Microbleeds Research Articles

Risk of hemorrhage in ischemic stroke and its relationship with cerebral microbleeds

ObjectivesStroke is an important public health problem in most countries. Therefore, the treatment of stroke and its complications is important. Intracerebral hemorrhage is one of the complications of ischemic stroke. This study aimed to investigate the risk of hemorrhage in patients with acute ischemic stroke and prospectively study its relationship with cerebral microbleeds (MBs) using susceptibility-weighted imaging (SWI) that is a magnetic resonance imaging (MRI) sequence. Patients and MethodsPatients with acute ischemic stroke were included. Those who underwent treatment with tissue plasminogen activator were excluded. The patients were analyzed according to their risk factors for stroke and their relationship with intracerebral hemorrhage. ResultsA total of 148 patients were included. Of these, 41 (28%) had hemorrhages in the ischemic area. The mean waist circumferences, left atrium diameter, and heart rate in these patients were higher than those in patients without hemorrhage. MBs were detected in 66 patients (44.6%) using SWI, and there was no significant relationship with the presence of hemorrhage. Intracerebral hemorrhages were significantly associated with the volume and localization of infarcts. ConclusionIntracerebral hemorrhage in patients with acute ischemic stroke within the first 7 days after stroke onset was related to their waist circumference as well as the volume and localization of the infarct. However, there was no relationship found between the risk of hemorrhage and MBs using SWI.

Abstract TP340: Centrum-semiovale Enlarged Perivascular Space and Amyloid Deposition in Primary Intracerebral Hemorrhage

Background: Higher load of MRI visible enlarged perivascular spaces in centrum-semiovale (CSO-EPVS) are found in cerebral amyloid angiopathy (CAA), but their association to brain amyloid has been rarely investigated, especially in Asians. We explored whether high degree of CSO-EPVS is associated to other MRI signatures of CAA and its relationship to brain amyloid retention in patients with primary intracerebral hemorrhage (ICH). Methods: 110 patients with either CAA-ICH, strictly lobar ICH and microbleeds (MB) or hypertensive ICH (HTN-ICH), strictly deep-seated ICH/MBs, were included in this study. CSO-EPVS and basal ganglia EPVS (BG-EPVS) were assesd using an established 4-point semiquantitative score. EPVS degree was classified as high (score>2) or low (≤2). We also evaluated MBs, cortical superficial siderosis (cSS), white matter hyperintensities (WMH) and brain atrophy severity on MRIs. Cerebral amyloid deposition was quantified on 11 C-Pittsburgh Compound B (PiB) PETs in 36 patients (15 CAA; 21 HA) as standardized uptake value ratio (SUVR). Results: Patients with CAA-related ICH (n=24) and HTN-ICH (n=86) had similar prevalence of high-degree CSO-EPVS (37.5% and 26.7%, p=0.305) and high-degree BG-EPVS (25% and 18.6%, p=0.489). Patients with high-degree CSO-EPVS were associated with presence of lobar MB (p=0.01) and higher WMH (p=0.008), while patients with high-degree EPVS-BG were associated with older age (p=0.002), higher WMH (p=0.021) and more cortical atrophy (p=0.023). The amyloid burden (global SUVR) was higher in high-degree vs low-degree EPVS-CSO in CAA-ICH (p=0.045), but not in HTN-ICH (p=0.586). On multivariate logistic regression analysis, the degree of EPVS-CSO remains an independent indicator for positive amyloid scan (defined as global SUVR>1.2) even after adjustment for age, WMH, the degree of EPVS-BG and ICH/MBs distribution (Odds ratio 6.2 [1.2-31.6], p=0.029). Conclusion: Although the presence of EPVS-CSO could not directly distinguish CAA-ICH and HTN-ICH in our Asian cohort, high-degree EPVS-CSO was associated with CAA-related MRI markers such as lobar MBs, and higher amyloid load on PiB-PET. The burden of CSO-EPVS can be seen as an indicator of higher brain amyloid deposition in patients with CAA-related ICH.

