{'fraction_non_alphanumeric': 0.023366484867928562, 'fraction_numerical': 0.021762378355256122, 'mean_word_length': 5.357239972807614, 'pattern_counts': {'":': 0, '<': 1, '<?xml version=': 0, '>': 0, 'https://': 0, 'lorem ipsum': 0, 'www.': 0, 'xml': 0}, 'pii_count': 0, 'substrings_counts': 0, 'word_list_counts': {'cursed_substrings.json': 2, 'profanity_word_list.json': 0, 'sexual_word_list.json': 0, 'zh_pornsignals.json': 0}}
Cerebral Microbleeds: Their Associated Factors, Radiologic Findings, and Clinical Implications

Cerebral microbleeds (CMBs) are tiny, round dark-signal lesions that are most often detected on gradient-echo MR images. CMBs consist of extravasations of blood components through fragile microvascular walls characterized by lipohyalinosis and surrounding macrophages. The prevalence of CMBs in elderly subjects with no history of cerebrovascular disease is around 5%, but is much higher in patients with ischemic or hemorrhagic stroke. Development of CMBs is closely related to various vascular risk factors; in particular, lobar CMBs are thought to be associated with cerebral amyloid angiopathy. The presence of CMBs has been hypothesized to reflect cerebral-hemorrhage-prone status in patients with hypertension or amyloid microangiopathy. Stroke survivors with CMBs have been consistently found to have an elevated risk of subsequent hemorrhagic stroke or an antithrombotic-related hemorrhagic complication, although studies have failed to establish a link between CMBs and hemorrhagic transformation after thrombolytic treatment. A large prospective study is required to clarify the clinical significance of CMBs and their utility in a decision-making index.


Introduction
The term cerebral microbleed (CMB) refers to small, round dark-signal lesions detected by T2*-weighted or gradient-echo (GRE) magnetic resonance imaging (MRI). 1 CMBs were introduced to stroke physicians in the late 1990s and early 2000s after development of MRI techniques sensitive to paramagnetic effects. 2 The clinical significance of CMBs has been actively investigated, especially in the stroke field and more recently in studies on cognitive impairment and aging. 3 Histological investigation has shown that CMBs are tiny foci containing hemosiderin-laden macrophages and abnormal microvessels showing fibrohyalinosis. 4,5 Clinical cases with frank symptoms caused by CMBs are uncommon. Because CMBs are manifestations of fo-cal extravascular leakage of blood components, however, investigators have suggested that accumulation of CMBs reflects a bleeding-prone status in individuals with an elevated risk of cerebral hemorrhage. Clinical studies have found strong associations between CMBs and chronic hypertension and low cholesterol levels, 6,7 and between the proximity and volume of CMBs and those of subsequent intracerebral hemorrhage (ICH). 8,9 Longitudinal studies have found that CMBs are linked to subsequent hemorrhagic stroke in stroke survivors, 10 and suggested that CMBs are related to antithrombotic-related hemorrhage. 11,12 In this review, we discuss fundamental findings of CMBs, and the clinical implications of these observations for the field of cerebrovascular disease.

