Inflammatory Biomarkers of Vascular Risk as Correlates of Leukoariosis
Background and Purpose— Inflammatory biomarkers, including lipoprotein-associated phospholipase A2 (Lp-PLA2), myeloperoxidase (MPO), and high-sensitivity C-reactive protein (hsCRP) are associated with ischemic stroke risk. White matter hyperintensities (WMH) seen on brain MRI scans are associated with vascular risk factors and an increased risk of incident stroke, but their relation to inflammatory biomarkers is unclear.
Methods— The Northern Manhattan Study includes a stroke-free community-based sample of Hispanic, black, and white participants with quantitative measurement of WMH volume (WMHV) and inflammatory biomarkers. We measured the association between Lp-PLA2, MPO, and hsCRP levels, and log-transformed WMHV after adjusting for sociodemographic and vascular risk factors.
Results— The hsCRP (median, 2.42 mg/L; IQR, 1.04, 5.19), Lp-PLA2 (median, 220.97 ng/mL; IQR, 185.77, 268.05), and MPO (median, 15.14 ng/mL; IQR, 12.32, 19.69) levels were available in 527 The Northern Manhattan Study participants with WMHV data but no subclinical infarcts. Those with hsCRP in the upper quartile (Q4 >4.92 mg/L or >3 mg/L), Lp-PLA2 in Q4 (≥264.9 ng/mL), or MPO levels in Q3 (15.04–19.39 ng/mL) or Q4 (>19.39 ng/mL) each had greater WMHV, adjusting for sociodemographic and vascular risk factors. Adjusting for all biomarkers simultaneously, WMHV was 1.3-fold greater for Lp-PLA2 levels in Q4 compared to Q1 (β=0.28; P=0.008) and 1.25-fold greater for MPO levels above the median compared to below (β=0.22; P=0.02), but hsCRP was not associated with WMHV.
Conclusions— Relative elevations of the inflammatory markers Lp-PLA2 and MPO were associated with a greater burden of WMH independent of hsCRP.
- C-reactive protein
- lipoprotein-associated phospholipase A2
- white matter disease
White matter hyperintensities (WMH) are often found incidentally on FLAIR or T2-weighted brain MRI scans of clinically asymptomatic individuals,1 and are associated with vascular risk factors and microangiopathy in pathological studies.2,3⇓ Individuals with extensive WMH are at risk for stroke; population-based studies show ≈2-fold increase, ≈3% yearly, compared to those with less damage.4,5⇓ A greater burden of WMH is also associated with an increased risk of vascular cognitive impairment and dementia.6 Inflammation has been implicated in blood–brain barrier permeability leading to the formation of WMH.7 Whereas certain inflammatory biomarkers have emerged as adjunctive measures of vascular risk, particularly in individuals at intermediate risk for vascular disease, their role in the formation of WMH is unclear.8
High-sensitivity C-reactive protein (hsCRP), myeloperoxidase (MPO), and lipoprotein-associated phospholipase A2 (Lp-PLA2) are Food and Drug Administration-approved predictors of vascular risk. Although hsCRP has been associated with incident MI and ischemic stroke, the association is questioned.9,10⇓ The Cardiovascular Health Study reported hsCRP was associated with WMH, but without quantitative measurement of WMH volume (WMHV) or comparison with other approved biomarkers.11 Lp-PLA2, a macrophage enzyme that hydrolyzes oxidized-phospholipids, has been associated with incident MI and ischemic stroke independently of hsCRP in case-control and prospective studies,12,13⇓ and with recurrent stroke independently of hsCRP in our cohort.14 An association between Lp-PLA2 and retinal venule dilatation in the Rotterdam cohort supports its role in small vessel arteriosclerosis.15 MPO, found in atherosclerotic plaque leukocytes and microglia, produces the bactericide hypochlorous acid, predicting incident MI, as well as prognosis after MI.16,17⇓ MPO predicts stroke in Fabry disease, and MPO polymorphisms correlate with extent of brain damage and outcome after stroke.18,19⇓
We hypothesized that hsCRP, Lp-PLA2, and MPO would be associated with WMH in our multi-ethnic stroke-free population. Most previous studies have used visual-rating methods that do not quantify WMH volume. Such methods have limited interrater reliability and the use of different scales has made comparison across studies difficult.20 Newer methods measure WMHV and allow study dose effects of WMH. However, few studies on the relationship between these novel inflammatory markers and WMH exist, especially in Hispanic and black people with greater prevalences of vascular risk factors that cause small vessel damage resulting in WMH, as well as a greater risk of stroke and vascular cognitive impairment than in whites.21
Materials and Methods
The Northern Manhattan Study includes 3298 initially stroke-free participants identified using random digit dialing with dual-frame sampling to identify published and unpublished telephone numbers. People were eligible if stroke was never diagnosed, age 40 years or older, and resident of Northern Manhattan ≥3 months in a household with a telephone. Participants were recruited for in-person assessments with an overall response rate of 68%. Data were collected between 1993 and 2001 by trained bilingual research assistants using standardized instruments, review of medical records, physical and neurological examinations by study physicians, and fasting blood samples for glucose and lipids. Study definitions for race–ethnicity, hypertension, diabetes, cardiac disease, and other risk factors have been previously described.22
Blood samples were collected at the MRI visit (91% on same day) in 5-mL serum-separator tubes, centrifuged at 3000g for 15 minutes, aliquotted into 2-mL tubes (Eppendorf), and stored at −80°C until being assayed for Lp-PLA2 mass (PLAC assay; diaDexus Inc), hsCRP (BioCheck Inc), and MPO (Prognostix) using enzyme-linked immunosorbent assay. Assays for hsCRP and Lp-PLA2 were performed at diaDexus Inc, and MPO was performed at Columbia University. Laboratory personnel were blinded to patient clinical data and markers were performed in the same participants.
