Development Of Cerebral Microbleeds Research Articles

Development of cerebral microbleeds and its impact on cognitive function in adult patients receiving medical management alone for ischemic moyamoya disease: supplementary analysis of a 5-year prospective cohort

ABSTRACT Objective De novo cerebral microbleeds (CMBs) on T2*-weighted magnetic resonance imaging (MRI) develop over time in adult moyamoya disease (MMD) and are generally associated with a decline in global cognitive function. The present supplementary analysis of a 5-year prospective cohort aimed to elucidate the incidence of an interval increase in CMBs in adult patients receiving medical management alone for ischemic MMD and its impact on cognitive function. Methods Sixty-four patients without misery perfusion in the symptomatic cerebral hemispheres at inclusion who did not experience any further ischemic symptoms or new hemorrhagic events during a 5-year follow-up period underwent T2*-weighted MRI and five kinds of neuropsychologic tests at inclusion and the end of the 5-year follow-up. Results When T2*-weighted MRI was compared between inclusion and the end of the 5-year follow-up, 10 patients (15%) had an interval increase in CMBs in the symptomatic cerebral hemisphere at inclusion. The scores from two kinds of neuropsychologic tests significantly deteriorated at the end of the 5-year follow-up compared with those at inclusion in patients with an interval increase in CMBs, whereas the scores of four kinds of neuropsychologic tests significantly improved at the end of the 5-year follow-up compared with those at inclusion in patients without interval increases in CMBs, asymptomatic ischemic lesions, or angiographic disease progression. Conclusions The incidence of an interval increase in CMBs was 15% per 5 years in adult patients receiving medical management alone for ischemic MMD, and this increase was associated with a decline in cognitive decline.

Development of cerebral microbleeds in patients with cerebral hyperperfusion following carotid endarterectomy and its relation to postoperative cognitive decline.

A primary cause of cognitive decline after carotid endarterectomy (CEA) is cerebral injury due to cerebral hyperperfusion. However, the mechanisms of how cerebral hyperperfusion induces cerebral cortex and white matter injury are not known. The presence of cerebral microbleeds (CMBs) on susceptibility-weighted imaging (SWI) is independently associated with a decline in global cognitive function. The purpose of this prospective observational study was to determine whether cerebral hyperperfusion following CEA leads to the development of CMBs and if postoperative cognitive decline is related to these developed CMBs. During the 27-month study period, patients who underwent CEA for ipsilateral internal carotid artery stenosis (≥ 70%) also underwent SWI and neuropsychological testing before and 2 months after surgery, as well as quantitative brain perfusion SPECT prior to and immediately after surgery. According to quantitative brain perfusion SPECT and SWI before and after surgery, 12 (16%) and 7 (9%) of 75 patients exhibited postoperative cerebral hyperperfusion and increased CMBs in the cerebral hemisphere ipsilateral to surgery, respectively. Cerebral hyperperfusion was associated with an increase in CMBs after surgery (logistic regression analysis, 95% CI 5.08-31.25, p < 0.0001). According to neuropsychological assessments before and after surgery, 10 patients (13%) showed postoperative cognitive decline. Increased CMBs were associated with cognitive decline after surgery (logistic regression analysis, 95% CI 6.80-66.67, p < 0.0001). Among the patients with cerebral hyperperfusion after surgery, the incidence of postoperative cognitive decline was higher in those with increased CMBs (100%) than in those without (20%; p = 0.0101). Cerebral hyperperfusion following CEA leads to the development of CMBs, and postoperative cognitive decline is related to these developed CMBs.