Visualization and detection of cerebral microbleeds
GRE sequences are more sensitive to susceptibility effects than are classical MRI sequences. Unlike classical T2-weighted imaging or echo-planar sequences, GRE sequences maximize the paramagnetic effects of blood components such as hemosiderin, deoxyhemoglobin, and ferritin. 2,13 Due to the dephasing of MRI signals, GRE sequences tend to exaggerate lesion sizes. Therefore, sub-millimeter CMBs appear as signal-loss lesions of several millimeters, a phenomenon referred to as the blooming effect.
Susceptibility-weighted imaging (SWI) is a MRI sequence that maximizes sensitivity to magnetic susceptibility effects. 14,15 SWI requires more time than does GRE, and also requires postprocessing, but because SWI accentuates the magnetic properties of tissues, it enables visualization of areas such as CMBs containing deoxygenated blood substances. 16 SWI permits visualization of a greater number of CMBs than can be seen with conventional GRE sequences, but the clinical implications of this increased sensitivity are not yet fully understood ( Figure 1). 17 Since CMBs are primarily a radiologic concept, their sizes and shapes are dependent upon the parameters of the GRE sequence. Visualization of CMBs is thought to be influenced by pulse sequence, sequence parameters, spatial resolution, mag-netic field strength, and post-processing of images. 1 Thus, lesions due to old parenchymal hemorrhage, cortical or deep-seated mineralizations, or vascular malformations potentially all can be misinterpreted as CMBs. Small cortical vessels, partial volume effects of the cerebellar cortex, and cavernous hemangiomas also should be considered ( Figure 2). 21 Moreover, multifocal bleeding spots caused by diffuse axonal injury are virtually impossible to distinguish from cortico-subcortical CMBs.
Comparison of magnetic field strength in detection of CMBs revealed 0.5 more microbleeds on average could be observed using a 3.0 Tesla MRI compared to a 1.5 Tesla unit (2.1 in 3.0 T and 1.6 in 1.5 T). 18 No universal standard MR parameters exist for the detection of CMBs, and in addition, the definition of CMB size also varies. In published reports, the lower limit of CMB size is usually ≤ 2 mm, and the upper limit is usually between 5 and 10 mm. 19 Greenberg et al. reported that the size distribution of microbleeds and macrobleeds is bimodal, and proposed that the most appropriate cut-off point between them is 5.7 mm. 20 Those researchers suggested elsewhere that an upper size limitation is impractical, and that instead, a more desirable approach is to carefully exclude CMB-mimicking lesions such as those described above. 1 Other investigators have proposed a specified rating scale for CMBs, the Microbleed Anatomical Rating Scale. 21 In our view, setting an appropriate upper-size limitation, and determination of intra-and inter-rater

Pathology of cerebral microbleeds
Pathologic-radiologic correlation studies have revealed that CMBs are focal accumulations of hemosiderin adjacent to abnormal blood vessels demonstrating fibrolipohyalinosis or amyloid microangiopathy. 4,5 CMBs usually develop adjacent to capillaries, small arteries, or arterioles; hemosiderin-laden macrophages are usually present. 22 A recent pathological investigation of CMBs in patients with cerebral amyloid angiopathy demonstrated extravasation of blood and hemosiderin through vulnerable vascular walls, with β-amyloid pigmentation and surrounding inflammation. 23 These findings suggest that CMBs are the radiologic correlates of extravasation of blood components through injured or fragile vascular walls, or of frank small hemorrhage spots. In the context of cerebral amyloid angiopathy, Greenberg et al. suggested that increased vascular wall thickness was indicative of microbleeds. 20 Because blooming artifact on GRE images exaggerates the size of CMBs, it has been proposed that the actual size of hemosiderin deposition is too small to cause apparent neurological deficit. 22 Selected cases, however, have suggested that CMBs can cause neurological symptoms and signs. 24,25 Prevalence and associated factors for cerebral microbleeds

Cerebral microbleeds in healthy subjects
In subjects without a history of cerebrovascular disease, the prevalence of CMBs was reported to be between 3-7%. [26][27][28][29][30][31][32][33] Significant associations have been consistently reported between CMBs and advanced age, as well as hypertension. 33 In contrast, association between CMBs and diabetes has been inconsistent across published reports. 19,34,35 The Rotterdam Scan Study described CMBs in 1,062 older subjects. 39 In a group of patients with mean age 69.6 years and a hypertension prevalence of 71.9%, CMBs were detected in 17.8% of patients aged 60-69, in 31.3% of patients aged 70-79, and in 38.3% of patients aged 80-97. The prevalence of multiple CMBs was also found to increase significantly with age. 37 A single-hospital-based cross-sectional study performed in Japan found no deep-seated CMBs in subject younger than 40 years old. 38 The Rotterdam Scan Study also noted a strong association of very low serum cholesterol levels ( < 4.42 mmol/L versus higher values) with the presence of strictly lobar microbleeds, 39 an observation consistent with our earlier findings. 7

