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Increased level of procalcitonin is associated with total MRI burden of cerebral small vessel disease in patients with ischemic stroke
Accepted Manuscript Title: Increased level of procalcitonin is associated with total MRI burden of cerebral small vessel disease in patients with ischemic stroke Authors: Guangzong Li, Chen Zhu, Jing Li, Xiangming Wang, Qingbin Zhang, Hongjia Zheng, Cheng Zhan PII: DOI: Reference:
S0304-3940(17)30866-2 https://doi.org/10.1016/j.neulet.2017.10.040 NSL 33184
To appear in:
Neuroscience Letters
Received date: Revised date: Accepted date:
1-8-2017 27-9-2017 19-10-2017
Please cite this article as: Guangzong Li, Chen Zhu, Jing Li, Xiangming Wang, Qingbin Zhang, Hongjia Zheng, Cheng Zhan, Increased level of procalcitonin is associated with total MRI burden of cerebral small vessel disease in patients with ischemic stroke, Neuroscience Letters https://doi.org/10.1016/j.neulet.2017.10.040 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Increased level of procalcitonin is associated with total MRI burden of cerebral small vessel disease in patients with ischemic stroke Cover Title: PCT and risk of cSVD
Authors and Affiliations: Guangzong Li, MD1; Chen Zhu, MD1; Jing Li, MD2; Xiangming Wang MD1; Qingbin Zhang, MD1; Hongjia Zheng, MD1; Cheng Zhan, MD1 1
Department of Neurology, Central Hospital of Panzhihua City, Panzhihua, Sichuan Province
617000, China. 2
Department of Clinical Laboratory, Central Hospital of Panzhihua City, Panzhihua, Sichuan
Province 617000, China.
Address for Correspondence and Reprints Cheng Zhan Department of Neurology Central Hospital of Panzhihua City No. 34 Yikang Street, Panzhihua, 617000, Sichuan Province, China Telephone number: +86 0816-2222566 Fax number: +86 0816-2222566 E-Mail address: [email protected]
Highlights：
Higher concentrations of PCT are correlated to the increasing risk of silent lacunar infarctions, white matter lesions, and high-grade enlarged perivascular spaces.
No substantial association is detected between PCT levels with cerebral microbleeds.
Higher PCT levels might augment the risk of total cerebral small vessel disease burden on
magnetic resonance imaging in ischemic stroke patients.
Abstract Background. Procalcitonin (PCT) has been found to be associated with subclinical cerebrovascular damage. The relationship between PCT levels and cerebral small vessel disease (cSVD), especially cSVD burden, has not been fully understood. This study aimed to investigate the association between PCT levels and cSVD in patients with first-ever acute ischemic stroke or transient ischemic attack (TIA). Methods. Two hundred and seventy-eight consecutive patients were prospectively recruited during Jan 2016 to Jun 2017. Serum PCT concentrations measurement was performed after admission. The presence and burden of cSVD was determined by magnetic resonance imaging (MRI). Multivariable logistic regression was used to assess whether serum PCT levels were associated with cSVD. Results. The median PCT level was 0.042 µg/L (interquartile range, 0.025–0.065 µg/L). Univariable logistic regression analysis indicated that patients with PCT level in the top quartile, compared with the lowest quartile, were more likely to have silent lacunar infarctions [odds ratio (OR), 2.266; 95% confidence interval (CI) 1.131–4.538, P = 0.021], white matter lesions (OR, 1.793; 95% CI 1.029–3.574, P = 0.047), high-grade enlarged perivascular spaces (OR, 8.061; 95% CI 3.599–14.055, P = 0.001) and increased total MRI cSVD burden (OR, 3.743; 95% CI 1.998–7.008, P = 0.002). These results persisted even after adjusting for potential confounders. Conclusions. This study demonstrated that elevated PCT levels might be associated with total MRI cSVD burden in patients with ischemic stroke or TIA.
Key Words: Ischemic stroke; Procalcitonin; Cerebral small vessel disease. Introduction Cerebral small-vessel disease (cSVD) is an intrinsic disorder that affects small arteries and arterioles of the brain, which embraces white matter lesions (WMLs), cerebral microbleeds (CMBs), enlarged perivascular spaces (EPVs) and silent lacunar infarctions (SLIs) in brain magnetic resonance imaging (MRI) [1-3]. Epidemiological study demonstrated that cSVD is a leading cause of functional loss and cognitive deficits in old age [4, 5]. Moreover, increasing evidences attach cSVD to a higher risk of cognitive impairment [4-6], post-stroke affective disorder [7, 8], unfavorable stroke outcomes and stroke recurrence [9, 10]. However, there is little data to date on blood prognostic biomarkers and their association with cSVD. Procalcitonin (PCT) was first described in the early 1990s as a sepsis-induced protein [11]. PCT has been widely recognized as a prognostic inflammatory biomarker for cardiovascular diseases [12]. Increased serum PCT level was reported to be associated with adverse clinical outcomes including higher mortality in cerebrovascular diseases [13-15]. In a study nested within the Northern Manhattan Study, PCT concentrations are also independently related to the severity of SLIs and WMLs [16]. However, considering that these MRI cSVD markers do not occur separately in a patient, a total cSVD burden might better capture the overall influences of CSVD on the brain. Recently, a validated scale of the ordinal MRI cSVD burden has been proposed by counting the presence of each of these 4 MRI cSVD features [17]. This total cSVD burden has been found to be correlated with chronic kidney disease [18], cognitive function [4-6] and post-stroke depression [7] in ischemic stroke patients. Therefore, in this study we aimed to determine whether serum PCT levels at admission were associated with cSVD features and total
MRI cSVD burden in a cohort of Chinese sample who initially presented with acute ischemic stroke or transient ischemic attack (TIA).
Subjects and Methods Study population Between Jan 2016 to Jun 2017, 412 consecutive patients with first-ever acute ischemic stroke or TIA were admitted to the Central Hospital of Panzhihua City within 72 hours after symptoms onset. According to the standard protocol of our stroke unit, all subjects performed routine blood tests, chest radiography, 12-lead electrocardiography, MRI and cerebrovascular imaging examinations. The exclusion criteria were as the following: (1) age < 18 years old; (2) unable to perform MRI examination; (3) infarct size ≥ 1/3 ipsilateral cerebral hemisphere area; (4) pre-stroke diagnosis of active or chronic inflammatory diseases, malignant tumor, intracerebral hemorrhage, thyroid diseases, autoimmune diseases, and a history of any central nervous system disease. This study was approved by the Medical Ethics Committee of the Central Hospital of Panzhihua City and all participants gave written informed consent.
