Research Fellow of Japan Society for the Promotion of Science, Tokyo, Japan; Department of Neurology, Graduate School of Medicine, Kyoto, Japan; Department of Neurology, National Cerebral and Cardiovascular Center, Osaka, Japan; Department of Vascular Physiology, Research Institute of National Cerebral and Cardiovascular Center, Osaka, Japan.
Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore; Healthy Longevity Translational Research Program, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
Neurochem Int. 2021 Sep;148:105073. doi: 10.1016/j.neuint.2021.105073. Epub 2021 May 25.
Vascular dementia is the second leading cause of dementia after Alzheimer's disease in the elderly population worldwide. Cerebral microbleeds (CMBs) are frequently observed in MRI of elderly subjects and considered as a possible surrogate marker. The number and location of CMBs reflect the severity of diseases and the underlying pathologies may involve cerebral amyloid angiopathy or hypertensive vasculopathy. Accumulating evidence demonstrated the clinicopathological discrepancies of CMBs, the clinical significance of CMBs associated with other MRI markers of cerebral small vessel disease, cognitive impairments, serum, and cerebrospinal fluid biomarkers. Moreover, emerging evidence has shown that genetic factors and gene-environmental interactions might shed light on the underlying etiologies of CMBs, focusing on blood-brain-barrier and inflammation. In this review, we introduce recent genetic and microbiome studies as a cutting-edge approach to figure out the etiology of CMBs through the "microbe-brain-oral axis" and "microbiome-brain-gut axis." Finally, we propose novel concepts, "microvascular matrisome" and "imbalanced proteostasis," which may provide better perspectives for elucidating the pathophysiology of CMBs and future development of therapeutics for vascular dementia using CMBs as a surrogate marker.
血管性痴呆是全球老年人群中仅次于阿尔茨海默病的第二大痴呆症病因。脑微出血（CMB）在老年患者的 MRI 中经常观察到，被认为是一种可能的替代标志物。CMB 的数量和位置反映了疾病的严重程度，其潜在的病理可能涉及脑淀粉样血管病或高血压性血管病。越来越多的证据表明 CMB 的临床病理差异，CMB 与脑小血管疾病的其他 MRI 标志物、认知障碍、血清和脑脊液生物标志物相关的临床意义。此外，新出现的证据表明，遗传因素和基因-环境相互作用可能揭示 CMB 的潜在病因，重点是血脑屏障和炎症。在这篇综述中，我们介绍了最近的遗传和微生物组研究，这是一种通过“微生物-脑-口腔轴”和“微生物组-脑-肠轴”来阐明 CMB 病因的前沿方法。最后，我们提出了新的概念，“微血管基质组”和“失衡的蛋白质稳态”，这可能为阐明 CMB 的病理生理学以及未来使用 CMB 作为替代标志物治疗血管性痴呆提供更好的视角。
