CAA-associated Intracerebral Hemorrhage Research Articles

APOE and Cerebral Small Vessel Disease Markers in Patients With Intracerebral Hemorrhage.

We investigated the associations between the APOE genotype, intracerebral hemorrhage (ICH), and neuroimaging markers of cerebral amyloid angiopathy (CAA). We included patients from a prospective, multicenter UK observational cohort study of patients with ICH and representative UK population controls. First, we assessed the association of the APOE genotype with ICH (compared with controls without ICH). Second, among patients with ICH, we assessed the association of APOE status with the hematoma location (lobar or deep) and brain CT markers of CAA (finger-like projections [FLP] and subarachnoid extension [SAE]). We included 907 patients with ICH and 2,636 controls. The mean age was 73.2 (12.4 SD) years for ICH cases vs 69.6 (0.2 SD) for population controls; 50.3% of cases and 42.1% of controls were female. Compared with controls, any APOE ε2 allele was associated with all ICH (lobar and nonlobar) and lobar ICH on its own in the dominant model (OR 1.38, 95% CI 1.13-1.7, p = 0.002 and OR 1.50, 95% CI 1.1-2.04, p = 0.01, respectively) but not deep ICH in an age-adjusted analyses (OR 1.26, 95% CI 0.97-1.63, p = 0.08). In the cases-only analysis, the APOE ε4 allele was associated with lobar compared with deep ICH in an age-adjusted analyses (OR 1.56, 95% CI 1.1-2.2, p = 0.01). When assessing CAA markers, APOE alleles were independently associated with FLP (ε4: OR 1.74, 95% CI 1.04-2.93, p = 0.04 and ε2/ε4: 2.56, 95% CI 0.99-6.61, p = 0.05). We did not find an association between APOE alleles and SAE. We confirmed associations between APOE alleles and ICH including lobar ICH. Our analysis shows selective associations between APOE ε2 and ε4 alleles with FLP, a CT marker of CAA. Our findings suggest that different APOE alleles might have diverging influences on individual neuroimaging biomarkers of CAA-associated ICH.

Simplified Edinburgh CT Criteria for Identification of Lobar Intracerebral Hemorrhage Associated With Cerebral Amyloid Angiopathy.

In patients with lobar intracerebral hemorrhage (ICH), etiologic characterization represents a tradeoff between feasibility, resource allocation, and diagnostic certainty. This study investigated the accuracy and clinical utility of the simplified Edinburgh CT criteria to identify underlying cerebral amyloid angiopathy (CAA). This external validation analyzed 210 consecutive patients with lobar ICH and available CT and MRI studies from a prospective single-center observational cohort study (2006-2015, Longitudinal Cohort Study on ICH Care [UKER-ICH,] NCT03183167). We investigated the interrater variability and diagnostic accuracy of the simplified Edinburgh CT-based criteria for identification of ICH associated with probable CAA according to MRI-based modified Boston criteria as a reference standard. We evaluated the utility of the simplified Edinburgh criteria by decision curve analysis, comparing the theoretical clinical net benefit (weighted benefit-harm at varying threshold probabilities) of the high-risk category (finger-like projections and subarachnoid hemorrhage) for ruling in and the low-risk category (neither finger-like projections nor subarachnoid hemorrhage) for ruling out with the assumptions of no or all patients having CAA (default strategies). Of 210 patients, 70 (33.3%) had high risk, 67 (31.9%) had medium risk, and 73 (34.8%) had low risk for CAA-associated ICH according to simplified Edinburgh CT criteria, showing moderate interrater variability. Discrimination was good (area under the receiver operating characteristics curve 0.74, 95% CI 0.67-0.81) without evidence of poor calibration (Hosmer-Lemeshow, p = 0.54) for validation of MRI-based diagnosis of probable CAA (n = 94 of 210, 44.8%). The rule-in criteria (high risk), had 87.1% (79.3%-92.3%) specificity, and the rule-out criteria (low risk), had 80.9% (71.1%-88.0%) sensitivity. Decision curve analysis suggested a theoretical clinical net benefit for ruling in but not for ruling out probable CAA compared to default strategies. Applying the simplified Edinburgh CT criteria during diagnostic workup seems clinically useful and may accurately identify CAA in patients with lobar ICH. ClinicalTrials.gov Identifier: NCT03183167. This study provides Class II evidence that in patients with lobar hemorrhages, the simplified Edinburgh criteria accurately identify those at high risk of CAA.