Collection of demographic and clinical data Clinical data were collected by trained neurologists blinded to the subject's diagnosis. The following information was collected: demographic characteristics, traditional vascular risk factors (including: hypertension, diabetes mellitus, hyperlipidemia, and coronary heart disease), clinical and laboratory data. As used previously [19], hypertension was defined as systemic blood pressure measurements ≥ 140/90 mmHg on two different occasions or a history of hypertension. Diabetes mellitus was diagnosed as a fasting serum glucose levels ≥ 7.0 mmol/L or a history of diabetes.
Hyperlipidemia was described when satisfying one of the conditions: 1) total cholesterol levels ≥ 5.70 mmol/L; 2) triglyceride levels ≥ 1.70 mmol/L; 3) low-density lipoprotein levels ≥ 3.64 mmol/L; 4) a history of hyperlipidemia. Severity of stroke was assessed at admission using the National Institute of Health Stroke Scale (NIHSS) [20]. Estimated Glomerular Filtration Rate (eGFR) was calculated individually by Chronic Kidney Disease Epidemiology Collaboration equation for the Asian population [21]. Stroke subtype was classified according to TOAST (Trial of Org 10172 in Acute Stroke Treatment) criteria [22].
Assessment of PCT concentrations After admission, blood samples were collected from all subjects. For measuring serum PCT concentrations, the specimens were immediately separated by centrifugation at 1500 rpm for 10 minutes and the isolated serum frozen at −80 °C for later measurements. A rapid and sensitive assay (PCT sensitive LIA; BRAHMS GmbH, Hennigsdorf, Germany) was used for detection of PCT serum levels. The lowest functional detection limit of the assay is 0.006 μg/L. All procedures were performed in strict accordance to manufacturers’ instructions.
Imaging analysis MRI was conducted during 7 days after admission with a 3.0T MRI system (MAGNETOM Trio 3.0T, Siemens, Amberg, Germany) in all patients. The definition of MRI markers of cSVD (including WMLs, CMBs, EPVs and SLIs) was in accordance with previous study [23]. SLIs was defined as a diameter < 20 mm lesion showing as a hyperintense on axial T2-weighted images (T2WI) and a hypointense on axial T1-weighted images (T1WI) in a subject lacking a relevant
clinical findings. The extent of WMLs was graded using the Fazekas score. One point was awarded if irregular periventricular hyperintensities extending into the deep white matter (Fazekas score 3) or confluent deep WMLs (Fazekas score 2 or 3). CMBs was identified as punctate hypointense lesions on T2*-gradient recalled echo (GRE) images with a diameter < 10 mm. Symmetrical hypointensities in the globipallidi, likely to represent calcification, sulcal flow voids from cortical vessels, and hypointensities possibly due to partial volume artifacts from bone were disregarded. One point was awarded if deep CMBs were present. EPVs was defined as punctate or linear hyperintense lesions with signal intensity equal to cerebrospinal fluid on T2WI in the basal ganglia, and (if visible) hypointense on fluid-attenuated inversion recovery images (FLAIR) without a hyperintense rim to distinguish them from old lacunar infarcts. We counted EPVs on the slide with the highest number in one hemisphere and graded them using a 3-category ordinal scale (0–10; 10–25; >25). One point was awarded if moderate to extensive (>10) EPVs were present. All images were independently rated by two neurologists for the presence of cSVD markers. In case of disagreement, lesions were ascertained by consensus. Limited intra-rater reliability testing (50 scans) demonstrated a good reliability with kappa values of 0.84 for the presence of EPVs, 0.86 for CMBs, 0.83 for WMLs and 0.79 for SLIs. An established ordinal scale [17,23,24] was used to represent the total MRI cSVD burden. The total cSVD score was calculated for each patient on an ordinal scale from 0 to 4, with a score of 1 point awarded for the presence of each of the 4 MRI cSVD features mentioned above.
Statistical analysis Continuous variables were presented as the means (Standard deviation) or medians (interquartile
range) and categorical variables were expressed as n (%). Differences in baseline characteristics between the increasing cSVD burden groups were determined by Chi-square test, Fisher exact test, analysis of variance, or Kruskal-Wallis where appropriated. Furthermore, logistic regression analysis was used to assess the relationship between PCT levels and cSVD markers and its total burden. We dichotomized basal ganglia EPVs into mild (EPVs 0–10) and high grade (EPVs > 10), reflecting mild versus high-grade EPVs. For the analysis of cSVD burden as an ordinal outcome, we used ordinal logistic regression analysis. All multivariable analyses were adjusted for the factors with a P value < 0.1 in the univariable analysis (including: age, smoking, eGFR ≤ 60 mL/min/1.73 m2, systolic blood pressure and homocysteine levels). Furthermore, the association between PCT levels and the severity of cSVD features was evaluated using Spearman correlation analysis. All statistical analysis was performed using SPSS software (SPSS version 20, SPSS, Chicago, USA). Statistical significance was established at P < 0.05 in all tests. Results During Jan 2016 to Jun 2017, 278 consecutive patients (157 male) met the entry criteria. The average age of the patient sample was 62.4 ± 8.5 years (from 40 to 82 years old). Among these participants, 89 (32.0%) had WMLs, 135 (48.6%) had CMBs, 108 (38.8%) had EPVs, and 144 (51.8%) had SLIs. For cSVD burden, 50 patients (18.0%) had a cSVD score of 0 and 13 patients (4.7%) presented with a cSVD score of 4. Table 1 demonstrated the demographic characteristics and clinical data of the study population stratified by the total MRI cSVD burden. Increasing total cSVD burden showed a significant association with age (P = 0.046), smoking (P = 0.021), eGFR ≤ 60 mL/min/1.73 m2 (P = 0.001), systolic blood pressure (P = 0.002) and homocysteine levels (P= 0.008).
