Neuropathology and long-term outcome in cerebral amyloid angiopathy patients with intracerebral hemorrhage

Neuropathology and long-term outcome in cerebral amyloid angiopathy patients with intracerebral hemorrhage | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Neuropathology and long-term outcome in cerebral amyloid angiopathy patients with intracerebral hemorrhage Feng Liu, Jia Liu, Hao Wu, Pan Wang, Shuai Liu, Zihan Wang, Xuebin Zhang, and 4 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6857736/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 27 Nov, 2025 Read the published version in Scientific Reports → Version 1 posted 11 You are reading this latest preprint version Abstract Background Sporadic cerebral amyloid angiopathy (CAA) is a small-vessel disease. We sought to assess pathological findings and outcomes in CAA patients with non-traumatic intracerebral lobe hemorrhage (ICH). Methods Sixty-three CAA-ICH patients underwent Hematoxylin-eosin, amyloid-β, smooth muscle actin and CD34 staining. Arterioles were graded using a CAA-severity scale. Prospective ≥ 12-month follow-up identified prognostic factors via binary logistic regression. Cox proportional hazard regression models assessed mortality or recurrent ICH risk associations. Results Among 93 ICH patients, 63 (67.7%) had CAA. Pathological grading showed Grade 1: 8 (12.7%), Grade 2: 12 (19.0%), Grade 3 or 4: 43 (68.3%). Among 32 CAA patients with cortical specimens, 23 (71.9%) had dense-core plaques and 26 (81.3%) diffuse plaques. Dense-core plaques occurred exclusively in moderate-to-severe CAA. After adjusting for age, sex, antiplatelet medication and alcohol abuse, CAA severity predicted 1-year mortality (adjusted OR = 18.49; 95% CI 1.78–193.03; P = 0.015). CAA severity and age predicted mortality or recurrent ICH risk (adjusted HR = 4.16; 95% CI 1.54–11.24, P = 0.005 and adjusted HR = 1.08; 95% CI 1.02–1.14, P = 0.008, respectively). Conclusions Most CAA-ICH patients had moderate-to-severe CAA in cortico-leptomeningeal regions. Cortical biopsies revealed frequent Aβ deposition as dense-core and diffuse plaques, with dense-core plaques exclusive to moderate-to-severe CAA. CAA severity correlated with long-term outcomes in CAA-ICH. Biological sciences/Neuroscience Health sciences/Neurology Health sciences/Risk factors cerebral amyloid angiopathy intracerebral hemorrhage amyloid-β mortality recurrence Figures Figure 1 Figure 2 Figure 3 Figure 4 Introduction Cerebral amyloid angiopathy (CAA) is caused by the deposition of amyloid-β (Aβ) in the small to medium-sized vessels in the cerebral cortex and overlying leptomeninges 1 . It is the second most common etiology of spontaneous symptomatic intracerebral hemorrhage (ICH; accounting for 12–20% of cases) after hypertension 2 , 3 . CAA-associated ICH (CAA-ICH) characteristically occurs at lobar or superficial areas and has a high recurrence rate (estimated to exceed 10% per year), especially in patients receiving anti-thrombotic agents 1 , 4 . The prevalence of moderate-to-severe CAA based on pathology was reported to be around 50–60% in patients with lobar ICH 5 . Pathological features of CAA and Alzheimer's disease (AD) have been intensively studied using autopsy samples. The pathologies of CAA and AD frequently co-exist in the same brain, presumably because Aβ is pathogenic in both 6 , 7 . A pathological examination is needed for the reliable diagnosis of CAA, but it is difficult to obtain specimens from patients with suspected CAA while they are alive. Biopsies of cortical samples from postmortem brains with CAA of a known distribution showed that vascular amyloid is a sensitive marker for CAA-related hemorrhage 8 . The examination of cortical tissue obtained surgically is thus an important tool for diagnosing CAA. Meanwhile, extracellular Aβ plaques are the main pathological findings in AD-affected cortex, and the pathological processes underlying AD already start decades before symptoms appear 9 . Only a few studies with limited cases have analyzed biopsies from surgery on CAA-ICH patients 10 . The features of Aβ plaques in cortical samples of acute CAA-ICH patients after hematoma evacuation have also rarely been reported 11 . Against this background, the purpose of this study was to evaluate the level of severity of CAA and amyloid plaques of CAA in patients who underwent surgery for large lobar hemorrhage along with cortical biopsy at our hospital. The association of CAA severity with long-term outcomes was also analyzed after at least 1 year of follow-up. Materials and Methods This study was performed in accordance with the ethical standards of the Tianjin Huanhu Hospital Human Experimentation Committee. This study was approved by the Ethics Committee of Tianjin Huanhu Hospital (NO. 2024 − 270). Written informed consent was obtained from all participants or their legal representatives before enrollment. Participants We performed a prospective, single-center, hospital-based cohort study including all consecutive acute-phase spontaneous ICH patients with hematoma evacuations, with a diagnosis of probable CAA with supporting pathology, in accordance with the modified Boston Criteria v. 2.0 12 . The subjects were all patients admitted to Tianjin Huanhu Hospital between August 2016 and October 2024 who demonstrated lobar, cortical, or subcortical hemorrhage, with some degree of CAA in the specimen from evacuated hematoma or cortical biopsy. Exclusion criteria were as follows: 1) head trauma, 2) cavernous venous tumor, 3) arteriovenous malformation, 4) hemorrhagic cerebral infarction, 5) lobar hemorrhage due to venous sinus thrombosis, or 6) intracranial tumor with bleeding (on brain MRI or pathology). Pathological examinations Each sample was fixed in neutral buffered formalin, routinely processed, paraffin-embedded, and cut into sections of 4 µm thickness. These sections were subjected to hematoxylin-eosin staining. Immunohistochemical staining was also performed by the avidin-biotin-peroxidase complex method with antibodies against total Aβ protein (monoclonal antibody 6E10/4G8, mouse, 1:600–1:1000; Biolegend), cluster of differentiation 68 (CD68; mouse, ZM-0060; Beijing Zhongshan Golden Bridge Biological Technology Co.), smooth muscle actin (SMA; mouse, ZM-0003; ZSGB-BIO), CD20 (mouse, ZM-0039; ZSGB-BIO), and perivascular macrophages (CD163, mouse, ZM-0428; ZSGB-BIO). All stains were performed manually following a standardized immunohistochemical protocol. We evaluated the level of severity of CAA using the grading scale previously described by Greenberg et al 8 , 10 , 13 . In this scale, Grade 0 CAA is negative for CAA; Grade 1 involves the presence of some Aβ-positivity in otherwise normal-appearing vessels; Grade 2 involves complete replacement of the medium by Aβ-positive material; Grade 3 features cracking of the amyloid-laden vessel walls affecting at least 50% of the circumference of the vessels; and Grade 4 refers to the presence in an amyloid-laden vessel of fibrinoid necrosis. Evaluation of CAA based on this grading scale was performed by two pathologists blinded to the clinical data, except for in the case of specimens from patients with lobar hemorrhage. Clinical features We investigated the following potential risk factors for intracranial bleeding in all patients using the medical records: hypertension (HT) with or without medication, and receiving antiplatelet or anticoagulant medication. We also investigated previous history of ICH, cerebral infarction, diabetes mellitus, atrial fibrillation, and the lifestyle habits of current smoking and a history of excessive alcohol intake. The position of lobar hemorrhage on initial CT was also measured in each case. Follow-up assessments and outcomes All patients were followed up for at least 12 months and follow-up data was prospectively collected. We recorded information on recurrent ICH, defined as a symptomatic stroke syndrome with evidence from a CT scan of a corresponding ICH (> 10 mm in diameter) or death from any cause. Outcome events were assessed using all available clinical and radiological information. Statistical analysis For categorical variables shown in percentages, the chi-square test or Fisher’s exact test was used. Continuous data were tested for normality using the Kolmogorov–Smirnov test. If parameters were normally distributed, they are depicted as mean ± standard deviation; otherwise, they are presented as median with interquartile range (IQR). Continuous variables were tested by Student’s t -test (normally distributed data) or Mann–Whitney U-test (non-normally distributed data). Univariable and multivariable binary logistic regression models were used to evaluate the associations of CAA severity with clinical outcomes at 6 months and 12 months before and after adjusting for potential confounders. A cut-off of p < 0.1 was used to select variables for inclusion in the multivariable analysis. Associations are presented as odds ratios (ORs) with corresponding 95% confidence intervals (CIs). In the multivariable logistic regression analysis, statistical significance was considered to have been reached if the p value was ≤ 0.05. Moreover, Cox proportional hazard regression models were used to calculate the associations of CAA severity and age with the risk of death or recurrent ICH. For patients experiencing multiple symptomatic ICH events during follow-up, data was censored after the first symptomatic ICH event. All covariates demonstrating a univariable association with the outcome in Cox regression analysis ( p < 0.1) were considered for inclusion in the multivariable model. All tests of significance were two-tailed, and the significance level was set at 0.05 for all analyses. All statistical analyses were conducted using SPSS Statistics v.21.0. Results A total of 93 patients who underwent removal of lobar hemorrhage with brain biopsy, for whom sufficient specimens were available to evaluate cortical and/or leptomeningeal vessels were included in this study. Among the 93 specimens, 63 patients (67.7%) had CAA, and the other 30 patients (32.3%) did not. According to the pathological grading system for CAA, 8 patients (12.7%) had Grade 1 CAA, 12 (19.0%) had Grade 2, and 43 (68.3%) had Grade 3-4. According to the classification by Vonsattel et al., mild CAA corresponds to Grade 1 CAA, moderate CAA matches Grade 2, and severe CAA generally resembles Grade 3-4 13 . Among the 63 patients pathologically diagnosed with CAA, there were significantly more men (35, 55.6%) than women. The mean ages of Grade 1, Grade 2, and Grade 3-4 CAA patients were 49.0 (48.0–68.0), 65.5 (62.0–68.5), and 72.0 (68.0–76.0), respectively. The common locations of hemorrhages of CAA-positive patients were parietal lobe (55.6%), temporal lobe (52.4%), and frontal lobe (49.2%) patients, which differed significantly among Grade 1, Grade 2 and Grade 3-4 CAA groups. Overall, 24 (38.1%) patients showed subarachnoid hemorrhage (SAH) and 15 (23.8%) showed subdural hemorrhage (SDH), for which there were no significant differences among Grade 1, Grade 2, and Grade 3-4 CAA groups (Table 1). Table 1 Baseline characteristics in the study cohort based on pathology Grading scale of CAA Overall (n=63) Grade 1 (n=8) Grade 2 (n=12) Grade 3-4 (n=43) p Value Gender, Male 35 (55.6 %) 5 (62.5%) 10 (58.7%) 20 (46.5%) 0.070 Age 69.0 (65.0-74.0) 49.0 (48.0-68.0) 65.5 (62.0-68.5) 72.0 (68.0-76.0) <0.001 Age distribution 0.001 ＜50 years 3 (4.8%) 2 (25%) 1 (8.3%) 0 (0) 50-59 years 4 (6.3%) 2 (25%) 1 (8.3%) 1 (2.3%) 60-69 years 26 (41.3%) 4 (50%) 8 (66.7%) 14 (32.6%) 70-79 years 26 (41.3%) 0 2 (16.7%) 24 (55.8%) 80-89 years 4 (6.3%) 0 0 4 (9.3%) Smoking 11 (17.5%) 2 (25.0%) 2 (17.5%) 7 (16.3%) 0.834 Drinking 8 (12.7%) 3（37.5%） 0 5 (11.6%) 0.044 Medical history Hypertension 27 (42.9%) 3 (37.5%) 4 (33.3%) 20 (46.5%) 0.680 Diabetes mellitus 7 (11.1%) 0 0 7 (16.3%) 0.160 Previous cerebral hemorrhage 12 (19.1%) 1 (12.5%) 1 (8.3%) 10 (23.3%) 0.447 Cerebral infarction 9 (14.3%) 1 (12.9%) 0 8 (18.6%) 0.264 Atrial fibrillation 3 (3.2%) 0 2 (16.7%) 1 (2.3%) 0.968 Antiplatelet medicine 13 (20.6%) 1 (12.5%) 0 12 (27.9%) 0.089 Antihypertension 26 (41.3%) 3 (37.5%) 3 (25.0%) 20 (46.5%) 0.398 Hematoma location Frontal lobe 31 (49.2%) 2 (25.0%) 5 (58.3%) 21 (51.2%) 0.310 Occipital lobe 15 (23.8%) 2 (25.0%) 2 (16.7%) 11 (25.6%) 0.811 Temporal lobe 33 (52.4%) 5 (62.5%) 5 (41.7%) 23 (53.5%) 0.637 Parietal lobe 35 (55.6%) 5 (62.5%) 4 (33.3%) 20 (60.5%) 0.226 Subdural hemorrhage 15 (23.8%) 2 (25.0%) 3 (25.0%) 10 (23.3%) 0.989 Subarachnoid hemorrhage 24 (38.1%) 4 (50.0%） 4 (33.3%) 16 (37.2%) 0.737 Aβ plaques in CAA patients Among the 63 patients pathologically diagnosed with CAA, 31 patients for whom there were insufficient cortical specimens to evaluate Aβ plaques were excluded. As such, 32 patients had their Aβ plaques evaluated by anti-4G8/6E10 immunohistochemical staining. Among these, 23 (71.9%) patients had dense-core plaques and 26 (81.3%) had diffuse plaques. In addition, 18 (56.3%) patients had plaques around vessels. Dense-core plaques were found exclusively in moderate-to-severe CAA patients, while only one mild CAA patient had diffuse plaques. Moreover, plaques around vessels were found exclusively in severe CAA patients (Table 2). Table 2 Pathologic change in CAA patient Grading scale of CAA Overall (N=32) Grade 1 (n=3) Grade 2 (N=4) Grade 3-4 (N=25) p Value Dense-core plaques 23 (71.9%) 0 2 (50.0 %) 21 (84.0%) 0.070 Diffuse plaques 26 ( 81.3%) 1 (33.3%) 3 (75.0%) 22 (88.0%) <0.001 Plaques around vessels 18 (56.3%) 0 0 18 (72.0%) 0.001 Illustrative case 1 (ICH with mild CAA) A 51-year-old