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Intracerebral Hemorrhage Recurrence in Patients with and without Cerebral Amyloid Angiopathy.

ABSTRACT:

Background

Intracerebral hemorrhage (ICH) recurrence risk is known to be higher in patients with cerebral amyloid angiopathy (CAA) as compared to other causes of ICH. Risk factors for ICH recurrence are not completely understood, and our goal was to study specific imaging microangiopathy markers.

Methods

Retrospective case-control study of patients with non-traumatic ICH admitted to a single center between 2014 and 2017 who underwent magnetic resonance imaging (MRI). Clinical characteristics of the index event and occurrence of death and ICH recurrence were collected from clinical records. MRI images were independently reviewed by 2 neuroradiologists. Groups of patients with CAA-related and CAA-unrelated ICH defined were compared. Presence of CAA was defined according to the Boston modified criteria. Survival analysis with Kaplan-Meier curves and Cox-regression analyses was performed to analyze ICH recurrence-free survival.

Results

Among 448 consecutive patients with non-traumatic ICH admitted during the study period, 104 were included in the study, mean age 64 years (±13.5), median follow-up of 27 months (interquartile range, IQR 16-43), corresponding to 272 person-years of total follow-up. CAA-related ICH patients presented higher burden of lobar microbleeds (p < 0.001), higher burden of enlarged perivascular spaces (EPVS) in centrum semiovale (p < 0.001) and more frequently presented cortical superficial siderosis (cSS; p < 0.001). ICH recurrence in patients with CAA was 12.7 per 100 person-years, and no recurrence was observed in patients without CAA. Variables associated with ICH recurrence in the whole population were age (hazard ratio [HR] per 1-year increment = 1.05, 95% CI 1.00-1.11, p = 0.046), presence of disseminated cSS (HR 3.32, 95% CI 1.09-10.15, p = 0.035) and burden of EPVS in the centrum semiovale (HR per 1-point increment = 1.80, 95% CI 1.04-3.12, p = 0.035).

Conclusions

This study confirms a higher ICH recurrence risk in patients with CAA-related ICH and suggests that age, disseminated cSS, and burden of EPVS in the centrum semiovale are associated with ICH recurrence.

SUBMITTER: Pinho J

PROVIDER: S-EPMC7989769 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundCerebral amyloid angiopathy (CAA) is the most common cause of lobar intracerebral hemorrhage (ICH) in the elderly, and its multifocal and recurrent nature leads to high rates of disability and mortality. Therefore, this study aimed to summarize the evidence regarding the recurrence rate and risk factors for CAA-related ICH (CAA-ICH).MethodsWe performed a systematic literature search of all English studies published in PubMed, Embase, Web of Science, Cochrane Library, Scopus, and CINAHL from inception to June 10, 2023. Studies reporting CAA-ICH recurrence rates and risk factors for CAA-ICH recurrence were included. We calculated pooled odds ratios (ORs) with their corresponding 95% confidence intervals (CIs) using a random/fixed-effects model based on the I2 assessment of heterogeneity between studies. Publication bias was assessed using Egger's test.ResultsThirty studies were included in the final analysis. Meta-analysis showed that the recurrence rate of CAA-ICH was 23% (95% CI: 18-28%, I2 = 96.7%). The risk factors significantly associated with CAA-ICH recurrence were: previous ICH (OR = 2.03; 95% CI: 1.50-2.75; I2 = 36.8%; N = 8), baseline ICH volume (OR = 1.01; 95% CI: 1-1.02; I2 = 0%; N = 4), subarachnoid hemorrhage (cSAH) (OR = 3.05; 95% CI: 1.86-4.99; I2 = 0%; N = 3), the presence of cortical superficial siderosis (cSS) (OR = 2.04; 95% CI: 1.46-2.83; I2 = 0%; N = 5), disseminated cSS (OR = 3.21; 95% CI: 2.25-4.58; I2 = 16.0%; N = 6), and centrum semiovale-perivascular spaces (CSO-PVS) severity (OR = 1.67; 95% CI: 1.14-2.45; I2 = 0%; N = 4).ConclusionCAA-ICH has a high recurrence rate. cSAH, cSS (especially if disseminated), and CSO-PVS were significant markers for recurrent CAA-ICH. The onset of ICH in patients with CAA is usually repeated several times, and recurrence is partly related to the index ICH volume. Identifying clinical and neuroimaging predictors of CAA-ICH recurrence is of great significance for evaluating outcomes and improving the prognosis of patients with CAA-ICH.Systematic review registrationhttps://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=400240, identifier [CRD42023400240].

Project description:Background and purposeCerebral amyloid angiopathy (CAA) is a common cause of recurrent intracerebral hemorrhage in the elderly. Previous studies have shown that CAA induces inflammation and expression of matrix metalloproteinase-2 and matrix metalloproteinase-9 (gelatinases) in amyloid-laden vessels. Here, we inhibited both using minocycline in CAA mouse models to determine whether spontaneous intracerebral hemorrhage could be reduced.MethodsTg2576 (n=16) and 5xFAD/ApoE4 knockin mice (n=16), aged 17 and 12 months, respectively, were treated with minocycline (50 mg/kg, IP) or saline every other day for 2 months. Brains were extracted and stained with X-34 (to quantify amyloid), Perls' blue (to quantify hemorrhage), and immunostained to examined β-amyloid peptide load, gliosis (glial fibrillary acidic protein [GFAP], Iba-1), and vascular markers of blood-brain barrier integrity (zonula occludins-1 [ZO-1] and collagen IV). Brain extracts were used to quantify mRNA for a variety of inflammatory genes.ResultsMinocycline treatment significantly reduced hemorrhage frequency in the brains of Tg2576 and 5xFAD/ApoE4 mice relative to the saline-treated mice, without affecting CAA load. Gliosis (GFAP and Iba-1 immunostaining), gelatinase activity, and expression of a variety of inflammatory genes (matrix metalloproteinase-9, NOX4, CD45, S-100b, and Iba-1) were also significantly reduced. Higher levels of microvascular tight junction and basal lamina proteins were found in the brains of minocycline-treated Tg2576 mice relative to saline-treated controls.ConclusionsMinocycline reduced gliosis, inflammatory gene expression, gelatinase activity, and spontaneous hemorrhage in 2 different mouse models of CAA, supporting the importance of matrix metalloproteinase-related and inflammatory pathways in intracerebral hemorrhage pathogenesis. As a Food and Drug Administration-approved drug, minocycline might be considered for clinical trials to test efficacy in preventing CAA-related intracerebral hemorrhage.