The median PCT level was 0.042 µg/L, with quartile levels as follows: < 0.025 µg/L (first quartile), 0.025–0.041µg/L (second quartile), 0.042–0.065µg/L (third quartile), and > 0.065µg/L (fourth quartile). Spearman correlation analysis showed a positive correlation between PCT levels and severity of SLIs (SLIs number, Spearman's rho = 0.267, P = 0.001), WMLs (Fazekas score, Spearman's rho = 0.122, P = 0.042) and EPVs (EPVs degree, Spearman's rho = 0.319, P = 0.001). However, there was no significant difference between PCT concentrations and CMBs severity (CMBs number, Spearman's rho = -0.010, P = 0.869). Table 2 demonstrated the results of the binary logistic regression of cSVD markers, and the ordinal logistic regression of cSVD burden. Univariable regression analysis indicated that patients with PCT level in the top quartile, compared with the lowest quartile, were more likely to have SLIs [odds ratio (OR), 2.266; 95% confidence interval (CI) 1.131–4.538, P = 0.021], WMLs (OR, 1.793; 95% CI 1.029–3.574, P = 0.047), high-grade EPVs (OR, 8.061; 95% CI 3.599–14.055, P = 0.001) and increased total MRI cSVD burden (OR, 3.743; 95% CI 1.998–7.008, P = 0.002). Furthermore, association between PCT levels and SLIs, WMLs, high-grade EPVs and total cSVD burden remained significant after adjusting for control variables (Table 2, adjusted model).
Discussion In this hospital-based study of 278 patients with acute ischemic stroke or TIA, we found that higher levels of PCT were positively associated with SLIs, WMLs, high-grade EPVs and increasing total MRI burden of cSVD. PCT is a 13-kDa 116-amino acid prohormone of calcitonin which is released ubiquitously in response to endotoxin and other pro-inflammatory cytokines (e.g., interleukin-1β, interleukin-2, interleukin-6 and tumor necrosis factor-α) [25-28]. Mimoz et al. [29] found that circulating PCT
levels seemed proportionally to be positively correlated with the severity of tissue injury and local inflammation. The available evidences suggest that patients with higher PCT levels may experience higher risk of developing atherosclerosis and unfavorable outcome in cerebrovascular diseases. In Chinese sample, serum level of PCT at admission was established as an independent predictor of long-term functional outcome (OR, 2.33; 95% CI 1.33–3.44; P < 0.001) and mortality (OR, 3.11; 95% CI 2.02–4.43; P < 0.001) after ischemic stroke [15]. Furthermore, in the population-based Northern Manhattan Study of 3298 initially stroke-free participants [16], subjects with higher PCT levels were significantly associated with presence of silent brain infarcts (adjusted OR, 2.2; 95% CI, 1.3–3.7) and increased white matter hyper-intensity volume (adjusted mean change in white matter hyper-intensity volume, 0.29; 95% CI, 0.13–0.44). Consistent with those finding, our prospective study indicated that serum PCT level was a predictor for SLIs, WMLs, and high-grade EPVs in patients with acute ischemic stroke or TIA. Unexpectedly, we did not detect significant association between PCT levels and CMBs. One possible explanation is that the development of CMBs may be different from other cSVD features, in that CMBs could arise from cerebral microvascular ruptures, while the others might represent the ischemic conditions including arteriolar narrowing and occlusion. Other important confounding variables such as cardiovascular risk factors may also be considered as possible interventions in the relations [2,3,30]. Therefore, further investigations are needed to determine relationship between PCT and CMBs. As cSVD substantially contributes to one quarter of stroke worldwide and cognition impairment in the elderly population [4,5,31], studies involving in the damage of brain small vessels may have significant public health implications. Although the pathogenesis of cSVD is not
completely understood, it is fundamental to bear in mind that all the features of cSVD are strictly inter-related [1,32]. Proceeding from this point, we used an established validated scale to represent the MRI cSVD burden, which might better capture the total subcortical microstructural brain damage caused by cSVD. Our findings underline the importance of a higher PCT level as a risk factor for increased MRI burden of cSVD. PCT might act as a chemoattractant and is initially produced in adherent monocytes, and participate in mediating monocyte adhesion and migration, representing key features of inflammatory process [33,34]. Also, PCT has an adverse effect on iNOS gene expression, which partially contributes to the endothelial function impairment [33-35]. Thus serum PCT may cause subclinical inflammatory status and endothelial dysfunction, which has been suggested as major determinants of the structural and functional brain-vessel alterations in cSVD [36-38]. This study has several strengths, including reasonable sample size, use of carefully standardized research methods, extensive assessments of MRI cSVD characteristics, and homogeneous population of patient with ischemic stroke. Moreover, a total cSVD score was applied to represent the combined effect of cSVD, which all make this study appropriate for examining the association between PCT levels and cSVD. Nonetheless, the following limitations of our study must be taken into account. Firstly, the study was performed in one stroke center with favors less disabled patients, which could have selection bias. Secondly, this was a cross-sectional study, which cannot determine the causal relationship between PCT levels and severity of cSVD. Thirdly, PCT levels were only measured once upon initial enrolment of subjects into the study, which may predispose to intra-individual variations. Finally, all participants in the present study were free of clinical signs of infection. However, subclinical infections and inflammatory
conditions prior to the disease onset that could stimulate PCT production cannot be excluded with certainty. In conclusion, our results found that PCT levels might be associated with cSVD burden. Considering that measuring PCT levels is relatively simple and easy, PCT could be used as a screening tool for cSVD. Interventional trials are required to determine if managing serum PCT levels within the appropriate range can lower the risk of cSVD in patients with ischemic stroke.
Conflict of interest All the authors declare that there is no conflict of interest
Acknowledgments We also express our gratitude to Yun Zhang (Central Hospital of Mianyang City) for excellent statistical advice.