Abstract TP165: The Association Between Coronary Artery Calcium And Cerebral Small Vessel Disease: A Population Based Cross Sectional Study

Cerebral small vessel disease (CSVD) is an important cause of stroke and dementia. Recent evidence showed that coronary artery calcium (CAC), a robust measure of subclinical atherosclerosis, independently predicts future dementia. One potential explanation for this observed link between CAC and dementia is that CAC is related to CSVD. However, limited study directly examined such association. Aim: To provide mechanistic explanation for the already-observed positive association between atherosclerosis and dementia. Methods: A total of 702 community dwelling men randomly sampled from Kusatsu City, Japan were analyzed. CAC was scored by Agatston’s method. Using MRI (magnetic resonance imaging) we assessed the following components as the measures of CSVD: lacunar infarcts (LI), microbleeds (MB), deep and subcortical white matter hyperintensity (DSWMH) and periventricular hyperintensity (PVH). CAC were categorized as absent (Agatston score=0), mild (more than zero and <100) and moderate to severe (≥100). The associations were assessed by binomial logistic regression analyses. Age (at the time of MRI examination), ever smoker, hypertension, diabetes mellitus and dyslipidemia were used as risk factors covariates. P trends were performed treating CAC category as ordinal. Results: Mean age of the participants was 69.7± 8.8 years. Prevalence of CSVD components was significantly higher in groups with higher CAC. LI was significantly associated with mild and moderate-to-severe CAC groups in unadjusted, age and risk factors adjusted analyses. Moreover, DSWMH was significantly associated with moderate-to-severe CAC group in unadjusted analysis as well as in age and risk factors adjusted analyses. But, MB and PVH were significantly associated with mild and moderate-to-severe CAC groups only in unadjusted analysis. After age and risk factors adjusted analyses the associations were no longer significant. Trend for a dose-response relation of CAC with LI and DSWMH were significant in unadjusted, age and risk factors adjusted analyses, but for MB and PVH, trends were significant only in unadjusted analysis. In Conclusion, those with higher CAC were associated with higher odds of having LI and DSWMH. Presence and degree of CAC may be useful in predicting CSVD.

NON-ALCOHOLIC FATTY LIVER DISEASE AND CEREBRAL SMALL-VESSEL DISEASE IN COGNITIVELY NORMAL INDIVIDUALS

Many studies investigated the association between nonalcoholic fatty liver disease (NALFD) and cardiovascular diseases. However, the relationship between NAFLD and cerebral small vessel disease has not been thoroughly investigated yet. A total of 1283 participants from health promotion center cohort were included in analysis. The cerebral SVD burdens were assessed with white matter hyperintensities (WMH), lacunes, and microbleeds (MB). US diagnosis of fatty liver was made based on standard criteria, and NFS was used to assess severity of fibrosis and to classify participants with NAFLD in two groups: high-intermediate (NFS ≥ -1.455) and low probability (NFS < -1.455) of advanced fibrosis. Multivariable logistic regression was used to assess the association between NAFLD and severity of WMH, and presence of lacunes and MB after controlling for age, sex, smoking, alcohol, Body mass index, intracranial volume, systolic blood pressure, LDL cholesterol, use of lipid lowering medications, use of antidiabetic medications, and use of antihypertensive medications. The association of NAFLD with the severity of WMH was also explored in clinically relevant subgroups, and the interaction of NAFLD with clinical characteristics was tested using Wald tests for cross-product terms in regression models. NAFLD had a significant association with WMH severity but not with presence of lacunes nor MB. Multivariable logistic regression showed that compared to participants without NAFLD, participants with NAFLD had more frequent moderate to severe WMH. compared to participants without NAFLD, the OR for WMH in participants with low NFS and with intermediate to high NFS were 0.97 (0.57, 1.65) and 2.12 (1.44, 3.12), respectively. Especially, linear trend tests showed a significant trend for more severe WMH among non-NAFLD, NAFLD with low NFS and NAFLD with high NFS (P for trend <0.001). The positive association between NAFLD and WMH was prominent in the subgroups with middle age, female, low education, and non-obesity. Our findings suggested that NAFLD has a significant association with moderate to severe WMH in cognitively normal individuals and NAFLD severity also predicted more severe WMH. Odds ratios for prevalence of moderate or severe white matter hyperintensity by non-alcoholic fatty liver disease status in predefined subgroups.* Adjusted for age and sex, body mass index (underweight, normal, overweight, and obese), education (< middle school and ≥ middle school), smoking (never, former or current, and missing), and alcohol (none, and moderate), systolic blood pressure, fasting glucose, LDL cholesterol, use of diabetes medication use of antihyperlipidemia medication, and use of antihypertensive medication.

