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

Abstract

Background and Objective:We investigated the associations between Apolipoprotein E (APOE) genotype, intracerebral haemorrhage (ICH) and neuroimaging markers of cerebral amyloid angiopathy (CAA).Methods:We included patients from a prospective, multi-centre UK observational cohort study of patients with ICH and representative UK population controls. First, we assessed association of APOE genotype with ICH (compared to controls without ICH). Second, among patients with ICH, we assessed the association of APOE status with haematoma location (lobar or deep) and brain computed tomography (CT) markers of CAA (finger like projections [FLP] and subarachnoid extension [SAE]).Results:We included 907 patients with ICH and 2636 controls. Mean age was 73.2 (12.4 SD) years for ICH cases vs. 69.6 (0.2 SD) for population controls; 50.3% of cases and 42.1% of controls were female. Compared to controls, APOE ε2 allele was associated with all (lobar and non-lobar) as well as lobar ICH on its own in the dominant model, i.e. any APOE ε2 allele (OR 1.38, 95%CI 1.13-1.7, p=0.002 and OR 1.50, 95%CI 1.1-2.04, p=0.01, respectively), but not deep ICH in an age-adjusted analyses (OR 1.26, 95%CI 0.97-1.63, p=0.08) compared to controls. In the cases only analysis, APOE ε4 allele was associated with lobar compared to deep ICH in an age-adjusted analyses (OR 1.56, 95%CI 1.1-2.2, p=0.01). When assessing CAA markers, APOE alleles were independently associated with FLP (ε4: OR 1.74, 95%CI 1.04-2.93, p=0.04 and ε2/ε4: 2.56, 95%CI 0.99-6.61, p=0.05). We did not find an association between APOE alleles and SAE.Discussion:We confirmed associations between APOE alleles and ICH including lobar ICH. Our analysis shows selective associations between APOE ε2 and ε4 alleles with FLP, a CT marker of CAA. Our findings suggest that different APOE alleles might have diverging influences on individual neuroimaging biomarkers of CAA-associated ICH.

Cerebral Amyloid Angiopathy

“…Along with previous recurrent ICHs, features associated with the highest risk of future CAA-related ICH include higher cerebral microbleed count, disseminated or multifocal cSS, and appearance of new cSS foci over time. 7,8 cSS appears to confer increased ICH risk even for patients with probable CAA without prior ICH, 9 underlining the importance of this marker for predicting future ICH.…”

“…The risk of recurrent CAA-related ICH, estimated across studies in the range of 7.4% to 8.5% per year, 7,8 is the highest of all ICH types and indeed among the highest of any form of recurrent stroke. Along with previous recurrent ICHs, features associated with the highest risk of future CAA-related ICH include higher cerebral microbleed count, disseminated or multifocal cSS, and appearance of new cSS foci over time.…”

Associations of Cerebral Small Vessel Disease and Chronic Kidney Disease in Patients With Acute Intracerebral Hemorrhage

“…The Graz ICH cohort study has been described previously 14 ; in brief, it retrospectively identified all consecutive adult patients presenting to the University Hospital of Graz with firstever ICH, between 2008 and 2021, and collected all baseline data using standardized data collection sheets. Similar to the SIGNAL registry, neuroimaging with MRI was the standard of care for all patients unless contraindicated.…”

“…We classified ICH as arteriolosclerosis in patients with a nonlobar ICH and relevant accompanying SVD (at least one of the following: ≥1 lacune; moderate or severe WMH; ≥1 deep (including brainstem) CMB; or severely ePVS in the basal ganglia [BGPVS] without lobar CMB or cSS); CAA when criteria for probable CAA based on the Boston 2.0 criteria 20 were fulfilled; mixed location SVD when there was a mixture of both lobar and deep signs of SVD; and cryptogenic in patients without any MRIvisible signs of SVD, as previously reported. 14 Cerebellar hemorrhages could be classified as any of the 4 neuroimaging phenotypes depending on the other imaging findings. Lobar ICH with SVD biomarkers but not meeting Boston 2.0 criteria was classified as mixed SVD.…”

Genetic considerations in cerebral small vessel diseases

“…In an additional study of white individuals from the UK presence of any APOE ε2 alleles was associated with all ICH (lobar and non-lobar) and with lobar ICH but not with deep only ICH. The APOE ε4 allele was associated with lobar ICH and with finger-like projects on head CT, a marker considered to represent probable CAA ( 83 ). However, ethnic and racial differences have been suggested in the relation of APOE genotype and ICH.…”