Brain Microbleeds Research Articles

Brain microbleeds: more evidence, but still a clinical dilemma

Brain microbleeds (BMBs) are a radiological construct that is meant to represent a specific underlying microscopic pathology: perivascular collections of hemosiderin deposits. BMBs may represent two different types of underlying vasculopathies: hypertensive vasculopathy and cerebral amyloid angiopathy. This brief review highlights some recent works discussing their nature, and both their diagnostic and prognostic values. The improvement of detection techniques has modified our perception of BMBs prevalence, which can reach 35% among healthy people compared with 5% when conventional techniques are used. Our knowledge on BMBs is evolving very quickly. The careful study of their anatomical distribution sheds light on their histological significance: deep BMBs may represent hypertensive vasculopathies and lobar ones cerebral amyloid angiopathy. Despite an explosion of publications on BMBs, their diagnostic and prognostic values have only received indirect support and remain to be explored. To date, BMBs should not contraindicate antithrombotic treatment in settings wherein benefits have clearly been demonstrated in clinical trials and meta-analyses. One intriguing field is Alzheimer's disease, in which BMBs may be a missing link between two important theories on the neuropathogenesis of Alzheimer's disease: the amyloid cascade hypothesis and the vascular hypothesis.

Brain microbleeds and Alzheimer’s disease: innocent observation or key player?

Brain microbleeds are small dot-like lesions appearing as hyposignals on gradient echo magnetic resonance sequences. In Alzheimer's disease, brain microbleeds are of special interest as they may play a crucial role in the pathophysiology. They may be a missing link between two important theories on the neuropathogenesis of Alzheimer's disease-the amyloid cascade hypothesis and the vascular hypothesis. Moreover, they may affect the clinical course of the disease and may have therapeutic consequences. The aim of this article is to review available data to understand the meaning of brain microbleeds in clinical terms and underlying pathology in the context of Alzheimer's disease. We also review the available evidence and highlight the pitfalls of our current knowledge on brain microbleeds in the setting of clinical trials design.

Iron quantification of microbleeds in postmortem brain

Brain microbleeds (BMB) are associated with chronic and acute cerebrovascular disease and present a source of pathologic iron to the brain proportional to extravasated blood. Therefore, BMB iron content is potentially a valuable biomarker. We tested noninvasive phase image methods to quantify iron content and estimate true source diameter (i.e., unobscured by the blooming effect) of BMB in postmortem human tissue. Tissue slices containing BMB were imaged using a susceptibility weighted imaging protocol at 11.7T. BMB lesions were assayed for iron content using atomic absorption spectrometry. Measurements of geometric features in phase images were related to lesion iron content and source diameter using a mathematical model. BMB diameter was estimated by image feature geometry alone without explicit relation to the magnetic susceptibility. A strong linear relationship (R(2) = 0.984, P < 0.001) predicted by theory was observed in the experimental data, presenting a tentative standardization curve where BMB iron content in similar tissues could be calculated. In addition, we report BMB iron mass measurements, as well as upper bound diameter and lower bound iron concentration estimates. Our methods potentially allows the calculation of brain iron load indices based on BMB iron content and classification of BMB by size unobscured by the blooming effect.

Reduced severity of strokes in patients with silent brain infarctions

Silent brain infarctions (SBIs), leukoaraiosis (LA), and microbleeds (MBs) are ischaemic silent radiologic abnormalities that act as predictors of subsequent strokes. This study investigated the independent effect of silent radiologic abnormalities on initial stroke severity and short-term outcome. A consecutive series of patients who had their first ischaemic stroke within 72 h of symptom onset were included. Demographic and clinical characteristics were collected on admission, and magnetic resonance imaging was performed to evaluate the ischaemic lesion, SBI, LA, and MB. Factors potentially associated with lower initial stroke severity (admission NIH Stroke Scale 0-5) and good short-term outcome (discharge NIH Stroke Scale 0-5, modified Rankin Scale 0-1) were validated by multivariate analysis. Silent brain infarctions were noted in 82 (45%) of the 182 patients. Although there were no statistically significant differences in stroke subtypes and lesion location, univariate analysis revealed that patients with SBI had reduced stroke severity (P = 0.005) and infarction volume (P = 0.001). After adjusting for covariates, the presence of SBI was independently associated with lower stroke severity and good short-term outcome when the NIH Stroke Scale was used as dependent variable (OR 3.368, 95% CI 1.361-8.332, P = 0.009; OR 3.459, 95% CI 1.227-9.755, P = 0.019, respectively). However, the presence of SBI lost significance when the discharge-modified Rankin Scale was used as dependent variable (P = 0.058). Amongst silent radiologic abnormalities, SBI was the only predictor of reduced stroke severity and infarct volume. Silent brain infarction deserves more attention in evaluating stroke severity.

