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Aging and disease    2019, Vol. 10 Issue (4) : 834-846     DOI: 10.14336/AD.2019.0304
Orginal Article |
Plasma Lipoprotein-associated Phospholipase A2 and Superoxide Dismutase are Independent Predicators of Cognitive Impairment in Cerebral Small Vessel Disease Patients: Diagnosis and Assessment
Shuzhen Zhu1, Xiaobo Wei1, Xiaohua Yang1, Zifeng Huang1, Zihan Chang1, Fen Xie1, Qin Yang1, Changhai Ding2,3, Wei Xiang4, Hongjun Yang4, Ying Xia5, Zhong-Ping Feng6, Hong-Shuo Sun6,7, Midori A Yenari8, Lin Shi9,10, Vincent CT Mok11,*, Qing Wang1,*
1Department of Neurology and
2Department of Orthopedics, Zhujiang Hospital of Southern Medical University, Guangdong, China.
3Menzies Institute for Medical Research, University of Tasmania, Hobart, Australia.
4Department of Neurology, Guangzhou General Hospital of Guangzhou Military Command, Guangdong, China.
5Shanghai Key Laboratory of Acupuncture Mechanism and Acupoint Function, Fudan University, Shanghai, China.
6Department of Physiology and
7Department of Surgery, Faculty of Medicine, University of Toronto, Toronto, Ontario M5S 1A8, Canada.
8Department of Neurology, University of California, San Francisco & the San Francisco Veterans Affairs Medical Center, San Francisco, USA.
9Department of Imaging and Interventional Radiology, The Chinese University of Hong Kong, Hong Kong, China.
10BrainNow Research Institute, Shenzhen, China.
11Gerald Choa Neuroscience Centre, Department of Medicine and Therapeutics, Faculty of Medicine, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, China.
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Lipoprotein-associated phospholipase A2 (Lp-PLA2) and superoxide dismutase (SOD) are linked to regulating vascular/neuro-inflammation and stroke. Using a retrospective design, we investigated whether circulating Lp-PLA2 and SOD in cerebral small vessel disease (CSVD) patients were associated with cognitive impairment. Eighty-seven CSVD patients were recruited. Plasma Lp-PLA2 and SOD were determined, and cognitive status was measured by the Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA). The severity of white matter hypoerintensities (WMHs) in CSVD patients was rated according to Fazekas scales, and Lp-PLA2/SOD levels and MMSE/MoCA were compared. Multiple linear regressions were used to evaluate the relationship between Lp-PLA2 and SOD and the cognitive impairment. Ordinal logistic regression and generalized linear models (OLRGLMs) were applied to confirm whether Lp-PLA2 and SOD are independent risk factors for cognitive impairment in CVSD. Lp-PLA2 and SOD with mild or severe cognitive impairment were lower than those with normal congnition. Lp-PLA2 and SOD in CSVD patients with severe WMHs were significantly lower than those with mild or moderate WMH lesions. We noted positive linear associations of Lp-PLA and SOD with cognitive impairment in CSVD, independent of LDL-C. OLRGLMs confirmed that Lp-PLA2 and SOD were independent risk factors of cognitive impairment in CSVD. Lp-PLA2 and SOD are independently associated with cognitive impairment and WMH lesion, and may be useful for the rapid evaluation of cognitive impairment in CSVD. Lp-PLA2/SOD are modifiable factors that may be considered as therapeutic targets for preventing cognitive impairment in CSVD.

Keywords Lp-PLA2      superoxide dismutase      cerebral small vessel disease      cognition     
Corresponding Authors: Mok Vincent CT,Wang Qing   
About author:

These authors contributed equally.