female was due to headache, vomiting for 12 h, and disturbance of consciousness for 4 h. CT showed hemorrhage at the left frontal lobe. MRI showed left frontal hematoma and edema (Fig. 1). She had been taking antiplatelet medication (aspirin 100 mg QD) for six months for cerebral infarction. Pathological examinations showed patchy Aβ deposition in some vessels, which corresponded to Grade 1 CAA, and inflammatory infiltrate surrounding the vessels. Most of the perivascular and leptomeningeal lymphocytes were CD3-immunopositive T cells. Some CD68-positive macrophages were identified around the vessels (Fig. 2). After 13 months of follow-up, the patient had only mild decline in recent memory, which didn’t significantly impact on daily life. Illustrative case 2 (ICH with severe CAA) A 76-year-old male suffered from headache and disturbance of consciousness for 6 h. He had hypertension for 11 years but taken no regular medication and suffered ICH three times. CT showed lobar hemorrhage at the right temporoparietal lobe (Fig. 3a). Pathological examinations showed that most of the cortical and leptomeningeal vessels had been completely replaced by Aβ-positive material, while some amyloid-laden vessels showed thickened vessel walls and splitting, which corresponded to Grade 3 CAA. Some dense-core, diffuse plaques and plaques surrounding vessels were scattered in the cortical specimen (Fig. 3b–f). After one week of follow-up, the patient died due to cerebral herniation. Illustrative case 3 (ICH with severe CAA) A 77-year-old male suffered from headache and vomiting for 6 h. He had been taking antiplatelet medication for coronary atherosclerotic heart disease 1 year. CT showed lobar hemorrhage at the right temporoparietal lobe (Fig. 4a). Pathological examinations showed that most of the vessels had been completely replaced by Aβ-positive material and some amyloid-laden vessels showed thickened walls, with disrupted cytoarchitecture, which corresponded to Grade 4 CAA. Many dense-core, diffuse plaques and plaques surrounding vessels were shown in the cortical specimen (Fig. 4b–e). After 14 months of follow-up, this patient developed global cognitive decline and was diagnosed with severe dementia. Outcomes and predictors of death or ICH recurrence Overall, 57 patients were followed up for at least 12 months or until death. Six patients were lost to follow-up. During the follow-up period, 27 patients died. Twelve deaths occurred within 1 month after surgery: 10 of these were caused by brain hernia, 1 by status epilepticus, and 1 by gastrointestinal hemorrhage. Of the other 15 deaths, 9 were due to pneumonia and 5 were due to recurrent ICH (1 month after surgery) while 1 patient died at home of an unknown cause. Five patients experienced recurrent non-lethal symptomatic ICH during the follow-up period. Among the 63 patients, 18 (28.6%) experienced recurrent ICH at least once. Sixteen patients (28.1%) died within 6 months of hematoma evacuation. The mortality rate within 6 months was significantly higher in severe CAA (Grade 3–4) patients than in mild-to-moderate ones [unadjusted OR, 12.96; 95% confidence interval (CI), 1.56–107.41; P=0.018]. During 12 months of follow-up, 20 patients (35.1%) died. Similarly, the mortality rate within 12 months was significantly higher in severe CAA patients than in mild-to-moderate ones (unadjusted OR, 20.06; 95% CI, 2.43–165.70; P=0.005). These findings remained significant after adjustment for age, sex, antiplatelet medication, and history of excessive alcohol intake (6 months: adjusted OR, 11.06, 95% CI, 1.05–116.62, P=0.046; 12 months: adjusted OR, 18.49, 95% CI, 1.78–193.03, P=0.015) (Table 3). Table 3 Outcomes in six and twelve months in CAA-ICH patients Overall (N=57) Grade 1- 2 (N=20) Grade 3-4 (N=37) p Value Mortality within 6 months 16 (28.1%) 1 (8.3%) 15 (40.5%) Crude OR (95% CI) 1 12.96 (1.56-107.41) 0.018 Ajusted OR* (95% CI) 1 11.06 (1.05-116.62) 0.046 Mortality within 12 months 20 (35.1%) 1(8.3%) 19 (51.4%) Crude OR (95% CI) 20.06 (2.43-165.70) 0.005 Ajusted OR* (95% CI) 1 18.49 (1.78-193.03) 0.015 Abbreviations: CI indicates confidence interval; OR, odds ratio. *Adjusted for age, sex, Antiplatelet medicine, history of excessive alcohol intake. In a univariable Cox regression model with death or recurrent ICH as endpoints, CAA severity and old age were risk factors of death or recurrent ICH (HR: 3.71, 95% CI: 1.42–9.67, P= 0.007; and HR: 1.07, 95% CI: 1.02–1.13, P=0.007, respectively). These findings remained significant after adjustment for sex, antiplatelet medication, and history of excessive alcohol intake (adjusted HR, 4.16, 95% CI, 1.54–11.24, P=0.005; and adjusted HR, 1.08, 95% CI, 1.02–1.14, P=0.008, respectively) (Table 4). However, in multivariable Cox regression models, including CAA severity, age, sex, antiplatelet medication, and history of excessive alcohol intake, these findings were no longer significant. Table 4 Association of CAA severity with mortality or recurrent ICH in CAA-ICH patients B HR 95% CI p Value CAA severity Crude HR 1.131 3.71 1.42-9.67 0.007 Ajusted HR* 1.425 4.16 1.54-11.24 0.005 Age Crude HR 0.074 1.07 1.02-1.13 0.007 Ajusted HR* 0.077 1.08 1.02-1.14 0.008 Abbreviations: CI indicates confidence interval; HR, hazard ratio. *Adjusted for, sex, Antiplatelet medicine, history of excessive alcohol intake. Discussion In our study, 63 patients with lobar hemorrhage were pathologically diagnosed with CAA, with severe CAA (Grades 3-4) comprising the majority (68.3%) and the vast majority (87.3%) having moderate-to-severe CAA. Although the specimens obtained during surgery were only a tiny part of the whole brain, this result suggests that pathologically severe CAA with vasculopathic change has a high possibility of inducing large lobar hemorrhage. Severe CAA might have been present in some patients with low-grade CAA in this study. Among 32 CAA patients for whom sufficient cortical specimens were available, 23 (71.9%) patients had dense-core plaques and 26 (81.3%) diffuse plaques. Three (9.4%) patients showed negativity for Aβ plaques in their cortical specimen. This indicated that extracellular Aβ plaques are common in CAA-ICH patients, especially in those with severe CAA. Among all 63 CAA-positive patients, the recurrence rate of CAA-ICH was 28.6%. The mortality rate in CAA-ICH patients was 28.1% in 6 months and 35.1% in 12 months following hematoma evacuation. The findings suggested that ICH patients with severe CAA have higher mortality rates in 1 year than patients with mild-to-moderate CAA. CAA was considered to be one of the significant causes of lobar hemorrhage; however, the incidence of primary CAA-related lobar hemorrhage is unknown. Our study showed that, in severe spontaneous lobar hemorrhage patients, the prevalence of moderate-to-severe CAA was 59.1%. Meanwhile, a recent meta-analysis showed that the prevalence of mild-to-severe CAA in patients with lobar ICH was 52.2%, while that of moderate-to-severe CAA was 49.7% in an East Asian cohorts 14 . Although our study examined the prevalence of CAA in only surgical cases with lobar hemorrhage, the majority of previous studies examined specimens from autopsy, which might explain why the prevalence was higher than in previous studies. The high prevalence rates were partly due to exclusion criteria including head trauma, cavernous venous tumor, arteriovenous malformation, or intracranial tumor with bleeding in our study. Another possible reason is that surgical cases with more severe lobe hemorrhage were selected in our study, which is more likely to be associated with severe primary CAA pathology. Indeed, previous studies have shown that more severe CAA pathology is associated with more severe consequences such as micro- or macro-hemorrhage or infarct 13,15,16 . CAA involves the cerebrovascular deposition of Aβ, which is also the primary constituent of neuritic plaques in AD. The two conditions often overlap, presumably because of the shared role of Aβ. Our study on CAA-ICH patients showed that 23 (71.9%) patients had dense-core plaques and 26 (81.3%) had diffuse plaques. Dense-core plaques were found exclusively in moderate-to-severe CAA patients. Previous brain autopsy-based and neuropathological studies showed that CAA was strongly associated with AD pathology 6,17 . Additionally, an autopsy study of 3,976 brains in the US National Alzheimer’s Coordinating Center database revealed that the pathological grade of CAA was moderate to severe in 5.3% of brains without neuritic plaques, 16.1% of brains with mild neuritic plaques, 31.7% of brains with moderate neuritic plaques, and 45.3% of brains with severe neuritic plaques 7 . Elsewhere, it was shown that Aβ deposition in brain capillaries is specifically associated with neuritic plaques and severe AD pathology 18,19 . In our 57 CAA-ICH patients after surgery, the mortality rate was 28.1% at 6 months and 35.1% at 1 year. Meanwhile, a meta-analysis revealed that, after surgical treatment, the CAA-ICH mortality rate was 24% at 1 year 20 . Moreover, a recent review showed that the outcome of CAA-ICH was predominantly poor with a pooled 3-month mortality rate of 19% 21 . Furthermore, the results from management of all-cause ICH in the STICH trial reported a 6-month mortality rate of 36% 22 . These results suggest the possibility that surgical management of CAA-associated ICH may reduce mortality. Severe CAA was associated with a high risk of mortality within 1 year in our CAA-ICH patients. For long-term follow-up, severe CAA and old age also predicted a high mortality rate or recurrent ICH. A recent study from China identified Glasgow Coma Score (GCS), recurrence of ICH, white matter lesion (WML) grade and cerebral atrophy as independent prognostic factors of long-term outcome 23 . In addition, a review showed that factors associated with poor outcome of CAA-ICH in 3 months were advanced age, poor condition on admission, preexisting dementia, and concomitant intraventricular, subarachnoid, or subdural hemorrhage 20,21 . Antiplatelet use in patients with previous ischemic stroke or coronary atherosclerotic heart disease was also reported as a predictor of CAA-CH 24 , and antithrombotic therapy, particularly warfarin therapy, was associated with a high risk of postoperative rebleeding 25 . However, in our study, 6-month mortality of CAA-ICH was not significantly related to previous antiplatelet use. During the follow-up period, 10 (17.5%) patients experienced recurrent symptomatic ICH. Among all 63 patients, 18 (28.6%) experienced recurrent ICH at least once. A previous meta-analysis showed that the recurrence rate of CAA-ICH was 23% and also revealed convexity subarachnoid haemorrhage (cSAH), foci of cortical superficial siderosis (cSS), and visible perivascular spaces in the centrum semiovale (CSO-PVS) as significant markers for recurrent CAA-ICH 26 . In addition, a study performed in Greece showed that the recurrence rate of CAA-ICH was 28%, while cSS emerged as the only risk factor of recurrent ICH 27 . The recurrence rate of CAA-ICH in our cohort was consistent with that in previous studies. However, given that only about half of the patients had undergone a brain MRI scan, the association of neuroimaging markers with recurrent ICH was not examined in this study. This study is associated with some limitations. First, all patients with both large hematoma and disturbance of consciousness were enrolled in our study. The obtained results thus differ to some extent from clinical research findings from consecutive ICH patients with and without surgery due to cases of small lobar hemorrhage not being included in this study. In addition, pathological examination involved only a small part of the cortex or leptomeningeal vessels, which contrasts with the situation of autopsies involving evaluation of the whole brain. Moreover, to evaluate amyloid-β deposition as dense-core plaques and diffuse plaques, we only used amyloid-β antibody, which was insufficient to differentiate AD pathology from benign plaques caused by old age. This was exacerbated by the fact that our patients had also not undergone cognitive assessment prior to acute hemorrhage, with the exception of two patients with a history of dementia. As a final limitation, the association of amyloid-β plaque with cognitive status was not evaluated in this study. Conclusions In this study, most patients with large or multiple lobar hemorrhage related to CAA had moderate-to-severe CAA in the cerebral cortex and overlying leptomeninges. Amyloid-β deposition as dense-core plaques always co-existed with moderate-to-severe CAA in cortical biopsy samples of CAA-ICH. The pathologically definable severity of CAA from evacuated hematoma and cortical biopsy was associated with long-term outcome following ICH surgery. These results highlight the importance of the severity of CAA in predicting the long-term outcomes of patients with CAA-related-ICH. This study provides a valuable basis for clinicians to develop targeted postoperative management strategies, which can contribute to improving patient prognosis and guiding future therapeutic interventions. Declarations Author contributions Conceptualization: Z.Shi., X.Y., Y.J.; Methodology: F.L., J.L, H.W., P.W., Sh.L., Z.W., X.Zh, Sh.J., X.Y.; Formal Analysis and Investigation: F.L., J.L, H.W., P.W., Sh.L., Z.W., X.Zh, Sh.J., X.Y.; Figures preparation 1–4: F.L., J.L., H.W., P.W., X.Zh, Sh.J., X.Y.; Writing—original draft preparation: F.L., J.L.; Writing—review and editing: H.W., P.W., Sh.L., X.Zh, Sh.J., X.Y. All authors read and approved the final manuscript. Data availability The datasets used and/or analysed during the current study available from the corresponding author on reasonable request. Funding This work was supported by National Natural Science Foundation of China (grant number 82171182). Declaration of conflicting interests The authors declared no potential conflicts of interests. Additional information Correspondence and requests for materials should be addressed to Z. Shi. Reprints and permissions information is available at www.nature.com/reprints. Publisher ’ s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommo ns.org/licenses/by-nc-nd/4.0/. References Charidimou, A. et al. Emerging concepts in sporadic cerebral amyloid angiopathy. Brain 140 , 1829–1850. 