CAA-related Intracerebral Hemorrhage Research Articles

Risk factors for intracerebral hemorrhage in small-vessel disease and non-small-vessel disease etiologies-an observational proof-of-concept study.

Sporadic cerebral small-vessel disease (CSVD), i.e., hypertensive arteriopathy (HA) and cerebral amyloid angiopathy (CAA), is the main cause of spontaneous intracerebral hemorrhage (ICH). Nevertheless, a substantial portion of ICH cases arises from non-CSVD etiologies, such as trauma, vascular malformations, and brain tumors. While studies compared HA- and CAA-related ICH, non-CSVD etiologies were excluded from these comparisons and are consequently underexamined with regard to additional factors contributing to increased bleeding risk beyond their main pathology. As a proof of concept, we conducted a retrospective observational study in 922 patients to compare HA, CAA, and non-CSVD-related ICH with regard to factors that are known to contribute to spontaneous ICH onset. Medical records (available for n = 861) were screened for demographics, antithrombotic medication, and vascular risk profile, and CSVD pathology was rated on magnetic resonance imaging (MRI) in a subgroup of 185 patients. The severity of CSVD was assessed with a sum score ranging from 0 to 6, where a score of ≥2 was defined as advanced pathology. In 922 patients with ICH (median age of 71 years), HA and CAA caused the majority of cases (n = 670, 73%); non-CSVD etiologies made up the remaining quarter (n = 252, 27%). Individuals with HA- and CAA-related ICH exhibited a higher prevalence of predisposing factors than those with non-CSVD etiologies. This includes advanced age (median age: 71 vs. 75 vs. 63 years, p < 0.001), antithrombotic medication usage (33 vs. 37 vs. 19%, p < 0.001), prevalence of vascular risk factors (70 vs. 67 vs. 50%, p < 0.001), and advanced CSVD pathology on MRI (80 vs. 89 vs. 51%, p > 0.001). However, in particular, half of non-CSVD ICH patients were either aged over 60 years, presented with vascular risk factors, or had advanced CSVD on MRI. Risk factors for spontaneous ICH are less common in non-CSVD ICH etiologies than in HA- and CAA-related ICH, but are still frequent. Future studies should incorporate these factors, in addition to the main pathology, to stratify an individual's risk of bleeding.

Cerebral Amyloid Angiopathy and Risk of Isolated Nontraumatic Subdural Hemorrhage

Cerebral amyloid angiopathy (CAA) is a common cause of spontaneous intracerebral hemorrhage in older patients. Although other types of intracranial hemorrhage can occur in conjunction with CAA-related intracerebral hemorrhage, the association between CAA and other subtypes of intracranial hemorrhage, particularly in the absence of intracerebral hemorrhage, remains poorly understood. To determine whether CAA is an independent risk factor for isolated nontraumatic subdural hemorrhage (SDH). A population-based cohort study was performed using a 2-stage analysis of prospectively collected data in the UK Biobank cohort (discovery phase, 2006-2022) and the All of Us Research Program cohort (replication phase, 2018-2022). Participants included those who contributed at least 1 year of data while they were older than 50 years, in accordance with the diagnostic criteria for CAA. Participants with prevalent intracranial hemorrhage were excluded. Data were analyzed from October 2022 to October 2023. A diagnosis of CAA, identified using the International Classification of Diseases, Tenth Revision, Clinical Modification (ICD-10-CM) diagnosis code. The outcome was an isolated nontraumatic SDH, identified using ICD-10-CM codes. Two identical analyses were performed separately in the 2 cohorts. First, the risk of SDH in patients with and without CAA was assessed using Cox proportional hazards models, adjusting for demographic characteristics, cardiovascular comorbidities, and antithrombotic medication use. Second, multivariable logistic regression was used to study the association between CAA and SDH. The final analytical sample comprised 487 223 of the total 502 480 individuals in the UK Biobank cohort and 158 008 of the total 372 082 individuals in the All of Us cohort. Among the 487 223 participants in the discovery phase of the UK Biobank, the mean (SD) age was 56.5 (8.1) years, and 264 195 (54.2%) were female. There were 649 cases of incident SDH. Of the 126 participants diagnosed with CAA, 3 (2.4%) developed SDH. In adjusted Cox regression analyses, participants with CAA had an increased risk of having an SDH compared with those without CAA (hazard ratio [HR], 8.0; 95% CI, 2.6-24.8). Multivariable logistic regression analysis yielded higher odds of SDH among participants with CAA (odds ratio [OR], 7.6; 95% CI, 1.8-20.4). Among the 158 008 participants in the All of Us cohort, the mean (SD) age was 63.0 (9.5) years, and 89 639 (56.7%) were female. The findings were replicated in All of Us, in which 52 participants had CAA and 320 had an SDH. All of Us participants with CAA had an increased risk of having an SDH compared with those without CAA (HR, 4.9; 95% CI, 1.2-19.8). In adjusted multivariable logistic regression analysis, CAA was associated with higher odds of SDH (OR, 5.2; 95% CI, 0.8-17.6). In 2 large, heterogeneous cohorts, CAA was associated with increased risk of SDH. These findings suggest that CAA may be a novel risk factor for isolated nontraumatic SDH.

