Serum levels and clinical significance of ANGPTL2 and NRG-1 in Parkinson's disease patients

doi:10.11958/20252282

Abstract

Abstract:

Objective To explore the clinical significance of serum angiopoietin-like protein 2 (ANGPTL2) and neuregulin-1 (NRG-1) levels in patients with Parkinson's disease (PD). Methods A total of 274 PD patients and 266 healthy volunteers were selected as the observation group and the control group, respectively. The Montreal Cognitive Assessment (MoCA) was used to evaluate the cognitive function of PD patients, and patients were divided into the cognitive impairment group (MoCA score <26, n=161) and the non-cognitive impairment group (MoCA score ≥26, n=113). The Hoehn-Yahr (H-Y) scale was used to grade the severity of PD, and patients were classified into the H-Y stages 1-2 (118 cases), the stage 3 (94 cases) and the stage 4 (62 cases). Enzyme-linked immunosorbent assay (ELISA) was used to measure serum ANGPTL2 and NRG-1 levels in both groups. Pearson correlation analysis was used to examine the relationship between serum ANGPTL2 and NRG-1 levels in PD patients. Logistic regression was used to analyze influencing factors of PD. Receiver operating characteristic (ROC) curves were used to evaluate the diagnostic efficacy of both markers for PD. Results The serum NRG-1 and education years of PD patients were prominently lower in the observation group than those of the healthy group (P<0.05), and the serum ANGPTL2 and proportion of PD family history were prominently higher in the observation group than those of the control group (P<0.05). The serum ANGPTL2 levels were higher in the cognitive impairment group than those of the non cognitive impairment group (P<0.05), and NRG-1 prominently lower than the non cognitive impairment group (P<0.05). The serum ANGPTL2 levels increased successively in PD patients with H-Y stages 1-2, 3 and 4, and serum NRG-1 lvevels decreased successively (P<0.05). The serum levels of ANGPTL2 and NRG-1 were negatively correlated in PD patients (r=-0.373, P<0.001). Logistic regression analysis showed that elevated serum ANGPTL2 levels were the independent risk factors affecting the occurrence of PD, while high level of NRG-1 was an independent protective factor for PD (P<0.05). The area under the curve (AUC) of serum ANGPTL2, NRG-1 and their combined diagnosis for PD was 0.689 (95%CI: 0.645-0.733), 0.717 (95%CI: 0.674-0.760) and 0.768 (95%CI: 0.729-0.808), respectively. The combined diagnosis of the two was superior to the individual prediction of ANGPTL2 and NRG-1 (Z_{ANGPTL2-combination}=2.608, Z_{NRG-1-combination}=2.017, P=0.009, P=0.044). Conclusion PD patients have elevated serum ANGPTL2 levels and reduced NRG-1 levels, with the extent of these changes correlating with disease severity. Combined testing of these two indicators has important clinical value for the diagnosis of PD.

Key words: Parkinson disease, angiopoietin-like proteins, nerve growth factors, ANGPTL2, NRG-1

CLC Number:

R742.5

Figures/Tables 7

References 20

[1]	BROOKER S M, GONZALEZ-LATAPI P. Biomarkers in Parkinson's disease[J]. Neurol Clin, 2025, 43(2):229-248. doi:10.1016/j.ncl.2024.12.005.
[2]	GANDOR F, BERGER L, GRUBER D, et al. Dysphagie bei Parkinson-Syndromen [Dysphagia in Parkinsonian Syndromes][J]. Nervenarzt, 2023, 94(8):685-693. doi:10.1007/s00115-023-01475-7.
[3]	XIAO B, ZHOU Z, CHAO Y, et al. Pathogenesis of Parkinson's disease[J]. Neurol Clin, 2025, 43(2):185-207. doi:10.1016/j.ncl.2024.12.003.
[4]	RIBOLDI G M, FRATTINI E, MONFRINI E, et al. A practical approach to early-onset Parkinsonism[J]. J Parkinsons Dis, 2022, 12(1):1-26. doi:10.3233/JPD-212815.
[5]	HORIGUCHI H, KADOMATSU T, YAMASHITA T, et al. ANGPTL2 promotes immune checkpoint inhibitor-related murine autoimmune myocarditis[J]. Commun Biol, 2023, 6(1):965-972. doi:10.1038/s42003-023-05338-4.
[6]	AMADATSU T, MORINAGA J, KAWANO T, et al. Macrophage-derived angiopoietin-like protein 2 exacerbates brain damage by accelerating acute inflammation after ischemia-reperfusion[J]. PLoS One, 2016, 11(11):e0166285. doi:10.1371/journal.pone.0166285.
[7]	BAI Q, CHEN H, LIU H, et al. Molecular structure of NRG-1 protein and its impact on adult hypertension and heart failure:A new clinical Indicator diagnosis based on advanced machine learning[J]. Int J Biol Macromol, 2025, 304(2):140955-140968. doi:10.1016/j.ijbiomac.2025.140955.
[8]	赵翠红, 宋蕾, 宋世雄, 等. 血清IL-33和神经调节蛋白1与帕金森病患者认知障碍的相关性分析[J]. 北京医学, 2024, 46(7):551-555.
	ZHAO C H, SONG L, SONG S X, et al. Correlation between serum IL-33 and neuregulin 1 with cognitive impairment in patients with Parkinson's disease[J]. Beijing Medical Journal, 2024, 46(7):551-555. doi:10.15932/j.0253-9713.2024.07.004.
[9]	中华医学会, 中华医学会杂志社, 中华医学会全科医学分会, 等. 帕金森病基层诊疗指南(2019年)[J]. 中华全科医师杂志, 2020, 19(1):5-17.
	Chinese Medical Association, Chinese Medical Journals Publishing House,Chinese Society of General Practice, et al. Guideline for primary care of Parkinson's disease (2019)[J]. Chinese Journal of General Practitioners, 2020, 19(1):5-17.
[10]	NIKOLCHEVA T, PAGANO G, PROSS N, et al. A Phase 2b,multicenter,randomized,double-blind,placebo-controlled study to evaluate the efficacy and safety of intravenous prasinezumab in early-stage Parkinson's disease (PADOVA):Rationale,design,and baseline data[J]. Parkinsonism Relat Disord, 2025, 132(3):107257-107269. doi:10.1016/j.parkreldis.2024.107257.
[11]	MARTÍNEZ-IGLESIAS O, NAIDOO V, CACABELOS N, et al. Epigenetic biomarkers as diagnostic tools for neurodegenerative disorders[J]. Int J Mol Sci, 2021, 23(1):13-29. doi:10.3390/ijms23010013.
[12]	HUANG X, SU Z, ZHANG S, et al. ANGPTL2 deletion attenuates neuroinflammation and cognitive dysfunction induced by isoflurane in aged mice through modulating MAPK pathway[J]. Mediators Inflamm, 2023, 2023(21):2453402-2453411. doi:10.1155/2023/2453402.
[13]	HORIGUCHI H, KADOMATSU T, YAMASHITA T, et al. ANGPTL2 promotes immune checkpoint inhibitor-related murine autoimmune myocarditis[J]. Commun Biol, 2023, 6(1):965-977. doi:10.1038/s42003-023-05338-4.
[14]	SECHI G P, SECHI M M. Small molecules,α-synuclein pathology,and the search for effective treatments in Parkinson's disease[J]. Int J Mol Sci, 2024, 25(20):11198-11215. doi:10.3390/ijms252011198.
[15]	KALBE E, FOLKERTS A K, WITT K, et al. German Society of Neurology guidelines for the diagnosis and treatment of cognitive impairment and affective disorders in people with Parkinson's disease:new spotlights on diagnostic procedures and non-pharmacological interventions[J]. J Neurol, 2024, 271(11):7330-7357. doi:10.1007/s00415-024-12503-0.
[16]	张恒, 袁莉, 王佩, 等. 血管生成素样蛋白2(ANGPTL2)对大鼠局灶性脑缺血/再灌注损伤的炎症保护机制研究[J]. 现代检验医学杂志, 2019, 34(6):32-35,46.
	ZHANG H, YUAN L, WANG P, et al. Study on the protective mechanism of Angiopoietin-like protein 2 against inflammation in focal cerebral ischemia/reperfusion injury in rats[J]. Modern Journal of Laboratory Medicine, 2019, 34(6):32-35,46.
[17]	CESPEDES J C, LIU M, HARBUZARIU A, et al. Neuregulin in health and disease[J]. Int J Brain Disord Treat, 2018, 4(1):24-37. doi:10.23937/2469-5866/1410024.
[18]	MOUTON-LIGER F, DUMURGIER J, COGNAT E, et al. CSF levels of the BACE1 substrate NRG1 correlate with cognition in Alzheimer's disease[J]. Alzheimers Res Ther, 2020, 12(1):88-98. doi:10.1186/s13195-020-00655-w.
[19]	XUE J, TAO K, WANG W, et al. What can inflammation tell us about therapeutic strategies for Parkinson's disease?[J]. Int J Mol Sci, 2024, 25(3):1641-1651. doi:10.3390/ijms25031641.
[20]	姚丽红, 徐婉秋, 许晓航, 等. 神经调节素-1在神经损伤修复中的作用机制及研究现状[J]. 口腔医学, 2022, 42(6):567-570.
	YAO L H, XU W Q, XU X H, et al. Mechanism and research status of neuregulin-1 in nerve injury repair[J]. Stomatology, 2022, 42(6):567-570. doi:10.13591/j.cnki.kqyx.2022.06.016.