10.1093/brain/awx047 (2017). Yeh, S. J., Tang, S. C., Tsai, L. K. & Jeng, J. S. Pathogenetical subtypes of recurrent intracerebral hemorrhage: designations by SMASH-U classification system. Stroke 45 , 2636–2642. 10.1161/strokeaha.114.005598 (2014). Meretoja, A. et al. SMASH-U: a proposal for etiologic classification of intracerebral hemorrhage. Stroke 43 , 2592–2597. 10.1161/strokeaha.112.661603 (2012). Yamada, M. Cerebral amyloid angiopathy: emerging concepts. J. Stroke . 17 , 17–30. 10.5853/jos.2015.17.1.17 (2015). Jäkel, L., De Kort, A. M., Klijn, C. J. M., Schreuder, F. & Verbeek, M. M. Prevalence of cerebral amyloid angiopathy: A systematic review and meta-analysis. Alzheimers Dement. 18 , 10–28. 10.1002/alz.12366 (2022). Arvanitakis, Z. et al. Cerebral amyloid angiopathy pathology and cognitive domains in older persons. Ann. Neurol. 69 , 320–327. 10.1002/ana.22112 (2011). Brenowitz, W. D., Nelson, P. T., Besser, L. M., Heller, K. B. & Kukull, W. A. Cerebral amyloid angiopathy and its co-occurrence with Alzheimer's disease and other cerebrovascular neuropathologic changes. Neurobiol. Aging . 36 , 2702–2708. 10.1016/j.neurobiolaging.2015.06.028 (2015). Greenberg, S. M. & Vonsattel, J. P. Diagnosis of cerebral amyloid angiopathy. Sensitivity and specificity of cortical biopsy. Stroke 28 , 1418–1422. 10.1161/01.str.28.7.1418 (1997). Trejo-Lopez, J. A., Yachnis, A. T. & Prokop, S. Neuropathology of Alzheimer's Disease. Neurotherapeutics 19 , 173–185. 10.1007/s13311-021-01146-y (2022). Lin, C. M. et al. Pathological examination of cerebral amyloid angiopathy in patients who underwent removal of lobar hemorrhages. J. Neurol. 265 , 567–577. 10.1007/s00415-018-8740-z (2018). Poyuran, R. et al. Cerebrovascular pathology in cerebral amyloid angiopathy presenting as intracerebral haemorrhage. Virchows Arch. 474 , 235–245. 10.1007/s00428-018-2505-z (2019). Greenberg, S. M. & Charidimou, A. Diagnosis of Cerebral Amyloid Angiopathy: Evolution of the Boston Criteria. Stroke 49 , 491–497. 10.1161/strokeaha.117.016990 (2018). Vonsattel, J. P. et al. Cerebral amyloid angiopathy without and with cerebral hemorrhages: a comparative histological study. Ann. Neurol. 30 , 637–649. 10.1002/ana.410300503 (1991). De Kort, A. M., Verbeek, M. M., Schreuder, F., Klijn, C. J. M. & Jäkel, L. Prevalence of Cerebral Amyloid Angiopathy Pathology and Strictly Lobar Microbleeds in East-Asian Versus Western Populations: A Systematic Review and Meta-Analysis. J. Stroke . 26 , 179–189. 10.5853/jos.2023.04287 (2024). Thal, D. R. et al. Two types of sporadic cerebral amyloid angiopathy. J. Neuropathol. Exp. Neurol. 61 , 282–293. 10.1093/jnen/61.3.282 (2002). Thal, D. R. et al. Capillary cerebral amyloid angiopathy identifies a distinct APOE epsilon4-associated subtype of sporadic Alzheimer's disease. Acta Neuropathol. 120 , 169–183. 10.1007/s00401-010-0707-9 (2010). Tsering, W. & Prokop, S. Neuritic Plaques - Gateways to Understanding Alzheimer's Disease. Mol. Neurobiol. 61 , 2808–2821. 10.1007/s12035-023-03736-7 (2024). Mäkelä, M., Paetau, A., Polvikoski, T., Myllykangas, L. & Tanskanen, M. Capillary amyloid-β protein deposition in a population-based study (Vantaa 85+). J. Alzheimers Dis. 49 , 149–157. 10.3233/jad-150241 (2016). Attems, J. & Jellinger, K. A. Only cerebral capillary amyloid angiopathy correlates with Alzheimer pathology–a pilot study. Acta Neuropathol. 107 , 83–90. 10.1007/s00401-003-0796-9 (2004). Mehndiratta, P. et al. Cerebral amyloid angiopathy-associated intracerebral hemorrhage: pathology and management. Neurosurg. Focus . 32 , E7. 10.3171/2012.1.Focus11370 (2012). de Bruin, O. F. et al. Surgical intervention for cerebral amyloid angiopathy-related lobar intracerebral hemorrhage: a systematic review. J. Neurosurg. 141 , 955–965. 10.3171/2024.1.Jns231852 (2024). Mendelow, A. D. et al. Early surgery versus initial conservative treatment in patients with spontaneous supratentorial intracerebral haematomas in the International Surgical Trial in Intracerebral Haemorrhage (STICH): a randomised trial. Lancet 365 , 387–397. 10.1016/s0140-6736(05)17826-x (2005). Che, R. et al. Long-term outcome of cerebral amyloid angiopathy-related hemorrhage. CNS Neurosci. Ther. 28 , 1829–1837. 10.1111/cns.13922 (2022). Fakan, B. et al. Predictors of localization, outcome, and etiology of spontaneous intracerebral hemorrhages: focus on cerebral amyloid angiopathy. J. Neural Transm (Vienna) . 127 , 963–972. 10.1007/s00702-020-02174-2 (2020). Yanagawa, T. et al. Association of antithrombotic therapy with postoperative rebleeding in patients with cerebral amyloid angiopathy. Chin. Neurosurg. J. 9 10.1186/s41016-023-00324-5 (2023). Jia, X. et al. Risk factors for recurrent cerebral amyloid angiopathy-related intracerebral hemorrhage. Front. Neurol. 14 , 1265693. 10.3389/fneur.2023.1265693 (2023). Theodorou, A. et al. Clinical Characteristics, Neuroimaging Markers, and Outcomes in Patients with Cerebral Amyloid Angiopathy: A Prospective Cohort Study. J. Clin. Med. 12 10.3390/jcm12175591 (2023). Additional Declarations No competing interests reported. Cite Share Download PDF Status: Published Journal Publication published 27 Nov, 2025 Read the published version in Scientific Reports → Version 1 posted Editorial decision: Revision requested 05 Sep, 2025 Reviews received at journal 18 Aug, 2025 Reviewers agreed at journal 12 Aug, 2025 Reviewers agreed at journal 12 Aug, 2025 Reviews received at journal 09 Aug, 2025 Reviewers agreed at journal 22 Jul, 2025 Reviewers invited by journal 18 Jul, 2025 Editor assigned by journal 18 Jul, 2025 Editor invited by journal 17 Jun, 2025 Submission checks completed at journal 12 Jun, 2025 First submitted to journal 12 Jun, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-6857736","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":488177406,"identity":"b3ae3aab-4722-427b-9da7-1e7afb2c5acf","order_by":0,"name":"Feng Liu","email":"","orcid":"","institution":"Tianjin Medical University","correspondingAuthor":false,"prefix":"","firstName":"Feng","middleName":"","lastName":"Liu","suffix":""},{"id":488177407,"identity":"3125b4cf-bb66-4a41-bf22-94a9d226f8d4","order_by":1,"name":"Jia Liu","email":"","orcid":"","institution":"Tianjin Medical University","correspondingAuthor":false,"prefix":"","firstName":"Jia","middleName":"","lastName":"Liu","suffix":""},{"id":488177408,"identity":"baaf5421-b251-4f7d-8cde-e7f6dc6e6b82","order_by":2,"name":"Hao Wu","email":"","orcid":"","institution":"Tianjin Medical University","correspondingAuthor":false,"prefix":"","firstName":"Hao","middleName":"","lastName":"Wu","suffix":""},{"id":488177409,"identity":"860321b0-9226-475a-bf38-e920e60dbb5e","order_by":3,"name":"Pan Wang","email":"","orcid":"","institution":"Tianjin Medical University","correspondingAuthor":false,"prefix":"","firstName":"Pan","middleName":"","lastName":"Wang","suffix":""},{"id":488177410,"identity":"98e61c24-b7b6-4fa2-8ce9-433f3daeb429","order_by":4,"name":"Shuai Liu","email":"","orcid":"","institution":"Tianjin Medical 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University","correspondingAuthor":false,"prefix":"","firstName":"Shumei","middleName":"","lastName":"Jin","suffix":""},{"id":488177414,"identity":"9263e46f-e6ee-4166-842a-fa50408aa65d","order_by":8,"name":"Yong Ji","email":"","orcid":"","institution":"Tianjin Medical University","correspondingAuthor":false,"prefix":"","firstName":"Yong","middleName":"","lastName":"Ji","suffix":""},{"id":488177415,"identity":"dc3d47d8-43b5-45cd-a99a-31ebd85266c9","order_by":9,"name":"Xiaoling Yan","email":"","orcid":"","institution":"Tianjin Medical University","correspondingAuthor":false,"prefix":"","firstName":"Xiaoling","middleName":"","lastName":"Yan","suffix":""},{"id":488177416,"identity":"a4c72419-fe4d-4941-967a-f435d2e4537b","order_by":10,"name":"Zhihong Shi","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAzklEQVRIiWNgGAWjYDACCQY2ZgYDGx7G9sbGBx+I11KQJsfcc7jZcAbxWj4cNmafkd4mzUGMDvnZ7c8eFxgwJ/bOfNggzcBgJ6fbQECLwZ0D6cYzDNgSZ85ObDAuYEg2NjtASItEwjFpHgOexI1ALckzGA4kbiOkRX5GYhtQi0Ti/psHGw7zEKOF4UYyG1CLgTHjDMbGZqK0GNxIA2lJkGPsSWxmnGFAhF/kZ6Q/k+b58x8Ylcef//hQYSdHUAu6paQpHwWjYBSMglGAAwAARVZCIhKkUnIAAAAASUVORK5CYII=","orcid":"","institution":"Tianjin Medical University","correspondingAuthor":true,"prefix":"","firstName":"Zhihong","middleName":"","lastName":"Shi","suffix":""}],"badges":[],"createdAt":"2025-06-10 00:08:10","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6857736/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6857736/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1038/s41598-025-26540-w","type":"published","date":"2025-11-27T15:57:35+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":87346800,"identity":"baced09c-6494-4603-b938-c18a828d16c5","added_by":"auto","created_at":"2025-07-23 02:30:56","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":625604,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eCase 1-MRI\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e(a, b)\u003c/strong\u003e MRI T2 FLAIR showing multispot white-matter hyperintensity, along with two patchy hyperintense lesions at the left frontal and right parietal lobes, located in the cortex and subcortically and periventricularly. \u003cstrong\u003e(c)\u003c/strong\u003e CT showing large irregular lobar hemorrhage at the left frontal lobe.\u003cstrong\u003e (d, e) \u003c/strong\u003eMRI T2 FLAIR showing hemorrhage at the right frontal lobe with severe edema and multispot white-matter hyperintensity. \u003cstrong\u003e(f)\u003c/strong\u003e MRI gradient recalled echo showing multiple irregular hypointensity at the left frontal lobe.\u003c/p\u003e","description":"","filename":"floatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-6857736/v1/a555424986637a29c79cf79d.png"},{"id":87346799,"identity":"322c9c16-57d6-4b2c-a32a-f9469a42596a","added_by":"auto","created_at":"2025-07-23 02:30:56","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":1036261,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eCase 1-Physiology\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e(a, b)\u003c/strong\u003e Multiple patchy hemorrhage in the cortical section, with the vessels surrounded by inflammatory infiltrate.\u003cstrong\u003e (c) \u003c/strong\u003eMild patchy Aβ deposition in some vessels surrounded by inflammatory infiltrate. \u003cstrong\u003e(d)\u003c/strong\u003e Most of the perivascular and leptomeningeal lymphocytes are CD3-immunopositive T cells; HE staining \u003cstrong\u003e(a, b)\u003c/strong\u003e, 4G8 \u003cstrong\u003e(c)\u003c/strong\u003e, CD3\u003cstrong\u003e (d)\u003c/strong\u003e. Scale bars: 300 μm \u003cstrong\u003e(a)\u003c/strong\u003e, 100 μm\u003cstrong\u003e (b–d)\u003c/strong\u003e.\u003c/p\u003e","description":"","filename":"floatimage2.png","url":"https://assets-eu.researchsquare.com/files/rs-6857736/v1/f8f0b61b749c340724ec6ff5.png"},{"id":87346809,"identity":"a5db2d54-9d11-434b-9288-85c3d565b4b1","added_by":"auto","created_at":"2025-07-23 02:30:56","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":1367841,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eCase 2-CT and Physiology\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e(a)\u003c/strong\u003e CT showed lobar hemorrhage at the right temporoparietal lobe. \u003cstrong\u003e(b, d) \u003c/strong\u003eSome hyalinized thick vessels, one in the center of patchy hematoma in the cortical section, and some thickened vessel walls with eosinophilic infiltrate and disrupted cytoarchitecture. \u003cstrong\u003e(c, e, f) \u003c/strong\u003eThickened amyloid-laden vessel walls are strongly positive for anti-β-amyloid protein antibody; there are some vessels with disrupted cytoarchitecture with positivity or negativity for anti-β-amyloid protein antibody, along with many dense-core plaques and diffuse plaques in the cortex. HE staining \u003cstrong\u003e(b, d)\u003c/strong\u003e, 4G8\u003cstrong\u003e (c, e, f)\u003c/strong\u003e. Scale bars: 250 μm \u003cstrong\u003e(b, f)\u003c/strong\u003e, 100 μm\u003cstrong\u003e (d, e)\u003c/strong\u003e, 200 μm\u003cstrong\u003e (c)\u003c/strong\u003e.\u003c/p\u003e","description":"","filename":"floatimage3.png","url":"https://assets-eu.researchsquare.com/files/rs-6857736/v1/00c3bc2fbc10a1b8cc2f6661.png"},{"id":87346812,"identity":"05b1a09d-3b5a-4b91-ba07-599b6688ac12","added_by":"auto","created_at":"2025-07-23 02:30:57","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":100899,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eCase 3-CT and Physiology\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e(a)\u003c/strong\u003e CT showed lobar hemorrhage at the right temporoparietal lobe. \u003cstrong\u003e(b)\u003c/strong\u003e Some hyalinized vessels with eosinophilic amorphous deposit in the walls in cortical section.