Abstract WP52: White Matter Hyperintensity, Cerebral Microbleeds and Risk of Hemorrhagic Transformation with Intravenous rt-PA

Background and Purpose: Intravenous rt-PA is associated with risk of hemorrhagic transformation. We sought to determine if the degree of white matter hyperintensity on Fluid Attenuated Inversion Recovery (FLAIR) and the presence of cerebral microbleeds (MB) on Gradient Recalled Echo (GRE) sequences on MRI was associated with increased risk of hemorrhagic transformation following intravenous rt-PA. Methods: Acute ischemic stroke patients admitted to University of Iowa Hospitals and Clinics between 1/1/2009 and 12/31/2013 were included in the study if - i) received intravenous rt-PA ii) had MRI brain with Diffusion Weighted Imaging (DWI), GRE and FLAIR sequence within the first 48 hours of stroke onset, and iii) had CT head or MRI at 20-36hr post rt-PA to evaluate for hemorrhagic transformation. White matter hyperintensity on FLAIR was evaluated based on Fazekas scale from 0-4. A score of 0 and 1 on Fazekas scale was combined to form group 1 and a score 3 and 4 was combined to form group 2 for analysis. MB were evaluated on GRE. Presence of MB was categorized as group 1 (1-5 MB) and 2 (6 or more MB). CT or MRI head performed at 20-36 hours after rt-PA was evaluated for hemorrhagic transformation. If present it was classified as group 1 (HI 1 and 2) and 2 (PH 1 and 2). Results: A total of 402 patients met the study criteria among 607 patients. Mean age was 67±14 years. Among them 45% were women and 88% whites. FLAIR deep white matter hyperintensity was graded on Fazekas as 0 - 26%, 1-51%, 2-12% and 3-11%. FLAIR periventricular white matter hyperintensity was graded as 0 - 10%, 1-49%, 2-25% and 3- 16%. MB were present in 26% of the study population with only 3 patients in group 2. Hemorrhagic transformation was seen in 24% of the patients with 66% of these having petechial hemorrhage. Deep white matter (p=0.47) and periventricular (p=0.73) white matter hyperintensity was not significantly associated with hemorrhagic transformation. However, presence of MB was significantly associated with hemorrhagic transformation (p=0.006, OR = 2.03, CI 1.215-3.392). Conclusion: Microbleeds increases the risk of hemorrhagic transformation following administration of intravenous rt-PA. However, white matter hyperintensity did not result in increased risk of hemorrhagic transformation after rt-PA.

Abstract TP323: Prevalence And Clinical Character Of Cortical Superficial Siderosis In Stroke Patient

Background and purpose: Cortical superficial siderosis (CSS) is a neuroimaging marker of cerebral amyloid angiopathy and has been associated with a high risk for intracerebral hemorrhage. However, CSS in acute stroke patients have not been fully investigated. The aim of this study was to assess the prevalence of CSS in both ischemic and hemorrhagic stroke patients. Furthermore, we aimed to assess the relation between CSS and clinical or radiologic characteristics. Methods: From September 2014 through June 2016, consecutive acute ischemic and hemorrhagic stroke patients who were admitted to our department within 7 days from symptom onset were retrospectively recruited from the prospective registry. CSS was defined as a homogeneous curvilinear signal intensity (black) on T2*-GRE sequences in the superficial layers of the cerebral cortex, within the subarachnoid space, away from at least three sulci of the hematoma with no corresponding signal hyperintensity on FLAIR sequences, to exclude potential hemorrhagic mimics. We analyzed the association between CSS and the topographic distribution of cerebral microbleeds (MBs), white matter lesions plus cardiovascular risk factors. Results: A total of 680 patients (530 ischemic stroke and 150 hemorrhagic stroke; median age 71 years) were enrolled in the present study. CSS was detected in 6 patients (1.1 %) with ischemic stroke and 7 patients (4.7%) with hemorrhagic stroke ( P &lt; 0.0001). CSS are associated with previous stroke ( P = 0.0234), hemorrhagic stroke ( P &lt; 0.0001), white matter lesions ( P = 0.0105), and lobar and non-lobar MBs (both P &lt; 0.0001), but no relationship between age, sex, cardiovascular risk factors and CSS were found. On multivariable logistic regression analysis, high lobar MBs (≥ 2; odds ratio [OR], 74.39; 95% confidence interval [CI], 10.24-1553.25; P &lt; 0.0001) and hemorrhagic stroke (OR, 4.30; 95% CI, 1.12-18.14; P = 0.0336) were independently associated with the presence of CSS. Conclusions: Our results suggest that CSS occurs with high prevalence in hemorrhagic stroke patients and is associated with lobar MBs, while the association between CSS and age, sex and cardiovascular risk factors were not observed.

