Clinical Relevance of Cerebral Small Vessel Diseases.

Background and Purpose: Cerebral microbleed (CMB) in the lobar region is regarded as an image marker for cerebral amyloid angiopathy (CAA), but it is sometimes encountered in patients with intracerebral hemorrhage (ICH) owing to hypertension or other small vessel disease (SVD). Recently, enlarged perivascular space (EPVS) in white matter and deep region was suggested to be another potential marker for SVD. Knowledge of CMB location and EPVS in patients with ICH in relation to amyloid deposition might help us understand its heterogeneous pathophysiology. Methods: Fifty-seven primary, spontaneous ICH patients underwent magnetic resonance imaging (MRI) with susceptibility-weighted imaging (SWI) to analyze the CMB, the EPVS in basal ganglia (BG) and centrum semiovale (CSO), and the overall white matter hyperintensity (WMH). 11 C-Pittsburgh Compound B (PiB) positron emission tomography was also performed to measure the global amyloid deposition and was quantified as standardized uptake value ratio (SUVR) using cerebellum as the reference. Results: Twenty-six patients with lobar ICH and 31 patients with deep ICH were included. Positive PiB scan (SUVR >1.13) was found in 37% of patients (11 lobar ICH, 10 deep ICH). Presence of lobar CMB was found in 65% of patients irrespective of PiB scan status (p=0.084), but PiB (+) had higher number of lobar CMB (14.6 ± 16.9 vs. 5.4± 10.1, p=0.014) compared with PiB (-) patients. In PiB (-) patients, the number of lobar CMB is positively correlated with the number of deep CMB (p<0.001, r=0.773). The presence of lobar CMB in PiB (-) patients is also associated with severe EPVS in BG (70% vs. 31%, p=0.042), but not in CSO (p=0.073). Conclusions: Lobar CMB can be found in more than half of ICH patients irrespective of PiB scan status, but higher number of lobar CMB is seen in PiB (+) ICH patients. In PiB (-) patients, the presence of lobar CMB is associated with higher deep CMB number and EPVS in BG, suggesting the contribution of hypertensive angiopathy instead of amyloid angiopathy.

Cerebral amyloid angiopathy (CAA) is characteristically associated with magnetic resonance imaging (MRI) biomarkers of small vessel brain injury, including strictly lobar cerebral microbleeds, cortical superficial siderosis, centrum semiovale perivascular spaces, and white matter hyperintensities. Although these neuroimaging markers reflect distinct pathophysiologic aspects in CAA, no studies to date have combined these structural imaging features to gauge total brain small vessel disease burden in CAA. To investigate whether a composite score can be developed to capture the total brain MRI burden of small vessel disease in CAA and to explore whether this score contributes independent and complementary information about CAA severity, defined as intracerebral hemorrhage during life or bleeding-related neuropathologic changes. This retrospective, cross-sectional study examined a single-center neuropathologic CAA cohort of eligible patients from the Massachusetts General Hospital from January 1, 1997, through December 31, 2012. Data analysis was performed from January 2, 2015, to January 9, 2016. Patients with pathologic evidence of CAA (ie, any presence of CAA from routinely collected brain biopsy specimen, biopsy specimen at hematoma evacuation, or autopsy) and available brain MRI sequences of adequate quality, including T2-weighted, T2*-weighted gradient-recalled echo, and/or susceptibility-weighted imaging and fluid-attenuated inversion recovery sequences, were considered for the study. Brain MRIs were rated for lobar cerebral microbleeds, cortical superficial siderosis, centrum semiovale perivascular spaces, and white matter hyperintensities. All 4 MRI lesions were incorporated into a prespecified ordinal total small vessel disease score, ranging from 0 to 6 points. Associations with severity of CAA-associated vasculopathic changes (fibrinoid necrosis and concentric splitting of the wall), clinical presentation, number of intracerebral hemorrhages, and other imaging markers not included in the score were explored using logistic and ordinal regression. In total, 105 patients with pathologically defined CAA were included: 52 with autopsies, 22 with brain biopsy specimens, and 31 with pathologic samples from hematoma evacuations. The mean (range) age of the patients was 73 (71-74) years, and 55 (52.4%) were women. In multivariable ordinal regression analysis, severity of CAA-associated vasculopathic changes (odds ratio, 2.40; 95% CI, 1.06-5.45; P = .04) and CAA presentation with symptomatic intracerebral hemorrhage (odds ratio, 2.23; 95% CI, 1.07-4.64; P = .03) were independently associated with the total MRI small vessel disease score. The score was associated with small, acute, diffusion-weighted imaging lesions and posterior white matter hyperintensities in adjusted analyses. This study provides evidence of concept validity of a total MRI small vessel disease score in CAA. After further validation, this approach can be potentially used in prospective clinical studies.