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Table 1. Demographic and clinical characteristics of the study population stratified by total sSVD burden. Variable cSVD0 (n = 50) cSVD1 (n = 74) cSVD2 (n = 93) cSVD3 (n = 48) cSVD4 (n = 13) Age, years 59.5 ± 6.5 63.0 ± 9.4 62.3 ± 9.3 64.4 ± 6.5 64.3 ± 8.2 Male, % 33 (66.0) 43 (58.1) 53 (57.0) 21 (43.8) 7 (53.8) Vascular risk factors, % Hypertension 37 (74.0) 47 (63.5) 72 (77.4) 36 (75.0) 7 (53.8) Diabetes mellitus 13 (26.0) 19 (25.7) 27 (29.0) 11 (22.9) 4 (30.8) Hyperlipidemia 6 (12.0) 16 (21.6) 18 (19.4) 7 (4.6) 2 (15.4) Smoking 18 (36.0) 23 (31.1) 23 (24.7) 13 (27.1) 9 (69.2) Coronary heart disease 2 (4.0) 9 (12.2) 8 (8.6) 2 (4.2) 1 (7.7) Clinical data Antithrombotic treatment, % 6 (12.0) 5 (6.8) 16 (17.2) 9 (18.8) 2 (15.2) Statin therapy, % 4 (8.0) 10 (13.5) 13 (14.0) 5 (10.4) 3 (23.1) Systolic blood pressure, mmHg 134.1 ± 14.8 133.4 ± 12.4 136.4 ± 15.0 144.2 ± 20.0 153.3 ± 25.6 Diastolic blood pressure, mmHg 84.5 ± 9.3 82.1 ± 10.1 81.8 ± 10.6 80.8 ± 10.2 86.2 ± 12.7 Body mass index, kg/m2 25.0 ± 3.4 25.2 ± 2.5 24.7 ± 3.4 26.0 ± 2.6 24.7 ± 3.9 NIHSS, score 3.0 (2.0, 4.5) 4.0 (2.0, 6.0) 4.0 (2.0, 6.5) 4.0 (2.0, 7.0) 4.0 (2.0, 8.0) eGFR≤ 60 mL/min/1.73 m2 2 (4.0) 5 (6.8) 20 (21.5) 18 (37.5) 8 (61.5) Transient ischemic attack, % 3 (6.0) 6 (8.1) 8 (8.6) 4 (8.3) 1 (7.7) Stroke subtype (TOAST) , % Large artery atherosclerosis 18 (36.0) 25 (33.8) 31 (33.3) 18 (37.5) 4 (30.8) Cardioembolism 6 (12.0) 17 (23.0) 19 (20.4) 12 (25.0) 3 (23.1) Small artery occlusion 20 (40.0) 22 (29.7) 27 (29.0) 11 (22.9) 4 (30.8) Other determined etiology 0 2 (2.7) 2 (2.2) 2 (4.2) 1 (7.7) Undetermined etiology 3 (6.0) 2 (2.7) 66.5) 1 (2.1) 0 Laboratory data Total cholesterol, mmol/L 4.0 ± 0.9 3.8 ± 0.9 4.2 ± 1.1 3.9 ± 1.2 4.2 ± 1.3 Triglyceride, mmol/L 1.6 (0.9, 1.8) 1.4 (1.0, 1.9) 1.3 (0.9, 2.0) 1.4 (1.1, 1.9) 1.4 (1.1, 1.5) Low density lipoprotein, mmol/L 2.4 ± 0.5 2.3 ± 0.7 2.5 ± 0.9 2.5 ± 0.9 2.6 ± 1.0 High density lipoprotein, mmol/L 1.0 ± 0.2 1.1 ± 0.2 1.1 ± 0.2 1.0 ± 0.2 1.1 ± 0.2 Homocysteine, mmol/L 14.4 ± 6.0 14.6 ± 9.1 14.9 ± 5.7 14.1 ± 5.1 15.5 ± 6.4 Hs-CRP, mg/L 3.0 (1.0, 6.2) 3.5 (1.0, 6.0) 4.0 (1.5, 7.0) 4.0 (2.2, 7.8) 4.0 (2.7, 6.0) 0.033 (0.026, 0.053) 0.038 (0.024, 0.054) 0.036 (0.022, 0.064) 0.060 (0.033, 0.080) 0.080 (0.054, 0.092) Procalcitonin,μg/L Abbreviations: eGFR: estimated glomerular filtration rate; Hs-CRP, high-sensitivity C-reactive protein; NIHSS, national institutes of health stroke scale.
P value 0.046 0.274 0.174 0.942 0.654 0.021 0.356 0.269 0.612 0.002 0.260 0.176 0.395 0.001 0.988 0.983 0.534 0.470 0.509 0.557 0.125 0.686 0.374 0.647 0.008 0.612 0.001
Table 2. Univariate and multivariate logistic regression analysis for the associations between PCT levels and cSVD. OR (95% CI) for SLIs
OR (95% CI) for WMLs
OR (95% CI) for CMBs
OR (95% CI) for high-grade EPVs
OR (95% CI) for total cSVD burden
Crude model PCT levels First quartile Reference Reference Reference Reference Reference Second quartile 0.589 (0.298–1.165) 0.489 (0.226–1.158) 0.467 (0.238–1.129) 1.794 (0.775–4.151) 0.550 (0.299–1.014) Third quartile 1.293 (0.664–2.518) 0.715 (0.346–1.479) 0.725 (0.372–1.415) 3.578 (1.607–7.966)** 1.313 (0.718–2.400) Fourth quartile 2.266 (1.131–4.538)* 1.793 (1.029–3.574)* 0.913 (0.466–1.789) 8.061 (3.599–14.055)** 3.743 (1.998–7.088)** Adjusted model PCT levels First quartile Reference Reference Reference Reference Reference Second quartile 0.545 (0.266–1.116) 0.511 (0.228–1.143) 0.506 (0.241–1.062) 2.015 (0.839–4.836) 0.554 (0.294–1.040) Third quartile 1.169 (0.584–2.338) 0.648 (0.302–1.389) 0.750 (0.363–1.546) 3.018 (1.612–8.576) ** 1.310 (0.706–2.433) Fourth quartile 1.915 (1.029–3.947)* 1.633 (1.087–3.371) * 0.821 (0.395–1.705) 7.924 (3.411–14.406) ** 3.152 (1.657–6.001) ** Abbreviations: CMBs, cerebral microbleeds; cSVD: cerebral small vessel disease; CI, confidence interval; SD, standard deviation; EPVs, enlarged perivascular spaces; PCT, procalcitonin; WMLs, white matter lesions; SLIs, silent lacunar infarcts. *P< 0.05;
**P < 0.01;
Adjusted model: adjusted for age, smoking, eGFR≤ 60 mL/min/1.73 m2, systolic blood pressure and homocysteine levels.