Sensitivity of the Edinburgh Criteria for Lobar Intracerebral Hemorrhage in Hereditary Cerebral Amyloid Angiopathy.

The Edinburgh computed tomography and genetic criteria enable diagnosis of cerebral amyloid angiopathy (CAA) associated lobar intracerebral hemorrhage (ICH) but have not been validated in living patients. We assessed the sensitivity of the Edinburgh criteria in patients with acute lobar ICH due to Dutch-type hereditary CAA; a genetic and pure form of CAA. We retrospectively analyzed computed tomography-scans from a cohort of consecutive Dutch-type hereditary CAA patients who presented with ≥1 episode(s) of acute lobar ICH at the Leiden University Medical Center. Presence of subarachnoid hemorrhage (SAH) and finger-like projections (FLP) were determined. Association of SAH and FLP with ICH volume was analyzed using multivariate linear regression. We included 55 Dutch-type hereditary CAA patients (mean age 56 years, 55% men) with a total of 107 episodes of acute lobar ICH. SAH was present in 82/107 (76%) and FLP in 62/107 (58%), resulting in a sensitivity of 76% for SAH and 58% for FLP. In 56 (52%), both markers were present. Nineteen (18%) lobar ICH showed no SAH extension or FLP. ICH volume was significantly associated with presence of SAH (median volume 4 versus 28 mL; P=0.001) and presence of FLP (median volume 7 versus 39 mL; P<0.001). With an ICH volume of ≥40 mL, the sensitivity of the presence of both SAH and FLP was >81% (95% CI, 70%-92%), whereas in ICH volumes <15 mL the sensitivity was <50%. The computed tomography-based Edinburgh criteria seem to be a sensitive diagnostic test for CAA-associated lobar ICH, although they should be used with caution in small-sized lobar ICH.

Correction: Imaging features of intracerebral hemorrhage with cerebral amyloid angiopathy: Systematic review and meta-analysis.

[This corrects the article DOI: 10.1371/journal.pone.0180923.].

Imaging features of intracerebral hemorrhage with cerebral amyloid angiopathy: Systematic review and meta-analysis.

BackgroundWe sought to summarize Computed Tomography (CT)/Magnetic Resonance Imaging (MRI) features of intracerebral hemorrhage (ICH) associated with cerebral amyloid angiopathy (CAA) in published observational radio-pathological studies.MethodsIn November 2016, two authors searched OVID Medline (1946-), Embase (1974-) and relevant bibliographies for studies of imaging features of lobar or cerebellar ICH with pathologically proven CAA (“CAA-associated ICH”). Two authors assessed studies’ diagnostic test accuracy methodology and independently extracted data.ResultsWe identified 22 studies (21 cases series and one cross-sectional study with controls) of CT features in 297 adults, two cross-sectional studies of MRI features in 81 adults and one study which reported both CT and MRI features in 22 adults. Methods of CAA assessment varied, and rating of imaging features was not masked to pathology. The most frequently reported CT features of CAA-associated ICH in 21 case series were: subarachnoid extension (pooled proportion 82%, 95% CI 69–93%, I2 = 51%, 12 studies) and an irregular ICH border (64%, 95% CI 32–91%, I2 = 85%, five studies). CAA-associated ICH was more likely to be multiple on CT than non-CAA ICH in one cross-sectional study (CAA-associated ICH 7/41 vs. non-CAA ICH 0/42; χ2 = 7.8, p = 0.005). Superficial siderosis on MRI was present in 52% of CAA-associated ICH (95% CI 39–65%, I2 = 35%, 3 studies).ConclusionsSubarachnoid extension and an irregular ICH border are common imaging features of CAA-associated ICH, but methodologically rigorous diagnostic test accuracy studies are required to determine the sensitivity and specificity of these features.