PATH56 MRI correlates of vascular cognitive impairment: contribution of microbleeds, white matter changes and infarcts in a large hospital-based cross-sectional study

BackgroundThe mechanisms underlying vascular cognitive impairment remain poorly understood. Brain microbleeds may contribute, particularly to executive dysfunction. We investigated the cognitive effects of microbleeds and other neuroimaging markers for cerebrovascular...

Clinical Characteristics by Topographical Distribution of Brain Microbleeds, With a Particular Emphasis on Diffuse Microbleeds

From the perspective of the underlying pathogenesis of primary intracerebral hemorrhage (pICH), the topographical distribution of brain microbleeds (MBs) is divided into the lobar area and the deep brain or infratentorial areas. We investigated clinical features, including ambulatory blood pressure (ABP), of patients with MBs distributed in both areas (diffuse MBs). A total of 124 patients with first-ever acute stroke were enrolled prospectively. Gradient-echo T2∗-weighted magnetic resonance imaging (MRI) was performed using a 1.5-T scanner. Patients were classified into 4 groups: MBs-negative group (n=68), those with MBs in lobar areas (lobar group; n=6), those with MBs in deep or infratentorial areas (deep or infratentorial group; n=31), and those with MBs in both areas (diffuse group; n=19). The admission casual BP (CBP) was recorded in all patients, and ABP was measured in the ischemic stroke patients. There were significant differences in the distribution of MBs (P=.004) among the 6 stroke subtypes. All stroke subtypes except transient ischemic attack had diffuse MBs; pICH had the highest prevalence of it (35%). The severity of white matter hyperintensity (WMH) differed among the 4 groups (P < .0001), with the diffuse group having the highest prevalence of early confluent (47%) and confluent types (21%). ABP and CBP were significantly higher in the deep and diffuse groups compared with the MBs-negative group, but did not differ between the lobar group and the MBs-negative group. Our data suggest that diffuse MBs are associated with hypertensive stroke, elevated BP, and severe WMH. The pathogenesis of diffuse MBs may be related to the more severe microangiopathy involved in hypertensive arteriopathy and cerebral amyloid angiopathy.

Brain microbleeds as a potential risk factor for antiplatelet-related intracerebral haemorrhage: hospital-based, case–control study

BackgroundIntracerebral haemorrhage (ICH) is an uncommon but devastating complication of regular antiplatelet use: identifying high-risk patients before treatment could potentially reduce this hazard. Brain microbleeds on gradient-recalled echo (GRE) T2*-weighted...

PREVALENCE AND SIMULTANEOUS OCCURENCE OF MRI ASSESSED CARDIAC AND CEREBRAL TARGET ORGAN DAMAGE AND MICROALBUMINURIA: 7A.07

