Diagnostic accuracy of interleukin-6, interleukin-10 and tumor necrosis factor alpha cytokine levels in patients with mild cognitive impairment: systematic review and meta-analysis

Aquino, Alana Mara Inácio de; Gomes, Kedma Anne Lima; Brito, Letícia Lorena Melo de; Lima, Luciana Domingos de; Gomes, Eneas Ricardo de Morais; Andrade, Suellen Mary Marinho dos Santos

doi:10.1590/1980-5764-DN-2023-0027

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Dementia & Neuropsychologia

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View & Review • Dement. neuropsychol. 18 • 2024 • https://doi.org/10.1590/1980-5764-DN-2023-0027 copy

Diagnostic accuracy of interleukin-6, interleukin-10 and tumor necrosis factor alpha cytokine levels in patients with mild cognitive impairment: systematic review and meta-analysis

Precisão diagnóstica dos níveis das citocinas IL-6, IL-10 e TNF-α em pacientes com comprometimento cognitivo leve: revisão sistemática e metanálise

Authorship SCIMAGO INSTITUTIONS RANKINGS

ABSTRACT

There is growing evidence suggesting an association between neurodegeneration and inflammation playing a role in the pathogenesis of age-associated diseases, including Alzheimer's disease (AD) and Mild Cognitive Impairment (MCI).

Objective:

A systematic review and meta-analysis were performed to verify evidence on the diagnostic accuracy parameters of the inflammatory cytokines interleukin-6 (IL-6), interleukin-10 (IL-10) and tumor necrosis factor alpha (TNF-α).

Methods:

A search of Medical Literature Analysis and Retrieval System Online (Medline), Scientific Electronic Library Online (SciELO), Web of Science and Science Direct databases was performed and nine observational studies associated with peripheral inflammatory biomarkers in MCI were identified. Mean (±standard deviation — SD) concentrations of these biomarkers and values of true positives, true negatives, false positives and false negatives for MCI and healthy controls (HC) were extracted from these studies.

Results:

Significantly higher levels of IL-10 were observed in subjects in the MCI group and Mini-Mental State Examination (MMSE) scores were lower compared to HC. For the other investigations, no differences were found between the groups. Our meta-analysis for the TNF-α biomarker revealed high heterogeneity between studies in terms of sensitivity and specificity.

Conclusion:

These findings do not support the involvement of inflammatory biomarkers for detection of MCI, although significant heterogeneity was observed. More studies are needed to evaluate the role of these cytokines in MCI, as well as in other stages of cognitive decline and all-cause dementias.

Keywords:
Cognitive Dysfunction; Inflammation; Interleukins; Tumor Necrosis Factor-alpha

Study	Typ	Sample		Age		% Women		MMSE		IL-6		IL-10		TNF -α
Study	Typ	MCI	ctrl	MCI	ctrl	MCI	ctrl	MCI	ctrl	MCI	ctrl	MCI	ctrl	MCI	ctrl
Zhao et al.²⁰20 Zhao SJ, Guo CN, Wang MQ, Chen WJ, Zhao YB. Serum levels of inflammation factors and cognitive performance in amnestic mild cognitive impairment: a Chinese clinical study. Cytokine. 2012;57(2): 221-5. https://doi.org/10.1016/j.cyto.2011.11.006 https://doi.org/10.1016/j.cyto.2011.11.0...	serum	150	150	70.67	69.85	47.30	41.30	26.55	27.06	1.86	1.72	-	-	-	-
Wennberg et al.²¹21 Wennberg AMV, Hagen CE, Machulda MM, Knopman, DS, Petersen RC, Mielke MM. The cross-sectional and longitudinal associations between IL-6, IL-10, and TNFα and cognitive outcomes in the Mayo Clinic Study of Aging. J Gerontol A Biol Sci Med Sci. 2019;74(8):1289-95. https://doi.org/10.1093/gerona/gly217 https://doi.org/10.1093/gerona/gly217...	plasma	186	1416	79.70	71.90	40.90	47.30	-	-	3.10	2.50	0.91	0.80	3.30	4.30
Shen et al.²²22 Shen XN, Lu Y, Tan CTY, Liu LY, Yu JT, Feng L, et al. Identification of inflammatory and vascular markers associated with mild cognitive impairment. Aging (Albany NY). 2019;11(8):2403-19. https://doi.org/10.18632/aging.101924 https://doi.org/10.18632/aging.101924...	plasma	57	57	68.77	67.77	31.58	31.58	25.82	29.46	-	-	-	-	15.43	14.29
Magalhães et al.²³23 Magalhães TNC, Weiler M, Teixeira CVL, Hayata T, Moraes AS, Boldrini VO, et al. Systemic inflammation and multimodal biomarkers in amnestic mild cognitive impairment and Alzheimer's disease. Mol Neurobiol. 2018;55(7):5689-97. https://doi.org/10.1007/s12035-017-0795-9 https://doi.org/10.1007/s12035-017-0795-...	serum	55	42	71.00	68.00	63.54	71.43	28.51	25.80	3.75	3.40	1.08	0.71	4.86	3.76
King et al.²⁴24 King E, O'Brien JT, Donaghy P, Morris C, Barnett N, Olsen K, et al. Peripheral inflammation in mild cognitive impairment with possible and probable Lewy body disease and Alzheimer's disease. Int Psychogeriatr. 2019;31(4):551-60. https://doi.org/10.1017/S1041610218001126 https://doi.org/10.1017/S104161021800112...	plasma	77	20	76.13	75.90	40.00	25.00	26.47	29.10	2.07	1.70	1.03	0.50	1.70	4.30
Johansson et al.²⁵25 Johansson P, Almqvist EG, Wallin A, Johansson JO, Andreasson U, Blennow K, et al. Reduced cerebrospinal fluid concentration of interleukin-12/23 subunit p40 in patients with cognitive impairment. PLoS One. 2017;12(5):e0176760. https://doi.org/10.1371/journal.pone.0176760 https://doi.org/10.1371/journal.pone.017...	serum	11	18	72.00	76.00	54.54	44.44	28.00	29.00	0.88	1.04	-	-	-	-
Kim et al.²⁶26 Kim YS, Lee KJ, Kim H. Serum tumour necrosis factor-α and interleukin-6 levels in Alzheimer's disease and mild cognitive impairment. Psychogeriatrics. 2017;17(4):224-30. https://doi.org/10.1111/psyg.12218 https://doi.org/10.1111/psyg.12218...	us	29	28	75.03	72.00	61.50	57.10	23.62	27.41	9.72	4.60	-	-	5.89	4.60
King et al.²⁷27 King E, O'Brien JT, Donaghy P, Morris C, Barnett N, Olsen K, et al. Peripheral inflammation in prodromal Alzheimer's and Lewy body dementias. J Neurol Neurosurg Psychiatry. 2018;89(4):339-45. https://doi.org/10.1136/jnnp-2017-317134 https://doi.org/10.1136/jnnp-2017-317134...	plasma	58	20	77.05	75.90	45.76	25.00	26.45	29.10	3.11	1.66	0.95	0.46	2.66	4.26
Dursun et al.²⁸28 Dursun E, Gezen-Ak D, Hanağası H, Bilgiç B, Lohmann E, Ertan S, et al. The interleukin 1 alpha, interleukin 1 beta, interleukin 6 and alpha-2-macroglobulin serum levels in patients with early or late onset Alzheimer's disease, mild cognitive impairment or Parkinson's disease. J Neuroimmunol. 2015;283:50-7. https://doi.org/10.1016/j.jneuroim.2015.04.014 https://doi.org/10.1016/j.jneuroim.2015....	serum	30	32	74.40	72.10	-	-	27.59	28.57	-	-	-	-	-	-