ApoA1, ApoJ and ApoE Plasma Levels and Genotype Frequencies in Cerebral Amyloid Angiopathy

The involvement of apolipoproteins, such as the ApoE4 isoform, in Alzheimer's disease (AD) and cerebral amyloid angiopathy (CAA) highlights the fact that certain lipid carriers may participate in soluble β-amyloid (Aβ) transport. Our general aim was to characterize the soluble levels of the apolipoproteins apoE, apoA1 and apoJ/clusterin and their genotype status in patients with CAA. We analyzed the genotypes frequency of APOA1 (rs5069, rs670), CLU (rs11136000, rs1532278, rs7012010, rs9331888) and APOE (rs429358, rs7412) in a cohort of patients with CAA-associated intracerebral hemorrhage (ICH) (n=59) and compared the results with those from hypertension-associated ICH (n=42), AD patients (n=73) and controls (n=88). In a subgroup of patients, we also determined the plasma concentrations of apoE, apoA1 and apoJ/clusterin. We found increased plasma apoJ/clusterin levels in CAA patients compared to AD patients or controls after adjusting for sex and age (CAA vs. controls, p=0.033; CAA vs. AD, p=0.013). ApoA1 levels were not altered between groups, although a strong correlation was observed between plasma Aβ(1-40) and apoA1 among CAA patients (r=0.583, p=0.007). Regarding plasma apoE concentration, a robust association between circulating levels and genotype status was confirmed (p<0.001). Whereas the APOE4 frequency was higher in AD (p<0.001) and CAA (p=0.013), the APOA1 and CLU genotypes were not different among groups. In the CAA cohort, the risk-linked CLU variant (C) rs11136000 was associated with white matter hyperintensities (p=0.045) and the presence of lobar microbleeds (p=0.023) on MRI. In summary, our findings suggest that apoA1 may act as a physiological transporter of Aβ(1-40) and that apoJ/clusterin appears to be a chaperone related to distinctive lesions in CAA brains.

Cerebral amyloid angiopathy-associated intracerebral hemorrhage in the very elderly: clinical manifestations, diagnosis and treatment

Objective To analyze the clinical manifestations, diagnosis and treatment of cerebral amyloid angiopathy (CAA)-associated intracerebral hemorrhage. Methods The clinical manifestations, treatment and prognosis of CAA-associated intracerebral hemorrhage were analyzed in 4 patients who were identified as CAA-related hemorrhage (CAAH) by pathology. Results All of the 4 patients showed massive lobar intracranial hemorrhage, and underwent craniotomy evacuation of hematoma. One patient had postoperative hemorrhage, and 2 patients were treated with recombinant activated factor VII after operation. In the next 6 months, re-hemorrhage was found in 3 patients in whom one patient died due to massive hemorrhage. Conclusions CAAH has varied clinical manifestations with high risk of cerebral hemorrhage, and pathological diagnosis is necessary for a definite diagnosis. The very elderly patients with CAAH can benefit from the craniotomy evacuation of hematoma. Although surgery for massive hemorrhage has risks in very elderly patients, it is a better treatment to save their lives. Key words: Cerebral amyloid angiopathy; Cerebral hemorrhage

Influence of Antithrombotics on the Etiology of Intracerebral Hemorrhage

To determine the influence of antithrombotic use on the etiology of primary intracerebral hemorrhage (ICH). We conducted a retrospective review of consecutive patients admitted with primary ICH from 2009 to 2012. Data recorded included age, history of hypertension, and use of antithrombotic medications. Imaging was reviewed to determine hemorrhage location and the presence and the location of any microhemorrhages. Etiologies were classified using a predetermined algorithm, which was based on existing literature. In total, 292 patients were included. Median age was 74 years (range, 18-101), and 52% were male (n = 151). Hemorrhage etiology was hypertension in 50.6% (n = 148), indeterminate in 29.5% (n = 86), and cerebral amyloid angiopathy (CAA) in 19.9% (n = 58). Most patients were on antithrombotics (61.3%, n = 179). Nearly half of the patients (49%) were 75 years of age or older, and the most common etiology in this group was hypertension (n = 77, 53%). There was a nonsignificant trend toward older age and CAA-ICH (median age, 77 years; interquartile range [IQR], 70-82 years) compared with other causes (median age, 74 years; IQR, 61-82 years; P = .07). There was no difference between CAA-ICH and other-cause ICH with respect to proportion of patients on antithrombotics in general (67% versus 60%; P = .367) or anticoagulants in particular (24% versus 25%; P = 1.000). The most common ICH etiology in this study was hypertension, regardless of age. Our findings do not suggest that the higher occurrence of ICH in older patients or in patients with CAA-associated ICH is because of a higher frequency of anticoagulant use.