Objective: Target organ damage (TOD) contributes importantly to treatment decisions in patients with arterial hypertension. However, available evidence on the prevalence of multiple TOD is limited. We examined the prevalence and simultaneous occurrence of microalbuminuria (MA) and MRI assessed subclinical TOD of the heart and brain in patients with hypertension. Methods: Seventy-three patients with treated hypertension without known overt cardiovascular disease (41 women; 32 men; mean age ± sd, 44.5years ± 13.3; mean systolic blood pressure, 149.1 mmHg ± 23.9; mean diastolic blood pressure, 89.6 mmHg ± 13.1) were enrolled for the evaluation of subclinical TOD at our hypertension referral center. Patients underwent cardiac and cerebral MRI assessment in addition to standard evaluation including 24-h urine collection for MA. MA was used as a marker of renal TOD, increased left ventricular mass index (left ventricular hypertrophy -LVH- male >85.1 g/m2, female >66.9 g/m2) as marker for cardiac TOD, lacunar brain infarcts, periventricular and deep white matter hyperintensities (PWMH and DWMH) and brain-micro-bleeds (BMB) as markers for cerebral TOD. Results: In 49.3% of the patients TOD was observed. The prevalence of involvement of one, two or three organs was 38.8%, 9.0% and 1.5%, respectively. Microalbuminuria was present in 21.9% and LVH in 9.7% of the patients. Cerebral TOD was present in 30.1% of the patients defined as positive for at least one of following cerebral changes: PWMH (20.5%), SWMH (17.8%), lacunar brain infarcts (9.6%) and BMB (5.5%). The most frequent combinations were MA and cerebral TOD: 5.5% and LVH and cerebral TOD: 4.1%. Conclusions: This is the first time that clustering of MRI assessed TOD and MA are reported. Our results show that: (i) subclinical cerebral TOD is a frequently present phenotypic expression of hypertensive TOD; (ii) multiple target organ abnormalities were observed in approximately 10% of the patients, cerebral/renal and cerebral/cardiac being the most frequent combinations. Early recognition of patients developing organ damage with MRI should be further studied regarding treatment outcome since this may select a target population needing more intensive treatment.

Choice of echo time on GRE T2*-weighted MRI influences the classification of brain microbleeds

Choice of echo time on GRE T2*-weighted MRI influences the classification of brain microbleeds

Quantification of punctate iron sources using magnetic resonance phase

Iron-mediated tissue damage is present in cerebrovascular and neurodegenerative diseases and neurotrauma. Brain microbleeds are often present in these maladies and are assuming increasing clinical importance. Because brain microbleeds present a source of pathologic iron to the brain, the noninvasive quantification of this iron pool is potentially valuable. Past efforts to quantify brain iron have focused on content estimation within distributed brain regions. In addition, conventional approaches using "magnitude" images have met significant limitations. In this study, a technique is presented to quantify the iron content of punctate samples using phase images. Samples are modeled as magnetic dipoles and phase shifts due to local dipole field perturbations are mathematically related to sample iron content and radius using easily recognized geometric features in phase images. Phantoms containing samples of a chitosan-ferric oxyhydroxide composite (which serves as a mimic for hemosiderin) were scanned with a susceptibility-weighted imaging sequence at 11.7 T. Plots relating sample iron content and radius to phase image features were compared to theoretical predictions. The primary result is the validation of the technique by the excellent agreement between theory and the iron content plot. This research is a potential first step toward quantification of punctate brain iron sources such as brain microbleeds.

Correlation of hypointensities in susceptibility-weighted images to tissue histology in dementia patients with cerebral amyloid angiopathy: a postmortem MRI study

Neuroimaging with iron-sensitive MR sequences [gradient echo T2* and susceptibility-weighted imaging (SWI)] identifies small signal voids that are suspected brain microbleeds. Though the clinical significance of these lesions remains uncertain, their distribution and prevalence correlates with cerebral amyloid angiopathy (CAA), hypertension, smoking, and cognitive deficits. Investigation of the pathologies that produce signal voids is necessary to properly interpret these imaging findings. We conducted a systematic correlation of SWI-identified hypointensities to tissue pathology in postmortem brains with Alzheimer’s disease (AD) and varying degrees of CAA. Autopsied brains from eight AD patients, six of which showed advanced CAA, were imaged at 3T; foci corresponding to hypointensities were identified and studied histologically. A variety of lesions was detected; the most common lesions were acute microhemorrhage, hemosiderin residua of old hemorrhages, and small lacunes ringed by hemosiderin. In lesions where the bleeding vessel could be identified, β-amyloid immunohistochemistry confirmed the presence of β-amyloid in the vessel wall. Significant cellular apoptosis was noted in the perifocal region of recent bleeds along with heme oxygenase 1 activity and late complement activation. Acutely extravasated blood and hemosiderin were noted to migrate through enlarged Virchow–Robin spaces propagating an inflammatory reaction along the local microvasculature; a mechanism that may contribute to the formation of lacunar infarcts. Correlation of imaging findings to tissue pathology in our cases indicates that a variety of CAA-related pathologies produce MR-identified signal voids and further supports the use of SWI as a biomarker for this disease.