Just Accepted Date: 06 March 2019   Issue Date: 01 August 2019
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Shuzhen Zhu
Xiaobo Wei
Xiaohua Yang
Zifeng Huang
Zihan Chang
Fen Xie
Qin Yang
Changhai Ding
Wei Xiang
Hongjun Yang
Ying Xia
Zhong-Ping Feng
Hong-Shuo Sun
Midori A Yenari
Lin Shi
Vincent CT Mok
Qing Wang
Cite this article:   
Shuzhen Zhu,Xiaobo Wei,Xiaohua Yang, et al. Plasma Lipoprotein-associated Phospholipase A2 and Superoxide Dismutase are Independent Predicators of Cognitive Impairment in Cerebral Small Vessel Disease Patients: Diagnosis and Assessment[J]. Aging and disease, 2019, 10(4): 834-846.
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Figure 1.  All 120 CSVD patients who met the clinical diagnostic criteria of white matter hyperintensities were enrolled in this study from Jul 2017 to Aug 2018

Of 33 participants met the excluded criteria and 87 participants were included in this study for further analyzing. 30 age and gender-matched non-CSVD healthy controls (HC) were enrolled from physical examnination center. The plasma level of Lp-PLA2 and SOD was compared between CSVD and HC groups. In addition, The cognitive function and white matter hyperintensity were evaluated and the variables were collected and analyzed among groups.

Figure 2.  Comparison of biomarkers for Lp-PLA2 and SOD levels in the CSVD patients with different severity of cognitive impairment

(A) Comparison was made using independent t-test between the CSVD patients and HC (healthy control). The level of Lp-PLA2 increased and SOD decreased in CSVD patients. (B) Comparisons were made using one-way covariance with adjusted for the confounders (sex, age, education, BMI, cholesterol, HDL-C, LDL-C, urea, Cr, UA, hypertension, diabetes, CHD, APOE genotype, and medication use) followed by a post hoc Bonferroni test. Cognitive impairment group (MCI and SCI) displayed significantly lower levels of Lp-PLA2 and SOD than the normal cognition (NC) group (see also table 1). (C) The plasma Lp-PLA2 was linear correlated with SOD (r=0.327, p <0.05). Abbreviations: APOE, apolipoprotein E; BMI, body mass index; CHD, coronary heart disease; Cr, creatinine; CSVD, cerebral small vessel disease; HC, healthy control; HDL-C, High-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; Lp-PLA2, Lipoprotein-associated Phospholipase A2; MCI: mild cognitive impairment; MMSE, Mini-Mental State Examination; MoCA, Montreal Cognitive Assessment; NC, normal cognition; SCI, severe cognitive impairment; SOD, Superoxide Dismutase; UA, uric acid. * Compared to NC p <0.05, ** Compared to NC p <0.01, *** Compared to NC p <0.001, ## Compared to MCI p <0.01.

VariableSubgroup comparison
NC (N= 46)MCI (N=30)SCI (N=11)F or X2 *p value
Age, mean (SD), y63.9(10.1)67.9 (12.1)74.2(13.7)4.039.021#
Male, N (%)29 (63.4)19 (63.3)8 (72.7)0.384.902
Education, mean (SD), y9.0 (3.4)7.5 (2.1)6.6 (2.7)4.243.018##
BMI, mean (SD)23.9(2.8)23.1(3.2)24.0(4.5)0.600.551
Hypertension, N (%)28 (60.9)16 (53.3)9 (81.80)2.743.274
Diabetes, N (%)13(28.3)7(23.3)4(36.4)0.706.706
CHD, N (%)20 (43.5)11(36.7)7 (63.6)2.381.301
Statin Use, N (%)43 (93.5)24 (80.0)9 (81.8)3.336.165
Antithrombotic use, N (%)44 (95.7)24 (80.0)9 (81.8)4.9260.072
Laboratory mean (SD)
Cholesterol, (mmol/L)4.8±1.04.4±1.04.1±1.12.874.062
HDL-C, (mmol/L)1.3±0.51.2±0.41.2±0.20.621.540
LDL-C, (mmol/L)2.7±0.92.6±0.72.5±0.90.561.573
Urea, (mmol/L)5.3±1.46.0±1.56.0±2.91.909.155
Cr, (umol/L)78.6±28.184.2±34.197.7±36.51.690.191
UA, (umol/L)408.8±115.0384.3±110.2386.3±122.20.478.622
Leukocyte, (G/L)6.8±1.87.6±2.47.0±1.51.4560.239
NEU, (G/L)4.2±1.44.9±2.24.8±1.41.7020.189
Hs-CRP, (mg/L)3.4±4.14.4±10.23.0±2.00.1430.867
ESR, (mm/H)22.4±17.030.2±28.723.6±18.30.7520.476
Lp-PLA2 mass, (mg/L)246.2 ±45.4212.4±35.3189.2±30.711.82<0.001***
SOD, (KU/L)149.6±24.3135.4±16.4120.7± 12.310.354<0.001***
APOE4 carrier, No. (%)6 (13.0)3(10.0)1(9.1)0.237.897
Table 1  Baseline Characteristic of Study CSVD Population.
Adjusted OR
(95% CI)
p value
Age (years)1.050 (0.991-1.120)0.097
BMI0.887 (0.715-1.100)0.275
Education (years)0.693 (0.528-0.908)0.008**
Diabetes, n (%)2.176(0.450-10.525)0.334
CHD, n (%)2.236(0.522-9.528)0.278
Cholesterol (mmol/L)0.562(0.265-1.195)0.134
HDL cholesterol (mmol/L)0.966 (0.182-5.109)0.080
LDL cholesterol (mmol/L)2.601(0.942-7.184)0.065
Urea (mmol/L)1.521(1.015-2.280)0.042
Cr (umol/L)1.002(0.981-1.024)0.848
UA (umol/L)1.002(0.996-1.008)0.466
SOD (KU/L)0.933 (0.895-0.972)0.001**
Lp-PLA2 mass (mg/L)0.977 (0.962-0.992)0.003**
Antithrombotic use, n (%)8.069(0.327-199.032)0.202
Statin use, n (%)0.871(0.048-15.196)0.925
Table 2  Ordinal logistic regression of possible variables associated with cognitive decline in CSVD.
Figure 3.  Comparison of Lp-PLA2 and SOD in the CSVD patients with different severity of WMHs