Characterizing Deep White Matter Hyperintensities in Patients with Symptomatic Isolated Cortical Superficial Siderosis

In patient with cerebral amyloid angiopathy (CAA) presenting with lobar hemorrhage (LH), magnetic resonance imaging (MRI) white matter hyperintensities (WMH) tend to be predominant in posterior regions with the "multiple subcortical spots" WMH pattern as the most frequent topographical WMH pattern. Our aim was to analyze WMH severity and topographical distribution in patients with cortical superficial siderosis (CSS). We retrospectively analyzed MRIs from consecutive symptomatic isolated (i.e., without LH) CSS and LH-CAA (with or without associated CSS) patients. We analyzed baseline clinical characteristics including age, history of hypertension, diabetes, hypercholesterolemia, and pre-existing cognitive deficit. The presence of lobar microbleeds (MB) was scored on T2*. FLAIR (fluid-attenuated inversion recovery) WMH severity (using the Fazekas scale) and topographical distribution (using [slightly modified] earlier described WMH patterns) were analyzed and compared between both groups. Twenty CSS and 63 LH-CAA patients were analyzed. Baseline clinical characteristics were similar between both groups, except for hypercholesterolemia less frequently present in the CSS group (P = .026). Lobar MB were significantly less frequently present in the CSS group (P < .01), and CSS was more frequently focal in the CSS group compared with LH-CAA patients with associated CSS (P = .03). Mean Fazekas scale was significantly lower in CSS patients (P = .011). WMH patterns did not differ between both groups, with the multiple subcortical spots pattern as the most frequently observed pattern. Relative severe WMH scores and similar topographical distribution in CSS patients argue for WMH as a CAA-related feature in these patients with isolated CSS, adding level of evidence that isolated CSS could correspond to early manifestations of CAA.

Microbleeds in Alzheimer's Disease: A Neuropsychological Overview and Meta-Analysis.

The current literature on the role of brain microbleeds (MB) on the neuropsychological outcomes of Alzheimer's disease (AD) is heterogeneous. We therefore meta-analytically examined the neuropsychological literature pertaining to MBs in AD. Using a priori selected criteria, studies with cross-sectional neuropsychological assessment on MBs and AD were reviewed. Six of 122 studies met selection criteria and provided neuropsychological data on either AD with MB and without MB, or in contrast to healthy controls. The global neuropsychological difference between AD with MB and AD without MB based on random effect model was nonsignificant, heterogeneous, and small (Effect Size =-0.155; 95% confidence interval =-0.465 to 0.155; p value =0.326; Heterogenity: Q-value =12.744; degrees of freedom =5; p =0.026; I2 =61%). The contribution of MBs to cognitive deficits in AD remains unclear. Future studies of MB in AD should strive to use standardized neuroimaging techniques with high sensitivity for MB, a common standard for MB definition, and neuropsychological tests sensitive for detecting subtle cognitive impairment.

Neuropsychological Features of Microbleeds and Cortical Microinfarct Detected by High Resolution Magnetic Resonance Imaging.

Lobar microbleeds (MBs) and cortical microinfarct (CMI) are caused by cerebral amyloid angiopathy in the elderly and increase in number in Alzheimer's disease. The aim of this study is to elucidate the effects of lobar MBs and CMIs on cognitive function. The subjects were outpatients who visited the memory clinic of Mie University Hospital. Among 120 subjects, 109 patients fulfilled the inclusion criteria. We quantitatively estimated MBs and CMIs using double inversion recovery and 3D FLAIR images of 3T MRI. Neuropsychological assessments included intellectual, memory, constructional, and frontal lobe function. Of the 109 patients, MBs and CMIs were observed in 68 (62%) and 17 (16%) subjects, respectively. Of the 68 patients with MBs, lobar MBs were found in 28, deep MBs in 8 and mixed MBs in 31. In each age group, the number of MBs increased in patients with CMI (CMI+ group) than those without CMI (CMI- group), and MBs and CMIs additively decreased MMSE scores. In psychological screens, the MBs+ group with more than 10 MBs showed significantly lower scores of category- and letter-WF than MB- group. The CMI+ group showed significantly worse scores than CMI- group in Japanese Raven's coloured progressive matrices, Trail Making Test-A, category- and letter-word fluency and copy and drawing of figures. Lobar MBs and CMIs in the elderly frequently coexisted with each other and additively contributed to cognitive impairment, which is mainly predisposed to frontal lobe function.