Cerebral microbleeds in ischemic stroke patients
The reported prevalence of CMBs in ischemic stroke patients varies significantly (35%-71%; Table 1). 27,38,[40][41][42][43] This variability may be due to the heterogeneity of ischemic stroke per se, or to differences in recruited populations, rating strategies, and MRI parameters. Two studies investigating CMB frequency in different ischemic stroke subtypes found that CMBs were less frequent in cardioembolic stroke than in atherothrombotic stroke or lacunar stroke. 28,44 Accumulation of sublethal ischemic injuries in brain parenchyma is thought to differ in atherothrombotic stroke and cardioembolic stroke, 45 suggesting that the relationship of CMBs and stroke subtype in turn may reflect a different degree of fragility of vascular walls. A recent study found that the absolute number of CMBs, as well as variability indices of blood pressure (including coefficient of variance and successive variation), were elevated in cases of ischemic stroke with CMBs. 46 Another analysis of patients with ischemic stroke reported that serum uric acid level was associated in a dose-dependent manner with the presence of CMBs, but only in hypertensive patients. 47 Complex interactions have been observed between chronic medical conditions and individual serologic markers in development of CMBs, such as in ischemic stroke patients with chronic kidney disease. Proteinuria and impaired kidney function has been linked to with small vessel disease in the brain and to CMBs. [48][49][50][51] We further analyzed this issue, and found that chronic kidney disease is independently associated with cerebral microbleeds in patients without diabetes, but not in patients with diabetes. 52

Cerebral microbleeds in hemorrhagic stroke patients
The frequency of CMBs in hemorrhagic stroke patients has been consistently higher than that that in ischemic stroke patients, reaching 50% to 80%. 4,8,[53][54][55] (Table 2; Figure 3) The detection rate of CMBs is higher in Asian populations, which may reflect a higher prevalence of the hemorrhagic stroke subtype in this ethnic group. 56 CMBs also have been reported to be associated with hematoma volume, regardless of perihematomal edema volume. 9 Patients with cerebral amyloid angiopathy have a higher CMB detection rate, with a preference for a lobar location, 57,58 and the presence of the APOE e4 allele also has been reported to favor a lobar location ( Figure 4). 39,59 Longitudinal changes in the number of cerebral microbleeds The appearance and disappearance of CMBs over time have not been highlighted sufficiently. In an analysis of 237 acute ischemic stroke patients who underwent follow-up imaging,  74 Acute ischemic stroke patients with large artery atherosclerosis or cardioembolic stroke 377 66± 12 29 No incremental hemorrhagic transformation in presence of CMBs Seo (2008) 85 Acute ischemic stroke or TIA patients 255 64± 12 22 CMBs associated with pulse wave velocity Cho (2009) 51 Consecutive acute ischemic stroke patients 152 67± 12 30 MBs associated with impaired kidney function Jeon (2009) 60 Consecutive acute ischemic stroke patients within 24  13% had new CMBs (56 microbleeds in total) in the subsequent GRE images taken on average after 4 days. 60 Long-term follow-up also revealed that 23% of cases demonstrated new CMBs on GRE imaging performed on average over 5.6 years. 61 Development of new CMBs in this study was associated with high blood pressure and the presence of CMBs on baseline imaging. An additional follow-up study published in 2012 reported that the number of CMBs was increased in 54% of cases after 2.5 years. 62 The annual change of CMBs significantly correlated with the number of CMBs on the baseline study. Another inter-  esting finding in that report was that in 15% of patients, CMBs disappeared on the follow-up GREs. Follow-up analyses of CMBs must be interpreted with caution, however, since spatial registration of baseline and follow-up images has not been performed in any published studies. Use of rigorous rating criteria 21 is another important factor necessary for detailed evaluation of the natural history of CMBs, including their development and disappearance.