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Background and Purpose: Cerebral amyloid angiopathy (CAA) is a major cause of lobar intracerebral hemorrhage (ICH). A subgroup of patients with CAA experience multiple, recurrent ICHs over a short period of time. In this study, we investigated predictors of early lobar ICH recurrence (defined as ICH within six month after index event) in order to better understand the mechanisms for early recurrence in CAA-related ICH. Methods: Subjects were consecutive survivors (age≥55) of spontaneous symptomatic CAA-related lobar ICH according to the Boston criteria drawn from an ongoing longitudinal cohort study. All subjects had brain computed tomography (CT) scan and magnetic resonance imaging (MRI) at presentation. Baseline clinical, imaging and laboratory data were collected. Neuroimaging markers including focal (≤3 sulci) or disseminated (>3 sulci) cortical superficial siderosis (cSS), acute convexity subarachanoid hemorrhage (cSAH), cerebral microbleeds (CMBs), white matter hyperintensities and baseline ICH volume, on CT and/or MRI were evaluated. Subjects were followed prospectively for future recurrent symptomatic ICH. Cox proportional hazard models were used to identify predictors of early recurrent ICH adjusting for potential confounders. Results: A total of 296 patients with probable or possible CAA were enrolled. In univariable analysis, the presence of disseminated cSS, cSAH, and number of CMBs were predictors of early recurrent ICH (p<0.05 for all comparisons). After adjusting for age and previous symptomatic ICH history, disseminated cSS on MRI and cSAH on CT were independent predictors of early recurrent ICH (HR 3.79, 95% CI 1.46-9.84, p=0.006, HR 3.16, 95% CI 1.05-9.51, p=0.041, respectively). Conclusions: Disseminated cSS on MRI and cSAH on CT are independent imaging markers of increased risk for early recurrent ICH. These markers may provide additional insights into the mechanisms of ICH recurrence in patients with CAA.

OPINION article Front. Neurol., 15 September 2015Sec. Stroke Volume 6 - 2015 | https://doi.org/10.3389/fneur.2015.00203

Intra-cerebral Haemorrhage (ICH) seems more prevalent in sub-Saharan Africa (SSA) than in High-Income Countries (HIC) with poorer clinical outcome. Higher impact of hypertension and/or amyloid angiopathy could account for this disproportion. Here, we sought to (i) retrospectively compare ICH clinical and imaging patterns in Belgium and Guinea and in a subsequent cohort (ii) prospectively compare brain MRI characteristics to seek evidence for a different proportion of amyloid angiopathy patterns. Ninety one consecutive patients admitted for spontaneous ICH at Brussels Erasme-ULB Hospital and at Conakry Ignace Deen-UGANC were retrospectively compared in terms of ICH volume estimated with the ABC/2 method, clinical characteristics and modified ranking (mRS) score at 30days. mRS was dichotomised as good outcomes (≤3) and poor outcomes (>3). A prospective cohort of 30 consecutive patients with ICH admitted at CHU Conakry Ignace Deen-UGANC was prospectively included to undergo brain MRI. Results of the Guinean MRI were compared to 30 patients randomly selected from Brussels' initial cohort. Paired Student's t-test and Mann-Whitney u-test were used for group comparisons. Age of ICH onset was higher in Belgium (68±17years vs. 56±14years, P<0.01) while ICH volume and 30-day mortality rate were higher in Guinea (20ml vs. 11ml, P<0.01 and mortality 33% vs. 10 %, P<0.01). ICH burden in survivors in Conakry and Brussels showed respectively good outcomes in 56.7% and 60.4% (P=0.09) and poor outcomes in 10.3% vs. 29.6% (P<0.001). MRI analysis of the prospective cohort failed to disclose significant differences regarding brain MRI characteristics. Intra-cerebral Haemorrhage affected patients 15years younger in Guinea with larger haematoma volumes and higher mortality than in Belgium. MRI findings did not show more prevalent amyloid angiopathy pathology suggesting that better primary prevention of hypertension could positively impact ICH epidemiology in Guinea.