Quality control was maintained by running 20% of the samples tested for Lp-PLA2 and hsCRP in duplicate, with 97% producing coefficients of variation of ≤10%. All samples had coefficients of variation <15% for Lp-PLA2. For hsCRP, 3% had coefficients of variation >15% but were in the low range of the assay and were repeated before acceptance.
Participants were recruited sequentially during annual follow-up of the sample using the following criteria: (1) age older than 55; (2) no contraindications to MRI; and (3) signed Institutional Review Board-approved informed consent. Imaging was performed on a 1.5-T MRI system (Philips Medical Systems) at the Hatch Research Center. The processing of MRI scans has been described.23 Analyses were performed using semiautomated measurements of pixel distributions using mathematical modeling of pixel-intensity histograms for cerebrospinal fluid and brain (white and gray matter) to identify the optimal pixel-intensity threshold to distinguish cerebral spinal fluid from brain matter. Analyses were performed using a custom-designed image analysis package (QUANTA 6.2 using a Sun Microsystems Ultra 5 workstation).23 The WMHV was expressed as a proportion of total cranial volume (WMH/total cranial volume*100) to correct for head size. The presence or absence of brain infarction on MRI was determined according to previously published protocol from the size, location, and imaging characteristics of the lesion.24 All analyses were performed blind to participant identifying information.
We examined sample characteristics in relation to inflammatory markers and log-transformed WMHV (log-WMHV) using linear regression, adjusting for age. Because clinically relevant cut-offs are not well-established for MPO or LP-PLA2, we studied quartiles of marker levels (Q1=lowest) to measure the dose effect of each in relation to log-WMHV. To aid comparison with other markers, we examined quartiles of hsCRP and also clinically accepted cut-points (<1 mg/L, 1 to 3 mg/L, >3 mg/L).8 Using multivariable linear regression to measure the association between inflammatory markers and log-WMHV, we adjusted for sociodemographic variables (age, gender, race–ethnicity, education, insurance status) and vascular risk factors known to be associated with inflammatory markers or WMH (current smoking, high-density lipoprotein, low-density lipoprotein, diabetes, systolic blood pressure, diastolic blood pressure, and the interaction between diastolic blood pressure and antihypertensive medication use); significance was set at P<0.05. We tested for effect modification by including interaction terms. We entered all biomarkers into a fully adjusted model simultaneously to evaluate the independent effect of each marker and also conducted a sensitivity analysis by including those with silent cerebral infarction (N=99) in the final model.
All participants with data on inflammatory marker and WMHV were included in the study (N=527). Participants were stroke-free and restricted, in our primary analysis, to those without subclinical infarcts on brain MRI. Compared to those who did not have MRI there were no subjects younger than 55 years, fewer women (58% vs 64%; P<0.05), more Hispanics (63% vs 50%), and fewer black (18% vs 26%) and white (17% vs 22%; P<0.05) participants. Participants were healthier than nonparticipants, with a lower prevalence of diabetes (18% vs 22%; P<0.05), hypertension (65% vs 75%; P<0.05), lower mean systolic blood pressures (139.5 mm, SD, 19.3; vs 144.5 mm Hg, SD, 10.39; P<0.05) and slightly lower mean high-density lipoprotein cholesterol levels (45.6 mg/dL, SD, 13.8; vs 47.0, SD, 14.8 mg/dL; P=0.05).