Cerebral microbleeds development after stroke thrombolysis: A secondary analysis of the THAWS randomized clinical trial

Background and aim We determined to investigate the incidence and clinical impact of new cerebral microbleeds after intravenous thrombolysis in patients with acute stroke. Methods The THAWS was a multicenter, randomized trial to study the efficacy and safety of intravenous thrombolysis with alteplase in patients with wake-up stroke or unknown onset stroke. Prescheduled T2*-weighted imaging assessed cerebral microbleeds at three time points: baseline, 22–36 h, and 7–14 days. Outcomes included new cerebral microbleeds development, modified Rankin Scale (mRS) ≥3 at 90 days, and change in the National Institutes of Health Stroke Scale (NIHSS) score from 24 h to 7 days. Results Of all 131 patients randomized in the THAWS trial, 113 patients (mean 74.3 ± 12.6 years, 50 female, 62 allocated to intravenous thrombolysis) were available for analysis. Overall, 46 (41%) had baseline cerebral microbleeds (15 strictly lobar cerebral microbleeds, 14 mixed cerebral microbleeds, and 17 deep cerebral microbleeds). New cerebral microbleeds only emerged in the intravenous thrombolysis group (seven patients, 11%) within a median of 28.3 h, and did not additionally increase within a median of 7.35 days. In adjusted models, number of cerebral microbleeds (relative risk (RR) 1.30, 95% confidence interval (CI): 1.17–1.44), mixed distribution (RR 19.2, 95% CI: 3.94–93.7), and cerebral microbleeds burden ≥5 (RR 44.9, 95% CI: 5.78–349.8) were associated with new cerebral microbleeds. New cerebral microbleeds were associated with an increase in NIHSS score ( p = 0.023). Treatment with alteplase in patients with baseline ≥5 cerebral microbleeds resulted in a numerical shift toward worse outcomes on ordinal mRS (median [IQR]; 4 [3–4] vs. 0 [0–3]), compared with those with &lt;5 cerebral microbleeds (common odds ratio 17.1, 95% CI: 0.76–382.8). The association of baseline ≥5 cerebral microbleeds with ordinal mRS score differed according to the treatment group ( p interaction = 0.042). Conclusion New cerebral microbleeds developed within 36 h in 11% of the patients after intravenous thrombolysis, and they were significantly associated with mixed-distribution and ≥5 cerebral microbleeds. New cerebral microbleeds development might impede neurological improvement. Furthermore, cerebral microbleeds burden might affect the effect of alteplase.

Brain Endothelial Erythrophagocytosis and Hemoglobin Transmigration Across Brain Endothelium: Implications for Pathogenesis of Cerebral Microbleeds

Peripheral endothelial cells are capable of erythrophagocytosis, but data on brain endothelial erythrophagocytosis are limited. We studied the relationship between brain endothelial erythrophagocytosis and cerebral microhemorrhage, the pathological substrate of MRI-demonstrable cerebral microbleeds. To demonstrate the erythrophagocytic capability of the brain endothelium, we studied the interactions between brain endothelial cells and red blood cells exposed to oxidative stress in vitro, and developed a new in vitro cerebral microbleeds model to study the subsequent passage of hemoglobin across the brain endothelial monolayer. Using multiple approaches, our results show marked brain endothelial erythrophagocytosis of red blood cells exposed to oxidative stress compared with control red blood cells in vitro. This brain endothelial erythrophagocytosis was accompanied by passage of hemoglobin across the brain endothelial monolayer with unaltered monolayer integrity. In vivo and confocal fluorescence microscopy studies confirmed the extravasation of RBC exposed to oxidative stress across brain endothelium. These findings, demonstrating erythrophagocytosis mediated by the brain endothelial monolayer and the subsequent passage of iron-rich hemoglobin in vitro and RBC in vivo, may have implications for elucidating mechanisms involved in the development of cerebral microbleeds that are not dependent on disruption of the microvasculature.

