临床医学进展  >> Vol. 11 No. 2 (February 2021)

脑微出血危险因素的研究进展
Research Progress on Risk Factors of Cerebral Microbleeds

DOI: 10.12677/ACM.2021.112105, PDF, HTML, XML, 下载: 39  浏览: 74 

作者: 张 艺, 谈 跃*:昆明医科大学第二附属医院脑血管病科,云南 昆明

关键词: 脑微出血危险因素研究进展Cerebral Microbleeds Risk Factors The Research Progress

摘要: 脑微出血是脑内微小血管病变导致的以微小出血为主要特征的亚临床损害,是脑小血管病的重要表现之一。脑微出血好发于老年人,目前研究认为,脑微出血与卒中风险的增加、认知功能障碍、步态障碍等密切相关。高龄、高血压和脑淀粉样血管病是公认的脑微出血的病因,同时一些危险因素与脑微出血的发病相关,这些危险因素与脑微出血发病相关的机制目前尚未完全清楚。本文对脑微出血相关危险因素的研究进展进行综述,旨在为脑微出血的预防和治疗提供一定依据。
Abstract: Cerebral microbleeds is one of the important manifestations of cerebrovascular disease, which is mainly characterized by subclinical damage caused by microhemorrhage in the brain cereal microbleeds tend to occur in the elderly, current studies believe that cerebral microblees is closely related to the increased risk of stroke, cognitive dysfunction, gait disorders and so on. Advanced age, hypertension and cerebral amyloid vascular disease are recognized causes of cerebral microblees, at the same time, some risk factors are associated with the incidence of cerebral microbleeds, the mechanism of these risk factors and the pathogenesis of cerebral microbleeds is not fully understood. This article reviews the research progress on the risk factors related to cerebral microbleeds, aiming to provide some basis for the prevention and treatment of cerebral microbleeds.

文章引用: 张艺, 谈跃. 脑微出血危险因素的研究进展[J]. 临床医学进展, 2021, 11(2): 736-743. https://doi.org/10.12677/ACM.2021.112105

1. 引言

脑微出血(Cerebral Microbleeds, CMBs)是一种常见的亚临床脑血管疾病,由脑小血管的破裂或结构异常导致血液从受损血管泄漏后产生的含铁血黄素沉积引起,其在核磁共振梯度回波T2*加权成像和磁敏感加权成像上呈均匀的圆形或卵圆形的(通常直径为2~5 mm,最大可达10 mm)低信号缺损 [1]。CMBs的患者没有明显的临床症状或体征,在健康人群中CMBs的患病率为4.5% [2],在卒中患者中的患病率因卒中类型的差异而波动在16.1%~71% [3] [4] [5],在血管性痴呆患者中CMBs的患病率约为14.3% [6],而在阿尔茨海默病患者中CMBs的患病率高达37.3% [7]。虽然CMBs没有明显的临床症状,但会导致认知功能障碍、情绪改变、老年精神病综合征、步态异常、溶栓后出血转化等一系列并发症 [8]。此外,CMBs与未来卒中风险增加有关,可作为卒中复发的预测因子 [9]。目前研究表明,CMBs的发生率与高龄、高血压、糖尿病、血脂异常、脑淀粉样血管病、脑白质病变等危险因素有关 [10] [11] [12]。不同位置的CMBs涉及不同的病因,脑叶微出血与脑淀粉样血管病有关,深部或幕下微出血与高血压或动脉粥样硬化性微血管病变有关 [13],这些危险因素与CMBs发病相关的机制尚未完全清楚。现就CMBs发病危险因素的研究进展进行综述。