Deep Medullary Vein and MRI Markers Were Related to Cerebral Hemorrhage Subtypes.

To explore the performance of deep medullary vein (DMV) and magnetic resonance imaging (MRI) markers in different intracerebral hemorrhage (ICH) subtypes in patients with cerebral small vessel disease (CSVD). In total, 232 cases of CSVD with ICH were included in this study. The clinical and image data were retrospectively analyzed. Patients were divided into hypertensive arteriopathy (HTNA)-related ICH, cerebral amyloid angiopathy (CAA)-related ICH, and mixed ICH groups. The DMV score was determined in the cerebral hemisphere contralateral to the ICH. The DMV score was different between the HTNA-related and mixed ICH groups (p < 0.01). The MRI markers and CSVD burden score were significant among the ICH groups (p < 0.05). Compared to mixed ICH, HTNA-related ICH diagnosis was associated with higher deep white matter hyperintensity (DWMH) (OR: 0.452, 95% CI: 0.253-0.809, p < 0.05) and high-degree perivascular space (PVS) (OR: 0.633, 95% CI: 0.416-0.963, p < 0.05), and CAA-related ICH diagnosis was associated with increased age (OR: 1.074; 95% CI: 1.028-1.122, p = 0.001). The DMV score correlated with cerebral microbleed (CMB), PVS, DWMH, periventricular white matter hyperintensity (PWMH), and CSVD burden score (p < 0.05) but not with lacuna (p > 0.05). Age was an independent risk factor for the severity of DMV score (OR: 1.052; 95% CI: 0.026-0.076, p < 0.001). DMV scores, CSVD markers, and CSVD burden scores were associated with different subtypes of ICH. In addition, DMV scores were associated with the severity of CSVD and CSVD markers.

Abstract 164: Cerebral Amyloid Angiopathy Is Associated With A Higher Risk Of Subdural Hemorrhage: Combined Analysis Of The Uk Biobank And All Of Us

Background: Cerebral amyloid angiopathy (CAA) is a condition characterized by amyloid deposition in the brain’s blood vessels. CAA is a common cause of spontaneous intracerebral hemorrhage (ICH) in older patients. Although other types of intracranial hemorrhages can occur in conjunction with CAA-related ICH, it is unknown whether CAA is a risk factor for other types of intracranial hemorrhage in the absence of ICH. Hypothesis: CAA is an independent risk factor for isolated non-traumatic subdural hemorrhage (SDH). Methods: We conducted a 2-stage (discovery and replication) observational study that retrospectively analyzed data from the UK Biobank (discovery phase) and the All of Us (replication phase) study. We included participants over 55 years of age to meet the age threshold for the modified Boston Criteria. The exposure was a diagnosis of CAA and the outcome was non-traumatic SDH, both identified using ICD-9 and ICD-10 codes. We used survival analyses with log-rank tests and multivariable Cox proportional hazards models adjusted for demographic characteristics and vascular risk factors. Results: The discovery phase included 283,452 UK Biobank participants comprising 123 CAA cases and 504 SDH cases. SDH subsequently occurred in 2.4% of participants with CAA versus 0.2% of those without CAA. In a multivariable Cox model, CAA was associated with a significantly increased risk of SDH (hazard ratio [HR], 7.3; 95% CI, 2.3-22.7). This finding was replicated among 168,370 study participants in All of US, where 66 had CAA and 443 had a SDH (HR, 11.66; 95% CI, 5.2-26.2). Conclusion: In two large heterogeneous cohorts conducted in different countries, CAA was independently associated with a higher risk of isolated non-traumatic SDH. Further research is needed to further determine causality and identify biological pathways that may mediate this association.

The Use of Serum Matrix Metalloproteinases in Cerebral Amyloid Angiopathy-Related Intracerebral Hemorrhage and Cognitive Impairment.

