Differential effects of serum lipoprotein-associated phospholipase A2 on periventricular and deep subcortical white matter hyperintensity in brain

doi:10.21203/rs.3.rs-44790/v1

Background: High lipoprotein-associated phospholipase A2 (Lp-PLA2) was associated with white matter hyperintensity (WMH). There were differences in the anatomical structure and pathophysiological mechanism between periventricular WMH (PVWMH) and deep subcortical WMH (DSWMH). In this study, we aimed to investigate the effects of serum Lp-PLA2 on the PVWMH and DSWMH.

Methods: This cross-sectional study recruited 711 Chinese adults aged ≥45 years presented to the Department of Neurology, the Affiliated Jiangning Hospital of Nanjing Medical University between January 2016 and July 2019. Enzyme linked immunosorbent assay (ELISA) was utilized to determine the serum Lp-PLA2. Fazekas scale was used to measure the severity of PVWMH and DSWMH. Ordinal logistic regression analysis was carried out to investigate the relationship between serum Lp-PLA2 and PVWMH or DSWMH.

Results: A total of 567 cases were included in this study. Ordinal logistic regression analysis indicated that, after adjusting for the confounding variables, there was a lower risk of PVWMH in the patients with normal and moderately elevated serum Lp-PLA2 compared with those with significantly elevated serum Lp-PLA2. In addition, PVWMH was correlated to advanced age, hypertension, diabetes mellitus, and lacunar infarction. DSWMH was correlated to advanced age and lacunar infarction. There was no correlation between serum Lp-PLA2 and DSWMH.

Conclusions: Serum Lp-PLA2 was closely associated with the pathogenesis of PVWMH rather than DSWMH. There might be different pathological mechanisms between PVWMH and DSWMH.

Neurology

lipoprotein-associated phospholipase A2

periventricular white matter hyperintensity

deep subcortical white matter hyperintensity

Fazekas score

Table 1 Baseline characteristics of the cohort

Clinical characteristics	Results
Age, yr	65.51±9.86
FBG, mmol/L	5.95±2.12
TC, mmol/L	4.41±1.05
TG, mmol/L	2.20±9.62
LDL-C, mmol/L	2.41±0.82
HDL-C, mmol/L	1.21±0.34
H-CRP, mg/L	4.15±12.28
BUN, mmol/L	5.50±4.14
Cr, μmol/L	69.15±21.23
Hcy, μmol/L	12.00±7.80
Sex, men	51.68%
Hypertension, %	70.90%
Diabetes mellitus, %	23.28%
Coronary disease, %	9.70%
Atrial fibrillation, %	2.65%
Smoking, %	19.22%
Alcohol, %	12.00%
Carotid atherosclerosis, %	58.91%
WMH, %	82.54%
PVWMH, %	76.19%
DSWMH, %	66.66%
LI, %	49.74%
LP-PLA2, <200ng/mL, %	59.96%
LP-PLA2,200-223ng/mL, %	4.59%
LP-PLA2, >223ng/mL, %	35.45%

WMH, white matter hyperintensity; PVWMH, periventricular WMH; DSWMH, deep subcortical WMH; LI , Lacunar infarction; FPG, fasting blood glucose; TC, total cholesterol; TG, triglyceride; LDL-C, low density lipoprotein cholesterol; HDL-C, high density lipoprotein cholesterol; BUN, blood urea nitrogen; Cr, creatinine; H-CRP, high C-reactive protein; Hcy, homocysteine; LP-PLA2, lipoprotein-associated phospholipase A2.