2. 不可干预的危险因素

2.1. 年龄

年龄是CMBs最重要的独立危险因素之一,既往研究表明,CMBs的患病率随着年龄的增长而逐渐增加,其发生率从45~50岁人群的6.5%上升至80岁以上人群的35.7% [13]。国外的一项动物实验研究对注射了低剂量脂多糖的幼龄(3个月)和老龄(18个月)小鼠的大脑切片进行组织化学染色后发现,与幼龄小鼠相比,老龄小鼠的CMBs数量、大小及总面积显著增加(p < 0.01),表明衰老使小鼠的大脑更容易受到炎症诱导而产生急性的CMBs。同时研究者还发现,用脂多糖处理的老龄小鼠的星形胶质细胞活化增加,进一步表明衰老增加了大脑对神经炎症的敏感性 [14]。目前,与年龄相关的CMBs增加的潜在机制尚不清楚,可能与衰老使血脑屏障通透性增加 [15] 和大脑对炎症的易感性增加有关 [14]。

2.2. 性别

性别对CMBs的影响目前尚存争议,Tomohiro等 [16] 发现男性在任何部位患CMBs的风险均高于女性,在对多种危险因素进行调整后,深部和幕下CMBs的性别差异较前缩小,而脑叶CMBs的性别差异没有变化,这可能是由于男性比女性有更多的心血管危险因素所致。也有研究表明,性别不是CMBs的危险因素 [17]。目前,CMBs患病率存在性别差异的相关机制尚不清楚,需进一步研究。

2.3. 遗传因素

与CMBs发生相关的遗传因素包括与散发性CMBs相关的基因多态性和家族性疾病相关的基因突变。与散发性CMBs相关的最常见的基因多态性是19号染色体上的载脂蛋E (APolip-oprotein E, ApoE)基因,其编码一种参与脂质和胆固醇代谢的蛋白质,在神经元生长、突触可塑性、膜修复和β-淀粉样蛋白(amyloid β-protein, Aβ)清除中起重要作用 [18]。在人类中,存在3种ApoE等位基因,分别是ε1ε2ε4 [19]。Silvia [20] 等对比了564名受试者ApoE基因分型与CMBs的关系后发现,ApoE-ε4与脑叶微出血显著相关,而ApoE-ε2和CMBs没有关联,可能与APOE-ε4增加Aβ血管沉积和血管壁增厚有关。ApoE-ε2对CMBs的影响尚存争议,有研究者提出ApoE-ε2与CMBs呈正相关,可能是因为ApoE-ε2会导致血管纤维蛋白样坏死,加重血管内皮损伤,诱发CMBs [21]。此外,全基因组关联研究也证实,ApoE-ε4与CMBs的存在和进展独立相关,同时还发现单核苷酸多态性与CMBs有关 [22]。家族性疾病中与CMBs相关的基因突变包括常染色体显性遗传性脑动脉病伴皮质下梗死和白质脑病中的NOTCH-3 (neurogenic locus notch homolog protein 3)基因突变 [23],家族性阿尔茨海默病中的APP (amyloid precursor protein)和早老素基因突变 [24]。基于目前的研究结果,需进一步探索这些已确定的基因多态性及突变引发CMBs的相关机制。

3. 可干预的危险因素

3.1. 高血压

高血压是CMBs最重要的危险因素,有效控制血压能降低CMBs的发生。研究表明,血压未得到控制的患者患CMBs的风险高于血压正常的患者 [25]。林 [10] 等对比460例高血压患者血压水平和CMBs严重程度的关系后发现,与无CMBs的患者相比,CMBs的患者收缩压和舒张压均显著升高,同时CMBs的严重程度随着高血压等级的增加而显著增加。说明应重视高血压患者的降压治疗,以避免CMBs的增加。有研究者提出,高血压会增加大脑后动脉区域以及深部和幕下部位CMBs的风险,穿透深部灰质核团和白质的小血管更容易受高血压影响,引起血脑屏障破坏,血管渗漏,最终导致CMBs [26]。因此,高血压能预测CMBs发生的位置。目前高血压诱发CMBs的机制尚不完全清楚,除了血脑屏障破坏和异常渗透外,可能与动脉硬化有关,高血压会引起一系列的微血管结构改变,例如管壁增厚、管腔狭窄、微血管延长和弯曲,导致脑血管自动调节紊乱,进而引起血管壁弹性和顺应性降低,血管壁脆性增大,使血管更容易受血压波动和由此产生的机械应力损伤的影响,最终引起CMBs的发生 [25]。