Neuroimaging has played a primary role in predicting intracerebral hemorrhage (ICH) recurrence of cerebral amyloid angiopathy (CAA); however, the utilities of biomarkers in CAA-related ICH and cognitive impairment remain unexplored. To investigate the correlations of serum levels of matrix metalloproteinase-2 (MMP-2), MMP-3, and MMP-9 with CAA-related MRI markers, ICH recurrence, and cognitive status. 68 cases with first probable CAA-ICH and 69 controls were recruited. Clinical and imaging data were obtained at baseline and serum MMPs in the acute phase were measured by Luminex multiplex assays. Cognitive status was assessed with the Chinese version of Mini-Mental State Examination within 10-14 days after ICH onset. Serum MMP-2 level was significantly lower in CAA-ICH patients than controls while MMP-9 was significantly higher. In CAA-ICH patients, MMP-3 level was significantly associated with lobar cerebral microbleeds count after adjusting age, sex, and hypertension (adjusted coefficient 0.368, 95%CI 0.099-0.637, p = 0.008). During a median follow-up of 2.4 years, higher level of MMP-2 predicted lower CAA-ICH recurrence after adjusting age (adjusted HR 0.326, 95%CI 0.122-0.871, p = 0.025), ICH volume (adjusted HR 0.259, 95%CI 0.094-0.715, p = 0.009), total MRI burden of SVD score (adjusted HR 0.350, 95%CI 0.131-0.936, p = 0.037) respectively. Besides, higher level of MMP-2 was significantly associated with decreased risk of cognitive impairment independent of age and ICH volume (adjusted OR 0.054, 95%CI 0.005-0.570, p = 0.015). Serum MMP-2 in acute phase might be a promising biomarker to predict CAA-ICH recurrence and to evaluate the risk of cognitive impairment.

Centrum Semiovale Perivascular Space and Amyloid Deposition in Spontaneous Intracerebral Hemorrhage.

We explored whether high-degree magnetic resonance imaging–visible perivascular spaces in centrum semiovale (CSO) are more prevalent in cerebral amyloid angiopathy (CAA) than hypertensive small vessel disease and their relationship to brain amyloid retention in patients with primary intracerebral hemorrhage (ICH). One hundred and eight spontaneous ICH patients who underwent magnetic resonance imaging and Pittsburgh compound B were enrolled. Topography and severity of enlarged perivascular spaces were compared between CAA-related ICH (CAA-ICH) and hypertensive small vessel disease–related ICH (non-CAA ICH). Clinical and image characteristics associated with high-degree perivascular spaces were evaluated in univariate and multivariable analyses. Univariate and multivariable models were performed to evaluate associations between the severity of perivascular spaces in CSO and amyloid retention in CAA-ICH and non–CAA-ICH cases. Patients with CAA-ICH (n=29) and non–CAA-ICH (n=79) had similar prevalence of high-degree perivascular spaces in CSO (44.8% versus 36.7%; P=0.507) and in basal ganglia (34.5% versus 51.9%; P=0.131). High-degree perivascular spaces in CSO were independently associated with the presence of lobar microbleed (odds ratio, 3.0 [95% CI, 1.1–8.0]; P=0.032). The amyloid retention was higher in those with high-degree than those with low-degree CSO-perivascular spaces in CAA-ICH (global Pittsburgh compound B standardized uptake value ratio, 1.55 [1.33–1.61] versus 1.13 [1.01–1.48]; P=0.003) but not in non–CAA-ICH. In CAA-ICH, the association between cerebral amyloid retention and the degree of perivascular spaces in CSO remained significant after adjustment for age and lobar microbleed number (P=0.004). Although high-degree magnetic resonance imaging–visible perivascular spaces are equally prevalent between CAA-ICH and non–CAA-ICH in the Asian cohort, the severity of magnetic resonance imaging–visible CSO-perivascular spaces may be an indicator of higher brain amyloid deposition in patients with CAA-ICH.

Circulating AQP4 Levels in Patients with Cerebral Amyloid Angiopathy-Associated Intracerebral Hemorrhage.

Cerebral amyloid angiopathy (CAA) is a major cause of lobar intracerebral hemorrhage (ICH) in elderly patients. Growing evidence suggests a potential role of aquaporin 4 (AQP4) in amyloid-beta-associated diseases, including CAA pathology. Our aim was to investigate the circulating levels of AQP4 in a cohort of patients who had suffered a lobar ICH with a clinical diagnosis of CAA. AQP4 levels were analyzed in the serum of 60 CAA-related ICH patients and 19 non-stroke subjects by enzyme-linked immunosorbent assay (ELISA). The CAA–ICH cohort was divided according to the time point of the functional outcome evaluation: mid-term (12 ± 18.6 months) and long-term (38.5 ± 32.9 months) after the last ICH. Although no differences were found in AQP4 serum levels between cases and controls, lower levels were found in CAA patients presenting specific hemorrhagic features such as ≥2 lobar ICHs and ≥5 lobar microbleeds detected by magnetic resonance imaging (MRI). In addition, CAA-related ICH patients who presented a long-term good functional outcome had higher circulating AQP4 levels than subjects with a poor outcome or controls. Our data suggest that AQP4 could potentially predict a long-term functional outcome and may play a protective role after a lobar ICH.