(A) The representative MRI imagings of WMHs in CSVD patients with different severity classified by Fazekas Scores. The levels of Lp-PLA2 (B) and SOD (C) were relatively lower in the CSVD patients of Severe-W compared to those in the Mild-W. The scores of MMSE (D) and MoCA (E) were lower in patients in the Severe-W group compared to those in the Mild-W group. Abbreviations: CSVD, cerebral small vessel diseases; MMSE, Mini-Mental State Examination; Mild-W, Mild-White matter hyperintensities, MoCA, Montreal Cognitive Assessment; Modest-W, Modest- White matter hyperintensities, MRI, Magnetic Resonance Imaging; Severe-W, Severe-White matter hyperintensities, SOD, Superoxide Dismutase; WMHs, White matter hyperintensities. * Compared to Mild-W p <0.05, ** Compared to Mild-W p <0.01.

Figure 4.  Linear correlation of plasma Lp-PLA2 and SOD with MMSE or MoCA

(A) Lp-PLA2 level in plasma samples were measured. After adjusting for confounders, Lp-PLA2 linear correlated with cognitive impairment severity as measured by MMSE scores (r=0.438, p <0.001). (B) A similar trend was observed between SOD and MMSE score, and the correlation was statistically significant (r=0.379, p <0.01). (C) After adjusting for confounders, Lp-PLA2 linear correlated with cognitive impairment severity as measured by MoCA scores (r=0.397, p <0.001). (D) A similar trend was observed between SOD and MoCA score, and the correlation was statistically signficant (r=0.443, p<0.001). Abbreviations: Lp-PLA2, Lipoprotein-associated Phospholipase A2; MMSE, Mini-Mental State Examination; MoCA, Montreal Cognitive Assessment; SOD, Superoxide Dismutase.

Figure 5.  ROC analysis of Lp-PLA2 and SOD

(A) Lp-PLA2 and SOD for CSVD patients with MCI versus CSVD patients with NC. The combined graph showed the Lp-PLA2 (black curve), SOD (red curve) and the combination curve (green curve) respectively. The combination of Lp-PLA2 and SOD was the best discriminating parameters compared to Lp-PLA2 and SOD alone. (B) ROC analysis of Lp-PLA2 and SOD for CSVD patients with SCI versus NC. The AUC was 0.85 for Lp-PLA2 (black curve), 0.84 for SOD (red curve) and 0.90 for the combination of Lp-PLA2 and SOD (green curve). Abbreviations: CSVD, Lp-PLA2, Lipoprotein-associated Phospholipase A2; SOD, Superoxide Dismutase; MCI, Mild Cognitive Impairment; SCI, severe cognitive impairment.

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