3.2. 糖尿病

糖尿病也是一个重要的危险因素。一项基于人群的梅奥衰老临床研究(The Mayo Clinic Study of Aging, MCSA)发现,糖尿病与CMBs的进展有关,在已存在CMBs的基础上,可增加后续发生CMBs的风险 [27]。国内的一项前瞻性研究表明,较高的血糖水平与深部或幕下的CMBs相关,与脑叶CMBs无关 [28],证实CMBs的血管病理改变因位置而异。Shima [5] 等对比不同种族的缺血性卒中患者CMBs的数量及相关因素后发现,糖尿病与多发性CMBs密切相关。既往研究表明 [29],糖尿病前期状态或糖尿病家族史可能与血管内皮功能障碍和血管壁损伤有关。血管内皮功能障碍可能会增加血脑屏障通透性,从而导致血浆成分泄露到血管壁和周围脑实质中,形成CMBs [30]。研究发现 [31],糖尿病药物的合理使用与CMBs呈负相关,目前尚需进行更大规模的研究来阐明使用药物控制的糖尿病患者是否比未控制的糖尿病患者具有更少的CMBs。

3.3. 血脂异常

血脂异常被认为与CMBs密切相关,其中血清总胆固醇(total cholesterol, TC)、高密度脂蛋白胆固醇(high-density lipoprotein cholesterol, HDL-C)、甘油三酯(triglyceride, TG)均与CMBs相关。日本的一项研究发现,较低的TC和HDL-C水平与深部CMBs的高患病率有关 [32]。Tomohiro [16] 等在社区老年人群中进行的前瞻性研究显示,较低水平的TC是深部或幕下CMBs的重要危险因素,表明TC是与CMBs发生相关的保护性因素。胆固醇是细胞膜的基本结构元素,随着脂质水平的降低,红细胞膜的渗透性会增加 [33]。据报道,TC水平较低会导致脑内小动脉平滑肌变性和内皮损伤,增加血管壁的脆性,进而形成微动脉瘤,从而导致CMBs的发生 [34]。也有研究者认为,较高水平的HDL-C与任何部位CMBs的风险增加显著相关,TG水平与CMBs风险呈负相关 [35]。目前尚不清楚HDL-C引起CMBs的相关机制,HDL-C水平的增加对脑血管有“双重相反的影响”,一方面,HDL-C具有抗氧化及抗炎特性,能改善内皮功能,促进内皮修复 [36];另一方面,较高水平的HDL-C可能会导致胆固醇从大脑向外周组织的反向转运减少,造成胆固醇堆积,这可能有助于淀粉样蛋白的血管沉积,进而导致淀粉样血管病 [37]。需要进一步研究HDL-C对CMBs产生差异性影响的相关机制,同时监测CMBs患者的血脂水平,可能有助于预防新发的CMBs。

3.4. 高同型半胱氨酸血症

同型半胱氨酸(homocysteine, Hcy)是一种含硫氨基酸,参与甲硫氨酸循环。较高的同型半胱氨酸水平会对血管壁的内皮细胞和神经元产生毒性反应,导致内皮功能障碍,并通过各种机制促进动脉粥样硬化形成,因而高同型半胱氨酸血症被认为是CMBs的一种独立危险因素 [38]。国内的一项回顾性研究发现 [39],Hcy水平与CMBs的存在呈正相关,尤其与脑叶CMBs显著相关。Nam [40] 等的研究也证实,Hcy水平是脑叶CMBs的独立预测因素。其可能的相关机制是:较高的Hcy水平通过触发内质网应激和炎症级联反应来破坏血脑屏障 [41] [42],使血脑屏障通透性增加,导致血浆成分泄露到血管周围,形成CMBs。此外,升高的Hcy水平也可能会增加Aβ的形成,同时通过淋巴途径使Aβ清除减少,导致Aβ的血管沉积,加剧血脑屏障的破坏,最终诱发脑叶CMBs [43]。既往研究表明 [44],补充叶酸和维生素B12能降低血浆Hcy水平,叶酸具有抗氧化作用,有助于血管内皮修复。目前补充B族维生素是否有助于降低CMBs发生的风险,有待前瞻性干预研究的进一步探讨。