S0304-3940(17)30866-2 https://doi.org/10.1016/j.neulet.2017.10.040 NSL 33184
To appear in:
Neuroscience Letters
Received date: Revised date: Accepted date:
1-8-2017 27-9-2017 19-10-2017
Please cite this article as: Guangzong Li, Chen Zhu, Jing Li, Xiangming Wang, Qingbin Zhang, Hongjia Zheng, Cheng Zhan, Increased level of procalcitonin is associated with total MRI burden of cerebral small vessel disease in patients with ischemic stroke, Neuroscience Letters https://doi.org/10.1016/j.neulet.2017.10.040 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Increased level of procalcitonin is associated with total MRI burden of cerebral small vessel disease in patients with ischemic stroke Cover Title: PCT and risk of cSVD
Authors and Affiliations: Guangzong Li, MD1; Chen Zhu, MD1; Jing Li, MD2; Xiangming Wang MD1; Qingbin Zhang, MD1; Hongjia Zheng, MD1; Cheng Zhan, MD1 1
Department of Neurology, Central Hospital of Panzhihua City, Panzhihua, Sichuan Province
617000, China. 2
Department of Clinical Laboratory, Central Hospital of Panzhihua City, Panzhihua, Sichuan
Province 617000, China.
Address for Correspondence and Reprints Cheng Zhan Department of Neurology Central Hospital of Panzhihua City No. 34 Yikang Street, Panzhihua, 617000, Sichuan Province, China Telephone number: +86 0816-2222566 Fax number: +86 0816-2222566 E-Mail address: [email protected]
Highlights：
Higher concentrations of PCT are correlated to the increasing risk of silent lacunar infarctions, white matter lesions, and high-grade enlarged perivascular spaces.
No substantial association is detected between PCT levels with cerebral microbleeds.
Higher PCT levels might augment the risk of total cerebral small vessel disease burden on
magnetic resonance imaging in ischemic stroke patients.
Abstract Background. Procalcitonin (PCT) has been found to be associated with subclinical cerebrovascular damage. The relationship between PCT levels and cerebral small vessel disease (cSVD), especially cSVD burden, has not been fully understood. This study aimed to investigate the association between PCT levels and cSVD in patients with first-ever acute ischemic stroke or transient ischemic attack (TIA). Methods. Two hundred and seventy-eight consecutive patients were prospectively recruited during Jan 2016 to Jun 2017. Serum PCT concentrations measurement was performed after admission. The presence and burden of cSVD was determined by magnetic resonance imaging (MRI). Multivariable logistic regression was used to assess whether serum PCT levels were associated with cSVD. Results. The median PCT level was 0.042 µg/L (interquartile range, 0.025–0.065 µg/L). Univariable logistic regression analysis indicated that patients with PCT level in the top quartile, compared with the lowest quartile, were more likely to have silent lacunar infarctions [odds ratio (OR), 2.266; 95% confidence interval (CI) 1.131–4.538, P = 0.021], white matter lesions (OR, 1.793; 95% CI 1.029–3.574, P = 0.047), high-grade enlarged perivascular spaces (OR, 8.061; 95% CI 3.599–14.055, P = 0.001) and increased total MRI cSVD burden (OR, 3.743; 95% CI 1.998–7.008, P = 0.002). These results persisted even after adjusting for potential confounders. Conclusions. This study demonstrated that elevated PCT levels might be associated with total MRI cSVD burden in patients with ischemic stroke or TIA.
Key Words: Ischemic stroke; Procalcitonin; Cerebral small vessel disease. Introduction Cerebral small-vessel disease (cSVD) is an intrinsic disorder that affects small arteries and arterioles of the brain, which embraces white matter lesions (WMLs), cerebral microbleeds (CMBs), enlarged perivascular spaces (EPVs) and silent lacunar infarctions (SLIs) in brain magnetic resonance imaging (MRI) [1-3]. Epidemiological study demonstrated that cSVD is a leading cause of functional loss and cognitive deficits in old age [4, 5]. Moreover, increasing evidences attach cSVD to a higher risk of cognitive impairment [4-6], post-stroke affective disorder [7, 8], unfavorable stroke outcomes and stroke recurrence [9, 10]. However, there is little data to date on blood prognostic biomarkers and their association with cSVD. Procalcitonin (PCT) was first described in the early 1990s as a sepsis-induced protein [11]. PCT has been widely recognized as a prognostic inflammatory biomarker for cardiovascular diseases [12]. Increased serum PCT level was reported to be associated with adverse clinical outcomes including higher mortality in cerebrovascular diseases [13-15]. In a study nested within the Northern Manhattan Study, PCT concentrations are also independently related to the severity of SLIs and WMLs [16]. However, considering that these MRI cSVD markers do not occur separately in a patient, a total cSVD burden might better capture the overall influences of CSVD on the brain. Recently, a validated scale of the ordinal MRI cSVD burden has been proposed by counting the presence of each of these 4 MRI cSVD features [17]. This total cSVD burden has been found to be correlated with chronic kidney disease [18], cognitive function [4-6] and post-stroke depression [7] in ischemic stroke patients. Therefore, in this study we aimed to determine whether serum PCT levels at admission were associated with cSVD features and total
MRI cSVD burden in a cohort of Chinese sample who initially presented with acute ischemic stroke or transient ischemic attack (TIA).
Subjects and Methods Study population Between Jan 2016 to Jun 2017, 412 consecutive patients with first-ever acute ischemic stroke or TIA were admitted to the Central Hospital of Panzhihua City within 72 hours after symptoms onset. According to the standard protocol of our stroke unit, all subjects performed routine blood tests, chest radiography, 12-lead electrocardiography, MRI and cerebrovascular imaging examinations. The exclusion criteria were as the following: (1) age < 18 years old; (2) unable to perform MRI examination; (3) infarct size ≥ 1/3 ipsilateral cerebral hemisphere area; (4) pre-stroke diagnosis of active or chronic inflammatory diseases, malignant tumor, intracerebral hemorrhage, thyroid diseases, autoimmune diseases, and a history of any central nervous system disease. This study was approved by the Medical Ethics Committee of the Central Hospital of Panzhihua City and all participants gave written informed consent.