\u003cstrong\u003e (c, d) \u003c/strong\u003eThickened amyloid-laden vessel walls are strongly positive for anti-β-amyloid protein antibody and there are some dense-core plaques in the cortex; there are many strongly anti-β-amyloid-positive leptomeningeal vessels. \u003cstrong\u003e(e) \u003c/strong\u003eSome amyloid-laden vessels show thickened vessel walls and splitting (4G8 immunostaining, original magnification ×100). HE staining \u003cstrong\u003e(a)\u003c/strong\u003e, 4G8 \u003cstrong\u003e(b–e)\u003c/strong\u003e. Scale bars: 200 μm \u003cstrong\u003e(a, b)\u003c/strong\u003e, 500 μm\u003cstrong\u003e(c)\u003c/strong\u003e, 100 μm \u003cstrong\u003e(d)\u003c/strong\u003e.\u003c/p\u003e","description":"","filename":"Onlinefloatimage4.png","url":"https://assets-eu.researchsquare.com/files/rs-6857736/v1/1a8b82bb73a3ef7900d4652c.png"},{"id":97178692,"identity":"862fe22b-48f0-4d90-b392-d534f13be1a0","added_by":"auto","created_at":"2025-12-01 16:12:48","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":4828046,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6857736/v1/d1937943-f5d4-4908-8f39-9257f356d5df.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Neuropathology and long-term outcome in cerebral amyloid angiopathy patients with intracerebral hemorrhage","fulltext":[{"header":"Introduction","content":"\u003cp\u003eCerebral amyloid angiopathy (CAA) is caused by the deposition of amyloid-β (Aβ) in the small to medium-sized vessels in the cerebral cortex and overlying leptomeninges \u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e. It is the second most common etiology of spontaneous symptomatic intracerebral hemorrhage (ICH; accounting for 12\u0026ndash;20% of cases) after hypertension \u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e,\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e. CAA-associated ICH (CAA-ICH) characteristically occurs at lobar or superficial areas and has a high recurrence rate (estimated to exceed 10% per year), especially in patients receiving anti-thrombotic agents \u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e,\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e. The prevalence of moderate-to-severe CAA based on pathology was reported to be around 50\u0026ndash;60% in patients with lobar ICH \u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003ePathological features of CAA and Alzheimer's disease (AD) have been intensively studied using autopsy samples. The pathologies of CAA and AD frequently co-exist in the same brain, presumably because Aβ is pathogenic in both \u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e,\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u003c/sup\u003e. A pathological examination is needed for the reliable diagnosis of CAA, but it is difficult to obtain specimens from patients with suspected CAA while they are alive. Biopsies of cortical samples from postmortem brains with CAA of a known distribution showed that vascular amyloid is a sensitive marker for CAA-related hemorrhage \u003csup\u003e\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e. The examination of cortical tissue obtained surgically is thus an important tool for diagnosing CAA. Meanwhile, extracellular Aβ plaques are the main pathological findings in AD-affected cortex, and the pathological processes underlying AD already start decades before symptoms appear \u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e. Only a few studies with limited cases have analyzed biopsies from surgery on CAA-ICH patients \u003csup\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e. The features of Aβ plaques in cortical samples of acute CAA-ICH patients after hematoma evacuation have also rarely been reported \u003csup\u003e\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003eAgainst this background, the purpose of this study was to evaluate the level of severity of CAA and amyloid plaques of CAA in patients who underwent surgery for large lobar hemorrhage along with cortical biopsy at our hospital. The association of CAA severity with long-term outcomes was also analyzed after at least 1 year of follow-up.\u003c/p\u003e"},{"header":"Materials and Methods","content":"\u003cp\u003eThis study was performed in accordance with the ethical standards of the Tianjin Huanhu Hospital Human Experimentation Committee. This study was approved by the Ethics Committee of Tianjin Huanhu Hospital (NO. 2024\u0026thinsp;\u0026minus;\u0026thinsp;270). Written informed consent was obtained from all participants or their legal representatives before enrollment.\u003c/p\u003e\u003cp\u003eParticipants\u003c/p\u003e\u003cp\u003eWe performed a prospective, single-center, hospital-based cohort study including all consecutive acute-phase spontaneous ICH patients with hematoma evacuations, with a diagnosis of probable CAA with supporting pathology, in accordance with the modified Boston Criteria v. 2.0 \u003csup\u003e12\u003c/sup\u003e. The subjects were all patients admitted to Tianjin Huanhu Hospital between August 2016 and October 2024 who demonstrated lobar, cortical, or subcortical hemorrhage, with some degree of CAA in the specimen from evacuated hematoma or cortical biopsy. Exclusion criteria were as follows: 1) head trauma, 2) cavernous venous tumor, 3) arteriovenous malformation, 4) hemorrhagic cerebral infarction, 5) lobar hemorrhage due to venous sinus thrombosis, or 6) intracranial tumor with bleeding (on brain MRI or pathology).\u003c/p\u003e\u003cp\u003ePathological examinations\u003c/p\u003e\u003cp\u003eEach sample was fixed in neutral buffered formalin, routinely processed, paraffin-embedded, and cut into sections of 4 \u0026micro;m thickness. These sections were subjected to hematoxylin-eosin staining. Immunohistochemical staining was also performed by the avidin-biotin-peroxidase complex method with antibodies against total Aβ protein (monoclonal antibody 6E10/4G8, mouse, 1:600\u0026ndash;1:1000; Biolegend), cluster of differentiation 68 (CD68; mouse, ZM-0060; Beijing Zhongshan Golden Bridge Biological Technology Co.), smooth muscle actin (SMA; mouse, ZM-0003; ZSGB-BIO), CD20 (mouse, ZM-0039; ZSGB-BIO), and perivascular macrophages (CD163, mouse, ZM-0428; ZSGB-BIO). All stains were performed manually following a standardized immunohistochemical protocol.\u003c/p\u003e\u003cp\u003eWe evaluated the level of severity of CAA using the grading scale previously described by Greenberg et al \u003csup\u003e\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e,\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e,\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u003c/sup\u003e. In this scale, Grade 0 CAA is negative for CAA; Grade 1 involves the presence of some Aβ-positivity in otherwise normal-appearing vessels; Grade 2 involves complete replacement of the medium by Aβ-positive material; Grade 3 features cracking of the amyloid-laden vessel walls affecting at least 50% of the circumference of the vessels; and Grade 4 refers to the presence in an amyloid-laden vessel of fibrinoid necrosis. Evaluation of CAA based on this grading scale was performed by two pathologists blinded to the clinical data, except for in the case of specimens from patients with lobar hemorrhage.\u003c/p\u003e\u003cp\u003eClinical features\u003c/p\u003e\u003cp\u003eWe investigated the following potential risk factors for intracranial bleeding in all patients using the medical records: hypertension (HT) with or without medication, and receiving antiplatelet or anticoagulant medication. We also investigated previous history of ICH, cerebral infarction, diabetes mellitus, atrial fibrillation, and the lifestyle habits of current smoking and a history of excessive alcohol intake. The position of lobar hemorrhage on initial CT was also measured in each case.\u003c/p\u003e\u003cp\u003eFollow-up assessments and outcomes\u003c/p\u003e\u003cp\u003eAll patients were followed up for at least 12 months and follow-up data was prospectively collected. We recorded information on recurrent ICH, defined as a symptomatic stroke syndrome with evidence from a CT scan of a corresponding ICH (\u0026gt;\u0026thinsp;10 mm in diameter) or death from any cause. Outcome events were assessed using all available clinical and radiological information.\u003c/p\u003e\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003ch2\u003eStatistical analysis\u003c/h2\u003e\u003cp\u003eFor categorical variables shown in percentages, the chi-square test or Fisher\u0026rsquo;s exact test was used. Continuous data were tested for normality using the Kolmogorov\u0026ndash;Smirnov test. If parameters were normally distributed, they are depicted as mean\u0026thinsp;\u003cem\u003e\u0026plusmn;\u003c/em\u003e\u0026thinsp;standard deviation; otherwise, they are presented as median with interquartile range (IQR). Continuous variables were tested by Student\u0026rsquo;s \u003cem\u003et\u003c/em\u003e-test (normally distributed data) or Mann\u0026ndash;Whitney U-test (non-normally distributed data).\u003c/p\u003e\u003cp\u003eUnivariable and multivariable binary logistic regression models were used to evaluate the associations of CAA severity with clinical outcomes at 6 months and 12 months before and after adjusting for potential confounders. A cut-off of \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.1 was used to select variables for inclusion in the multivariable analysis. Associations are presented as odds ratios (ORs) with corresponding 95% confidence intervals (CIs). In the multivariable logistic regression analysis, statistical significance was considered to have been reached if the \u003cem\u003ep\u003c/em\u003e value was \u003cem\u003e\u0026le;\u003c/em\u003e\u0026thinsp;0.05.\u003c/p\u003e\u003cp\u003eMoreover, Cox proportional hazard regression models were used to calculate the\u003c/p\u003e\u003cp\u003eassociations of CAA severity and age with the risk of death or recurrent ICH. For patients experiencing multiple symptomatic ICH events during follow-up, data was censored after the first symptomatic ICH event. All covariates demonstrating a univariable association with the outcome in Cox regression analysis (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.1) were considered for inclusion in the multivariable model. All tests of significance were two-tailed, and the significance level was set at 0.05 for all analyses. All statistical analyses were conducted using SPSS Statistics v.21.0.\u003c/p\u003e\u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003eA total of 93 patients who underwent removal of lobar hemorrhage with brain biopsy, for whom sufficient specimens were available to evaluate cortical and/or leptomeningeal vessels were included in this study. Among the 93 specimens, 63 patients (67.7%) had CAA, and the other 30 patients (32.3%) did not. According to the pathological grading system for CAA, 8 patients (12.7%) had Grade 1 CAA, 12 (19.0%) had Grade 2, and 43 (68.3%) had Grade 3-4. According to the classification by Vonsattel et al., mild CAA corresponds to Grade 1 CAA, moderate CAA matches Grade 2, and severe CAA generally resembles Grade 3-4 \u003csup\u003e13\u003c/sup\u003e.\u003c/p\u003e\n\u003cp\u003eAmong the 63 patients pathologically diagnosed with CAA, there were significantly more men (35, 55.6%) than women. The mean ages of Grade 1, Grade 2, and Grade 3-4 CAA patients were 49.0 (48.0\u0026ndash;68.0), 65.5 (62.0\u0026ndash;68.5), and 72.0 (68.0\u0026ndash;76.0), respectively. The common locations of hemorrhages of CAA-positive patients were parietal lobe (55.6%), temporal lobe (52.4%), and frontal lobe (49.2%) patients, which differed significantly among Grade 1, Grade 2 and Grade 3-4 CAA groups. Overall, 24 (38.1%) patients showed subarachnoid hemorrhage (SAH) and 15 (23.8%) showed subdural hemorrhage (SDH), for which there were no significant differences among Grade 1, Grade 2, and Grade 3-4 CAA groups (Table 1).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eTable 1 Baseline characteristics in the study cohort based on pathology\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"694\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 183px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 107px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"3\" style=\"width: 346px;\"\u003e\n \u003cp\u003eGrading scale of CAA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 58px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 183px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 107px;\"\u003e\n \u003cp\u003eOverall (n=63)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 108px;\"\u003e\n \u003cp\u003e\u0026nbsp;Grade 1 (n=8)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 117px;\"\u003e\n \u003cp\u003eGrade 2 \u0026nbsp;(n=12)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003eGrade 3-4\u0026nbsp;(n=43)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 58px;\"\u003e\n \u003cp\u003ep Value\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 183px;\"\u003e\n \u003cp\u003eGender, Male\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 107px;\"\u003e\n \u003cp\u003e35 (55.6 %)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 108px;\"\u003e\n \u003cp\u003e5 (62.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 117px;\"\u003e\n \u003cp\u003e10 (58.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003e20 (46.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 58px;\"\u003e\n \u003cp\u003e0.070\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 183px;\"\u003e\n \u003cp\u003eAge\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 107px;\"\u003e\n \u003cp\u003e69.0 (65.0-74.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 108px;\"\u003e\n \u003cp\u003e49.0 (48.0-68.