3.5. 抗栓治疗

一些研究者提出抗血栓治疗可能与CMBs的进展有关。先前发表的一项研究表明,阿司匹林与缺血性卒中患者CMBs的发生率显著相关,长期服用阿司匹林的患者容易出现CMBs [45]。Jia [46] 等在急性卒中患者中进行的研究显示,在抗血小板治疗前,有5个或更多CMBs的急性脑梗死患者接受抗血小板治疗后CMBs的数量显著增加,表明抗血小板治疗增加了缺血性卒中患者新发CMBs的风险。Cheng [47] 等的研究发现,既往使用抗血栓药物与伴有房颤或风湿性心脏病的缺血性卒中患者CMBs的存在独立相关,尤其与脑叶的CMBs有关。抗血栓药物本身是否会引起CMBs仍不清楚,需进一步研究。抗栓治疗会增加CMBs发生的风险,在开始长期抗栓治疗前筛查CMBs可能有助于降低药物相关性CMBs的发生率,此外,在CMBs尤其是多发性CMBs的患者中,需权衡与CMBs进展相关的风险与抗栓治疗的益处之间的关系,慎用抗血栓药物。

4. 其他危险因素

4.1. 脑淀粉样血管病

脑淀粉样血管病(cerebral amyloid angiopathy, CAA)是广泛认可的危险因素,既往研究已证实,脑叶CMBs与脑淀粉样血管病有关 [13]。一个针对老年人群的MCSA研究发现,即使考虑了已存在的CMBs,淀粉样蛋白负荷依然会增加新发的脑叶CMBs的风险,尤其是枕叶的CMBs [27]。Jonathan [11] 等的研究显示,淀粉样蛋白负荷与脑叶CMBs相关,尤其在顶叶、枕叶和颞叶区域,但与深部或幕下CMBs无关,这与CMBs不同部位的血管病理学研究结果一致 [8]。CAA首先累及软脑膜和皮质血管,而高血压性血管病首先累及深部的穿支动脉。血管受累的差异可能与血流速度有关。在CAA中,当皮质表面的小动脉到达血流减慢的毛细血管时,淀粉样蛋白容易沉积在软脑膜血管壁上;而穿支动起源于大动脉,血流速度较快,较少引起淀粉样蛋白的沉积 [48]。因此,CMBs在CAA和高血压性血管病中具有明显的分布差异,这两种血管病理机制均会对血脑屏障造成破坏,引起血液渗漏,最终形成CMBs。

4.2. 脑白质病变

脑白质病变(white matter lesions, WMLs)是多种病因引起的神经传导纤维脱髓鞘的改变,在老年人群中较常见 [49]。WMLs和CMBs均属于脑小血管病,既往研究显示,较严重的WMLs是CMBs的显著独立预测因素,且这一相关性比年龄更密切 [12]。Zhou等的研究也得出了相同的结论。CMBs是含铁血黄素沉积在病变血管周围,而WMLs是神经纤维脱髓鞘改变,这两种病变同时存在时,可能会加重对血脑屏障的破坏,引起CMBs [50]。目前CMBs与WMLs相关的机制尚不清楚,有待进一步研究证实二者是否存在共同的发病机制。

5. 小结与展望

综上所述,高龄、高血压、糖尿病、高同型半胱氨酸血症、抗栓治疗、脑淀粉样血管病及脑白质病变均与CMBs的发病密切相关,而其他危险因素目前尚存争议,有待进一步研究证实。随着影像技术的发展,CMBs的检出率日益增高,明确CMBs的危险因素,阐明其相关的发病机制,对CMBs的预防和治疗具有重要意义。未来的研究应将发病机制与危险因素作为可干预的靶点,探索有效的治疗策略,以减少CMBs的发生。