Abstract P457: Cerebral Small Vessel Disease and Depression Severity Among Intracerebral Hemorrhage Survivors

Introduction: Intracerebral Hemorrhage (ICH) is an acute manifestation of underlying Cerebral Small Vessel Disease (CSVD), usually Cerebral Amyloid Angiopathy (CAA) or Hypertensive Arteriopathy (HTNA). CSVD-related imaging and histopathology findings were previously associated with increased depression incidence in the general population. CSVD evaluation via neuroimaging may therefore provide insight on depression risk among ICH survivors. We sought to determine whether hematoma location and CSVD MRI markers are associated with depression risk (before and after ICH) and resistance to treatment. Methods: We analyzed data from the single-center longitudinal ICH study conducted at Massachusetts General Hospital (MGH-ICH) since 1994 and currently ongoing. All participants underwent CT and MRI imaging, and were then followed longitudinally via a combination of semi-automated review of Electronic Medical Records (EMR) and phone-based research interviews. We extracted information for hematoma location and MRI neuroimaging markers of CSVD subtype and severity. We conducted univariable and multivariable analyses of depression prevalence before ICH, new-onset of depression after ICH, and resolution of depressive symptoms during follow-up. Results: We enrolled 612 ICH survivors, and followed them for a median of 46.3 months (Inter-Quartile Range: 35.5-58.7). Multiple CSVD-related markers were associated with depression outcomes of interest. Survivors of CAA-related lobar ICH were at highest risk for depression (before and after ICH), as well as treatment resistance (all p&lt;0.05). CAA disease burden on MRI was also associated with depression risk and treatment resistance, whereas HTNA disease burden was only associated with risk of depression after ICH. Conclusions: CSVD severity on neuroimaging is associated with depression prevalence and treatment-resistance among ICH survivors. CAA-related ICH survivors are at higher risk for depression (both before and after ICH) than patients diagnosed with HTNA-related ICH. The potential role of CSVD evaluation in guiding care of ICH survivors with -or at high risk for- depression warrants additional investigative efforts

Taxifolin: A Potential Therapeutic Agent for Cerebral Amyloid Angiopathy.

Cerebral amyloid angiopathy (CAA) is characterized by the accumulation of β-amyloid (Aβ) in the walls of cerebral vessels, leading to complications such as intracerebral hemorrhage, convexity subarachnoid hemorrhage and cerebral microinfarcts. Patients with CAA-related intracerebral hemorrhage are more likely to develop dementia and strokes. Several pathological investigations have demonstrated that more than 90% of Alzheimer’s disease patients have concomitant CAA, suggesting common pathogenic mechanisms. Potential causes of CAA include impaired Aβ clearance from the brain through the intramural periarterial drainage (IPAD) system. Conversely, CAA causes restriction of IPAD, limiting clearance. Early intervention in CAA could thus prevent Alzheimer’s disease progression. Growing evidence has suggested Taxifolin (dihydroquercetin) could be used as an effective therapy for CAA. Taxifolin is a plant flavonoid, widely available as a health supplement product, which has been demonstrated to exhibit anti-oxidative and anti-inflammatory effects, and provide protection against advanced glycation end products and mitochondrial damage. It has also been shown to facilitate disassembly, prevent oligomer formation and increase clearance of Aβ in a mouse model of CAA. Disturbed cerebrovascular reactivity and spatial reference memory impairment in CAA are completely prevented by Taxifolin treatment. These results highlight the need for clinical trials on the efficacy and safety of Taxifolin in patients with CAA