To evaluate intracerebral hemorrhage (ICH) risk in patients with ischemic stroke (IS) and cerebral microbleeds (CMBs) undergoing anticoagulation therapy for non-valvular atrial fibrillation (AF). We conducted a comprehensive search across multiple databases, including Embase, PubMed, Cochrane, UpToDate, Scopus, WOS, and SinoMed. The search covered observational literature published from each database inception until February 1, 2023. We analyzed the prevalence of CMBs during the follow-up period, compared future ICH risk between patients with and without baseline CMBs (CMBs presence/absence, ≧5 CMBs), and examined factors influencing ICH occurrence in patients with CMBs. Also studied recurrent stroke during anticoagulation therapy, the risk of future ICH when white matter hyperintensity (WMH) and CMBs coexist, and the effects of anticoagulants vitamin K antagonists (VKAs) and direct oral anticoagulants (DOACs) on future ICH. We included 7 articles involving 5,134 participants. The incidence of CMBs was 24%; baseline CMBs were associated with an increased ICH risk compared to patients without CMBs. ICH-risk was more significant in patients with baseline ≥5 CMBs. After anticoagulant therapy, ICH risk was higher than that of recurrent IS. The risk of future ICH was significantly increased with anticoagulant VKAs compared with NOAC. Anticoagulant therapy for ischemic stroke patients with non-valvular AF and CMBs increases future ICH risk. Discontinuing anticoagulation due to ICH risk should be avoided. NOACs are safe and effective for patients with CMBs and IS.

Elderly and forgetful with transient neurological spells: A story of two amyloids?

Maximizing Brain Health After Hemorrhagic Stroke: Bugher Foundation Centers of Excellence.

CT scanning to diagnose CAA: back to the future?

Aim: To explore the predictive values of different small vessel disease (SVD) scores on functional recoveries and the clinical cerebrovascular events in mild intracerebral hemorrhage (ICH). Methods: In this study, we enrolled conscious and mild ICH patients without surgery and further divided them into the cerebral amyloid angiopathy (CAA)-ICH group and hypertension (HTN)-ICH group. The severity of individual SVD markers, including lacunes, cerebral microbleeds (CMBs), enlarged perivascular spaces (EPVS), white matter hyperintensity (WMH), and cortical superficial siderosis (cSS), was evaluated. The original SVD score, modified SVD score, refined SVD score, and CAA-SVD score and the total number of SVD markers were further calculated. Functional recoveries were evaluated using the modified Rankin scale. Recurrences of stroke were defined as readmission to the hospital with a definite diagnosis of stroke. Results: A total of 163 ICH patients (60 CAA-ICH and 103 HTN-ICH) were included in the study. The CAA-SVD score (OR=3.429; 95% confidence interval (CI)=1.518–7.748) had the best predictive effect on functional dependence in the CAA-ICH group, among which cSS severities probably played a vital role (OR=4.665; 95% CI=1.388–15.679). The total number of SVD markers [hazard ratio (HR)=3.765; 95% CI=1.467–9.663] can better identify stroke recurrences in CAA-ICH. In HTN-ICH, while the total number of SVD markers (HR=2.136; 95% CI=1.218–3.745) also demonstrated association with recurrent stroke, this effect seems to be related with the influence of lacunes (HR=5.064; 95% CI=1.697–15.116). Conclusions: The CAA-SVD score and the total number of SVD markers might identify mild CAA-ICH patients with poor prognosis. However, it would be better to focus on lacunes rather than on the overall burden of SVD to predict recurrent strokes in HTN-ICH.