NOTES

*通讯作者。

参考文献

[1] Buch, S., Cheng, Y.N., Hu, J., et al. (2017) Determination of Detection Sensitivity for Cerebral Microbleeds Using Susceptibility-Weighted Imaging. NMR in Biomedicine, 30.
https://doi.org/10.1002/nbm.3551
[2] Schrag, M. and Greer, D.M. (2014) Clinical Associations of Cerebral Microbleeds on Magnetic Resonance Neuroimaging. Journal of Stroke and Cerebrovascular Diseases, 23, 2489-2497.
https://doi.org/10.1016/j.jstrokecerebrovasdis.2014.07.006
[3] Shoamanesh, A., Catanese, L., Romero, J.R., et al. (2016) High Prevalence of Cerebral Microbleeds in Inner City Young Stroke Patients. Journal of Stroke and Cerebrovascular Diseases, 25, 733-738.
https://doi.org/10.1016/j.jstrokecerebrovasdis.2015.11.022
[4] Shoamanesh, A., Kwok, C.S., Lim, P.A., et al. (2013) Postthrombolysis Intracranial Hemorrhage Risk of Cerebral Microbleeds in Acute Stroke Patients: A Systematic Review and Meta-Analysis. International Journal of Stroke, 8, 348-356.
https://doi.org/10.1111/j.1747-4949.2012.00869.x
[5] Shahjouei, S., Tsivgoulis, G., Singh, M., et al. (2017) Racial Difference in Cerebral Microbleed Burden among Ischemic Stroke Patients. Journal of Stroke and Cerebrovascular Diseases, 26, 2680-2685.
https://doi.org/10.1016/j.jstrokecerebrovasdis.2017.06.040
[6] Ding, J., Sigurðsson, S., Jónsson, P.V., et al. (2017) Space and Location of Cerebral Microbleeds, Cognitive Decline, and Dementia in the Community. Neurology, 88, 2089-2097.
https://doi.org/10.1212/WNL.0000000000003983
[7] Mendes, A., Noblet, V., Mondino, M., et al. (2020) Association of Cerebral Microbleeds with Cerebrospinal Fluid Alzheimer-Biomarkers and Clinical Symptoms in Early Dementia with Lewy Bodies. International Journal of Geriatric Psychiatry.
https://doi.org/10.1002/gps.5485
[8] Ungvari, Z., Tarantini, S., Kirkpatrick, A.C., et al. (2017) Cerebral Microhemorrhages: Mechanisms, Consequences, and Prevention. American Journal of Physiology: Heart and Circulatory Physiology, 312, H1128-H1143.
https://doi.org/10.1152/ajpheart.00780.2016
[9] Akoudad, S., Portegies, M.L., Koudstaal, P.J., et al. (2015) Cerebral Microbleeds Are Associated with an Increased Risk of Stroke: The Rotterdam Study. Circulation, 132, 509-516.
https://doi.org/10.1161/CIRCULATIONAHA.115.016261
[10] Lyu, L., Shen, J., Zeng, C., et al. (2020) Cerebral Microbleeds Are Associated with Blood Pressure Levels in Individuals with Hypertension. Clinical and Experimental Hypertension, 42, 328-334.
https://doi.org/10.1080/10641963.2019.1665673
[11] Graff-Radford, J., Botha, H., Rabinstein, A.A., et al. (2019) Cerebral Microbleeds: Prevalence and Relationship to Amyloid Burden. Neurology, 92, e253-e262.
https://doi.org/10.1212/WNL.0000000000006780
[12] Yamada, S., Saiki, M., Satow, T., et al. (2012) Periventricular and Deep White Matter Leukoaraiosis Have a Closer Association with Cerebral Microbleeds than Age. European Journal of Neurology, 19, 98-104.
https://doi.org/10.1111/j.1468-1331.2011.03451.x
[13] Poels, M.M., Vernooij, M.W., Ikram, M.A., et al. (2010) Prevalence and Risk Factors of Cerebral Microbleeds: An Update of the Rotterdam Scan Study. Stroke, 41, S103-S106.