The Microbleed Anatomical Rating Scale (MARS)

Brain microbleeds on gradient-recalled echo (GRE) T2*-weighted MRI may be a useful biomarker for bleeding-prone small vessel diseases, with potential relevance for diagnosis, prognosis (especially for antithrombotic-related bleeding risk), and understanding mechanisms of symptoms, including cognitive impairment. To address these questions, it is necessary to reliably measure their presence and distribution in the brain. We designed and systematically validated the Microbleed Anatomical Rating Scale (MARS). We measured intrarater and interrater agreement for presence, number, and anatomical distribution of microbleeds using MARS across different MRI sequences and levels of observer experience. We studied a population of 301 unselected consecutive patients admitted to our stroke unit using 2 GRE T2*-weighted MRI sequences (echo time [TE] 40 and 26 ms). Two independent raters with different MRI rating expertise identified, counted, and anatomically categorized microbleeds. At TE = 40 ms, agreement for microbleed presence in any brain location was good to very good (intrarater kappa = 0.85 [95% confidence interval (CI) 0.77-0.93]; interrater kappa = 0.68 [95% CI 0.58-0.78]). Good to very good agreement was reached for the presence of microbleeds in each anatomical region and in individual cerebral lobes. Intrarater and interrater reliability for the number of microbleeds was excellent (intraclass correlation coefficient [ICC] = 0.98 [95% CI 0.97-0.99] and ICC = 0.93 [0.91-0.94]). Very good interrater reliability was obtained at TE = 26 ms (kappa = 0.87 [95% CI 0.61-1]) for definite microbleeds in any location. The Microbleed Anatomical Rating Scale has good intrarater and interrater reliability for the presence of definite microbleeds in all brain locations when applied to different MRI sequences and levels of observer experience.

Brain Microbleeds Relate to Higher Ambulatory Blood Pressure Levels in First-Ever Lacunar Stroke Patients

Hypertension is an important risk factor for brain microbleeds (BMBs) in lacunar stroke patients. However, beyond the qualitative label "hypertension," little is known about the association with ambulatory blood pressure (BP) levels. In 123 first-ever lacunar stroke patients we performed 24-hour ambulatory BP monitoring after the acute stroke-phase. We counted BMBs on T2*-weighted gradient-echo MR images. Because a different etiology for BMBs according to location has been suggested, we distinguished between BMBs in deep and lobar location. BMBs were seen in 36 (29.3%) patients. After adjusting for age, sex, number of antihypertensive drugs, asymptomatic lacunar infarcts, and white matter lesions, we found 24-hour, day, and night systolic and diastolic BP levels to be significantly associated with the presence and number of BMBs (odds ratios 1.6 to 2.3 per standard deviation increase in BP). Distinguishing between different locations, various BP characteristics were significantly associated with the presence of deep (or combined deep and lobar) BMBs, but not with purely lobar BMBs. Our results underline the role of a high 24-hour BP load as an important risk factor for BMBs. The association of BP levels with deep but not purely lobar BMBs is in line with the idea that different vasculopathies might be involved. Deep BMBs may be a particular marker of BP-related small vessel disease, but longitudinal and larger studies are now warranted to substantiate these findings.