18 F]FDG PET may differentiate cerebral amyloid angiopathy from Alzheimer's disease.

Cerebral amyloid angiopathy (CAA) is a frequent cause of both intracerebral hemorrhage (ICH) and cognitive impairment in the elderly. Diagnosis relies on the Boston criteria, which use magnetic resonance imaging markers including ≥2 exclusively lobar cerebral microbleeds (lCMBs). Although amyloid positron emission tomography (PET) may provide molecular diagnosis, its specificity relative to Alzheimer's disease (AD) is limited due to the prevalence of positive amyloid PET in cognitively normal elderly. Using early-phase 11 C-Pittsburgh compound B as surrogate for tissue perfusion, a significantly lower occipital/posterior cingulate (O/PC) tracer uptake ratio in probable CAA relative to AD was recently reported, consistent with histopathological lesion distribution. We tested whether this finding could be reproduced using [18 F]fluorodeoxyglucose (FDG)-PET, a widely available modality that correlates well with early-phase amyloid PET in both healthy subjects and AD. From a large memory clinic database, we retrospectively included 14 patients with probable CAA (Boston criteria) and 21 patients with no lCMB fulfilling AD criteria including cerebrospinal fluid biomarkers. In all, [18 F]FDG-PET/computed tomography (CT) was available as part of routine care. No subject had a clinical history of ICH. Regional standardized [18 F]FDG uptake values normalized to the pons (standard uptake value ratio [SUVr]) were obtained, and the O/PC ratio was calculated. The SUVr O/PC ratio was significantly lower in CAA versus AD (1.02±0.14 vs. 1.19±0.18, respectively; p=0.024). Despite the small sample, our findings are consistent with the previous early-phase amyloid PET study. Thus, [18 F]FDG-PET may help differentiate CAA from AD, particularly in cases of amyloid PET positivity. Larger prospective studies, including in CAA-related ICH, are however warranted.

Intracerebral Hemorrhage Recurrence in Patients with and without Cerebral Amyloid Angiopathy

Background: Intracerebral hemorrhage (ICH) recurrence risk is known to be higher in patients with cerebral amyloid angiopathy (CAA) as compared to other causes of ICH. Risk factors for ICH recurrence are not completely understood, and our goal was to study specific imaging microangiopathy markers. Methods: Retrospective case-control study of patients with non-traumatic ICH admitted to a single center between 2014 and 2017 who underwent magnetic resonance imaging (MRI). Clinical characteristics of the index event and occurrence of death and ICH recurrence were collected from clinical records. MRI images were independently reviewed by 2 neuroradiologists. Groups of patients with CAA-related and CAA-unrelated ICH defined were compared. Presence of CAA was defined according to the Boston modified criteria. Survival analysis with Kaplan-Meier curves and Cox-regression analyses was performed to analyze ICH recurrence-free survival. Results: Among 448 consecutive patients with non-traumatic ICH admitted during the study period, 104 were included in the study, mean age 64 years (±13.5), median follow-up of 27 months (interquartile range, IQR 16–43), corresponding to 272 person-years of total follow-up. CAA-related ICH patients presented higher burden of lobar microbleeds (p < 0.001), higher burden of enlarged perivascular spaces (EPVS) in centrum semiovale (p < 0.001) and more frequently presented cortical superficial siderosis (cSS; p < 0.001). ICH recurrence in patients with CAA was 12.7 per 100 person-years, and no recurrence was observed in patients without CAA. Variables associated with ICH recurrence in the whole population were age (hazard ratio [HR] per 1-year increment = 1.05, 95% CI 1.00–1.11, p = 0.046), presence of disseminated cSS (HR 3.32, 95% CI 1.09–10.15, p = 0.035) and burden of EPVS in the centrum semiovale (HR per 1-point increment = 1.80, 95% CI 1.04–3.12, p = 0.035). Conclusions: This study confirms a higher ICH recurrence risk in patients with CAA-related ICH and suggests that age, disseminated cSS, and burden of EPVS in the centrum semiovale are associated with ICH recurrence.

Interhemispheric distribution of amyloid and small vessel disease burden in cerebral amyloid angiopathy-related intracerebral hemorrhage.

Intracerebral hemorrhage (ICH) is a devastating presentation of cerebral amyloid angiopathy (CAA), but the mechanisms leading from vascular amyloid deposition to ICH are not well known. Whether amyloid burden and magnetic resonance imaging (MRI) markers of small vessel disease (SVD) are increased in the ICH-affected hemisphere compared to the ICH-free hemisphere in patients with a symptomatic CAA-related ICH was investigated. Eighteen patients with CAA-related ICH and 18 controls with deep ICH who underwent brain MRI and amyloid positron emission tomography using 18 F-florbetapir were prospectively enrolled. In each hemisphere amyloid uptake using the standardized uptake value ratio and the burden of MRI markers of SVD including cerebral microbleeds, chronic ICH, cortical superficial siderosis, white matter hyperintensities and lacunes were evaluated. Interhemispheric comparisons were assessed by non-parametric matched-pair tests within each patient group. Amyloid burden was similarly distributed across the brain hemispheres in patients with CAA-related ICH (standardized uptake value ratio 1.11 vs. 1.12; P=0.74). Cortical superficial siderosis tended to be more common in the ICH-affected hemisphere compared to the ICH-free hemisphere (61% vs. 33%; P=0.063). Other MRI markers of SVD did not differ across brain hemispheres. In controls with deep ICH, no interhemispheric difference was observed either for amyloid burden or for MRI markers of SVD. Brain hemorrhage does not appear to be directly linked to amyloid burden in patients with CAA-related ICH. These findings provide new insights into the mechanisms leading to hemorrhage in CAA.