Collection of demographic and clinical data Clinical data were collected by trained neurologists blinded to the subject's diagnosis. The following information was collected: demographic characteristics, traditional vascular risk factors (including: hypertension, diabetes mellitus, hyperlipidemia, and coronary heart disease), clinical and laboratory data. As used previously [19], hypertension was defined as systemic blood pressure measurements ≥ 140/90 mmHg on two different occasions or a history of hypertension. Diabetes mellitus was diagnosed as a fasting serum glucose levels ≥ 7.0 mmol/L or a history of diabetes.
Hyperlipidemia was described when satisfying one of the conditions: 1) total cholesterol levels ≥ 5.70 mmol/L; 2) triglyceride levels ≥ 1.70 mmol/L; 3) low-density lipoprotein levels ≥ 3.64 mmol/L; 4) a history of hyperlipidemia. Severity of stroke was assessed at admission using the National Institute of Health Stroke Scale (NIHSS) [20]. Estimated Glomerular Filtration Rate (eGFR) was calculated individually by Chronic Kidney Disease Epidemiology Collaboration equation for the Asian population [21]. Stroke subtype was classified according to TOAST (Trial of Org 10172 in Acute Stroke Treatment) criteria [22].
Assessment of PCT concentrations After admission, blood samples were collected from all subjects. For measuring serum PCT concentrations, the specimens were immediately separated by centrifugation at 1500 rpm for 10 minutes and the isolated serum frozen at −80 °C for later measurements. A rapid and sensitive assay (PCT sensitive LIA; BRAHMS GmbH, Hennigsdorf, Germany) was used for detection of PCT serum levels. The lowest functional detection limit of the assay is 0.006 μg/L. All procedures were performed in strict accordance to manufacturers’ instructions.
Imaging analysis MRI was conducted during 7 days after admission with a 3.0T MRI system (MAGNETOM Trio 3.0T, Siemens, Amberg, Germany) in all patients. The definition of MRI markers of cSVD (including WMLs, CMBs, EPVs and SLIs) was in accordance with previous study [23]. SLIs was defined as a diameter < 20 mm lesion showing as a hyperintense on axial T2-weighted images (T2WI) and a hypointense on axial T1-weighted images (T1WI) in a subject lacking a relevant
clinical findings. The extent of WMLs was graded using the Fazekas score. One point was awarded if irregular periventricular hyperintensities extending into the deep white matter (Fazekas score 3) or confluent deep WMLs (Fazekas score 2 or 3). CMBs was identified as punctate hypointense lesions on T2*-gradient recalled echo (GRE) images with a diameter < 10 mm. Symmetrical hypointensities in the globipallidi, likely to represent calcification, sulcal flow voids from cortical vessels, and hypointensities possibly due to partial volume artifacts from bone were disregarded. One point was awarded if deep CMBs were present. EPVs was defined as punctate or linear hyperintense lesions with signal intensity equal to cerebrospinal fluid on T2WI in the basal ganglia, and (if visible) hypointense on fluid-attenuated inversion recovery images (FLAIR) without a hyperintense rim to distinguish them from old lacunar infarcts. We counted EPVs on the slide with the highest number in one hemisphere and graded them using a 3-category ordinal scale (0–10; 10–25; >25). One point was awarded if moderate to extensive (>10) EPVs were present. All images were independently rated by two neurologists for the presence of cSVD markers. In case of disagreement, lesions were ascertained by consensus. Limited intra-rater reliability testing (50 scans) demonstrated a good reliability with kappa values of 0.84 for the presence of EPVs, 0.86 for CMBs, 0.83 for WMLs and 0.79 for SLIs. An established ordinal scale [17,23,24] was used to represent the total MRI cSVD burden. The total cSVD score was calculated for each patient on an ordinal scale from 0 to 4, with a score of 1 point awarded for the presence of each of the 4 MRI cSVD features mentioned above.
Statistical analysis Continuous variables were presented as the means (Standard deviation) or medians (interquartile
range) and categorical variables were expressed as n (%). Differences in baseline characteristics between the increasing cSVD burden groups were determined by Chi-square test, Fisher exact test, analysis of variance, or Kruskal-Wallis where appropriated. Furthermore, logistic regression analysis was used to assess the relationship between PCT levels and cSVD markers and its total burden. We dichotomized basal ganglia EPVs into mild (EPVs 0–10) and high grade (EPVs > 10), reflecting mild versus high-grade EPVs. For the analysis of cSVD burden as an ordinal outcome, we used ordinal logistic regression analysis. All multivariable analyses were adjusted for the factors with a P value < 0.1 in the univariable analysis (including: age, smoking, eGFR ≤ 60 mL/min/1.73 m2, systolic blood pressure and homocysteine levels). Furthermore, the association between PCT levels and the severity of cSVD features was evaluated using Spearman correlation analysis. All statistical analysis was performed using SPSS software (SPSS version 20, SPSS, Chicago, USA). Statistical significance was established at P < 0.05 in all tests. Results During Jan 2016 to Jun 2017, 278 consecutive patients (157 male) met the entry criteria. The average age of the patient sample was 62.4 ± 8.5 years (from 40 to 82 years old). Among these participants, 89 (32.0%) had WMLs, 135 (48.6%) had CMBs, 108 (38.8%) had EPVs, and 144 (51.8%) had SLIs. For cSVD burden, 50 patients (18.0%) had a cSVD score of 0 and 13 patients (4.7%) presented with a cSVD score of 4. Table 1 demonstrated the demographic characteristics and clinical data of the study population stratified by the total MRI cSVD burden. Increasing total cSVD burden showed a significant association with age (P = 0.046), smoking (P = 0.021), eGFR ≤ 60 mL/min/1.73 m2 (P = 0.001), systolic blood pressure (P = 0.002) and homocysteine levels (P= 0.008).
