Review Cerebral microbleeds: Beyond the macroscope Maud Pe ´ trault 1 , Barbara Casolla 2 , Thavarak Ouk 1 , Charlotte Cordonnier 2 and Vincent Be ´re ´zowski 1,3 Abstract While being increasingly recognized in clinical routine, brain microbleeds remain a puzzling finding for physicians. These small dot-like lesions are thought to be old perivascular collections of hemosiderin deposits. They can be found in different neurological settings such as cerebrovascular or neurodegenerative diseases. While their microscopic size would suggest considering these lesions as anecdotal, they are now regarded as biomarkers of severity of an underlying cerebrovascular disease. Their natural history and the interactions with surrounding brain cells remain unknown. However, their presence may impact therapeutic decisions. Deciphering the biological mechanisms leading to, or following microbleeds would enable us to address a key question: do microbleeds arise and impact the surrounding parenchyma like a miniature version of intracerebral hemorrhages or do they represent a different kind of injury? We hereby discuss, based on both clinical and experimental literature, the gap between the definition of microbleeds coming from neuroimaging and the pathophysiological hypotheses raised from histopathological and experimental data. Our analysis supports the need for a convergent effort from clinicians and basic scientists to go beyond the current ‘‘macro’’ view and disclose the cellular and molecular insights of these cerebral hemorrhagic microlesions. Keywords Cerebral microbleed, cerebral amyloid angiopathy, intracerebral hemorrhage, experimental models Received: 4 September 2018; accepted: 13 December 2018 Introduction Cerebral microbleeds (CMBs) are radiological con- structs (Figure 1), observed and defined first on mag- netic resonance imaging (MRI). They are meant to represent perivascular focal collection of hemosiderin deposits, 1 but only a few studies have explored their histological correlates. 2–5 Until now, the literature has mainly focused on the epidemiology of CMBs. Prevalence, associated factors, and natural history of CMBs have been described in both community-based samples and specific clinical set- tings, such as cerebral amyloid angiopathy (CAA) 6 and Alzheimer’s disease (AD). 7 Indeed, CMBs can be found in around 5% of healthy people. Aging is a strong risk factor for CMBs’ presence as well as arterial hyperten- sion. In people with cerebrovascular diseases, CMBs are markers of the severity of the underlying vessel dis- ease; the prevalence of CMBs is around 23% in patients with a first ever ischemic stroke but is around 44% in patients suffering a recurrent ischemic stroke. In the context of intracerebral hemorrhage (ICH), the preva- lence reaches 60%. 7 Recently, CMBs have been described in other clinical conditions than stroke or cognitive decline. They have been associated with disability in a cohort of 445 patients with multiple sclerosis, suggesting that these parenchymal microlesions are not solely the expres- sion of a primary vascular process, but may be triggered by other situations such as neuro-inflammation. 8 Consistently, recent studies have suggested a role of systemic inflammation in CMBs’ development. 9–12 They have also been reported in patients with sepsis 13 or crit- ical illness. 14 1 Department of Medical Pharmacology, Univ Lille, Inserm U1171- Degenerative and Vascular Cognitive Disorders, CHU Lille, Lille, France 2 Department of Neurology, Univ Lille, Inserm U1171-Degenerative and Vascular Cognitive Disorders, CHU Lille, Lille, France 3 Univ Artois, Lens, France Corresponding author: Vincent Be ´re ´zowski, De ´partement de Pharmacologie Me ´dicale, Faculte ´ de Me ´decine—Po ˆ le Recherche, Universite ´ de Lille—Universite ´ d’Artois, Laboratoire Troubles Cognitifs De ´ge ´ne ´ratifs et Vasculaires—Inserm U1171, 1, Place de Verdun, Lille Cedex 59045, France. Email: vincent.berezowski@univ-lille.fr International Journal of Stroke, 0(0) International Journal of Stroke 0(0) 1–8 ! 2019 World Stroke Organization Article reuse guidelines: sagepub.com/journals-permissions DOI: 10.1177/1747493019830594 journals.sagepub.com/home/wso