Clinical implications of cerebral microbleeds
Further understanding of the characteristics of CMBs has generated interest in using detection of CMBs to enable hemorrhagic stroke risk stratification. A number of reports have described the hemorrhagic tendency of CMBs. 24,63,64 A hemorrhagic transformation after multiple embolic infarctions occurred only in the site of the known CMB. 63 A Hong Kong study followed 121 acute ischemic stroke patients, and observed that stroke survivors with CMBs on their initial MRI scans had a higher risk of subsequent hemorrhagic stroke. 10 Hemorrhage counts in initial scans also were found to be pro- portional to the elevated risk of a future hemorrhagic stroke. 54 The increased risk of hemorrhagic stroke conferred by the presence of CMBs was also confirmed in a prospective study of 112 ICH survivors. 65 Furthermore, association between CMBs and larger ICH volume has been suggested by two studies, 9,66 and the predictive value of CMBs in ICH in patients with advanced white matter lesions also has been documented. 67 The spot sign, an enhancing locus of contrast extravasation in a cerebral hematoma, suggesting ongoing bleeding, was reported to be negatively associated with the number of microbleeds; this result is not consistent with previous findings, and bears further investigation. 68 Patients with CMBs also have been reported to be 2.8 times more likely to have a subsequent disabling or fatal stroke. 69 A systematic review published in 2013 concluded that the presence of CMBs in patients with ischemic stroke was associated with greatly increased odds of a subsequent hemorrhagic stroke, but was only modestly linked to recurrence of ischemic stroke. 56 This meta-analysis also noted that the strength of association between CMBs and subsequent ICH risk was modified by ethnic background, with a greater odds ratio in Asian cohorts than in Western cohorts ( Figure 5).
The increased likelihood of cerebral hemorrhage associated with the presence of CMBs may allow prediction of hemorrhagic transformation after ischemic stroke. An earlier report suggested that hemorrhagic transformation after thrombolysis was associated with the presence of CMBs. 70 In a case series of 100 acute ischemic stroke patients with imaging follow-up, the presence of CMBs was indicative of early hemorrhagic transformation. 71 Embolic ischemic strokes occurring at the sites of previous CMBs were noted to become hemorrhagic. 63 Contrary to these positive associations, however, a retrospective study of 279 acute ischemic stroke patients reported no association between CMB count and subsequent hemorrhagic transformation, 72 and in an analysis of 70 stroke patients on thrombolytic treatment, CMBs failed to predict post-thrombolytic hemorrhagic transformation. 73 No relationship between CMBs and prediction of hemorrhagic transformation was observed in a group of 1,034 acute ischemic stroke patients recruited in a single hospital. 74 Finally, a pooled analysis of 570 acute ischemic stroke patients from 13 centers in Europe, North America, and Asia reported that symptomatic ICH after thrombolytic treatment developed regardless of the initial CMB frequency or extent. 75 These studies suggest that for patients in need of thrombolysis, any increased risk of ICH attributable to CMBs is negligible, and unlikely to exceed the benefits from thrombolytic therapy. A subsequent meta-analysis indicated that the published analyses were vulnerable to publication bias and limited power, and identified a trend toward increased odds of symptomatic hemorrhage after thrombolysis (odds ratio, 1.98; 95% confidence interval 0. 90-4.35). 76 At present, identification of CMBs on baseline GRE images should not be considered a contraindication to thrombolysis treatment, but further investigation is warranted on this important issue.
Different findings regarding CMBs and the development of ICH or hemorrhagic transformation may be explained by the different pathological mechanisms of the two phenomena. Essentially, ICH involves rupture of a fragile microvascular wall affected by lipohyalinosis or microaneurysms under the chronic influence of hypertension. 77 As CMBs have histological characteristics similar to those of vasculopathy, a correspondingly similar mechanism may underlie formation of CMBs and ICHs. 22 In contrast, hemorrhagic transformation develops after acute lethal injury in relatively healthy microvasculature.
Considerable interest also exists in utilizing detection of CMBs to estimate the risks of hemorrhagic complications in patients on antithrombotic treatment. Two patients on warfarin were reported to have developed lobar hemorrhages right at the location of CMBs. 64 I CMBs were found to be more frequent and extensive in patients with aspirin-associated ICH. 11,78 In a cross-sectional study, CMBs were more common in patients taking antithrombotic agents, and aspirin use was found to be related to a lobar location. 79 Results from our group demonstrated that patients with anticoagulation-associated hemorrhagic stroke complications are 3.6 times more likely to have CMBs than are age-and sex-matched controls. 12 A recent pooled analysis involving 1,460 hemorrhagic strokes and 3,817 ischemic strokes concluded that the number of CMBs was greater in warfarin users who developed ICH. 80 Given the strong association between CMBs and subsequent ICHs in stroke survivors, a prospective study is needed to assess the predictive power of CMBs in stroke patients on antithrombotic treatment.

Conclusion
CMBs were first identified as tiny, round dark-signal lesions on GRE MRI, and are frequently detected in patients with ischemic or hemorrhagic strokes. Pathological analysis demonstrated that CMBs are extravasations of blood components through fragile microvascular walls, and therefore reflect a bleeding-prone vasculopathy in brain. Several clinical studies have concluded that CMBs are associated with hemorrhagic stroke and hemorrhagic complications following antithrombotic medications. The currently available data do not support the exclusion of thrombolytic treatment based solely on CMB presence or extent. Prospective studies are warranted to confirm the clinical implications of CMBs, and to establish their use for predictive models of hemorrhagic stroke in various situations.