The mean age at time of brain MRI was 71.3 years. The WMHV (WMH/total cranial volume) ranged from 0.03% to 4.11%. Thus, no participant was entirely free of measurable WMH using this quantitative method. The median (interquartile range) for the inflammatory markers was: hsCRP, 2.42 (1.04, 5.19) mg/L; Lp-PLA2, 220.97 (185.77, 268.05) ng/mL; and MPO, 15.14 (12.32, 19.69) ng/mL. Inflammatory marker levels were not strongly correlated with one another (hsCRP and MPO, R=0.069, P=0.09; hsCRP and Lp-PLA2, R=0.076, P=0.06; MPO and Lp-PLA2, R=0.006, P=0.874). There were differences in inflammatory marker levels by sociodemographic characteristics (Table 1). Older participants had greater MPO levels than younger participants, white subjects had greater Lp-PLA2 levels than Hispanic or black participants, and those with greater levels of MPO and Lp-PLA2 were more educated. Participants with hypertension and those with diabetes had significantly lower Lp-PLA2 levels than those without, and current smokers had greater Lp-PLA2 levels than former or never smokers (Table 1). Baseline systolic (mean, 139.47 mm Hg; SD, 19.26 mm Hg) and diastolic (mean, 82.77 mm Hg; SD, 10.17 mm Hg) blood pressures, and high high-density lipoprotein cholesterol (mean, 45.6 mg/L; SD, 13.79 mg/L) and low-density lipoprotein levels (mean, 131.2; SD, 36.7 mg/L) were weakly correlated with the inflammatory markers (data not shown).
Associations Between Marker Levels and WMHV
Participants with hsCRP levels >3 mg/L or in Q4 (≥4.92 mg/dL), Lp-PLA2 levels in Q4 (≥264.9 ng/mL), or MPO levels in Q3 (15.04–19.39 ng/mL) or Q4 (>19.39 ng/mL) had significantly greater WMHV than those in the corresponding lowest quartile, in unadjusted analyses (Table 2, model 1). After adjusting for age, gender, race–ethnicity, insurance status, and education, the association of inflammatory markers with log-WMHV persisted (Table 2, model 2). Adjusting for diabetes mellitus, systolic and diastolic blood pressures, the interaction between diastolic blood pressure and antihypertensive medication use, current smoking, high-density lipoprotein, and low-density lipoprotein, the associations between the 3 inflammatory markers and log-WMHV remained (Table 2, model 3). Thus, those with hsCRP >3 mg/dL, or in Q4, had ≈20% greater WMHV than those in Q1. For Lp-PLA2 those in Q4 had 32% greater WMHV, and for MPO those in Q4 had 31% greater WMHV than those in the lowest quartiles.
Age and gender were not effect modifiers of the inflammatory marker WMHV association. However, there was an interaction between Hispanic ethnicity and MPO levels above the median such that this group had greater WMHV than white participants (P for interaction=0.009). Including participants with subclinical infarcts did not alter our findings for those with Lp-PLA2 and hsCRP levels in Q4, but the association with MPO levels in Q4 attenuated slightly (P=0.06). Adjusting for renal function did not alter our results (data not shown).
Adjusting for all 3 inflammatory biomarkers simultaneously, those with Lp-PLA2 in Q4 and MPO levels in Q3 or Q4 had greater WMHV than those in the lowest quartiles (35% and 22%, respectively), but the association with hsCRP was no longer significant (Table 2).
We found that Food and Drug Administration-approved inflammatory biomarkers of vascular risk are associated with greater WMHV in a stroke-free population-based urban cohort. Participants with Lp-PLA2 levels in Q4 and MPO levels above the median had greater WMHV, adjusting for sociodemographic and vascular risk factors. A less robust association was seen for hsCRP with WMHV, because the association disappeared after adjusting for other markers.