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 117px;\"\u003e\n \u003cp\u003e65.5 (62.0-68.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003e72.0 (68.0-76.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 58px;\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 183px;\"\u003e\n \u003cp\u003eAge distribution\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 107px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 108px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 117px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 58px;\"\u003e\n \u003cp\u003e0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 183px;\"\u003e\n \u003cp\u003e＜50 years\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 107px;\"\u003e\n \u003cp\u003e3 (4.8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 108px;\"\u003e\n \u003cp\u003e2 (25%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 117px;\"\u003e\n \u003cp\u003e1 (8.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 58px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 183px;\"\u003e\n \u003cp\u003e50-59 years\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 107px;\"\u003e\n \u003cp\u003e4 (6.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 108px;\"\u003e\n \u003cp\u003e2 (25%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 117px;\"\u003e\n \u003cp\u003e1 (8.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003e1 (2.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 58px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 183px;\"\u003e\n \u003cp\u003e60-69 years\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 107px;\"\u003e\n \u003cp\u003e26 (41.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 108px;\"\u003e\n \u003cp\u003e4 (50%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 117px;\"\u003e\n \u003cp\u003e8 (66.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003e14 (32.6%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 58px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 183px;\"\u003e\n \u003cp\u003e70-79 years\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 107px;\"\u003e\n \u003cp\u003e26 (41.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 108px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 117px;\"\u003e\n \u003cp\u003e2 (16.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003e24 (55.8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 58px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 183px;\"\u003e\n \u003cp\u003e80-89 years\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 107px;\"\u003e\n \u003cp\u003e4 (6.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 108px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 117px;\"\u003e\n \u003cp\u003e0\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003e4 (9.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 58px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 183px;\"\u003e\n \u003cp\u003eSmoking\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 107px;\"\u003e\n \u003cp\u003e11 (17.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 108px;\"\u003e\n \u003cp\u003e2 (25.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 117px;\"\u003e\n \u003cp\u003e2 (17.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003e7 (16.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 58px;\"\u003e\n \u003cp\u003e0.834\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 183px;\"\u003e\n \u003cp\u003eDrinking\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 107px;\"\u003e\n \u003cp\u003e8 (12.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 108px;\"\u003e\n \u003cp\u003e3（37.5%）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 117px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003e5 (11.6%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 58px;\"\u003e\n \u003cp\u003e0.044\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 183px;\"\u003e\n \u003cp\u003eMedical history\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 107px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 108px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 117px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 58px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 183px;\"\u003e\n \u003cp\u003eHypertension\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 107px;\"\u003e\n \u003cp\u003e27 (42.9%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 108px;\"\u003e\n \u003cp\u003e3 (37.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 117px;\"\u003e\n \u003cp\u003e4 (33.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003e20 (46.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 58px;\"\u003e\n \u003cp\u003e0.680\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 183px;\"\u003e\n \u003cp\u003eDiabetes mellitus\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 107px;\"\u003e\n \u003cp\u003e7 (11.1%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 108px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 117px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003e7 (16.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 58px;\"\u003e\n \u003cp\u003e0.160\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 183px;\"\u003e\n \u003cp\u003ePrevious cerebral hemorrhage\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 107px;\"\u003e\n \u003cp\u003e12 (19.1%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 108px;\"\u003e\n \u003cp\u003e1 (12.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 117px;\"\u003e\n \u003cp\u003e1 (8.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003e10 (23.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 58px;\"\u003e\n \u003cp\u003e0.447\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 183px;\"\u003e\n \u003cp\u003eCerebral infarction\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 107px;\"\u003e\n \u003cp\u003e9 (14.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 108px;\"\u003e\n \u003cp\u003e1 (12.9%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 117px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003e8 (18.6%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 58px;\"\u003e\n \u003cp\u003e0.264\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 183px;\"\u003e\n \u003cp\u003eAtrial fibrillation\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 107px;\"\u003e\n \u003cp\u003e3 (3.2%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 108px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 117px;\"\u003e\n \u003cp\u003e2 (16.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003e1 (2.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 58px;\"\u003e\n \u003cp\u003e0.968\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 183px;\"\u003e\n \u003cp\u003eAntiplatelet medicine\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 107px;\"\u003e\n \u003cp\u003e13 (20.6%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 108px;\"\u003e\n \u003cp\u003e1 (12.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 117px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003e12 (27.9%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 58px;\"\u003e\n \u003cp\u003e0.089\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 183px;\"\u003e\n \u003cp\u003eAntihypertension\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 107px;\"\u003e\n \u003cp\u003e26 (41.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 108px;\"\u003e\n \u003cp\u003e3 (37.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 117px;\"\u003e\n \u003cp\u003e3 (25.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003e20 (46.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 58px;\"\u003e\n \u003cp\u003e0.398\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 183px;\"\u003e\n \u003cp\u003eHematoma location\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 107px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 108px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 117px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 58px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 183px;\"\u003e\n \u003cp\u003eFrontal lobe\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 107px;\"\u003e\n \u003cp\u003e31 (49.2%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 108px;\"\u003e\n \u003cp\u003e2 (25.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 117px;\"\u003e\n \u003cp\u003e5 (58.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003e21 (51.2%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 58px;\"\u003e\n \u003cp\u003e0.310\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 183px;\"\u003e\n \u003cp\u003eOccipital lobe\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 107px;\"\u003e\n \u003cp\u003e15 (23.8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 108px;\"\u003e\n \u003cp\u003e2 (25.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 117px;\"\u003e\n \u003cp\u003e2 (16.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003e11 (25.6%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 58px;\"\u003e\n \u003cp\u003e0.811\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 183px;\"\u003e\n \u003cp\u003eTemporal lobe\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 107px;\"\u003e\n \u003cp\u003e33 (52.4%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 108px;\"\u003e\n \u003cp\u003e5 (62.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 117px;\"\u003e\n \u003cp\u003e5 (41.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003e23 (53.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 58px;\"\u003e\n \u003cp\u003e0.637\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 183px;\"\u003e\n \u003cp\u003eParietal lobe\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 107px;\"\u003e\n \u003cp\u003e35 (55.6%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 108px;\"\u003e\n \u003cp\u003e5 (62.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 117px;\"\u003e\n \u003cp\u003e4 (33.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003e20 (60.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 58px;\"\u003e\n \u003cp\u003e0.226\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 183px;\"\u003e\n \u003cp\u003eSubdural hemorrhage\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 107px;\"\u003e\n \u003cp\u003e15 (23.8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 108px;\"\u003e\n \u003cp\u003e2 (25.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 117px;\"\u003e\n \u003cp\u003e3 (25.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003e10 (23.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 58px;\"\u003e\n \u003cp\u003e0.989\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 183px;\"\u003e\n \u003cp\u003eSubarachnoid hemorrhage\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 107px;\"\u003e\n \u003cp\u003e24 (38.1%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 108px;\"\u003e\n \u003cp\u003e4 (50.0%）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 117px;\"\u003e\n \u003cp\u003e4 (33.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003e16 (37.2%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 58px;\"\u003e\n \u003cp\u003e0.737\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eA\u0026beta; plaques in CAA patients\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;Among the 63 patients pathologically diagnosed with CAA, 31 patients for whom there were insufficient cortical specimens to evaluate A\u0026beta; plaques were excluded. As such, 32 patients had their A\u0026beta; plaques evaluated by anti-4G8/6E10 immunohistochemical staining. Among these, 23 (71.9%) patients had dense-core plaques and 26 (81.3%) had diffuse plaques. In addition, 18 (56.3%) patients had plaques around vessels. Dense-core plaques were found exclusively in moderate-to-severe CAA patients, while only one mild CAA patient had diffuse plaques. Moreover, plaques around vessels were found exclusively in severe CAA patients (Table 2).\u003c/p\u003e\n\u003cp\u003eTable 2 Pathologic change in CAA patient\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"628\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 151px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 99px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"3\" style=\"width: 314px;\"\u003e\n \u003cp\u003eGrading scale of CAA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 151px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 99px;\"\u003e\n \u003cp\u003eOverall (N=32)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 102px;\"\u003e\n \u003cp\u003e\u0026nbsp;Grade 1 (n=3)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 101px;\"\u003e\n \u003cp\u003eGrade 2 (N=4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 112px;\"\u003e\n \u003cp\u003eGrade 3-4 (N=25)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003ep Value\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 151px;\"\u003e\n \u003cp\u003eDense-core plaques\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 99px;\"\u003e\n \u003cp\u003e23 (71.9%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 102px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 101px;\"\u003e\n \u003cp\u003e2 (50.0 %)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 112px;\"\u003e\n \u003cp\u003e21 (84.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003e0.070\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 151px;\"\u003e\n \u003cp\u003eDiffuse plaques\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 99px;\"\u003e\n \u003cp\u003e26 ( 81.