Serial Susceptibility Weighted MRI Measures Brain Iron and Microbleeds in Dementia

A new iron sensitive MR sequence (susceptibility weighted imaging - SWI) enabling the simultaneous quantitation of regional brain iron levels and brain microbleeds (BMB) has been acquired serially to study dementia. Cohorts of mildly cognitively impaired (MCI) elderly (n = 73) and cognitively normal participants (n = 33) have been serially evaluated for up to 50 months. SWI phase values (putative iron levels) in 14 brain regions were measured and the number of BMB were counted for each SWI study. SWI phase values showed a left putaminal mean increase of iron (decrease of phase values) over the study duration in 27 participants who progressed to dementia compared to Normals (p = 0.035) and stable MCI (p = 0.01). BMB were detected in 9 out of 26 (38%) MCI participants who progressed to dementia and are a significant risk factor for cognitive failure in MCI participants [risk ratio = 2.06 (95% confidence interval 1.37-3.12)]. SWI is useful to measure regional iron changes and presence of BMB, both of which may be important MR-based biomarkers for neurodegenerative diseases.

Improving interrater agreement about brain microbleeds: development of the Brain Observer MicroBleed Scale (BOMBS).

If the diagnostic and prognostic significance of brain microbleeds (BMBs) are to be investigated and used for these purposes in clinical practice, observer variation in BMB assessment must be minimized. Two doctors used a pilot rating scale to describe the number and distribution of BMBs (round, low-signal lesions, <10 mm diameter on gradient echo MRI) among 264 adults with stroke or TIA. They were blinded to clinical data and their counterpart's ratings. Disagreements were adjudicated by a third observer, who informed the development of a new Brain Observer MicroBleed Scale (BOMBS), which was tested in a separate cohort of 156 adults with stroke. In the pilot study, agreement about the presence of >/=1 BMB in any location was moderate (kappa=0.44; 95% CI, 0.32-0.56), but agreement was worse in lobar locations (kappa=0.44; 95% CI, 0.30-0.58) than in deep (kappa=0.62; 95% CI, 0.48-0.76) or posterior fossa locations (kappa=0.66; 95% CI, 0.47-0.84). Using BOMBS, agreement about the presence of >/=1 BMB improved in any location (kappa=0.68; 95% CI, 0.49-0.86) and in lobar locations (kappa=0.78; 95% CI, 0.60-0.97). Interrater reliability concerning the presence of BMBs was moderate to good, and could be improved with the use of the BOMBS rating scale, which takes into account the main sources of interrater disagreement identified by our pilot scale.

Increased Aortic Pulse Wave Velocity Is Associated With Silent Cerebral Small-Vessel Disease in Hypertensive Patients

Aortic stiffness predicts an excess risk of stroke, supposedly via cerebral small-vessel disease. White matter hyperintensities, silent lacunar infarcts, and brain microbleeds, manifestations of cerebral small-vessel disease on neuroimaging, may precede overt cerebrovascular disease. Therefore, we assessed whether aortic stiffness is also related to such lesions. In 167 hypertensive patients (85 men) without a history of cardiovascular or cerebrovascular disease, a mean age of 51.8+/-13.1 years, and untreated office blood pressure levels of 169+/-25/104+/-12 mm Hg, we determined aortic pulse wave velocity and office and ambulatory 24-hour pulse pressure (off medication), as well as the volume of white matter hyperintensities and the presence of lacunar infarcts and microbleeds using brain MRI. Linear and logistic regression analyses were performed to assess the relationships between the arterial stiffness measures and brain lesions. Aortic stiffness and pulse pressure were significantly related to each of the brain lesions in univariate analyses (P<0.05). Multivariate analyses, adjusted for age, sex, brain volume, mean arterial pressure, and heart rate, showed that a higher pulse wave velocity was significantly associated with a greater volume of white matter hyperintensities (unstandardized regression coefficient: 0.041; 95% CI: 0.005 to 0.078; P<0.05) and the presence of lacunar infarcts (odds ratio [per SD increase in pulse wave velocity]: 1.78; 95% CI: 1.06 to 2.99; P<0.05) but not with microbleeds. The models for pulse pressure failed to reach statistical significance in multivariate analyses. In conclusion, aortic stiffness is independently associated with manifestations of cerebral small-vessel disease in hypertensive patients, linking systemic large- to cerebral small-artery disease.