Table 2 Clinical characteristics of subjects with PVWMH

Variable	Fazekas grade 0 (n=135)	Fazekas grade 1 (n=251)	Fazekas grade 2 (n=107)	Fazekas grade 3 (n=74)	P value
Age, yr	59.83±9.22	64.06±8.98	70.44±7.74	73.65±8.01	<0.01
Men, n (%)	69(51.11)	120(47.81)	57(53.27)	47(63.51)	0.123
Hypertension, n (%)	71(52.59)	179(71.31)	86(80.37)	66(89.19)	<0.01
Diabetes mellitus, n (%)	17(12.59)	58(23.11)	34(31.78)	23(31.08)	<0.01
Coronary disease, n (%)	9(6.67)	21(8.37)	15(14.02)	7(9.46)	0.237
Atrial fibrillation , n (%)	0(0.00)	5(1.99)	6(5.61)	4(5.41)	0.019
LI , n (%)	19(14.07)	122(48.61)	74(69.16)	67(90.54)	<0.01
Smoking, n (%)	27(20.00)	44(17.53)	22(20.56)	16(21.62)	0.822
Alcohol, n (%)	20(14.81)	25(9.96)	15(14.02)	8(10.81)	0.473
LP-PLA2 grade 2, n (%)	43(31.85)	85(33.86)	33(30.84)	40(54.05)	0.007
FPG, median (IQR)	5.37 (4.88-6.07)	5.44 (4.91-6.18)	5.39 (4.90-6.41)	5.31 (4.75-6.22)	0.850
TC, mean ± SD	4.57±1.02	4.40±1.04	4.26±1.00	4.34±1.19	0.305
TG, median (IQR)	1.43 (1.03-2.10)	1.58 (1.09-2.17)	1.34(1.06-1.76)	1.53(1.02-2.24)	0.101
LDL-C, median (IQR)	2.46 (1.96-2.98)	2.38 (1.84-2.96)	2.25(1.73-2.79)	2.27(1.84-2.81)	0.465
HDL-C, median (IQR)	1.17 (1.00-1.38)	1.18 (0.99-1.35)	1.18(0.96-1.44)	1.10(0.97-1.39)	0.643
BUN, median (IQR)	5.02(4.02-5.90)	4.99(4.08-6.10)	5.10(4.11-6.40)	5.18(4.11-6.21)	0.526
Cr, median (IQR)	63.00(53.00-79.40)	65.00(55.00-77.00)	63.00(54.00-78.00)	70.50(62.98-86.13)	0.003
Hcy (IQR)	10.10(7.10-12.80)	10.40(7.93-13.20)	11.60(8.80-15.60)	12.65(9.80-15.58)	<0.01
H-CRP, median (IQR)	0.60(0.50-2.30)	0.80 (0.50-2.50)	0.50(0.50-2.40)	1.60(0.50-6.17)	0.004

WMH, white matter hyperintensity; PVWMH, periventricular WMH; DSWMH, deep subcortical WMH; LI, Lacunar infarction; FPG, fasting blood glucose; TC, total cholesterol; TG, triglyceride; LDL-C, low density lipoprotein cholesterol; HDL-C, high density lipoprotein cholesterol; BUN, blood urea nitrogen; Cr, creatinine; H-CRP, high C-reactive protein; Hcy, homocysteine; LP-PLA2, lipoprotein-associated phospholipase A2.

Table 3 Clinical characteristics of subjects with DSWMH

Variable	Fazekas grade 0 (n=189)	Fazekas grade 1 (n=244)	Fazekas grade 2 (n=84)	Fazekas grade 3 (n=50)	P value
Age, yr	60.40±9.13	66.17±8.93	69.30±8.71	75.20±7.42	<0.01
Men, n (%)	103(54.50)	115(47.13)	47(55.95)	28(55.95)	0.307
Hypertension, n (%)	112(59.26)	173(70.90)	73(86.90)	44(88.00)	<0.01
Diabetes mellitus, n (%)	34(17.99)	54(22.13)	30(35.71)	14(28.00)	0.012
Coronary disease, n (%)	12(6.35)	27(11.07)	9(10.71)	4(8.00)	0.365
Atrial fibrillation, n (%)	2(1.06)	7(2.87)	2(2.38)	4(8.00)	0.057
LI, n (%)	46(24.34)	130(53.28)	62(73.81)	44(88.00)	<0.01
Smoking, n (%)	44(23.28)	38(15.57)	18(21.43)	9(18.00)	0.221
Alcohol, n (%)	26(13.76)	25(10.25)	10(11.90)	7(14.00)	0.693
LP-PLA2 grade 2, n (%)	59(31.22)	84(34.43)	32(38.10)	26(52.00)	0.038
FPG, median (IQR)	5.43 (4.93-6.19)	5.34 (4.80-6.18)	5.45 (4.89-6.47)	5.43 (5.08-6.17)	0.637
TC, mean ± SD	4.52 ±1.00	4.43±1.03	4.08±1.02	4.45±1.27	0.059
TG, median (IQR)	1.43 (1.03-2.08)	1.56 (1.18-2.30)	1.34(1.00-1.82)	1.55(0.93-2.05)	0.038
LDL-C, median (IQR)	2.45(1.95-3.03)	2.36 (1.87-2.87)	2.16(1.53-2.64)	2.48(1.75-2.96)	0.052
HDL-C, median (IQR)	1.17 (0.97-1.40)	1.20 (1.00-1.38)	1.15(0.95-1.35)	1.17(0.97-1.48)	0.747
BUN, median (IQR)	5.01(4.10-5.90)	5.11(4.08-6.12)	4.77(3.93-6.22)	5.21(4.42-6.24)	0.623
Cr, median (IQR)	63.00(53.55-77.15)	65.00(56.00-77.93)	65.45(55.25-81.23)	70.50(60.35-88.03)	0.058
Hcy (IQR)	10.40(7.50-13.20)	10.40(7.93-14.28)	11.80(8.63-16.03)	12.60(9.98-15.10)	0.003
H-CRP, median (IQR)	0.60(0.50-2.33)	0.80 (0.50-2.50)	1.05(0.50-4.86)	0.85(0.50-3.85)	0.223