The median PCT level was 0.042 µg/L, with quartile levels as follows: < 0.025 µg/L (first quartile), 0.025–0.041µg/L (second quartile), 0.042–0.065µg/L (third quartile), and > 0.065µg/L (fourth quartile). Spearman correlation analysis showed a positive correlation between PCT levels and severity of SLIs (SLIs number, Spearman's rho = 0.267, P = 0.001), WMLs (Fazekas score, Spearman's rho = 0.122, P = 0.042) and EPVs (EPVs degree, Spearman's rho = 0.319, P = 0.001). However, there was no significant difference between PCT concentrations and CMBs severity (CMBs number, Spearman's rho = -0.010, P = 0.869). Table 2 demonstrated the results of the binary logistic regression of cSVD markers, and the ordinal logistic regression of cSVD burden. Univariable regression analysis indicated that patients with PCT level in the top quartile, compared with the lowest quartile, were more likely to have SLIs [odds ratio (OR), 2.266; 95% confidence interval (CI) 1.131–4.538, P = 0.021], WMLs (OR, 1.793; 95% CI 1.029–3.574, P = 0.047), high-grade EPVs (OR, 8.061; 95% CI 3.599–14.055, P = 0.001) and increased total MRI cSVD burden (OR, 3.743; 95% CI 1.998–7.008, P = 0.002). Furthermore, association between PCT levels and SLIs, WMLs, high-grade EPVs and total cSVD burden remained significant after adjusting for control variables (Table 2, adjusted model).
Discussion In this hospital-based study of 278 patients with acute ischemic stroke or TIA, we found that higher levels of PCT were positively associated with SLIs, WMLs, high-grade EPVs and increasing total MRI burden of cSVD. PCT is a 13-kDa 116-amino acid prohormone of calcitonin which is released ubiquitously in response to endotoxin and other pro-inflammatory cytokines (e.g., interleukin-1β, interleukin-2, interleukin-6 and tumor necrosis factor-α) [25-28]. Mimoz et al. [29] found that circulating PCT
levels seemed proportionally to be positively correlated with the severity of tissue injury and local inflammation. The available evidences suggest that patients with higher PCT levels may experience higher risk of developing atherosclerosis and unfavorable outcome in cerebrovascular diseases. In Chinese sample, serum level of PCT at admission was established as an independent predictor of long-term functional outcome (OR, 2.33; 95% CI 1.33–3.44; P < 0.001) and mortality (OR, 3.11; 95% CI 2.02–4.43; P < 0.001) after ischemic stroke [15]. Furthermore, in the population-based Northern Manhattan Study of 3298 initially stroke-free participants [16], subjects with higher PCT levels were significantly associated with presence of silent brain infarcts (adjusted OR, 2.2; 95% CI, 1.3–3.7) and increased white matter hyper-intensity volume (adjusted mean change in white matter hyper-intensity volume, 0.29; 95% CI, 0.13–0.44). Consistent with those finding, our prospective study indicated that serum PCT level was a predictor for SLIs, WMLs, and high-grade EPVs in patients with acute ischemic stroke or TIA. Unexpectedly, we did not detect significant association between PCT levels and CMBs. One possible explanation is that the development of CMBs may be different from other cSVD features, in that CMBs could arise from cerebral microvascular ruptures, while the others might represent the ischemic conditions including arteriolar narrowing and occlusion. Other important confounding variables such as cardiovascular risk factors may also be considered as possible interventions in the relations [2,3,30]. Therefore, further investigations are needed to determine relationship between PCT and CMBs. As cSVD substantially contributes to one quarter of stroke worldwide and cognition impairment in the elderly population [4,5,31], studies involving in the damage of brain small vessels may have significant public health implications. Although the pathogenesis of cSVD is not
completely understood, it is fundamental to bear in mind that all the features of cSVD are strictly inter-related [1,32]. Proceeding from this point, we used an established validated scale to represent the MRI cSVD burden, which might better capture the total subcortical microstructural brain damage caused by cSVD. Our findings underline the importance of a higher PCT level as a risk factor for increased MRI burden of cSVD. PCT might act as a chemoattractant and is initially produced in adherent monocytes, and participate in mediating monocyte adhesion and migration, representing key features of inflammatory process [33,34]. Also, PCT has an adverse effect on iNOS gene expression, which partially contributes to the endothelial function impairment [33-35]. Thus serum PCT may cause subclinical inflammatory status and endothelial dysfunction, which has been suggested as major determinants of the structural and functional brain-vessel alterations in cSVD [36-38]. This study has several strengths, including reasonable sample size, use of carefully standardized research methods, extensive assessments of MRI cSVD characteristics, and homogeneous population of patient with ischemic stroke. Moreover, a total cSVD score was applied to represent the combined effect of cSVD, which all make this study appropriate for examining the association between PCT levels and cSVD. Nonetheless, the following limitations of our study must be taken into account. Firstly, the study was performed in one stroke center with favors less disabled patients, which could have selection bias. Secondly, this was a cross-sectional study, which cannot determine the causal relationship between PCT levels and severity of cSVD. Thirdly, PCT levels were only measured once upon initial enrolment of subjects into the study, which may predispose to intra-individual variations. Finally, all participants in the present study were free of clinical signs of infection. However, subclinical infections and inflammatory
conditions prior to the disease onset that could stimulate PCT production cannot be excluded with certainty. In conclusion, our results found that PCT levels might be associated with cSVD burden. Considering that measuring PCT levels is relatively simple and easy, PCT could be used as a screening tool for cSVD. Interventional trials are required to determine if managing serum PCT levels within the appropriate range can lower the risk of cSVD in patients with ischemic stroke.
Conflict of interest All the authors declare that there is no conflict of interest
Acknowledgments We also express our gratitude to Yun Zhang (Central Hospital of Mianyang City) for excellent statistical advice.