Age-dependent cognitive and affective differences in Alzheimer's and Parkinson's diseases in relation to MRI findings

ObjectiveTo compare age-dependent changes in cognitive and affective functions related to white matter changes between patients with Alzheimer's disease (AD) and Parkinson's disease (PD). MethodsWe retrospectively compared age-dependent cognitive and affective functions in 216 AD patients, 153 PD patients, and 103 healthy controls with cerebral white matter lesions (WMLs), periventricular hyperintensity (PVH), deep white matter hyperintensity (DWMH), micro-bleeds (MBs), and lacunar infarcts (LIs). ResultsThe average mini-mental state examination (MMSE) scores were 19.6±6.1 and 26.8±3.6 in AD and PD patients, respectively. Significant decreases were found in the MMSE score, Hasegawa's dementia scale-revised (HDS-R) score, frontal assessment battery score, and Abe's BPSD score (ABS) among the age-dependent AD subgroups and in the MMSE, HDS-R, Montreal cognitive assessment, geriatric depression scale, and ABS scores among the age-dependent PD subgroups; they were worse in AD patients. White matter changes were observed in >88% and >72% of patients with AD and PD, respectively. An age-dependent direct comparison of AD and PD showed significant differences in the PVH and DWMH grades, and numbers of MBs and LIs. ConclusionWML-related cognitive and affective functions worsen with age in AD and PD patients; however, the abnormalities were more frequent and stronger in AD patients.

Abstract TMP37: Physicians’ Preferences in the Management of Silent Stroke: Results From a Worldwide Survey

Introduction: Patients with silent cerebral infarction (SCI) or microbleeds (MB) are at higher risk of developing a recurrent vascular event or suffering a hemorrhage as a consequence of thrombolysis or antithrombotic treatment. Additionally, the presence of occult cerebrovascular lesions on imaging may alter therapeutic or diagnostic recommendations. However, clinical guidelines are lacking. Hypothesis: We hypothesize that a wide variability in physician diagnostic and treatment preferences exist for individuals with SCI and MB. Methods: Respondents were practicing neurologists with expertise in stroke care identified from WSO, CSC, Vas-Cog and SORCan. Those who agreed to participate were sent a questionnaire which was completed online. Participants randomly received 10 cases from a pool of 20, assessing perception of risk for later stroke and treatment preferences, as well as demographic questions. Results: Among the 252 participants, 35 (13.9%) were excluded for incomplete responses. Of 217 participants included in this analysis, two thirds of participants would proceed with revascularization therapies (tPA: 40%, endovascular: 8%, combined: 22%) for a case scenario with acute global aphasia (NIHSS 6-7) and remote bilateral MB. Additionally, physicians would order an echocardiogram regardless of the location of the SCI (cortical SCI: 56%, lacunar SCI: 44%; p&gt;0.05). In a case-scenario with mild hypertension and 4 deep microbleeds presented with difficulty with balance, almost half of respondents did not recommend antiplatelet drugs or statins (40.2%), and 20% recommended both antiplatelet and statins. NOACS were the most commonly recommended antithrombotic treatment in a case-scenario with atrial fibrillation (AF), SCI, and a remote lobar intracerebral hemorrhage (46.4%), followed by aspirin (20.9%), no treatment (17.3%). Conclusion: There is a wide variability in the management of SCI and MB among stroke experts. The present study highlights the need for further research in treatment efficacy, as well as recommendations from scientific organizations to guide clinicians in the management of high risk patients with SCI and MB.

Abstract 121: Mechanisms of Cortical Superficial Siderosis in Cerebral Amyloid Angiopathy

Introduction: Mechanisms of cortical superficial siderosis (cSS) in cerebral amyloid angiopathy (CAA) are unknown, but might include in situ bleeding from amyloid laden superficial vessels or blood products redistribution from acute lobar intracerebral hemorrhage (ICH). Hypothesis: We aimed to identify factors related to the extent and multifocality of cSS. Methods: We analyzed consecutive CAA-related ICH patients diagnosed with Boston criteria from a prospective cohort. cSS multifocality, was rated for spatially distinct foci involvement and bi-hemispheric distribution on a 0-4 scale (1 point: 1 sulcus or focal immediately adjacent sulci, 2 points: 2 or more non-adjacent sulci OR more than 3 adjacent sulci, in each hemisphere) with excellent interrater reliability (k=0.87). Radiological markers of CAA and ICH characteristics were assessed using quantitative methods or validated visual scales, and their association with cSS multifocality was investigated in multivariable regression. Results: The cohort included 312 CAA patients (53% male; mean age 71.7). cSS was found in 34.6%: unifocal in 42 patients (13.5%), multifocal in 66 (23.1%). Presence and multifocality of cSS were not related with characteristics of the acute ICH such as ICH volume, ICH side or areas of acute subarachnoid blood on initial CT. ICH side did not predict cSS side or multifocality at that side. cSS multifocality was related to the presence of IVH in patients who had a single ICH without microbleeds (MB), but not in patients with multiple hemorrhagic lesions (ICH and/or MBs). In ordinal logistic regression, cSS multifocality was related to lobar microbleeds burden (OR: 1.57; 95%CI: 1.27-1.94; p&lt;0.0001) and MRI centrum semiovale perivascular spaces (PVS, OR: 2.05; 95%CI: 1.26-3.33; p=0.004) but not basal ganglia PVS or leukoaraiosis volume. A secondary analysis using Cox regression showed that cSS multifocality was an independent risk factor for recurrent ICH (HR: 2.21; 95%CI: 1.09-4.52 and 3.91; 95%CI: 1.40-10.9 for multifocality presence and severity) after adjusting for other confounders. Conclusion: Extent and multifocality of cSS appear to be markers of CAA severity and independent predictors of ICH recurrence, and can provide insights potential into pathomechanisms.

