Mavroudis I. The role of neurofilament light chain in frontotemporal dementia: a meta-analysis. Aging Clin Exp Res. 2021;33(4):869-81.
37. Yuan A, Rao MV, Veeranna, Nixon RA. Neurofilaments and Neurofilament Proteins in Health and Disease. Cold Spring Harb Perspect Biol. 2017;9(4):a018309.
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| Cognitive dysfunction Intercellular adhesion molecule-1 Interleukin-6 Neurofilament light chain Systemic lupus erythematosus | ||
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How to Cite
1.
Zheng G, Wang L, Cao J, Zheng X. Predictive Value of Combined Serological Indicators for Cognitive Dysfunction in Patients with Systemic Lupus Erythematosus. Iran J Allergy Asthma Immunol. 2026;:1-12.