Florbetapir Regional Distribution in Cerebral Amyloid Angiopathy and Alzheimer's Disease: A PET Study.

Background:Sporadic cerebral amyloid angiopathy shows progressive amyloid-β deposition in the wall of small arterioles and capillaries of the leptomeninges and cerebral cortex.Objective:To investigate whether amyloid load and distribution, assessed by florbetapir positron emission tomography (PET), differs between patients with probable CAA-related intracerebral hemorrhage (CAA-ICH) and mild cognitive impairment due to Alzheimer’s disease (MCI-AD).Methods:We assessed [18F]florbetapir uptake in 15 patients with probable CAA-ICH and 20 patients with MCI-AD patients. Global and regional florbetapir retention were assessed using standard uptake values ratio (SUVr) in region-based and voxel-wise approaches. Visual reading of florbetapir scans was performed for all participants. Group comparisons were performed using univariate and multivariate analysis.Results:Global florbetapir retention was lower in patients with CAA-ICH than MCI-AD (median SUVr, 1.33 [1.21–1.41] versus 1.44 [1.35–1.66]; p = 0.032). In the region-based analysis, regional florbetapir distribution was similar between the two groups. There was a trend for an increased occipital/global ratio in CAA-ICH patients compared to MCI-AD (p = 0.060). In the voxel-wise approach, two clusters, one in parietal regions and the other in temporal regions, had higher uptake in MCI-AD relative to CAA patients.Conclusions:Patients with CAA-ICH had a lower global florbetapir PET burden than patients with MCI-AD. Relative florbetapir retention in the posterior regions tended to be higher in CAA patients in region-based analysis but was not statistically different between groups. Investigation on differences in amyloid deposits distribution between groups required a fine-grained voxel-wise analysis. In future studies, selective amyloid tracers are needed to differentiate vascular from parenchymal amyloid.

Convexity subarachnoid hemorrhage in lobar intracerebral hemorrhage: A prognostic marker.

To investigate whether acute convexity subarachnoid hemorrhage (cSAH) associated with acute lobar intracerebral hemorrhage (ICH) increases the risk of ICH recurrence in patients with cerebral amyloid angiopathy (CAA). We analyzed data from a prospective cohort of consecutive survivors of acute spontaneous lobar ICH fulfilling the Boston criteria for possible or probable CAA (CAA-ICH). We analyzed baseline clinical and MRI data, including cSAH (categorized as adjacent or remote from ICH on a standardized scale), cortical superficial siderosis (cSS), and other CAA MRI markers. Multivariable Cox regression models were used to assess the association between cSAH and recurrent symptomatic ICH during follow-up. We included 261 CAA-ICH survivors (mean age 76.2 ± 8.7 years). Of them, 166 (63.6%, 95% confidence interval [CI] 57.7%-69.5%) had cSAH on baseline MRI. During a median follow-up of 28.3 (interquartile range 7.2-57.0) months, 54 (20.7%) patients experienced a recurrent lobar ICH. In Cox regression, any cSAH, adjacent cSAH, and remote cSAH were independent predictors of recurrent ICH after adjustment for other confounders, including cSS. Incidence rate of recurrent ICH in patients with cSAH was 9.9 per 100 person-years (95% CI 7.3-13.0) compared with 1.2 per 100 person-years (95% CI 0.3-3.2) in those without cSAH (adjusted hazard ratio 7.5, 95% CI 2.6-21.1). In patients with CAA-related acute ICH, cSAH (adjacent or remote from lobar ICH) is commonly observed and heralds an increased risk of recurrent ICH. cSAH may help stratify bleeding risk and should be assessed along with cSS for prognosis and clinical management.

Cerebral amyloid angiopathy-related intracerebral hemorrhage: Feasibility and safety of bedside catheter hematoma evacuation with urokinase