Abstract 47: White Matter Atrophy in Cerebral Amyloid Angiopathy

Background/Purpose: Cerebral Amyloid Angiopathy (CAA) leads to leukoaraiosis, lacunar infarcts and cortical tissue loss. We hypothesized that CAA is also associated with white matter atrophy (WMA). Methods: We have compared volumetric multimodal MRIs from 72 prospectively enrolled non-demented patients with probable CAA (per Boston criteria), to 3 other well-studied cohorts: 289 Healthy Controls (HC) from the Harvard Aging Brain (HAB) study, 231 HC and 198 patients with AD from the Alzheimer’s Disease Neuroimaging Initiative (ADNI). Validated FreeSurfer algorithms were used to calculate White Matter Volume (WMV), white matter hyperintensity volume (WMHv), and cortical thickness. Microbleeds (MBs) were counted on SWI-MRI. Measures were obtained from the contralateral hemisphere if intracerebral hemorrhage present. All volumes were corrected for total intracranial volume (ICV), so reported as percent of ICV. Results: The CAA patients were significantly younger (mean age: 70.1) compared to both HC cohorts (ADNI-HC: 76.0, p&lt;0.001, HAB-HC: 73.8, p &lt; 0.001), and to patients with AD (75.5, p &lt; 0.001). Despite being younger, patients with CAA presented significantly lower global WMV (28% ± 2.6) than both ADNI-HC (29.2% ± 2.2, p &lt; 0.001), HAB-HC (29.0% ± 2.5, p = 0.001), and patients with AD (28.7% ± 2.2, p = 0.02) [Figure]. The association persisted after correcting for age, gender and WMHv. Within the CAA cohort, there was a negative correlation between WMV and lobar MB counts (rho = -0.26, p = 0.03), it remained significant after correcting for age, gender, WMHv (p=0.016). There were no significant associations however between WMV and neither WMHv, nor cortical thickness (both p&gt;0.2). Conclusions: Patients with CAA show WMA when compared to older HC and AD. WMA independently correlates with MBs, a marker of CAA severity. Consistent spatial patterns of atrophy especially in posterior regions when compared to both HC and AD [Figure] might represent the “WMA signature of CAA”.

The clinical significance of brain microbleeds in patients with Alzheimer's disease: Preliminary study.

Background:Microbleeds (MBs) are observed frequently in Alzheimer's disease (AD) and suggested to play a crucial role in the pathophysiology, but their clinical significance remains unclear.Materials and Methods:The study recruited 100 patients with AD who were diagnosed at the memory clinic in Seoul Medical Center in 2014. For each patient, baseline characteristics, neuropsychological tests, cerebrovascular risk factors, medial temporal lobe atrophy (MTLA), and severity of small vessel disease (SVD) according to the existence of MBs were evaluated.Results:The prevalence of MBs in patients with AD was 33%. The percentage of male gender, the severity of SVD and MTLA were significantly increased in MB(+) group. The MB(+) group showed more severe MTLA and SVD than MB(−) group.Conclusions:These results suggested that MBs might reflect the burden of amyloid and ischemic vascular pathology.

Rust on the Brain from Microbleeds and Its Relevance to Alzheimer Studies: Invited Commentary on Cacciottolo Neurobiology of Aging, 2016.

Cerebral microbleeds (MB) and small vessel disease (SVD) with congophilic arterial angiopathy (CAA) are increasingly recognized as a variable factor in AD cognitive impairments. This commentary on our recent report on sex-ApoE interactions in MBs published this February, briefly explores three aspects of MBs that could not be fully discussed therein: I, A possible gap between the prevalence of MBs as detected by MRI and post mortem analysis; II, The role of hemoglobin-degradation products in amyloid-attributed neurodegenerative changes; and III, Possible assessment of MB by cerebrospinal fluid (CSF) assays for iron-related markers to better screen patient subgroups for AD interventions.