Lower serum uric acid levels in cerebral amyloid angiopathy: a pilot study

Cerebral amyloid angiopathy (CAA) is a common degenerative disease presenting intracerebral hemorrhage (ICH) in older people. Uric acid (UA) is a natural antioxidant, and may have a beneficial role in neurodegenerative diseases. Nevertheless, the role of UA in CAA remains unknown. In the present study, we compared serum UA levels in CAA-associated ICH patients (n = 82) and age/sex-matched controls (n = 82). Serum UA levels in possible CAA were significantly decreased when compared with healthy controls (232.68 ± 77.70 vs. 309.42 ± 59.83 μmol/L; p < 0.001). Furthermore, UA levels in patients clinically diagnosed as probable CAA were significantly lower than those in patients diagnosed as possible CAA (193.06 ± 56.98 vs. 232.68 ± 77.70 μmol/L; p = 0.014). These differences were still significant after adjusting for renal function and dyslipidemia (p < 0.001 and p = 0.002, respectively). However, there were no associations between serum UA levels and the distribution of hemorrhagic lesion, as well as neurological impairment. Our observations indicate that serum UA levels were decreased in CAA patients. UA might play a neuroprotective role in CAA and serve as a potential biomarker for reflecting the severity of Aβ deposition.

In vivo Detection of Cortical Microinfarcts on Ultrahigh‐Field MRI

Cortical microinfarcts (CMIs) are detected as small foci restricted to the cerebral cortex in autopsy brains. CMIs are thought to be caused by cerebral amyloid angiopathy (CAA) in the elderly and may be a risk for dementia. We aimed to visualize CMIs, which remain invisible on conventional MRI, using double inversion recovery (DIR) and 3-dimensional fluid attenuated inversion recovery (3D-FLAIR) on 3-Tesla MRI. We prospectively performed DIR and 3D-FLAIR images in 70 subjects with Alzheimer disease (AD; n = 47), mild cognitive impairment (n = 14), AD with cerebrovascular disease (CVD; n = 3), vascular dementia (VaD; n = 2), CAA-associated intracerebral hemorrhage (ICH; n = 2) and one each of normal pressure hydrocephalus and dementia with Lewy bodies (DLB). Susceptibility-weighted imaging (SWI) was performed to detect cerebral microbleeds (CMBs). Nine subjects (five of AD and one each of AD with CVD, ICH, VaD, and DLB) had small intracortical high signal lesions on both DIR and 3D-FLAIR images. All the nine subjects accompanied multiple lobar CMBs. These intracortical lesions were located in close proximity to CMBs, and were suggested to be CMIs. DIR and 3D-FLAIR images may open a way to visualize CMIs.

Cerebral amyloid angiopathy–associated intracerebral hemorrhage: pathology and management

Amyloid angiopathy-associated intracerebral hemorrhage (ICH) comprises 12%-15% of lobar ICH in the elderly. This growing population has an increasing incidence of thrombolysis-related hemorrhages, causing the management of hemorrhages associated with cerebral amyloid angiopathy (CAA) to take center stage. A concise reference assimilating the pathology and management of this clinical entity does not exist. Amyloid angiopathy-associated hemorrhages are most often solitary, but the natural history often progresses to include multifocal and recurrent hemorrhages. Compared with other causes of ICH, patients with CAA-associated hemorrhages have a lower mortality rate but an increased risk of recurrence. Unlike hypertensive arteriolar hemorrhages that occur in penetrating subcortical vessels, CAA-associated hemorrhages are superficial in location due to preferential involvement of vessels in the cerebral cortex and meninges. This feature makes CAA-associated hemorrhages easier to access surgically. In this paper, the authors discuss 3 postulates regarding the pathogenesis of amyloid hemorrhages, as well as the established clinicopathological classification of amyloid angiopathy and CAA-associated ICH. Common inheritance patterns of familial CAA with hemorrhagic strokes are discussed along with the role of genetic screening in relatives of patients with CAA. The radiological characteristics of CAA are described with specific attention to CAA-associated microhemorrhages. The detection of these microhemorrhages may have important clinical implications on the administration of anticoagulation and antiplatelet therapy in patients with probable CAA. Poor patient outcome in CAA-associated ICH is associated with dementia, increasing age, hematoma volume and location, initial Glasgow Coma Scale score, and intraventricular extension. The surgical management strategies for amyloid hemorrhages are discussed with a review of published surgical case series and their outcomes with a special attention to postoperative hemorrhage.

