Supplementary Material for: Cerebral Microbleeds Are Associated with the Progression of Ischemic Vascular Lesions

<b><i>Background:</i></b> Despite their different appearance on imaging, hemorrhagic and ischemic vascular lesions frequently co-occur in the brain and are hypothesized to progress concurrently. Although silent hemorrhagic and ischemic vascular brain lesions are highly prevalent in the general population, the concomitant progression of these lesions has only been studied to a limited extent in this population. We therefore aimed to investigate whether pre-existing and incident cerebral microbleeds (CMBs) are related to the progression of ischemic lesions in the general population. <b><i>Methods:</i></b> In the prospective population-based Rotterdam Scan Study, 803 individuals aged ≥60 years underwent magnetic resonance imaging at baseline and after an average interval of 3.4 years. The presence of microbleeds and lacunes was visually rated by trained research physicians, and white matter lesions (WMLs) were automatically segmented at both time points. Logistic regression was used to investigate the association of microbleeds with incident lacunes, and linear regression was used to investigate the relation between microbleeds and progression of WML volume. All analyses were adjusted for age, sex and the time interval between baseline and follow-up scanning. The analyses were repeated after additional adjustments for cardiovascular risk factors: blood pressures; total and high-density lipoprotein cholesterol; smoking; diabetes mellitus; lipid lowering, antihypertensive and antiplatelet medications, and <i>apolipoprotein E</i> ε4. The analyses involving WMLs were also adjusted for intracranial volume. <b><i>Results:</i></b> We found that pre-existing microbleeds in any location of the brain were related to a higher incidence of lacunes (odds ratio [OR] adjusted for age, sex and scan interval: 4.67; 95% confidence interval [CI]: 1.84-11.85). Pre-existing microbleeds were not related to progression of WML volume (mean difference in WML volume increase: -0.03; 95% CI: -0.15 to 0.09). Additional adjustments for cardiovascular risk factors did not change the results considerably. Incident microbleeds in any location of the brain were associated with a higher incidence of lacunes (OR: 9.18; 95% CI: 3.61-23.35), whereas only incident microbleeds located in cortico-subcortical regions were related to progression of WML volume (mean difference in WML volume increase: 0.41; 95% CI: 0.21-0.62). Again, adjustments for cardiovascular risk factors did not change the results significantly. <b><i>Conclusions:</i></b> Our findings suggest that in the general population, CMBs serve as a predictor of ischemic brain lesions and may represent an imaging marker of active vasculopathy. These results support the hypothesis of a common underlying pathway in the development of ischemic and hemorrhagic brain lesions.

<b><i>背景：</i></b>尽管出血性与缺血性脑血管病灶在影像学表现上存在差异，但二者常同时出现在脑部，且被推测会同步进展。尽管无症状性出血性及缺血性脑病灶在普通人群中患病率极高，但针对该人群中这类病灶的同步进展情况，相关研究仍较为有限。因此本研究旨在探究普通人群中，已存在的和新发的脑微出血（cerebral microbleeds, CMBs）是否与缺血性病灶的进展相关。<b><i>方法：</i></b>在基于人群的前瞻性队列研究鹿特丹扫描研究（Rotterdam Scan Study）中，803名年龄≥60岁的受试者在基线及平均间隔3.4年后接受了磁共振成像检查。经过培训的研究医师对微出血及腔隙性病灶进行了人工视觉评分，同时在两个时间点均对脑白质病变（white matter lesions, WMLs）进行了自动分割。采用Logistic回归分析微出血与新发腔隙性病灶的关联，采用线性回归分析微出血与脑白质病变体积进展的关系。所有分析均针对年龄、性别及基线与随访扫描的时间间隔进行了校正。后续又在额外校正心血管危险因素（血压、总胆固醇及高密度脂蛋白胆固醇、吸烟状况、糖尿病、降脂药物、降压药物及抗血小板药物，以及载脂蛋白E ε4）后重复了上述分析。针对脑白质病变的分析还额外校正了颅内体积。<b><i>结果：</i></b>我们发现，脑部任意部位存在的既往微出血与更高的腔隙性病灶发生率相关（校正年龄、性别及扫描间隔后的比值比[OR]为4.67；95%置信区间[CI]：1.84-11.85）。既往微出血与脑白质病变体积进展无显著关联（脑白质病变体积增加的均值差为-0.03；95%CI：-0.15至0.09）。对心血管危险因素进行额外校正后，结果并未发生显著改变。脑部任意部位的新发微出血与更高的腔隙性病灶发生率相关（OR：9.18；95%CI：3.61-23.35），而仅皮层-皮层下区域的新发微出血与脑白质病变体积进展相关（脑白质病变体积增加的均值差为0.41；95%CI：0.21至0.62）。同样，校正心血管危险因素后结果未发生显著变化。<b><i>结论：</i></b>我们的研究结果表明，在普通人群中，脑微出血可作为缺血性脑病灶的预测因子，或许可作为活动性血管病变的影像学标志物。上述结果支持了缺血性与出血性脑病灶具有共同潜在发病通路的假说。