组别		n	年龄/岁		男性		BMI/ （kg/m²）		吸烟史
对照组		266	59.46±7.01		147（55.26）		21.45±2.17		51（19.17）
观察组		274	59.73±6.75		161（58.76）		21.39±2.05		56（20.44）
t或χ²			0.456		0.673		0.330		0.136
组别	饮酒史			收缩压/ mmHg		舒张压/mmHg		受教育年限/年		PD 家族史
对照组	101（37.97）			126.49±15.54		75.28±9.46		11.04±1.54		12（4.51）
观察组	119（43.43）			128.74±19.25		76.23±8.72		7.19±1.28		34（12.41）
χ²或t	1.667			1.492		1.214		31.631^＊		10.802^＊

组别		n	年龄/岁		男性		BMI/ （kg/m²）		吸烟史
对照组		266	59.46±7.01		147（55.26）		21.45±2.17		51（19.17）
观察组		274	59.73±6.75		161（58.76）		21.39±2.05		56（20.44）
t或χ²			0.456		0.673		0.330		0.136
组别	饮酒史			收缩压/ mmHg		舒张压/mmHg		受教育年限/年		PD 家族史
对照组	101（37.97）			126.49±15.54		75.28±9.46		11.04±1.54		12（4.51）
观察组	119（43.43）			128.74±19.25		76.23±8.72		7.19±1.28		34（12.41）
χ²或t	1.667			1.492		1.214		31.631^＊		10.802^＊

组别	n	ANGPTL2/（μg/L）	NRG-1/（ng/L）
对照组	266	9.46±1.95	286.77±45.39
观察组	274	10.82±2.08	259.10±41.26
t		7.833^＊	7.417^＊

组别	n	ANGPTL2/（μg/L）	NRG-1/（ng/L）
对照组	266	9.46±1.95	286.77±45.39
观察组	274	10.82±2.08	259.10±41.26
t		7.833^＊	7.417^＊

组别	n	ANGPTL2/（μg/L）	NRG-1/（ng/L）
无认知障碍组	113	7.38±1.97	282.86±37.51
认知障碍组	161	13.24±4.28	242.43±41.50
t		13.575^＊	8.256^＊