ObjectiveCerebral amyloid angiopathy (CAA) is an important cause of intracerebral hemorrhage (ICH). However, data on surgical intervention in CAA-related ICH is very limited. In this retrospective study we assessed safety and efficacy of free-hand catheter aspiration followed by local thrombolysis in CAA-related large ICH. Patients and MethodsPatients with CAA-related lobar ICH>30 ml that were treated with this catheter technique were identified from our prospective database. The catheter was inserted at the bedside in the core of the hematoma and urokinase (5000IE) was administered every 6 h for a maximum of 4 days. Evolution of hematoma volume, perihemorrhagic edema (PHE) and midline-shift (MLS) as well as adverse events and functional outcome were analyzed. ResultsTwenty-one patients (median age 79 years) were treated between 2013-2018. Hematoma volume decreased from 70 ml at admission (IQR 49–98 ml) to 52 ml (IQR 35−76 ml, p < 0.001) immediately after catheter aspiration, and to 23.5 ml (IQR 17–47 ml, p < 0.001) at the end of urokinase treatment. At day 4, PHE volume (from 45 ml [IQR 33–71 ml] to 36 ml [IQR 22–50 ml]; p = 0.001) and MLS (from 5 mm [IQR 3.5–7 mm] to 1 mm [IQR 0.5–3 mm]; p < 0.001) were reduced significantly. No infection was observed, rebleeding after administration of 4 × 5000IE urokinase occurred in one patient (5 %). At discharge, modified Rankin Scale was 3 in 33 %, 4 in 24 %, and 5 in 43 % of patients, and had further improved after rehabilitation to an mRS of 2 in 10 %, 3 in 38 %, 4 in 19 %, and 5 in 33 % (median 9 weeks after ictus). There were no patient deaths during this time. ConclusionsBedside catheter hematoma evacuation in large CAA-related ICH seemed feasible and safe and could immediately decrease mass effect. Further studies assessing functional outcome are warranted.

Subarachnoid and Subdural Hemorrhages in Lobar Intracerebral Hemorrhage Associated With Cerebral Amyloid Angiopathy.

Background and Purpose- Identifying underlying cerebral amyloid angiopathy (CAA) in patients with intracerebral hemorrhage (ICH) has important clinical implication. Convexity subarachnoid hemorrhage (cSAH) and subdural hemorrhage (SDH) are computed tomography features of CAA-related ICH. We explored whether cSAH and SDH could be additional magnetic resonance imaging markers of CAA in lobar ICH survivors. Methods- We analyzed data from consecutive patients with acute lobar ICH associated with CAA (CAA-ICH) or not attributed to CAA (non-CAA-ICH). Magnetic resonance imaging scans were analyzed for cSAH, SDH, and markers of small vessel disease. The associations of cSAH and SDH with the diagnosis of probable CAA based on the modified Boston criteria were explored using multivariable models. Results- We included 165 patients with acute lobar ICH (mean age 70±13 years): 72 patients with CAA-ICH and 93 with non-CAA-ICH. Patients with CAA-ICH had a higher prevalence of cSAH (73.6% versus 39.8%; P<0.001) and SDH (37.5% versus 21.5%; P=0.02) than non-CAA-ICH. In multivariate logistic regression analysis, the presence of cSAH was independently associated with CAA-ICH (odds ratio, 2.97; 95% CI, 1.26-6.99; P=0.013), whereas there was no association between SDH and CAA-ICH. Conclusions- Among survivors of acute lobar ICH, the presence of cSAH is associated with the magnetic resonance imaging-based diagnosis of CAA. Further studies should investigate whether cSAH help improve the sensitivity of magnetic resonance imaging for in vivo diagnosis of CAA.

Cortical superficial siderosis and recurrent intracerebral hemorrhage risk in cerebral amyloid angiopathy: Large prospective cohort and preliminary meta-analysis.

We aimed to investigate cortical superficial siderosis as an MRI predictor of lobar intracerebral hemorrhage (ICH) recurrence risk in cerebral amyloid angiopathy (CAA), in a large prospective MRI cohort and a systematic review. We analyzed a single-center MRI prospective cohort of consecutive CAA-related ICH survivors. Using Kaplan-Meier and Cox regression analyses, we investigated cortical superficial siderosis and ICH risk, adjusting for known confounders. We pooled data with eligible published cohorts in a two-stage meta-analysis using random effects models. Covariate-adjusted hazard rations (adj-HR) from pre-specified multivariable Cox proportional hazard models were used. The cohort included 240 CAA-ICH survivors (cortical superficial siderosis prevalence: 36%). During a median follow-up of 2.6 years (IQR: 0.9-5.1 years) recurrent ICH occurred in 58 patients (24%). In prespecified multivariable Cox regression models, cortical superficial siderosis presence and disseminated cortical superficial siderosis were independent predictors of increased symptomatic ICH risk at follow-up (HR: 2.26; 95% CI: 1.31-3.87, p = 0.003 and HR: 3.59; 95% CI: 1.96-6.57, p < 0.0001, respectively). Three cohorts including 443 CAA-ICH patients in total were eligible for meta-analysis. During a mean follow-up of 2.5 years (range: 2-3 years) 92 patients experienced recurrent ICH (pooled risk ratio: 6.9% per year, 95% CI: 4.2%-9.7% per year). In adjusted pooled analysis, any cortical superficial siderosis and disseminated cortical superficial siderosis were the only independent predictors associated with increased lobar ICH recurrence risk (adj-HR: 2.4; 95% CI: 1.5-3.7; p < 0.0001, and adj-HR: 4.4; 95% CI: 2-9.9; p < 0.0001, respectively). In CAA-ICH patients, cortical superficial siderosis presence and extent are the most important MRI prognostic risk factors for lobar ICH recurrence. These results can help guide clinical decision making in patients with CAA.