Background and Purpose: Whether patients with both lobar and deep cerebral microbleeds (mixed CMB) have advanced cerebral amyloid angiopathy (CAA), hypertensive angiopathy (HA) or both is uncertain. To get insight into the underlying small vessel disease (SVD) associated with mixed CMB, we explored its association with cortical superficial siderosis (cSS), a key marker of CAA and other MRI markers of SVD in patients with intracerebral hemorrhage (ICH).Methods: Of 425 consecutive patients with acute ICH who had received brain MRIs, 260 had ≥1 CMB and were included in the analysis. They were categorized as strictly lobar CMB (suggesting CAA), strictly deep CMB (suggesting HA) or mixed CMB. Clinical and imaging characteristics were compared (1) between the three CMB groups and (2) within mixed CMB patients according to the symptomatic ICH location.Results: Overall, 111 (26%) patients had mixed CMB. Compared to strictly lobar CMB (n = 111) and strictly deep CMB (n = 38), patients with mixed CMB had a more severe burden of lacune, white matter hyperintensities and CMB. cSS was observed in 24.3% of patients with mixed CMB compared to 44.1% in strictly lobar CMB and 10.5% in strictly deep CMB (p < 0.0001). Among patients with mixed CMB, 44 (39.6%) had a lobar symptomatic ICH and 67 (60.4%) had a non-lobar ICH. Patients with non-lobar ICH were more likely to have hypertension, whereas those with lobar ICH were more likely to have cSS and chronic lobar ICH and had higher ratio lobar CMB count/total CMB count.Conclusions: Mixed CMB is frequently encountered in patients with ICH and appears as a heterogeneous group, suggesting that both CAA and HA may be contributing to mixed CMB. Neuroimaging markers including ICH location, cSS, and CMB distribution may indicate the predominant underlying vasculopathy, with potential prognostic implications.

Objective:We evaluated recurrent intracerebral hemorrhage (ICH) risk in ICH survivors, stratified by the presence, distribution, and number of cerebral microbleeds (CMBs) on MRI (i.e., the presumed causal underlying small vessel disease and its severity).Methods:This was a meta-analysis of prospective cohorts following ICH, with blood-sensitive brain MRI soon after ICH. We estimated annualized recurrent symptomatic ICH rates for each study and compared pooled odds ratios (ORs) of recurrent ICH by CMB presence/absence and presumed etiology based on CMB distribution (strictly lobar CMBs related to probable or possible cerebral amyloid angiopathy [CAA] vs non-CAA) and burden (1, 2–4, 5–10, and >10 CMBs), using random effects models.Results:We pooled data from 10 studies including 1,306 patients: 325 with CAA-related and 981 CAA-unrelated ICH. The annual recurrent ICH risk was higher in CAA-related ICH vs CAA-unrelated ICH (7.4%, 95% confidence interval [CI] 3.2–12.6 vs 1.1%, 95% CI 0.5–1.7 per year, respectively; p = 0.01). In CAA-related ICH, multiple baseline CMBs (versus none) were associated with ICH recurrence during follow-up (range 1–3 years): OR 3.1 (95% CI 1.4–6.8; p = 0.006), 4.3 (95% CI 1.8–10.3; p = 0.001), and 3.4 (95% CI 1.4–8.3; p = 0.007) for 2–4, 5–10, and >10 CMBs, respectively. In CAA-unrelated ICH, only >10 CMBs (versus none) were associated with recurrent ICH (OR 5.6, 95% CI 2.1–15; p = 0.001). The presence of 1 CMB (versus none) was not associated with recurrent ICH in CAA-related or CAA-unrelated cohorts.Conclusions:CMB burden and distribution on MRI identify subgroups of ICH survivors with higher ICH recurrence risk, which may help to predict ICH prognosis with relevance for clinical practice and treatment trials.