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 102px;\"\u003e\n \u003cp\u003e1 (33.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 101px;\"\u003e\n \u003cp\u003e3 (75.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 112px;\"\u003e\n \u003cp\u003e22 (88.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 151px;\"\u003e\n \u003cp\u003ePlaques around vessels\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 99px;\"\u003e\n \u003cp\u003e18 (56.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 102px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 101px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 112px;\"\u003e\n \u003cp\u003e18 (72.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003e0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIllustrative case 1 (ICH with mild CAA)\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eA 51-year-old female was due to headache, vomiting for 12 h, and disturbance of consciousness for 4 h. CT showed hemorrhage at the left frontal lobe. MRI showed left frontal hematoma and edema (Fig. 1). She had been taking antiplatelet medication (aspirin 100 mg QD) for six months for cerebral infarction. Pathological examinations showed patchy A\u0026beta; deposition in some vessels, which corresponded to Grade 1 CAA, and inflammatory infiltrate surrounding the vessels. Most of the perivascular and leptomeningeal lymphocytes were CD3-immunopositive T cells. Some CD68-positive macrophages were identified around the vessels (Fig. 2). After 13 months of follow-up, the patient had only mild decline in recent memory, which didn\u0026rsquo;t significantly impact on daily life.\u003c/p\u003e\n\u003cp\u003eIllustrative case 2 (ICH with severe CAA)\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003eA 76-year-old male suffered from headache and disturbance of consciousness for 6 h. He had hypertension for 11 years but taken no regular medication and suffered ICH three times. CT showed lobar hemorrhage at the right temporoparietal lobe (Fig. 3a). Pathological examinations showed that most of the cortical and leptomeningeal vessels had been completely replaced by A\u0026beta;-positive material, while some amyloid-laden vessels showed thickened vessel walls and splitting, which corresponded to Grade 3 CAA. Some dense-core, diffuse plaques and plaques surrounding vessels were scattered in the cortical specimen (Fig. 3b\u0026ndash;f). After one week of follow-up, the patient died due to cerebral herniation.\u003c/p\u003e\n\u003cp\u003eIllustrative case 3 (ICH with severe CAA)\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003eA 77-year-old male suffered from headache and vomiting for 6 h. He had been taking antiplatelet medication for coronary atherosclerotic heart disease 1 year. CT showed lobar hemorrhage at the right temporoparietal lobe (Fig. 4a). Pathological examinations showed that most of the vessels had been completely replaced by A\u0026beta;-positive material and some amyloid-laden vessels showed thickened walls, with disrupted cytoarchitecture, which corresponded to Grade 4 CAA. Many dense-core, diffuse plaques and plaques surrounding vessels were shown in the cortical specimen (Fig. 4b\u0026ndash;e). After 14 months of follow-up, this patient developed global cognitive decline and was diagnosed with severe dementia.\u003c/p\u003e\n\u003cp\u003eOutcomes and\u0026nbsp;predictors of death or ICH recurrence\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003eOverall,\u0026nbsp;57 patients were followed up for at least 12 months or until death. Six patients were lost to follow-up. During the follow-up period, 27 patients\u0026nbsp;died. Twelve deaths\u0026nbsp;occurred within 1 month after surgery: 10 of these were caused by brain hernia, 1 by\u0026nbsp;status epilepticus, and 1 by gastrointestinal hemorrhage. Of the other 15 deaths, 9 were due to pneumonia and 5 were due to recurrent ICH\u0026nbsp;(1 month after surgery)\u0026nbsp;while 1 patient died at home of an unknown cause. Five patients\u0026nbsp;experienced\u0026nbsp;recurrent non-lethal\u0026nbsp;symptomatic ICH during the follow-up period. Among the 63 patients, 18 (28.6%) experienced\u0026nbsp;recurrent ICH at least\u0026nbsp;once.\u003c/p\u003e\n\u003cp\u003eSixteen patients (28.1%) died within 6 months of hematoma evacuation. The mortality rate within 6 months was significantly higher in severe CAA (Grade 3\u0026ndash;4) patients than in mild-to-moderate ones [unadjusted OR, 12.96; 95% confidence interval (CI), 1.56\u0026ndash;107.41; P=0.018]. During 12 months of follow-up, 20 patients (35.1%) died. Similarly, the mortality rate within 12 months was significantly higher in severe CAA patients than in mild-to-moderate ones (unadjusted OR, 20.06; 95% CI, 2.43\u0026ndash;165.70; P=0.005). These findings remained significant after adjustment for age, sex, antiplatelet medication, and history of excessive alcohol intake (6 months: adjusted OR, 11.06, 95% CI, 1.05\u0026ndash;116.62, P=0.046; 12 months: adjusted OR, 18.49, 95% CI, 1.78\u0026ndash;193.03, P=0.015) (Table 3).\u003c/p\u003e\n\u003cp\u003eTable 3 Outcomes in six and twelve months in CAA-ICH patients\u0026nbsp;\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"583\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 168px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 101px;\"\u003e\n \u003cp\u003eOverall (N=57)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 119px;\"\u003e\n \u003cp\u003eGrade 1- 2 (N=20)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 130px;\"\u003e\n \u003cp\u003eGrade 3-4 (N=37)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003ep Value\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 168px;\"\u003e\n \u003cp\u003eMortality within 6 months\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 101px;\"\u003e\n \u003cp\u003e16 (28.1%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 119px;\"\u003e\n \u003cp\u003e1 (8.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 130px;\"\u003e\n \u003cp\u003e15 (40.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 168px;\"\u003e\n \u003cp\u003eCrude OR (95% CI)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 101px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 119px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 130px;\"\u003e\n \u003cp\u003e12.96 (1.56-107.41)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003e0.018\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 168px;\"\u003e\n \u003cp\u003eAjusted OR* (95% CI)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 101px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 119px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 130px;\"\u003e\n \u003cp\u003e11.06 (1.05-116.62)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003e0.046\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 168px;\"\u003e\n \u003cp\u003eMortality within 12 months\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 101px;\"\u003e\n \u003cp\u003e20 (35.1%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 119px;\"\u003e\n \u003cp\u003e1(8.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 130px;\"\u003e\n \u003cp\u003e19 (51.4%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 168px;\"\u003e\n \u003cp\u003eCrude OR (95% CI)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 101px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 119px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 130px;\"\u003e\n \u003cp\u003e20.06 (2.43-165.70)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003e0.005\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 168px;\"\u003e\n \u003cp\u003eAjusted OR* (95% CI)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 101px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 119px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 130px;\"\u003e\n \u003cp\u003e18.49 (1.78-193.03)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003e0.015\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eAbbreviations: CI indicates confidence interval; OR, odds ratio. *Adjusted for age, sex, Antiplatelet medicine, history of excessive alcohol intake.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp; \u0026nbsp;In a univariable Cox regression model with death or recurrent ICH as endpoints, CAA severity and old age were risk factors of death or recurrent ICH (HR: 3.71, 95% CI: 1.42\u0026ndash;9.67, \u003cem\u003eP=\u003c/em\u003e0.007; and HR: 1.07, 95% CI: 1.02\u0026ndash;1.13, P=0.007, respectively). These findings remained significant after adjustment for sex, antiplatelet medication, and history of excessive alcohol intake (adjusted HR, 4.16, 95% CI, 1.54\u0026ndash;11.24, P=0.005; and adjusted HR, 1.08, 95% CI, 1.02\u0026ndash;1.14, P=0.008, respectively) (Table 4). However, in multivariable Cox regression models, including CAA severity, age, sex, antiplatelet medication, and history of excessive alcohol intake, these findings were no longer significant.\u003c/p\u003e\n\u003cp\u003eTable 4 Association of CAA severity with mortality or recurrent ICH in CAA-ICH patients\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"507\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 129px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 83px;\"\u003e\n \u003cp\u003eB\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 77px;\"\u003e\n \u003cp\u003e\u0026nbsp;HR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 117px;\"\u003e\n \u003cp\u003e95% CI\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 101px;\"\u003e\n \u003cp\u003ep Value\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 129px;\"\u003e\n \u003cp\u003eCAA severity\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 83px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 77px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 117px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 101px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 129px;\"\u003e\n \u003cp\u003eCrude HR\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 83px;\"\u003e\n \u003cp\u003e1.131\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 77px;\"\u003e\n \u003cp\u003e3.71\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 117px;\"\u003e\n \u003cp\u003e1.42-9.67\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 101px;\"\u003e\n \u003cp\u003e0.007\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 129px;\"\u003e\n \u003cp\u003eAjusted HR*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 83px;\"\u003e\n \u003cp\u003e1.425\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 77px;\"\u003e\n \u003cp\u003e4.16\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 117px;\"\u003e\n \u003cp\u003e1.54-11.24\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 101px;\"\u003e\n \u003cp\u003e0.005\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 129px;\"\u003e\n \u003cp\u003eAge\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 83px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 77px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 117px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 101px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 129px;\"\u003e\n \u003cp\u003eCrude HR\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 83px;\"\u003e\n \u003cp\u003e0.074\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 77px;\"\u003e\n \u003cp\u003e1.07\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 117px;\"\u003e\n \u003cp\u003e1.02-1.13\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 101px;\"\u003e\n \u003cp\u003e0.007\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 129px;\"\u003e\n \u003cp\u003eAjusted HR*\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 83px;\"\u003e\n \u003cp\u003e0.077\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 77px;\"\u003e\n \u003cp\u003e1.08\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 117px;\"\u003e\n \u003cp\u003e1.02-1.14\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 101px;\"\u003e\n \u003cp\u003e0.008\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eAbbreviations: CI indicates confidence interval; HR, hazard ratio. *Adjusted for, sex, Antiplatelet medicine, history of excessive alcohol intake.\u0026nbsp;\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eIn our study, 63 patients with lobar hemorrhage were pathologically diagnosed with CAA, with severe CAA (Grades 3-4) comprising the majority (68.3%) and the vast majority (87.3%) having moderate-to-severe CAA. Although the specimens obtained during surgery were only a tiny part of the whole brain, this result suggests that pathologically severe CAA with vasculopathic change has a high possibility of inducing large lobar hemorrhage. Severe CAA might have been present in some patients with low-grade CAA in this study. Among 32 CAA patients for whom sufficient cortical specimens were available, 23 (71.9%) patients had dense-core plaques and 26 (81.3%) diffuse plaques.\u0026nbsp;Three (9.4%) patients showed negativity for A\u0026beta; plaques in their cortical specimen. This indicated that extracellular A\u0026beta; plaques are common in CAA-ICH patients, especially in those with severe CAA. Among all 63 CAA-positive patients, the recurrence rate of CAA-ICH was 28.6%. The\u0026nbsp;mortality\u0026nbsp;rate in CAA-ICH patients was 28.1% in 6 months and 35.1% in 12 months following hematoma evacuation. The findings suggested that ICH patients with severe CAA have higher mortality rates in 1 year than patients with mild-to-moderate CAA.