WMH, white matter hyperintensity; PVWMH, periventricular WMH; DSWMH, deep subcortical WMH; LI, Lacunar infarction; FPG, fasting blood glucose; TC, total cholesterol; TG, triglyceride; LDL-C, low density lipoprotein cholesterol; HDL-C, high density lipoprotein cholesterol; BUN, blood urea nitrogen; Cr, creatinine; H-CRP, high C-reactive protein; Hcy, homocysteine; LP-PLA2, lipoprotein-associated phospholipase A2.

Table 4 Ordinal logistic regression model analysis of influencing factors of PVWMH classifications

Predictor	PVWMH Fazekas grade
Predictor	Coefficient	Standard error	Z value	P value	OR	95%CI for OR
Age	0.085	0.010	73.770	<0.01	1.089	1.067-1.110
Hypertension	0.479	0.193	6.143	0.013	1.614	1.105-2.358
Diabetes mellitus	0.457	0.195	5.502	0.019	1.579	1.078-2.314
Atrial fibrillation	0.214	0.503	0.181	0.671	1.239	0.462-3.320
LI	1.640	0.192	73.072	<0.01	5.155	3.540-7.508
LP-PLA2, <200*	-0.056	0.176	0.102	0.749	0.946	0.669-1.335
LP-PLA2, 200-223*	-1.187	0.421	7.949	0.005	0.305	0.134-0.696
Cr	-0.003	0.004	0.408	0.523	0.997	0.989-1.006
Hcy	0.010	0.012	0.778	0.378	1.010	0.987-1.034
H-CRP	-0.002	0.007	0.107	0.743	0.998	0.984-1.011

LI, lacunar infarction; Cr, creatinine; H-CRP, high C-reactive protein; Hcy, homocysteine; Lp-PLA2, Lipoprotein-associated phospholipase A2; *LP-PLA2 of >223 serving as control.

Table 5 Ordinal logistic regression model analysis of influencing factors of DSWMH classifications

Predictor	DSWMH Fazekas grade
Predictor	Coefficient	Standard error	Z value	P value	OR	95%CI for OR
Age	0.078	0.010	66.428	<0.01	1.081	1.061-1.102
Hypertension	0.348	0.194	3.221	0.073	1.419	0.969-2.071
Diabetes mellitus	0.272	0.192	1.996	0.158	1.313	0.900-1.912
LI	1.341	0.185	52.774	<0.01	3.823	2.662-5.490
LP-PLA2, <200*	-0.102	0.174	0.344	0.557	0.903	0.641-1.271
LP-PLA2, 200-223*	-0.423	0.410	1.063	0.303	0.655	0.293-1.464
TG	0.027	0.025	1.109	0.292	1.027	0.977-1.080
Hcy	-0.000	0.011	0.002	0.969	1	0.979-1.020

LI, lacunar infarction; TG, triglyceride; Hcy, homocysteine; LP-PLA2, lipoprotein-associated phospholipase A2; *LP-PLA2 of >223 serving as control.

Differential effects of serum lipoprotein-associated phospholipase A2 on periventricular and deep subcortical white matter hyperintensity in brain

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