Objective To investigate the relationship between the imaging classification of cerebral microbleeds
(CMBs) and plasma vascular endothelial growth factor (VEGF) levels based on apolipoprotein E
(ApoE) phenotype, to provide valuable biomarkers for the early warning screening of CMBs.
Methods Patients with acute cerebral infarction who were admitted to the Huangdao Branch of the
Affiliated Hospital of Qingdao University and Weihai Central Hospital of Qingdao University from
August 2014 to August 2017 were selected. All the patients were divided into CMBs and non-CMBs
according to the presence or absence of CMBs. The baseline data included gender, age, mini-mental state examination (MMSE) score, NIHSS score, hypertension, systolic blood pressure, diabetes,
antihypertensive drugs, anticoagulation and antiplatelet agents and etc. With reference to the CMBs
Anatomical Rating Scale, the CMBs were divided into deep CMBs, lobe CMBs, subtentorial CMBs,
and mixed CMBs according to the distribution of CMBs. To facilitate the analysis, subtentorial
CMBs were classified as deep CMBs and mixed CMBs were excluded. ApoE genotyping of all
patients were measured using the ApoE genotyping Kit. Plasma VEGF level was measured by
ELISA. After adjusting for the potential confounding factors, logistic regression analysis was used
to analyze the relationship of plasma VEGF level and different imaging classification of CMBs.
Results Ninety nine cases of CMBs were identified, including 7 cases with mixed CMBs who were
excluded. Plasma VEGF levels in CMBs group was significantly higher than that in non-CMBs
group (P =0.05). The plasma VEGF level in deep CMBs group was significantly higher than that
in non-CMBs group (P =0.009). High level of plasma VEGF was a risk factor for CMBs (OR 1.59,
95%CI 1.02-2.47; P =0.05). In patients with deep CMBs, there was an interaction between plasma
VEGF levels and ApoE genotype (P =0.01). In patients with ApoE ε3 /ε3 , the adjusted OR of deep
CMBs for each standard deviation (SD) increase in plasma VEGF levels was 0.90 (95%CI 0.49-
1.20; P =0.73); in patients with ApoE ε2 or ε4 , the adjusted OR of deep CMBs for each SD increase
in plasma VEGF level was 2.83 (95%CI 1.31-6.10; P =0.008).
Conclusions Deep CMBs are associated with the high level of plasma VEGF. The relation of
plasma VEGF with CMBs may have ApoE genotype dependence.