Incident risk and progression of cerebral microbleeds in healthy adults: a multi-occasion longitudinal study

Decline in cerebrovascular health complicates brain aging, and development of cerebral microbleeds (CMBs) is one of its prominent indicators. In a large sample of healthy adults (N = 251, age 18–78 years at baseline, 70% women), the contributions of chronological age and vascular health indicators to the risk of developing a CMB, as well as the change in CMB size and iron content, were examined in a prospective 8-year longitudinal study using susceptibility weighted imaging. Twenty-six persons (10.4%), most of whom were 40 years of age or older, had at least 1 CMB during the study. Older age was associated with greater risk for developing a CMB (odds ratio 1.03). Elevation of combined metabolic syndrome indicators (b = 0.15, p = 0.001) conferred additional risk (odds ratio 1.02). High body mass index exacerbated the risk associated with poor vascular health (b = 0.75, p < 0.001) and frequent exercise mitigated it (b = −0.46, p = 0.03). CMBs persisted over time, yet their volume decreased (mean change = −0.32, p < 0.05), whereas their relative iron content remained stable (mean change = −0.14, p = 0.05). We conclude that although developing a CMB is unlikely during normal aging, risk increases with declining vascular health, which is modifiable via behavioral and pharmaceutical intervention.

Abstract WMP75: Age- and Sex-Specific Development of Cerebral Microbleeds in a Mouse Model

Cerebral microbleeds (CMB), a common MRI finding that may predict intracerebral hemorrhage, are based on a pathological substrate of cerebral microhemorrhages (CMH). Recent clinical and laboratory studies have demonstrated the importance of systemic inflammation in the development of CMB. The effects of age and sex on CMB development have not been well-defined. In the current study, we hypothesized that there are age and sex differences in the pathogenesis of inflammation-induced CMB in mice. We studied young (3 months, n=39) and old (17 months, n=25) male and female C57BL/6 mice injected with LPS (1mg/kg, i.p.) or saline at 0, 6, and 24h. 7 days after first LPS injection, cardiac perfusion was performed, mice were sacrificed, and brains were harvested. CMH grossly visible on the brain surface were examined and 40 μm brain sections were prepared and stained with hematoxylin and eosin (H&amp;E) to estimate the acute/fresh parenchymal CMH number, size and total area in young versus old mice. No surface CMH and negligible H&amp;E-positive parenchymal CMH were observed in young and old saline controls. LPS treatment significantly (p&lt;0.001) increased the development of surface CMH in aged male mice (mean±SEM=17±6 surface microhemorrhages/brain) compared to young male mice (2.8±1.5 surface microhemorrhages/brain). Negligible H&amp;E-positive CMH were observed in LPS-treated young mice. Aging increased the number (1.3±0.7 vs 0.09±0.05 CMH/section; p&lt;0.05), size (4510±1431 vs 471±188 μm 2 ; p&lt;0.001) and area (0.03±0.02 vs 0.0005±0.0003 % total area; p&lt;0.01) of H&amp;E-positive parenchymal CMH in old LPS-treated male mice compared to young LPS-treated male mice. Consistent with previous studies from our lab, H&amp;E-positive CMH were predominantly located in the cerebellum compared to the cortex and sub-cortex. No significant differences were observed in LPS-induced surface or parenchymal CMH development between young and aged female mice. In summary, effects of aging on LPS-induced microbleed development are demonstrable in males. Aging makes the brain more susceptible to inflammation-induced cerebral microbleeds in male mice.

Associations of Durations of Antiplatelet Use and Vascular Risk Factors with the Presence of Cerebral Microbleeds