Cerebral Amyloid Angiopathy-Related Microbleeds Correlate with Glucose Metabolism and Brain Volume in Alzheimer's Disease.

Microbleeds (MBs) are frequently observed in Alzheimer's disease (AD); however, the relevance to AD pathophysiology has not been elucidated. We investigated correlation of MBs, especially cerebral amyloid angiopathy (CAA)-related MBs with cognitive function, gray matter volume, and glucose metabolism in AD. We performed magnetic resonance imaging including T2*-weighted imaging sequence for 206 patients with AD. Among them, 158 AD patients with no focal brain lesions except for MBs were investigated with cognitive tests, voxel-based morphometry, and 18F-fluorodeoxyglucose positron emission tomography in a cross-sectional observational study. Of the 158 patients with no hemorrhagic and/or ischemic stroke lesions except for MBs, 27 patients had MBs, in which 17 patients showed CAA-related MBs that located only in cortex/subcortex (CAA-related MBs), and 10 patients showed CAA-unrelated MBs that located in deep regions regardless of the presence of MBs in cortical/subcortical regions. There were slightly but significant differences in cognitive functions between the patients without MBs, those with CAA-related MBs, and those with CAA-unrelated MBs. MBs were recognized frequently in the occipital lobe in the patients with CAA-related MBs. The patients with CAA-related MBs showed gray matter atrophy in the temporal lobe and cerebellum, and glucose hypometabolism in the temporal lobe compared with those without MBs. Our results indicate that MBs, particularly CAA-related MBs would cause gray matter atrophy and glucose hypometabolism in AD.

Diagnostic value of lobar microbleeds in individuals without intracerebral hemorrhage

IntroductionThe Boston criteria are the basis for a noninvasive diagnosis of cerebral amyloid angiopathy (CAA) in the setting of lobar intracerebral hemorrhage (ICH). We assessed the accuracy of these criteria in individuals with lobar microbleeds (MBs) without ICH. MethodsWe identified individuals aged >55 years having brain magnetic resonance imaging (MRI) and pathological assessment of CAA in a single academic hospital and a community-based population (Framingham Heart Study [FHS]). We determined the positive predictive value (PPV) of the Boston criteria for CAA in both cohorts, using lobar MBs as the only hemorrhagic lesion to fulfill the criteria. ResultsWe included 102 individuals: 55 from the hospital-based cohort and 47 from FHS (mean age at MRI 74.7 ± 8.5 and 83.4 ± 10.9 years; CAA prevalence 60% and 46.8%; cases with any lobar MB 49% and 21.3%; and cases with ≥2 strictly lobar MBs 29.1% and 8.5%, respectively). PPV of “probable CAA” (≥2 strictly lobar MBs) was 87.5% (95% confidence interval [CI], 60.4–97.8) and 25% (95% CI, 13.2–78) in hospital and general populations, respectively. DiscussionStrictly lobar MBs strongly predict CAA in non-ICH individuals when found in a hospital context. However, their diagnostic accuracy in the general population appears limited.

Contribution of Deep Microbleeds to Stroke Recurrence: Differences between Patients with Past Deep Intracerebral Hemorrhages and Lacunar Infarctions

This study investigated the contribution of deep cerebral microbleeds (MBs) to stroke recurrences in patients with histories of deep intracerebral hemorrhages (ICHs) or lacunar infarctions (LIs). We prospectively analyzed stroke recurrences in patients admitted to our hospital who were treated for deep ICHs or LIs between April 2004 and December 2011. The number of deep MBs was counted on admission. Stroke recurrence-free rate curves were generated with the Kaplan-Meier method using the log-rank test. The odds ratios (ORs) for recurrent strokes were derived using multivariate logistic regression models, based on deep MBs and risk factors. We evaluated magnetic resonance images or the recurrences of 231 deep-ICH patients (92 women, 68.0 ± 12.0 years old) and 309 LI patients (140 women, 70.7 ± 11.7 years old). The incidences of deep ICHs (1.5%/year) and LIs (2.1%/year) presenting as stroke recurrences were significantly larger in LI patients with deep MBs than in those without (.01 [P = .0001] and .08%/year [P = .005], respectively). However, there was no significant difference between deep-ICH patients with and without MBs in terms of incidence of recurrences. Multivariate analyses revealed that deep MBs independently and significantly elevated the rate of deep ICHs (OR, 19.0; P = .007) or LIs (OR, 3.62; P = .008) presenting as recurrences in LI patients, but not in deep-ICH patients, when adjusted for stroke risk factors. There may be differences between patients with deep ICHs and those with LIs in terms of the contribution of deep MBs to stroke recurrence.