Journal Club: Florbetapir imaging in cerebral amyloid angiopathy-related hemorrhages.

Cerebral amyloid angiopathy (CAA) is a common type of cerebral small vessel disease and a key cause of spontaneous lobar intracerebral hemorrhage (ICH) in the elderly.1,2 Currently, the clinical diagnosis of probable CAA is based on characteristic imaging findings including strictly lobar ICH and CAA-associated hemorrhagic lesions (e.g., cerebral microbleeds [CMB] and cortical superficial siderosis). Despite their high specificity for CAA,3 these lesions only provide indirect evidence of advanced disease. Currently, a definite CAA diagnosis can only be obtained on a brain biopsy or with a neuropathologic examination of the brain postmortem. Quantifying potential early stages of CAA in vivo through more direct biomarkers remains challenging.4 In order to assess the diagnostic yield of a direct amyloid PET tracer in the clinical setting, in the Journal club article “Florbetapir imaging in cerebral amyloid angiopathy-related hemorrhages,” Raposo and colleagues compared cortical florbetapir-PET retention between patients with CAA-related ICH and patients with hypertension-related deep ICH. The authors report increased cortical florbetapir-PET uptake in patients with CAA-related ICH compared to those with deep ICH. However, its diagnostic value in acute CAA-related ICH was proved to be limited by its moderate sensitivity and specificity. While these data do not yet have direct implications for CAA in clinical practice, they are useful in consolidating evidence on amyloid-PET performance in the setting of symptomatic CAA-related lobar ICH and may be informative for guiding future studies and trials in CAA.4

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&gt;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&gt;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 WP344: Basal Ganglia Atrophy in Cerebral Amyloid Angiopathy

Background/Purpose: Cerebral Amyloid Angiopathy (CAA) is associated with cortical and white matter atrophy. We hypothesized that atrophy in CAA extended into the subcortical gray matter as well and might explain previously observed alterations in subcortical gray matter diffusion-tensor properties. Methods: We compared multimodal MRIs from 80 prospectively enrolled non-demented patients with probable CAA, to two other cohorts: 80 Healthy Controls (HC) and 80 patients with Alzheimer’s Disease (AD) from the AD Neuroimaging Initiative. Validated FreeSurfer algorithms were used to calculate Gray Matter (GMV) and Basal Ganglia Volumes (BGV), expressed as percentage of intracranial volume (ICV). High-resolution diffusion scans were used to calculate the fractional anisotropy (FA) and apparent diffusion coefficient (ADC) within the basal ganglia. A visual basal ganglia atrophy scale was also developed to compare atrophy between 93 patients with CAA-related intracerebral hemorrhage (CAA-ICH) and 93 age-matched patients diagnosed with Hypertensive Arteriopathy and ICH (HTN-ICH). Results: CAA patients (mean age: 70.3 ± 8.5) were age-matched to HC (71.8 ± 3.7) and AD patients (70.4 ± 6.8). Patients with CAA had significantly lower BGV (1.16% ± 0.14) when compared to both HC (1.30% ± 0.13, p&lt;0.0001) and AD (1.23% ± 0.12, p=0.003). Within the CAA cohort, there was a positive association between BGV and GMV (r=0.45, p&lt;0.0001) and negative association between BGV and FA (r=-0.36, p=0.001). All associations remained independent after correcting for age, sex, and presence of hypertension. For the clinical ICH cohorts, patients diagnosed with CAA-ICH displayed significantly lower visually rated BGV when compared to similar aged patients with HTN-ICH (mean age: 68.5 for both groups, basal ganglia atrophy scale: 7.31 ± 1.03 vs 8.24 ± 1.14, p&lt;0.0001). Conclusions: Patients with CAA displayed substantial atrophy in the basal ganglia when compared to HC, AD, and HTN-ICH patients. Within the CAA cohort, greater basal ganglia atrophy was independently correlated with greater cortical atrophy and previously observed increases in basal ganglia anisotropy. The mechanisms for and clinical manifestations of CAA-related basal ganglia atrophy remain to be determined.