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u0026nbsp;CAA was considered to be one of the significant causes of lobar hemorrhage; however, the incidence of primary CAA-related lobar hemorrhage is unknown. Our study showed that, in severe spontaneous lobar hemorrhage patients, the prevalence of moderate-to-severe CAA was 59.1%. Meanwhile, a recent meta-analysis showed that the prevalence of mild-to-severe CAA in patients with lobar ICH was 52.2%, while that of\u0026nbsp;moderate-to-severe CAA was 49.7% in an East Asian cohorts \u003csup\u003e14\u003c/sup\u003e.\u0026nbsp;Although our study examined the prevalence of CAA in only surgical cases with lobar hemorrhage, the majority of previous studies examined specimens from autopsy, which might explain why the prevalence was higher than in previous studies. The high prevalence rates were partly due to exclusion criteria including head trauma, cavernous venous tumor, arteriovenous malformation, or intracranial tumor with bleeding in our study. Another possible reason is that surgical cases with more severe lobe hemorrhage were selected in our study, which is more likely to be associated with severe primary CAA pathology. Indeed, previous studies have shown that more severe CAA pathology is associated with more severe consequences such as micro- or macro-hemorrhage or infarct\u0026nbsp;\u003csup\u003e13,15,16\u003c/sup\u003e.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u0026nbsp; CAA involves the cerebrovascular deposition of A\u0026beta;, which is also the primary constituent of neuritic plaques in AD. The two conditions often overlap, presumably because of the shared role of A\u0026beta;. Our study on CAA-ICH patients showed that 23 (71.9%) patients had dense-core plaques and 26 (81.3%) had diffuse plaques. Dense-core plaques were found exclusively in moderate-to-severe CAA patients. Previous brain autopsy-based and neuropathological studies showed that CAA was strongly associated with AD pathology \u003csup\u003e6,17\u003c/sup\u003e. Additionally, an autopsy study of 3,976 brains in the US National Alzheimer\u0026rsquo;s Coordinating Center database revealed that the pathological grade of CAA was moderate to severe in 5.3% of brains without neuritic plaques, 16.1% of brains with mild neuritic plaques, 31.7% of brains with moderate neuritic plaques, and 45.3% of brains with severe neuritic plaques \u003csup\u003e7\u003c/sup\u003e.\u0026nbsp;Elsewhere, it was shown that\u0026nbsp;A\u0026beta; deposition in brain capillaries is specifically associated with neuritic plaques and severe AD pathology\u0026nbsp;\u003csup\u003e18,19\u003c/sup\u003e.\u003c/p\u003e\n\u003cp\u003eIn our 57 CAA-ICH patients after surgery, the mortality rate was\u0026nbsp;28.1% at 6 months and 35.1% at 1 year.\u0026nbsp;Meanwhile, a meta-analysis revealed that, after surgical treatment, the CAA-ICH mortality rate was 24% at 1 year \u003csup\u003e20\u003c/sup\u003e. Moreover, a recent review showed that the outcome of CAA-ICH was predominantly poor with a pooled 3-month mortality rate of 19% \u003csup\u003e21\u003c/sup\u003e. Furthermore, the results from management of all-cause ICH in the STICH trial reported a 6-month mortality rate of 36% \u003csup\u003e22\u003c/sup\u003e. These results suggest the possibility that surgical management of CAA-associated ICH may reduce mortality.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eSevere CAA was associated with a high risk of mortality within 1 year in our CAA-ICH patients. For long-term follow-up, severe CAA and old age also predicted a high mortality rate or recurrent ICH. A recent study from China identified Glasgow Coma Score (GCS), recurrence of ICH, white matter lesion (WML) grade and cerebral atrophy as independent prognostic factors of long-term outcome \u003csup\u003e23\u003c/sup\u003e. In addition, a review showed that factors associated with poor outcome of CAA-ICH in 3 months were advanced age, poor condition on admission, preexisting dementia, and concomitant intraventricular, subarachnoid, or subdural hemorrhage \u003csup\u003e20,21\u003c/sup\u003e. Antiplatelet use in patients with previous ischemic stroke or coronary atherosclerotic heart disease was also reported as a predictor of CAA-CH \u003csup\u003e24\u003c/sup\u003e, and antithrombotic therapy, particularly warfarin therapy, was associated with a high risk of postoperative rebleeding \u003csup\u003e25\u003c/sup\u003e. However, in our study, 6-month mortality of CAA-ICH was not significantly related to previous antiplatelet use.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eDuring the follow-up period, 10 (17.5%) patients experienced recurrent symptomatic ICH. Among all 63 patients, 18 (28.6%) experienced recurrent ICH at least once. A previous meta-analysis showed that the recurrence rate of CAA-ICH was 23% and also revealed convexity subarachnoid haemorrhage (cSAH), foci of cortical superficial siderosis (cSS), and visible perivascular spaces in the centrum semiovale (CSO-PVS) as significant markers for recurrent CAA-ICH \u003csup\u003e26\u003c/sup\u003e. In addition, a study performed in Greece showed that the recurrence rate of CAA-ICH was 28%, while cSS emerged as the only risk factor of recurrent ICH \u003csup\u003e27\u003c/sup\u003e. The recurrence rate of CAA-ICH in our cohort was consistent with that in previous studies. However, given that only about half of the patients had undergone a brain MRI scan, the association of neuroimaging markers with recurrent ICH was not examined in this study. \u0026nbsp; \u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u0026nbsp; This study is associated with some limitations. First, all patients with both large hematoma and disturbance of consciousness were enrolled in our study. The obtained results thus differ to some extent from clinical research findings from consecutive ICH patients with and without surgery due to cases of small lobar hemorrhage not being included in this study. In addition, pathological examination involved only a small part of the cortex or leptomeningeal vessels, which contrasts with the situation of autopsies involving evaluation of the whole brain. Moreover, to evaluate amyloid-\u0026beta; deposition as dense-core plaques and diffuse plaques, we only used amyloid-\u0026beta; antibody, which was insufficient to differentiate AD pathology from benign plaques caused by old age. This was exacerbated by the fact that our patients had also not undergone cognitive assessment prior to acute hemorrhage, with the exception of two patients with a history of dementia. As a final limitation, the association of amyloid-\u0026beta; plaque with cognitive status was not evaluated in this study.\u0026nbsp;\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eIn this study, most patients with large or multiple lobar hemorrhage related to CAA had moderate-to-severe CAA in the cerebral cortex and overlying leptomeninges. Amyloid-β deposition as dense-core plaques always co-existed with moderate-to-severe CAA in cortical biopsy samples of CAA-ICH. The pathologically definable severity of CAA from evacuated hematoma and cortical biopsy was associated with long-term outcome following ICH surgery. These results highlight the importance of the severity of CAA in predicting the long-term outcomes of patients with CAA-related-ICH. This study provides a valuable basis for clinicians to develop targeted postoperative management strategies, which can contribute to improving patient prognosis and guiding future therapeutic interventions.\u003c/p\u003e"},{"header":"Declarations","content":"\u003ch3\u003eAuthor contributions\u003c/h3\u003e\n\u003cp\u003eConceptualization: Z.Shi., X.Y., Y.J.; Methodology: F.L., J.L, H.W., P.W., Sh.L., Z.W., X.Zh, Sh.J., X.Y.; Formal Analysis and Investigation: F.L., J.L, H.W., P.W., Sh.L., Z.W., X.Zh, Sh.J., X.Y.; Figures preparation 1\u0026ndash;4: F.L., J.L., H.W., P.W., X.Zh, Sh.J., X.Y.; Writing\u0026mdash;original draft preparation: F.L., J.L.; Writing\u0026mdash;review and editing: H.W., P.W., Sh.L., X.Zh, Sh.J., X.Y. All authors read and approved the final manuscript.\u003c/p\u003e\n\u003ch3\u003eData availability\u003c/h3\u003e\n\u003cp\u003eThe datasets used and/or analysed during the current study available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis work was supported by National Natural Science Foundation of China (grant number 82171182).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDeclaration of conflicting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declared no potential conflicts of interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAdditional information\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCorrespondence\u003c/strong\u003e and requests for materials should be addressed to Z. Shi.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eReprints and permissions information\u003c/strong\u003e is available at www.nature.com/reprints.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePublisher\u003c/strong\u003e\u003cstrong\u003e\u0026rsquo;\u003c/strong\u003e\u003cstrong\u003es note\u003c/strong\u003e Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eOpen Access\u003c/strong\u003e This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article\u0026rsquo;s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article\u0026rsquo;s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommo ns.org/licenses/by-nc-nd/4.0/.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eCharidimou, A. et al. Emerging concepts in sporadic cerebral amyloid angiopathy. \u003cem\u003eBrain\u003c/em\u003e \u003cb\u003e140\u003c/b\u003e, 1829\u0026ndash;1850. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1093/brain/awx047\u003c/span\u003e\u003cspan address=\"10.1093/brain/awx047\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2017).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eYeh, S. J., Tang, S. C., Tsai, L. K. \u0026amp; Jeng, J. S. Pathogenetical subtypes of recurrent intracerebral hemorrhage: designations by SMASH-U classification system. \u003cem\u003eStroke\u003c/em\u003e \u003cb\u003e45\u003c/b\u003e, 2636\u0026ndash;2642. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1161/strokeaha.114.005598\u003c/span\u003e\u003cspan address=\"10.1161/strokeaha.114.005598\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2014).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eMeretoja, A. et al. SMASH-U: a proposal for etiologic classification of intracerebral hemorrhage. \u003cem\u003eStroke\u003c/em\u003e \u003cb\u003e43\u003c/b\u003e, 2592\u0026ndash;2597. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1161/strokeaha.112.661603\u003c/span\u003e\u003cspan address=\"10.1161/strokeaha.112.661603\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2012).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eYamada, M. Cerebral amyloid angiopathy: emerging concepts. \u003cem\u003eJ. Stroke\u003c/em\u003e. \u003cb\u003e17\u003c/b\u003e, 17\u0026ndash;30. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.5853/jos.2015.17.1.17\u003c/span\u003e\u003cspan address=\"10.5853/jos.2015.17.1.17\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2015).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eJ\u0026auml;kel, L., De Kort, A. M., Klijn, C. J. M., Schreuder, F. \u0026amp; Verbeek, M. M. Prevalence of cerebral amyloid angiopathy: A systematic review and meta-analysis. \u003cem\u003eAlzheimers Dement.\u003c/em\u003e \u003cb\u003e18\u003c/b\u003e, 10\u0026ndash;28. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1002/alz.12366\u003c/span\u003e\u003cspan address=\"10.1002/alz.12366\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2022).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eArvanitakis, Z. et al. Cerebral amyloid angiopathy pathology and cognitive domains in older persons. \u003cem\u003eAnn. Neurol.\u003c/em\u003e \u003cb\u003e69\u003c/b\u003e, 320\u0026ndash;327. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1002/ana.22112\u003c/span\u003e\u003cspan address=\"10.1002/ana.22112\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2011).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eBrenowitz, W. D., Nelson, P. T., Besser, L. M., Heller, K. B. \u0026amp; Kukull, W. A. Cerebral amyloid angiopathy and its co-occurrence with Alzheimer's disease and other cerebrovascular neuropathologic changes. \u003cem\u003eNeurobiol. Aging\u003c/em\u003e. \u003cb\u003e36\u003c/b\u003e, 2702\u0026ndash;2708. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.neurobiolaging.2015.06.028\u003c/span\u003e\u003cspan address=\"10.1016/j.neurobiolaging.2015.06.028\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2015).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eGreenberg, S. M. \u0026amp; Vonsattel, J. P. Diagnosis of cerebral amyloid angiopathy. Sensitivity and specificity of cortical biopsy. \u003cem\u003eStroke\u003c/em\u003e \u003cb\u003e28\u003c/b\u003e, 1418\u0026ndash;1422. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1161/01.str.28.7.1418\u003c/span\u003e\u003cspan address=\"10.1161/01.str.28.7.1418\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (1997).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eTrejo-Lopez, J. A., Yachnis, A. T. \u0026amp; Prokop, S. Neuropathology of Alzheimer's Disease. \u003cem\u003eNeurotherapeutics\u003c/em\u003e \u003cb\u003e19\u003c/b\u003e, 173\u0026ndash;185. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1007/s13311-021-01146-y\u003c/span\u003e\u003cspan address=\"10.1007/s13311-021-01146-y\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2022).