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Table 1. Demographic and clinical characteristics of the study population stratified by total sSVD burden. Variable cSVD0 (n = 50) cSVD1 (n = 74) cSVD2 (n = 93) cSVD3 (n = 48) cSVD4 (n = 13) Age, years 59.5 ± 6.5 63.0 ± 9.4 62.3 ± 9.3 64.4 ± 6.5 64.3 ± 8.2 Male, % 33 (66.0) 43 (58.1) 53 (57.0) 21 (43.8) 7 (53.8) Vascular risk factors, % Hypertension 37 (74.0) 47 (63.5) 72 (77.4) 36 (75.0) 7 (53.8) Diabetes mellitus 13 (26.0) 19 (25.7) 27 (29.0) 11 (22.9) 4 (30.8) Hyperlipidemia 6 (12.0) 16 (21.6) 18 (19.4) 7 (4.6) 2 (15.4) Smoking 18 (36.0) 23 (31.1) 23 (24.7) 13 (27.1) 9 (69.2) Coronary heart disease 2 (4.0) 9 (12.2) 8 (8.6) 2 (4.2) 1 (7.7) Clinical data Antithrombotic treatment, % 6 (12.0) 5 (6.8) 16 (17.2) 9 (18.8) 2 (15.2) Statin therapy, % 4 (8.0) 10 (13.5) 13 (14.0) 5 (10.4) 3 (23.1) Systolic blood pressure, mmHg 134.1 ± 14.8 133.4 ± 12.4 136.4 ± 15.0 144.2 ± 20.0 153.3 ± 25.6 Diastolic blood pressure, mmHg 84.5 ± 9.3 82.1 ± 10.1 81.8 ± 10.6 80.8 ± 10.2 86.2 ± 12.7 Body mass index, kg/m2 25.0 ± 3.4 25.2 ± 2.5 24.7 ± 3.4 26.0 ± 2.6 24.7 ± 3.9 NIHSS, score 3.0 (2.0, 4.5) 4.0 (2.0, 6.0) 4.0 (2.0, 6.5) 4.0 (2.0, 7.0) 4.0 (2.0, 8.0) eGFR≤ 60 mL/min/1.73 m2 2 (4.0) 5 (6.8) 20 (21.5) 18 (37.5) 8 (61.5) Transient ischemic attack, % 3 (6.0) 6 (8.1) 8 (8.6) 4 (8.3) 1 (7.7) Stroke subtype (TOAST) , % Large artery atherosclerosis 18 (36.0) 25 (33.8) 31 (33.3) 18 (37.5) 4 (30.8) Cardioembolism 6 (12.0) 17 (23.0) 19 (20.4) 12 (25.0) 3 (23.1) Small artery occlusion 20 (40.0) 22 (29.7) 27 (29.0) 11 (22.9) 4 (30.8) Other determined etiology 0 2 (2.7) 2 (2.2) 2 (4.2) 1 (7.7) Undetermined etiology 3 (6.0) 2 (2.7) 66.5) 1 (2.1) 0 Laboratory data Total cholesterol, mmol/L 4.0 ± 0.9 3.8 ± 0.9 4.2 ± 1.1 3.9 ± 1.2 4.2 ± 1.3 Triglyceride, mmol/L 1.6 (0.9, 1.8) 1.4 (1.0, 1.9) 1.3 (0.9, 2.0) 1.4 (1.1, 1.9) 1.4 (1.1, 1.5) Low density lipoprotein, mmol/L 2.4 ± 0.5 2.3 ± 0.7 2.5 ± 0.9 2.5 ± 0.9 2.6 ± 1.0 High density lipoprotein, mmol/L 1.0 ± 0.2 1.1 ± 0.2 1.1 ± 0.2 1.0 ± 0.2 1.1 ± 0.2 Homocysteine, mmol/L 14.4 ± 6.0 14.6 ± 9.1 14.9 ± 5.7 14.1 ± 5.1 15.5 ± 6.4 Hs-CRP, mg/L 3.0 (1.0, 6.2) 3.5 (1.0, 6.0) 4.0 (1.5, 7.0) 4.0 (2.2, 7.8) 4.0 (2.7, 6.0) 0.033 (0.026, 0.053) 0.038 (0.024, 0.054) 0.036 (0.022, 0.064) 0.060 (0.033, 0.080) 0.080 (0.054, 0.092) Procalcitonin,μg/L Abbreviations: eGFR: estimated glomerular filtration rate; Hs-CRP, high-sensitivity C-reactive protein; NIHSS, national institutes of health stroke scale.
P value 0.046 0.274 0.174 0.942 0.654 0.021 0.356 0.269 0.612 0.002 0.260 0.176 0.395 0.001 0.988 0.983 0.534 0.470 0.509 0.557 0.125 0.686 0.374 0.647 0.008 0.612 0.001
Table 2. Univariate and multivariate logistic regression analysis for the associations between PCT levels and cSVD. OR (95% CI) for SLIs
OR (95% CI) for WMLs
OR (95% CI) for CMBs
OR (95% CI) for high-grade EPVs
OR (95% CI) for total cSVD burden
Crude model PCT levels First quartile Reference Reference Reference Reference Reference Second quartile 0.589 (0.298–1.165) 0.489 (0.226–1.158) 0.467 (0.238–1.129) 1.794 (0.775–4.151) 0.550 (0.299–1.014) Third quartile 1.293 (0.664–2.518) 0.715 (0.346–1.479) 0.725 (0.372–1.415) 3.578 (1.607–7.966)** 1.313 (0.718–2.400) Fourth quartile 2.266 (1.131–4.538)* 1.793 (1.029–3.574)* 0.913 (0.466–1.789) 8.061 (3.599–14.055)** 3.743 (1.998–7.088)** Adjusted model PCT levels First quartile Reference Reference Reference Reference Reference Second quartile 0.545 (0.266–1.116) 0.511 (0.228–1.143) 0.506 (0.241–1.062) 2.015 (0.839–4.836) 0.554 (0.294–1.040) Third quartile 1.169 (0.584–2.338) 0.648 (0.302–1.389) 0.750 (0.363–1.546) 3.018 (1.612–8.576) ** 1.310 (0.706–2.433) Fourth quartile 1.915 (1.029–3.947)* 1.633 (1.087–3.371) * 0.821 (0.395–1.705) 7.924 (3.411–14.406) ** 3.152 (1.657–6.001) ** Abbreviations: CMBs, cerebral microbleeds; cSVD: cerebral small vessel disease; CI, confidence interval; SD, standard deviation; EPVs, enlarged perivascular spaces; PCT, procalcitonin; WMLs, white matter lesions; SLIs, silent lacunar infarcts. *P< 0.05;
**P < 0.01;
Adjusted model: adjusted for age, smoking, eGFR≤ 60 mL/min/1.73 m2, systolic blood pressure and homocysteine levels.