https://doi.org/10.1161/STROKEAHA.110.595181
[14] Sumbria, R.K., Grigoryan, M.M., Vasilevko, V., et al. (2018) Aging Exacerbates Development of Cerebral Microbleeds in a Mouse Model. Journal of Neuroinflammation, 15, 69.
https://doi.org/10.1186/s12974-018-1092-x
[15] Farrall, A.J. and Wardlaw, J.M. (2009) Blood-Brain Barrier: Ageing and Microvascular Disease—Systematic Review and Meta-Analysis. Neurobiology of Aging, 30, 337-352.
https://doi.org/10.1016/j.neurobiolaging.2007.07.015
[16] Yubi, T., Hata, J., Ohara, T., et al. (2018) Prevalence of and Risk Factors for Cerebral Microbleeds in a General Japanese Elderly Community. Neurology Clinical Practice, 8, 223-231.
https://doi.org/10.1212/CPJ.0000000000000464
[17] Wiegman, A.F., Meier, I.B., Schupf, N., et al. (2014) Cerebral Microbleeds in a Multiethnic Elderly Community: Demographic and Clinical Correlates. Journal of the Neurological Sciences, 345, 125-130.
https://doi.org/10.1016/j.jns.2014.07.024
[18] Bu, G. (2009) Apolipoprotein E and Its Receptors in Alzheimer’s Disease: Pathways, Pathogenesis and Therapy. Nature Reviews: Neuroscience, 10, 333-344.
https://doi.org/10.1038/nrn2620
[19] Mahley, R.W. (1988) Apolipoprotein E: Cholesterol Transport Protein with Expanding Role in Cell Biology. Science, 240, 622-630.
https://doi.org/10.1126/science.3283935
[20] Ingala, S., Mazzai, L., Sudre, C.H., et al. (2020) The Relation between APOE Genotype and Cerebral Microbleeds in Cognitively Unimpaired Middle- and Old-Aged Individuals. Neurobiology of Aging, 95, 104-114.
https://doi.org/10.1016/j.neurobiolaging.2020.06.015
[21] Groot, C., Sudre, C.H., Barkhof, F., et al. (2018) Clinical Phenotype, Atrophy, and Small Vessel Disease in APOE ε2 Carriers with Alzheimer Disease. Neurology, 91, e1851-e1859.
https://doi.org/10.1212/WNL.0000000000006503
[22] Li, H.Q., Cai, W.J., Hou, X.H., et al. (2020) Genome-Wide Association Study of Cerebral Microbleeds on MRI. Neurotoxicity Research, 37, 146-155.
https://doi.org/10.1007/s12640-019-00073-3
[23] Joutel, A., Bousser, M.G., Biousse, V., et al. (1993) A Gene for Familial Hemiplegic Migraine Maps to Chromosome 19. Nature Genetics, 5, 40-45.
https://doi.org/10.1038/ng0993-40
[24] Ryan, N.S., Bastos-Leite, A.J., Rohrer, J.D., et al. (2012) Cerebral Microbleeds in Familial Alzheimer’s Disease. Brain, 135, e201.
https://doi.org/10.1093/brain/awr126
[25] Elmståhl, S., Ellström, K., Siennicki-Lantz, A., et al. (2019) Association between Cerebral Microbleeds and Hypertension in the Swedish General Population “Good Aging in Skåne” Study. Journal of Clinical Hypertension (Greenwich, Conn), 21, 1099-1107.
https://doi.org/10.1111/jch.13606
[26] Jia, Z., Mohammed, W., Qiu, Y., et al. (2014) Hypertension Increases the Risk of Cerebral Microbleed in the Territory of Posterior Cerebral Artery: A Study of the Association of Microbleeds Categorized on a Basis of Vascular Territories and Cardiovascular Risk Factors. Journal of Stroke and Cerebrovascular Diseases, 23, e5-e11.
https://doi.org/10.1016/j.jstrokecerebrovasdis.2012.12.016