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eLin, C. M. et al. Pathological examination of cerebral amyloid angiopathy in patients who underwent removal of lobar hemorrhages. \u003cem\u003eJ. Neurol.\u003c/em\u003e \u003cb\u003e265\u003c/b\u003e, 567\u0026ndash;577. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1007/s00415-018-8740-z\u003c/span\u003e\u003cspan address=\"10.1007/s00415-018-8740-z\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2018).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003ePoyuran, R. et al. Cerebrovascular pathology in cerebral amyloid angiopathy presenting as intracerebral haemorrhage. \u003cem\u003eVirchows Arch.\u003c/em\u003e \u003cb\u003e474\u003c/b\u003e, 235\u0026ndash;245. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1007/s00428-018-2505-z\u003c/span\u003e\u003cspan address=\"10.1007/s00428-018-2505-z\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2019).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eGreenberg, S. M. \u0026amp; Charidimou, A. Diagnosis of Cerebral Amyloid Angiopathy: Evolution of the Boston Criteria. \u003cem\u003eStroke\u003c/em\u003e \u003cb\u003e49\u003c/b\u003e, 491\u0026ndash;497. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1161/strokeaha.117.016990\u003c/span\u003e\u003cspan address=\"10.1161/strokeaha.117.016990\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2018).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eVonsattel, J. P. et al. Cerebral amyloid angiopathy without and with cerebral hemorrhages: a comparative histological study. \u003cem\u003eAnn. Neurol.\u003c/em\u003e \u003cb\u003e30\u003c/b\u003e, 637\u0026ndash;649. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1002/ana.410300503\u003c/span\u003e\u003cspan address=\"10.1002/ana.410300503\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (1991).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eDe Kort, A. M., Verbeek, M. M., Schreuder, F., Klijn, C. J. M. \u0026amp; J\u0026auml;kel, L. Prevalence of Cerebral Amyloid Angiopathy Pathology and Strictly Lobar Microbleeds in East-Asian Versus Western Populations: A Systematic Review and Meta-Analysis. \u003cem\u003eJ. Stroke\u003c/em\u003e. \u003cb\u003e26\u003c/b\u003e, 179\u0026ndash;189. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.5853/jos.2023.04287\u003c/span\u003e\u003cspan address=\"10.5853/jos.2023.04287\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2024).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eThal, D. R. et al. Two types of sporadic cerebral amyloid angiopathy. \u003cem\u003eJ. Neuropathol. Exp. Neurol.\u003c/em\u003e \u003cb\u003e61\u003c/b\u003e, 282\u0026ndash;293. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1093/jnen/61.3.282\u003c/span\u003e\u003cspan address=\"10.1093/jnen/61.3.282\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2002).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eThal, D. R. et al. Capillary cerebral amyloid angiopathy identifies a distinct APOE epsilon4-associated subtype of sporadic Alzheimer's disease. \u003cem\u003eActa Neuropathol.\u003c/em\u003e \u003cb\u003e120\u003c/b\u003e, 169\u0026ndash;183. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1007/s00401-010-0707-9\u003c/span\u003e\u003cspan address=\"10.1007/s00401-010-0707-9\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2010).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eTsering, W. \u0026amp; Prokop, S. Neuritic Plaques - Gateways to Understanding Alzheimer's Disease. \u003cem\u003eMol. Neurobiol.\u003c/em\u003e \u003cb\u003e61\u003c/b\u003e, 2808\u0026ndash;2821. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1007/s12035-023-03736-7\u003c/span\u003e\u003cspan address=\"10.1007/s12035-023-03736-7\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2024).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eM\u0026auml;kel\u0026auml;, M., Paetau, A., Polvikoski, T., Myllykangas, L. \u0026amp; Tanskanen, M. Capillary amyloid-β protein deposition in a population-based study (Vantaa 85+). \u003cem\u003eJ. Alzheimers Dis.\u003c/em\u003e \u003cb\u003e49\u003c/b\u003e, 149\u0026ndash;157. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.3233/jad-150241\u003c/span\u003e\u003cspan address=\"10.3233/jad-150241\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2016).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eAttems, J. \u0026amp; Jellinger, K. A. Only cerebral capillary amyloid angiopathy correlates with Alzheimer pathology\u0026ndash;a pilot study. \u003cem\u003eActa Neuropathol.\u003c/em\u003e \u003cb\u003e107\u003c/b\u003e, 83\u0026ndash;90. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1007/s00401-003-0796-9\u003c/span\u003e\u003cspan address=\"10.1007/s00401-003-0796-9\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2004).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eMehndiratta, P. et al. Cerebral amyloid angiopathy-associated intracerebral hemorrhage: pathology and management. \u003cem\u003eNeurosurg. Focus\u003c/em\u003e. \u003cb\u003e32\u003c/b\u003e, E7. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.3171/2012.1.Focus11370\u003c/span\u003e\u003cspan address=\"10.3171/2012.1.Focus11370\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2012).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003ede Bruin, O. F. et al. Surgical intervention for cerebral amyloid angiopathy-related lobar intracerebral hemorrhage: a systematic review. \u003cem\u003eJ. Neurosurg.\u003c/em\u003e \u003cb\u003e141\u003c/b\u003e, 955\u0026ndash;965. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.3171/2024.1.Jns231852\u003c/span\u003e\u003cspan address=\"10.3171/2024.1.Jns231852\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2024).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eMendelow, A. D. et al. Early surgery versus initial conservative treatment in patients with spontaneous supratentorial intracerebral haematomas in the International Surgical Trial in Intracerebral Haemorrhage (STICH): a randomised trial. \u003cem\u003eLancet\u003c/em\u003e \u003cb\u003e365\u003c/b\u003e, 387\u0026ndash;397. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/s0140-6736(05)17826-x\u003c/span\u003e\u003cspan address=\"10.1016/s0140-6736(05)17826-x\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2005).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eChe, R. et al. Long-term outcome of cerebral amyloid angiopathy-related hemorrhage. \u003cem\u003eCNS Neurosci. Ther.\u003c/em\u003e \u003cb\u003e28\u003c/b\u003e, 1829\u0026ndash;1837. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1111/cns.13922\u003c/span\u003e\u003cspan address=\"10.1111/cns.13922\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2022).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eFakan, B. et al. Predictors of localization, outcome, and etiology of spontaneous intracerebral hemorrhages: focus on cerebral amyloid angiopathy. \u003cem\u003eJ. Neural Transm (Vienna)\u003c/em\u003e. \u003cb\u003e127\u003c/b\u003e, 963\u0026ndash;972. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1007/s00702-020-02174-2\u003c/span\u003e\u003cspan address=\"10.1007/s00702-020-02174-2\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2020).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eYanagawa, T. et al. Association of antithrombotic therapy with postoperative rebleeding in patients with cerebral amyloid angiopathy. \u003cem\u003eChin. Neurosurg. J.\u003c/em\u003e \u003cb\u003e9\u003c/b\u003e \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1186/s41016-023-00324-5\u003c/span\u003e\u003cspan address=\"10.1186/s41016-023-00324-5\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2023).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eJia, X. et al. Risk factors for recurrent cerebral amyloid angiopathy-related intracerebral hemorrhage. \u003cem\u003eFront. Neurol.\u003c/em\u003e \u003cb\u003e14\u003c/b\u003e, 1265693. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.3389/fneur.2023.1265693\u003c/span\u003e\u003cspan address=\"10.3389/fneur.2023.1265693\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2023).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eTheodorou, A. et al. Clinical Characteristics, Neuroimaging Markers, and Outcomes in Patients with Cerebral Amyloid Angiopathy: A Prospective Cohort Study. \u003cem\u003eJ. Clin. Med.\u003c/em\u003e \u003cb\u003e12\u003c/b\u003e \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.3390/jcm12175591\u003c/span\u003e\u003cspan address=\"10.3390/jcm12175591\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2023).\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"scientific-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"scirep","sideBox":"Learn more about [Scientific Reports](http://www.nature.com/srep/)","snPcode":"","submissionUrl":"","title":"Scientific Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Scientific Reports","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"cerebral amyloid angiopathy, intracerebral hemorrhage, amyloid-β, mortality, recurrence","lastPublishedDoi":"10.21203/rs.3.rs-6857736/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6857736/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e\u003cp\u003eSporadic cerebral amyloid angiopathy (CAA) is a small-vessel disease. We sought to assess pathological findings and outcomes in CAA patients with non-traumatic intracerebral lobe hemorrhage (ICH).\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e\u003cp\u003eSixty-three CAA-ICH patients underwent Hematoxylin-eosin, amyloid-β, smooth muscle actin and CD34 staining. Arterioles were graded using a CAA-severity scale. Prospective\u0026thinsp;\u0026ge;\u0026thinsp;12-month follow-up identified prognostic factors via binary logistic regression. Cox proportional hazard regression models assessed mortality or recurrent ICH risk associations.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e\u003cp\u003eAmong 93 ICH patients, 63 (67.7%) had CAA. Pathological grading showed Grade 1: 8 (12.7%), Grade 2: 12 (19.0%), Grade 3 or 4: 43 (68.3%). Among 32 CAA patients with cortical specimens, 23 (71.9%) had dense-core plaques and 26 (81.3%) diffuse plaques. Dense-core plaques occurred exclusively in moderate-to-severe CAA. After adjusting for age, sex, antiplatelet medication and alcohol abuse, CAA severity predicted 1-year mortality (adjusted OR\u0026thinsp;=\u0026thinsp;18.49; 95% CI 1.78\u0026ndash;193.03; P\u0026thinsp;=\u0026thinsp;0.015). CAA severity and age predicted mortality or recurrent ICH risk (adjusted HR\u0026thinsp;=\u0026thinsp;4.16; 95% CI 1.54\u0026ndash;11.24, P\u0026thinsp;=\u0026thinsp;0.005 and adjusted HR\u0026thinsp;=\u0026thinsp;1.08; 95% CI 1.02\u0026ndash;1.14, P\u0026thinsp;=\u0026thinsp;0.008, respectively).\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e\u003cp\u003eMost CAA-ICH patients had moderate-to-severe CAA in cortico-leptomeningeal regions. Cortical biopsies revealed frequent Aβ deposition as dense-core and diffuse plaques, with dense-core plaques exclusive to moderate-to-severe CAA. CAA severity correlated with long-term outcomes in CAA-ICH.\u003c/p\u003e","manuscriptTitle":"Neuropathology and long-term outcome in cerebral amyloid angiopathy patients with intracerebral hemorrhage","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-07-23 02:30:51","doi":"10.21203/rs.3.rs-6857736/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-09-05T05:33:00+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-08-18T09:35:41+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"337844871057168202152172227867667395286","date":"2025-08-12T15:49:51+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"146542799095656093385303315379378074763","date":"2025-08-12T08:46:54+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-08-10T03:23:23+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"324639749788682043533326320393414574698","date":"2025-07-23T01:59:04+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-07-18T13:49:36+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-07-18T13:48:19+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2025-06-17T11:36:37+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-06-12T12:03:07+00:00","index":"","fulltext":""},{"type":"submitted","content":"Scientific Reports","date":"2025-06-12T11:59:57+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"scientific-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"scirep","sideBox":"Learn more about [Scientific Reports](http://www.nature.com/srep/)","snPcode":"","submissionUrl":"","title":"Scientific Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Scientific Reports","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"502f841c-860b-4484-a8c2-fcfc487c4d11","owner":[],"postedDate":"July 23rd, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":51817679,"name":"Biological sciences/Neuroscience"},{"id":51817680,"name":"Health sciences/Neurology"},{"id":51817681,"name":"Health sciences/Risk factors"}],"tags":[],"updatedAt":"2025-12-01T16:05:53+00:00","versionOfRecord":{"articleIdentity":"rs-6857736","link":"https://doi.org/10.1038/s41598-025-26540-w","journal":{"identity":"scientific-reports","isVorOnly":false,"title":"Scientific Reports"},"publishedOn":"2025-11-27 15:57:35","publishedOnDateReadable":"November 27th, 2025"},"versionCreatedAt":"2025-07-23 02:30:51","video":"","vorDoi":"10.1038/s41598-025-26540-w","vorDoiUrl":"https://doi.org/10.1038/s41598-025-26540-w","workflowStages":[]},"version":"v1","identity":"rs-6857736","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6857736","identity":"rs-6857736","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}