Update on Amyloid-associated Intracerebral Hemorrhage

Cerebral congophilic or amyloid angiopathy (CAA) is a clinicopathological entity that is considered a common cause of primary non-traumatic brain hemorrhage in the elderly. CAA is frequently associated with Alzheimer’s disease (AD) and has become a primary focus of scientific inquiry. The spectrum of intracerebral hemorrhage (ICH) that may occur in CAA includes: cerebral lobar hemorrhages, deep hemorrhages, purely subarachnoid and subdural hemorrhages and cerebral microbleeds. CAA is also associated with microinfarcts, leukoencephalopathy and superficial siderosis. This brief article will provide an update on the advances in our understanding of CAA-associated ICH with a focus on the following topics: neuropathology and mechanism of CAA-related hemorrhage; epidemiology, including genetic and other possible risk factors; clinical presentation; diagnosis, including newer imaging modalities; and prospects for prevention and treatment.

Cocaine‐Induced Intracerebral Hemorrhage in a Patient with Cerebral Amyloid Angiopathy*

Intracerebral hemorrhage (ICH) is a well-recognized complication of recreational cocaine use. The precise mechanism of the cocaine-induced hemorrhagic event is unclear, although multiple factors have been implicated. We report a case of a 62-year-old woman who suffered left parieto-occipital ICH with herniation and death, following a cocaine binge. Microscopic examination also revealed extensive cerebral amyloid angiopathy (CAA) in the vicinity of the hemorrhage. We additionally studied brain tissue in eight subjects between ages of 60 and 80 who were positive for cocaine metabolites at autopsy; of these, none had vascular amyloid-β deposits by immunohistochemistry. Whereas we found no evidence that chronic cocaine use is a risk factor for CAA, given the age-associated nature of CAA and the aging population using cocaine, CAA-induced hemorrhage in the setting of cocaine use may be more common than recognized. This is the first reported case of CAA-associated ICH precipitated by cocaine.

Apolipoprotein E ϵ4 and cerebral hemorrhage associated with amyloid angiopathy

Cerebral amyloid angiopathy (CAA) is characterized by cerebrovascular deposition of the amyloid beta-peptide, leading to intracerebral hemorrhage in severe cases. Other than rare familial cases, the only identified risks for CAA are advancing age and accompanying Alzheimer's disease. We tested whether the apolipoprotein E epsilon 4 (apoE epsilon 4) allele was associated with CAA and hemorrhage and whether this association was independent of Alzheimer's disease. The apoE epsilon 4 genotype was determined without knowledge of the pathology for 93 postmortem cases systematically graded for severity of CAA and for 15 patients with CAA-associated intracerebral hemorrhage. We found a significant and independent effect of the apoE genotype in both cohorts. Among the postmortem cases, the presence of apoE epsilon 4 increased the odds ratio for moderate or severe CAA by 2.9-fold, relative to cases without epsilon 4; two copies of epsilon 4 increased the odds ratio 13.1-fold. In the cohort of CAA-associated cerebral hemorrhages, the apoE epsilon 4 allele frequency was 0.40, significantly greater than the control frequency of 0.14. The increase in CAA remained even after controlling for the presence of Alzheimer's disease, suggesting that apoE epsilon 4 is a risk factor for CAA and CAA-related hemorrhage, independent of its association with Alzheimer's disease.