[27] Graff-Radford, J., Lesnick, T., Rabinstein, A.A., et al. (2020) Cerebral Microbleed Incidence, Relationship to Amyloid Burden: The Mayo Clinic Study of Aging. Neurology, 94, e190-e199.
https://doi.org/10.1212/WNL.0000000000008735
[28] Lei, C., Zhong, L., Ling, Y., et al. (2018) Blood Glucose Levels Are Associated with Cerebral Microbleeds in Patients with Acute Ischaemic Stroke. European Neurology, 80, 187-192.
https://doi.org/10.1159/000494990
[29] Matteo Ciccone, M. (2014) Endothelial Function in Pre-Diabetes, Diabetes and Diabetic Cardiomyopathy: A Review. Journal of Diabetes & Metabolism, 5, 4.
https://doi.org/10.4172/2155-6156.1000364
[30] Poggesi, A., Pasi, M., Pescini, F., et al. (2016) Circulating Biologic Markers of Endothelial Dysfunction in Cerebral Small Vessel Disease: A Review. Journal of Cerebral Blood Flow and Metabolism, 36, 72-94.
https://doi.org/10.1038/jcbfm.2015.116
[31] Wilson, D., Ambler, G., Shakeshaft, C., et al. (2018) Cerebral Microbleeds and Intracranial Haemorrhage Risk in Patients Anticoagulated for Atrial Fibrillation after Acute Ischaemic Stroke or Transient Ischaemic Attack (CROMIS-2): A Multicentre Observational Cohort Study. Lancet Neurology, 17, 539-547.
https://doi.org/10.1016/S1474-4422(18)30145-5
[32] Mitaki, S., Nagai, A., Oguro, H., et al. (2017) Serum Lipid Fractions and Cerebral Microbleeds in a Healthy Japanese Population. Cerebrovascular Diseases, 43, 186-191.
https://doi.org/10.1159/000456623
[33] Kroes, J. and Ostwald, R. (1971) Erythrocyte Membranes—Effect of Increased Cholesterol Content on Permeability. Biochimica et Biophysica Acta, 249, 647-650.
https://doi.org/10.1016/0005-2736(71)90147-7
[34] Konishi, M., Iso, H., Komachi, Y., et al. (1993) Associations of Serum Total Cholesterol, Different Types of Stroke, and Stenosis Distribution of Cerebral Arteries. The Akita Pathology Study. Stroke, 24, 954-964.
https://doi.org/10.1161/01.STR.24.7.954
[35] Ding, J., Sigurdsson, S., Garcia, M., et al. (2015) Risk Factors Associated with Incident Cerebral Microbleeds According to Location in Older People: The Age, Gene/Environment Susceptibility (AGES)-Reykjavik Study. JAMA Neurology, 72, 682-688.
https://doi.org/10.1001/jamaneurol.2015.0174
[36] Choudhury, R.P., Rong, J.X., Trogan, E., et al. (2004) High-Density Lipoproteins Retard the Progression of Atherosclerosis and Favorably Remodel Lesions without Suppressing Indices of Inflammation or Oxidation. Arteriosclerosis, Thrombosis, and Vascular Biology, 24, 1904-1909.
https://doi.org/10.1161/01.ATV.0000142808.34602.25
[37] Mulder, M. and Terwel, D. (1998) Possible Link between Lipid Metabolism and Cerebral Amyloid Angiopathy in Alzheimer’s Disease: A Role for High-Density Lipoproteins? Haemostasis, 28, 174-194.
https://doi.org/10.1159/000022429
[38] Miwa, K., Tanaka, M., Okazaki, S., et al. (2016) Increased Total Homocysteine Levels Predict the Risk of Incident Dementia Independent of Cerebral Small-Vessel Diseases and Vascular Risk Factors. Journal of Alzheimer’s Disease, 49, 503-513.
https://doi.org/10.3233/JAD-150458