Lp-PLA2 is a macrophage-derived enzyme involved in the metabolism of low-density lipoprotein in arterial walls and causes the release of inflammatory mediators.25 Large epidemiological studies have found Lp-PLA2 is associated with an increased risk of incident coronary events and stroke as well as dementia.26–28⇓⇓ Lp-PLA2 is thought to be proatherogenic because it is found in atherosclerotic plaques vulnerable to rupture.29 We found that serum levels of Lp-PLA2 may be less correlated with stroke severity than hsCRP, and therefore a better marker of risk of recurrence after first stroke.14 We did not find previous studies assessing the relationship between Lp-PLA2 and WMH, but there was a “dose effect” with increasing quartiles of Lp-PLA2 (Table 2, model 1), providing cross-sectional evidence that Lp-PLA2-associated inflammatory mechanisms may be related to cerebral microangiopathy, consistent with evidence that Lp-PLA2 correlates with retinal vessel damage.15 Circulating Lp-PLA2 is largely bound to low-density lipoprotein and lipoprotein(a), a thrombogenic/atherogenic lipoprotein taken up by macrophages and forming foam cells contributing to atherosclerotic plaque. Foam cells are a hallmark of lipohyalinosis, and we speculate that relative elevations of Lp-PLA2 contribute to inflammation and small vessel damage causing some WMH.30,31⇓
We also found MPO was associated with WMH, and there was a threshold effect. Those with MPO levels above the median had greater WMHV, without a clear distinction between Q3 and Q4. Because MPO is found in microglia, immune activation could be involved in the formation of WMH seen on MRI. MPO predicts MI, but studies of its predictive value for stroke have been confined to specific populations, such as those with peripheral arterial disease or Fabry disease.18,32⇓ Others have found polymorphisms of MPO are associated with extent of cerebral infarction, and later functional outcome, but not with stroke risk.19 We found the association between MPO and WMH was stronger in Hispanics, but larger studies are needed to confirm this and examine other race–ethnic groups.
Those with hsCRP levels in Q4 had greater WMHV than those in Q1 adjusting for sociodemographic and vascular risk factors. However, this relationship was not significant after further adjusting for MPO and Lp-PLA2. An acute-phase reactant produced by the liver in response to IL-6, CRP is part of the innate immune response and contributes to chronic inflammation and atherosclerosis. However, associations of hsCRP with risk of stroke have been weaker than for MI, although hsCRP has been associated with dementia.33 Increasing hsCRP quartiles were related to progression of periventricular and subcortical white matter disease in Rotterdam, but not incident lacunes.34 Among participants in the Cardiovascular Health Study, hsCRP and IL-6 levels were modestly associated with WMH volume defined semiquantitatively, but the effects attenuated after excluding prevalent cerebrovascular and coronary disease cases.11 In Framingham, associations between hsCRP and WMHV were not found using the MRI methods used in this study, but WMHV levels are greater in the Northern Manhattan Study.35 Lack of an independent association between hsCRP and WMHV in the Northern Manhattan Study could reflect population differences across studies, with higher prevalences of other risk factors (particularly diabetes) in our cohort, and the predominance of Hispanics, an understudied group. Our hsCRP values were high, reflecting the greater prevalence of risk factors, but hsCRP did not predict incident stroke in our population.36
Strengths of our study include simultaneous measurement of inflammatory biomarkers, use of a well-validated quantitative WMH measure, and the multiethnic population. Limitations include the cross-sectional design limiting causal inferences. Also, measurement of the markers was performed at one visit. Whereas annual measures of hsCRP and Lp-PLA2 showed stability in a small sample (N=52), we lack data on intercurrent infection and rheumatological disease, and our measurements might not represent levels at other times.37
We found that Lp-PLA2 and MPO were associated with greater WMHV in stroke-free individuals from Northern Manhattan, suggesting a role for vascular inflammation in their etiology. Prospective studies are needed to examine the predictive value of these inflammatory markers in relation to cerebral microangiopathy and its consequences, such as stroke and vascular cognitive impairment. However, these cross-sectional associations contribute to data linking inflammation and leukoariosis.
Sources of Funding
This work is supported by the Evelyn F. McKnight Center for Age Related Memory Loss and grants from the National Institute of Neurological Disorders and Stroke (R37 NS 029993, R01 48134, K02 NS 059729) and the American Heart Association (0735387N and 0355596T). Funding for performance of assays of Lp-PLA2 and hsCRP was provided by diaDexus, Inc.
Dr Sacco serves as a consultant to Boehringer Ingelheim for the design and conduct of a clinical trial. Dr Elkind receives research support from diaDexus, Inc and BMS-Sanofi Partnership. Dr Elkind receives honoraria for lecturing from BMS-Sanofi Partnership and Boehringer-Ingelheim, Inc, and he receives consulting fees from Pfizer, GlaxoSmithKline, and Daichi Sankyo. Funding for the performance of assays for hsCRP and Lp-PLA2 was provided by diaDexus, Inc. diaDexus reviewed the contents of this manuscript, but the analyses and drafting of the manuscript were performed by the investigators independently of diaDexus. The first author had full access to all of the data in the study and takes responsibility for its integrity and the accuracy of the data analysis.
- Received June 9, 2009.
- Accepted July 8, 2009.
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