Variable	MCI (n=653)	Control (n=1,783)	p-value
Age	73.86±3.51	72.158±3.25	0.3020^* * Notes: Student's t test for independent samples;
% Women	48.14±11.06	42.89±16.07	0.4611^* * Notes: Student's t test for independent samples;
MMSE	26.63±1.51	28.19±1.29	0.0442^* * Notes: Student's t test for independent samples; ,^† † significant results; ‡ Wilcoxon-Mann-Whitney test.
IL-6	3.50±2.91	2.37±1.24	0.3735^* * Notes: Student's t test for independent samples;
IL-10	0.99±0.08	0.62±0.16	0.0126^* * Notes: Student's t test for independent samples; ,^† † significant results; ‡ Wilcoxon-Mann-Whitney test.
TNFα	5.64±5.03	5.92±4.11	0.8099²2 Jack Jr CR, Albert MS, Knopman DS, McKhann GM, Sperling RA, Carrillo MC, et al. Introduction to the recommendations from the National Institute on Aging Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease. Alzheimers Dement. 2011;7(3):257-62. https://doi.org/10.1016/j.jalz.2011.03.004 https://doi.org/10.1016/j.jalz.2011.03.0...

Study	Sensitivity	Specificity
Shen et al.²²22 Shen XN, Lu Y, Tan CTY, Liu LY, Yu JT, Feng L, et al. Identification of inflammatory and vascular markers associated with mild cognitive impairment. Aging (Albany NY). 2019;11(8):2403-19. https://doi.org/10.18632/aging.101924 https://doi.org/10.18632/aging.101924...	0.836 [0.721; 0.910]	0.181 [0.103; 0.299]
Magalhães et al.²³23 Magalhães TNC, Weiler M, Teixeira CVL, Hayata T, Moraes AS, Boldrini VO, et al. Systemic inflammation and multimodal biomarkers in amnestic mild cognitive impairment and Alzheimer's disease. Mol Neurobiol. 2018;55(7):5689-97. https://doi.org/10.1007/s12035-017-0795-9 https://doi.org/10.1007/s12035-017-0795-...	0.312 [0.206; 0.443]	0.988 [0.898; 0.999]

Study	DOR	PLR	NRL
Shen et al.²²22 Shen XN, Lu Y, Tan CTY, Liu LY, Yu JT, Feng L, et al. Identification of inflammatory and vascular markers associated with mild cognitive impairment. Aging (Albany NY). 2019;11(8):2403-19. https://doi.org/10.18632/aging.101924 https://doi.org/10.18632/aging.101924...	1.129 [0.430; 2.961]	1.021 [0.865; 1.206]	0.905 [0.407; 2.011]
Magalhãs et al.²³23 Magalhães TNC, Weiler M, Teixeira CVL, Hayata T, Moraes AS, Boldrini VO, et al. Systemic inflammation and multimodal biomarkers in amnestic mild cognitive impairment and Alzheimer's disease. Mol Neurobiol. 2018;55(7):5689-97. https://doi.org/10.1007/s12035-017-0795-9 https://doi.org/10.1007/s12035-017-0795-...	38.636 [2.247; 664.439]	26.875 [1.662; 434.454]	0.696 [0.581; 0.832]

Academia Brasileira de Neurologia, Departamento de Neurologia Cognitiva e Envelhecimento R. Vergueiro, 1353 sl.1404 - Ed. Top Towers Offices, Torre Norte, São Paulo, SP, Brazil, CEP 04101-000, Tel.: +55 11 5084-9463 | +55 11 5083-3876 - São Paulo - SP - Brazil
E-mail: revistadementia@abneuro.org.br | demneuropsy@uol.com.br

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[1] Correspondence: Alana Mara Inácio de Aquino; Email: alanamarajp@hotmail.com.