Objective: Cerebral amyloid angiopathy (CAA) is increasing recognized as a cause of cognitive impairment and dementia in older individuals. This study aimed to investigate predictors of dementia, including imaging markers, in CAA patients from a stroke unit. Methods: A total of 71 non-demented patients from a stroke unit were included according to modified Boston Criteria for probable CAA with available cognitive follow up. These CAA patients included both patients with and patients without previous intracerebral hemorrhage (ICH). At baseline, neuroimaging markers, including lobar microbleeds (CMBs), white matter hyperintensities (WMH), cortical superficial siderosis (cSS) and MRI-visible centrum semiovale perivascular spaces (CSO-PVS) were assessed. The small vessel disease (SVD) score for CAA was calculated by the scores of CMBs, WMH, cSS and CSO-PVS. The association between these neuroimaging markers and dementia conversion was analyzed. Results: The median follow up time is 1.91 years (quartiles 1.14-4.23 years). Fourteen (19.72%) CAA patients developed dementia during follow up period. Thirty-seven CAA patients (52.11%) had previous symptomatic ICH. Age, lobar CMBs≥20 and SVD score were selected from the univariate Cox-regression analysis with p value less than 0.1 (Table1). In a backward stepwise multivariabte analysis including age, previous ICH history and either SVD score or number of CMBs, age and SVD score independently predicted dementia conversion (Table 1). The individual neuroimaging markers for SVD related brain damage (CSO-PVS, cSS, lobar MBs and WMH) did not predict dementia conversion for probable CAA patients. Conclusion: Our results demonstrate that cognitive deterioration of CAA patients appears attributed to cumulative CAA related vasculopathic changes.

To assess MRI-visible enlarged perivascular spaces (EPVS) burden and different topographical patterns (in the centrum semiovale [CSO] and basal ganglia [BG]) in 2 common microangiopathies: cerebral amyloid angiopathy (CAA) and hypertensive arteriopathy (HA). Consecutive patients with spontaneous intracerebral hemorrhage (ICH) from a prospective MRI cohort were included. Small vessel disease MRI markers, including cerebral microbleeds (CMBs), cortical superficial siderosis (cSS), and white matter hyperintensities (WMH), were rated. CSO-EPVS/BG-EPVS were assessed on a validated 4-point visual rating scale (0 = no EPVS, 1 = <10, 2 = 11-20, 3 = 21-40, and 4 = >40 EPVS). We tested associations of predefined high-degree (score >2) CSO-EPVS and BG-EPVS with other MRI markers in multivariable logistic regression. We subsequently evaluated associations with CSO-EPVS predominance (i.e., CSO-EPVS > BG-EPVS) and BG-EPVS predominance pattern (i.e., BG-EPVS > CSO-EPVS) in adjusted multinomial logistic regression (reference group, BG-EPVS = CSO-EPVS). We included 315 patients with CAA-ICH and 137 with HA-ICH. High-degree CSO-EPVS prevalence was greater in CAA-related ICH vs HA-related ICH (43.8% vs 17.5%, p < 0.001). In multivariable logistic regression, high-degree CSO-EPVS was associated with lobar CMB (odds ratio [OR] 1.33, 95% confidence interval [CI] 1.10-1.61, p = 0.003) and cSS (OR 2.08, 95% CI 1.30-3.32, p = 0.002). Deep CMBs (OR 2.85, 95% CI 1.75-4.64, p < 0.0001) and higher WMH volume (OR 1.02, 95% CI 1.01-1.04, p = 0.010) were predictors of high-degree BG-EPVS. A CSO-EPVS-predominant pattern was more common in CAA-ICH than in HA-ICH (75.9% vs 39.4%, respectively, p < 0.0001). CSO-PVS predominance was associated with lobar CMB burden and cSS, while BG-EPVS predominance was associated with HA-ICH and WMH volumes. Different patterns of MRI-visible EPVS provide insights into the dominant underlying microangiopathy type in patients with spontaneous ICH.