Brain Microbleeds and Global Cognitive Function in Adults Without Neurological Disorder

Increasing attention has been paid to associations between cognitive dysfunction and brain microbleeds (MBs). Because all previous studies have investigated patients with neurological disorders, we examined subjects without neurological disorder in order to clarify pathogenic relationships. A total of 518 consecutive adults without neurological disorder who had undergone health-screening tests of the brain were studied prospectively. Gradient-echo T2*-weighted MRI using a 1.5-T system was used to detect MBs. The Mini-Mental State Examination (MMSE) was administered to determine cognitive functions. MMSE scores <27 or >1.5 SDs below the age-related mean were regarded as subnormal. MBs were found in 35 subjects (6.8%). MMSE score <27 was found in 25 subjects (4.8%), with MMSE score >1.5 SDs below the age-related mean in 34 subjects (6.6%). Univariate analysis showed presence and number of MBs, short duration of education, and severe white matter hyperintensities as significantly associated with subnormal scores. In logistic regression analysis, presence of MBs (odds ratio [OR], 5.44; 95% CI, 1.83 to 16.19) and number of MBs (OR, 1.32; 95% CI, 1.04 to 1.68) still displayed significant associations with MMSE score <27. Logistic regression analysis revealed a significant relationship between presence (OR, 3.93; 95% CI, 1.44 to 10.74) and number (OR, 1.26; 95% CI, 1.01 to 1.59) of MBs and MMSE score >1.5 SDs below the age-related mean. Among MMSE subscores, "attention and calculation" was significantly lower in MB-positive subjects (P=0.017). MBs appear to be primarily associated with global cognitive dysfunction.

Retinal and Cerebral Microvascular Signs and Diabetes

Diabetes increases the risk for microvascular disease. The retina and the brain both have intricate microvascular systems that are developmentally similar. We sought to examine whether microvascular lesions in the retina and in the brain are associated and whether this association differs among people with and without diabetes. The analysis included 4,218 participants of the Icelandic population-based Age, Gene/Environment Susceptibility-Reykjavik Study who were born in 1907-1935 and who were previously followed as a part of the Reykjavik Study. Retinal focal arteriolar narrowing, arteriovenous (AV) nicking, and microaneurysms/hemorrhages were evaluated on digital retinal images of both eyes. Cerebral microbleeds (CMBs) were evaluated from magnetic resonance images. Data were analyzed with logistic and multinomial logistic regression models controlling for demographics, major cardiovascular risk factors, cerebral infarcts, and white matter lesions. Evidence of brain microbleeds was found in 485 (11.5%) people, including 192 with multiple (>or=2) microbleeds. Subjects with signs of retinal microvascular lesions were at a significantly increased likelihood for having multiple CMBs. People with diabetes in combination with the presence of either retinal AV nicking (odds ratio [OR] 2.47 [95% CI 1.42-4.31]) or retinal microaneurysms/hemorrhages (2.28 [1.24-4.18]) were significantly more likely to have multiple CMBs. Retinal microvascular abnormalities and brain microbleeds may occur together in older adults. People with both diabetes and signs of retinal microvascular lesions (AV nicking and microaneurysms/hemorrhages) are more likely to have multiple microbleeds in the brain. Microvascular disease in diabetes extends to the brain.

Brain Microbleeds, Amyloid Plaques, Intellectual Deterioration, and Arterial Stiffness

To the Editor: The article by Henskens et al1 on brain microbleeds supports a view2 that cerebral microvascular disease in hypertensive patients is responsible for intellectual deterioration and is caused by abnormal flow pulsations extending into the small cerebral vessels as a consequence of aortic stiffening. The relationship between cognitive decline and aortic stiffness and pulse pressure, suspected previously on mechanistic grounds,2 has been confirmed by Waldstein et al3 for the Baltimore …

Response to Brain Microbleeds, Amyloid Plaques, Intellectual Deterioration, and Arterial Stiffness

We thank O’Rourke1 for the interest in our work2 and for placing our findings into a broader perspective. The mechanisms linking hypertension, cerebral small-vessel disease, and cognitive deterioration are complex and not well understood.3 Arterial stiffening, as speculated on …