[39] Ji, Y., Li, X., Teng, Z., et al. (2020) Homocysteine Is Associated with the Development of Cerebral Small Vessel Disease: Retrospective Analyses from Neuroimaging and Cognitive Outcomes. Journal of Stroke and Cerebrovascular Diseases, 29, Article ID: 105393.
https://doi.org/10.1016/j.jstrokecerebrovasdis.2020.105393
[40] Nam, K.W., Kwon, H.M., Jeong, H.Y., et al. (2019) Serum Homocysteine Level Is Related to Cerebral Small Vessel Disease in a Healthy Population. Neurology, 92, e317-e325.
https://doi.org/10.1212/WNL.0000000000006816
[41] Wu, X., Zhang, L., Miao, Y., et al. (2019) Homocysteine Causes Vascular Endothelial Dysfunction by Disrupting Endoplasmic Reticulum Redox Homeostasis. Redox Biology, 20, 46-59.
https://doi.org/10.1016/j.redox.2018.09.021
[42] Beard, R.S., Reynolds, J.J. and Bearden, S.E. (2011) Hyperhomocysteinemia Increases Permeability of the Blood-Brain Barrier by NMDA Receptor-Dependent Regulation of Adherens and Tight Junctions. Blood, 118, 2007-2014.
https://doi.org/10.1182/blood-2011-02-338269
[43] Zhuo, J.M., Portugal, G.S., Kruger, W.D., et al. (2010) Diet-Induced Hyperhomocysteinemia Increases Amyloid-Beta Formation and Deposition in a Mouse Model of Alzheimer’s Disease. Current Alzheimer Research, 7, 140-149.
https://doi.org/10.2174/156720510790691326
[44] Achour, O., Elmtaoua, S., Zellama, D., et al. (2016) The C677T MTHFR Genotypes Influence the Efficacy of B9 and B12 Vitamins Supplementation to Lowering Plasma Total Homocysteine in Hemodialysis. Journal of Nephrology, 29, 691-698.
https://doi.org/10.1007/s40620-015-0235-8
[45] Ge, L., Niu, G., Han, X., et al. (2011) Aspirin Treatment Increases the Risk of Cerebral Microbleeds. Canadian Journal of Neurological Sciences, 38, 863-868.
https://doi.org/10.1017/S0317167100012440
[46] Jia, C., Wei, C., Hu, M., et al. (2018) Correlation between Antiplatelet Therapy in Secondary Prevention of Acute Cerebral Infarction and Cerebral Microbleeds: A Susceptibility-Weighted Imaging (SWI) Study. Journal of X-Ray Science and Technology, 26, 623-633.
https://doi.org/10.3233/XST-17361
[47] Cheng, Y., Liu, J., Zhang, S., et al. (2018) Prior Antithrombotic Therapy Is Associated with Cerebral Microbleeds in Ischemic Stroke Patients with Atrial Fibrillation and/or Rheumatic Heart Disease. Frontiers in Neurology, 9, 1184.
https://doi.org/10.3389/fneur.2018.01184
[48] Jung, Y.H., Jang, H., Park, S.B., et al. (2020) Strictly Lobar Microbleeds Reflect Amyloid Angiopathy Regardless of Cerebral and Cerebellar Compartments. Stroke, 51, 3600-3607.
https://doi.org/10.1161/STROKEAHA.119.028487
[49] Wardlaw, J.M., Smith, E.E., Biessels, G.J., et al. (2013) Neuroimaging Standards for Research into Small Vessel Disease and Its Contribution to Ageing and Neurodegeneration. Lancet Neurology, 12, 822-838.
https://doi.org/10.1016/S1474-4422(13)70124-8
[50] Zhou, Y.N., Gao, H.Y., Zhao, F.F., et al. (2020) The Study on Analysis of Risk Factors for Severity of White Matter Lesions and Its Correlation with Cerebral Microbleeds in the Elderly with Lacunar Infarction. Medicine (Baltimore), 99, e18865.
https://doi.org/10.1097/MD.0000000000018865