Abstract 215: A Systemic Inflammation-Induced Mouse Model of Cerebral Microbleeds

Introduction: Cerebral microhemorrhages (CMH) are tiny deposits of blood degradation products in the brain and are the pathological substrate of cerebral microbleeds (MB). The existing animal models of MB are either β-amyloid-, anti-amyloid antibody-, or hypertension-induced; however, MB may develop independent of hypertension or amyloid deposition. In fact, MB are associated with normal aging, sepsis and neurodegenerative conditions. One common factor among the above pathologies is inflammation, and recent studies show a link between systemic inflammation and MB. Hence, we hypothesize that systemic inflammation (induced by lipopolysaccharide; LPS) will result in MB development, and an inflammation-induced animal model will be appropriate to study MB. In the current study we used two different dosing regimens for LPS and observed rapid and robust development of CMH and MB. Methods: Adult C57BL/6 mice were injected with LPS (1mg/kg or 3mg/kg, i.p.) or saline at 0, 6, and 24h. At 2 or 7 days after first LPS injection, brains were harvested. Hematoxylin and eosin (H&amp;E) and Prussian blue (PB) were used to stain fresh (acute) hemorrhages and hemosiderin (subacute hemorrhages), respectively. Results: No surface and negligible H&amp;E-positive CMH were observed in saline controls (n=4). LPS (3mg/kg; n=13) resulted in significantly higher number (p&lt;0.01), size (p&lt;0.05) and area (p&lt;0.01) of H&amp;E-positive CMH at 2 days. Negligible PB-positive CMH were observed at 2 days after LPS (3 or 1 mg/kg) injection. However, LPS (1mg/kg) resulted in robust development of PB-positive CMH at 7 days, with significantly higher number (p&lt;0.05), size (p&lt;0.05) and area (p&lt;0.01) in LPS (n=9) versus saline (n=4) treated mice. MRI confirmed the presence of MB in this model. The number of CMH was significantly higher in the cerebellum (p&lt;0.05) compared to cortical or subcortical regions. Conclusion: In summary, LPS produced rapid development of H&amp;E-positive CMH (at 2 and 7 days) and PB-positive CMH (at 7 days) with low mortality. Thus, this appears to be an appropriate model to study the pathophysiology of CMH and MB.

Abstract 98: Blood Pressure Control and Risk of Recurrent Lobar Intracerebral Hemorrhage

Introduction: Elevated blood pressure (BP) is a potent risk factor for risk and recurrence of Intracerebral Hemorrhage (ICH) in non-lobar regions, but its role in lobar ICH remains unclear. Hypothesis: We tested whether: elevated BP after index lobar ICH is associated with lobar ICH recurrence and whether the role of elevated BP is influenced by APOE genotype and microbleeds on MRI. Methods: Eligible subjects were survivors of primary lobar ICH enrolled in a single-center prospective cohort study. The number of MRI-defined lobar microbleeds (MB) and APOE genotype (ε2/ε3/ε4 alleles) were determined at time of index ICH. Survivors were followed prospectively for recurrent ICH. BP measurements were captured at 3, 6, 9, 12 months, and every 6 months thereafter. BP was treated as a time-varying variable, and analyzed in two ways: 1) a dichotomous variable based on AHA/ASA ICH secondary prevention guidelines goal; 2) a categorical variable for JNC7 hypertension stages. Results: Among 505 lobar ICH survivors, there were 102 recurrences during median follow-up of 30 months. Inadequate BP control (based on AHA/ASA guidelines) was associated with increased recurrence risk (Hazard Ratio [HR] 3.53, p=0.001). Effect size correlated with JNC7 stage: pre-hypertension (HR 2.76, p=0.007), hypertension stage 1 (HR 3.90, p=0.012); hypertension stage 2 (HR 5.21, p 2 MB, interaction p = 0.037) to increase risk of lobar ICH recurrence. Conclusions: Elevated BP is associated with increased risk of recurrent lobar ICH, with effect size rising with JNC7 stage. Presence of APOE ε2 / ε4 and &gt; 2 MB on MRI interacts with BP, further increasing risk of recurrence. Further studies are required to determine the clinical implications of these findings.