The association of the presence of cerebral microbleeds with antiplatelet use remains controversial. Long durations of antiplatelet use and vascular risk factors may have a greater impact on the development of cerebral microbleeds than short durations. The aim of this study was to determine whether the durations of antiplatelet use and vascular risk factors were associated with the presence of cerebral microbleeds in patients with ischemic cerebrovascular disease, who are frequently treated with antiplatelet agents. Two hundred twenty outpatients with ischemic cerebrovascular lesions (eg, cerebral infarcts and/or white matter lesions) detected by magnetic resonance imaging were examined. Patients with a history of cerebral hemorrhage were excluded. Cerebral microbleeds were observed in 71 (32.3%) patients. Deep or infratentorial microbleeds and strictly lobar microbleeds were observed in 53 (24.1%) patients and 18 (8.2%) patients, respectively. Aspirin use (odds ratio, 2.14; 95% confidence interval [CI], 1.02-4.73; P = .04) and a long duration (≥10 years) of aspirin use (odds ratio, 3.75; 95% CI, 1.31-10.86; P = .01) were significantly associated with deep or infratentorial microbleeds in the crude analysis, but this became nonsignificant after adjustment for hypertension and other confounding factors. The prevalence of antiplatelet use was significantly higher in the patients with hypertension than in those without hypertension (72.5% versus 49.1%, P = .002). Hypertension (odds ratio, 2.50; 95% CI, 1.11-6.41; P = .04) was significantly associated with the development of deep or infratentorial microbleeds even after adjustment for confounding factors and the association increased with the duration of hypertension. In conclusion, we found a significant association between aspirin use and deep or infratentorial microbleeds, but this association may reflect the presence of hypertension as a confounding factor.

MRI Detection of New Microbleeds in Patients With Ischemic Stroke

Little is known about the development of cerebral microbleeds in patients with ischemic stroke. We studied the incidence of new microbleeds in a cohort of patients with ischemic stroke or transient ischemic attack screened for microbleeds at baseline. Twenty-one surviving patients with ischemic stroke or transient ischemic attack were followed up after a mean interval of 5.5 years with repeat MRI and clinical assessment. Predictors of new microbleeds were tested in logistic regression. Of patients with microbleeds at baseline, 50% had new microbleeds at follow-up compared with 8% of those without baseline microbleeds (P=0.047). The presence of microbleeds at baseline predicted new microbleeds (OR, 12; 95% CI, 1.02 to 141.34; P=0.048), as did mean systolic blood pressure (OR, 1.28 per unit increase; 95% CI, 1.23 to 1.33; P<0.001). One patient had a stroke (intracerebral hemorrhage) during follow-up. Patients with ischemic stroke or transient ischemic attack are at risk of developing new microbleeds over 5.5 years, despite most surviving patients remaining clinically stable. Systolic blood pressure is the strongest predictor of microbleed development; better control of hypertension may help prevent new microbleed formation.

Rapid appearance of new cerebral microbleeds after acute ischemic stroke

It is unknown whether the development of cerebral microbleeds (MBs), small areas of signal loss on T2*-weighted gradient-echo imaging (GRE), follows a slow or a rapid process. We hypothesized that MBs may develop rapidly after certain critical events, such as strokes, and investigated the frequency, location, and factors associated with the formation of new MBs after acute ischemic stroke. We retrospectively examined 237 consecutive acute ischemic stroke patients who underwent MRI within 24 hours and follow-up MRI during the week after symptom onset. We defined new MBs as MBs that newly appeared on follow-up GRE outside the infarcted area. We examined the association of new MBs with demographics, risk factors, laboratory data, baseline MBs, and small vessel disease (SVD; leukoaraiosis and lacunar infarctions). Seventy-five patients (31.6%) had baseline MBs, and 30 (12.7%) developed new MBs. Multiple logistic regression analysis indicated that the presence of baseline MBs (odds ratio [OR] 5.72, 95% confidence interval [CI] 2.12-15.42, p = 0.001) and severe SVD (OR 2.94, 95% CI 1.12-7.77, p = 0.03) independently predicted the development of new MBs. Of the 56 new MBs, 29 (51.8%) appeared in the lobar location, 17 (30.4%) appeared in the deep location, and 10 (17.9%) appeared in the infratentorial location. This study suggests that new microbleeds (MBs) can develop rapidly after acute ischemic stroke. Baseline MBs and severe small vessel disease are predictors for the development of new MBs. Further studies will be needed to investigate the clinical implications and mechanisms of these findings.