Nonlobar Intracerebral Hemorrhage Research Articles

Factors associated with cognitive impairment before intracerebral haemorrhage: community-based neuropathological study.

Little is known about whether clinical, radiological or neuropathological features are associated with cognitive impairment before intracerebral haemorrhage. We conducted a community-based cohort study of 125 adults with intracerebral haemorrhage (lobar n = 71, non-lobar n = 54) with consent to brain autopsy. We compared small vessel disease biomarkers on diagnostic CT head and neuropathological findings including neurofibrillary tangles and amyloid plaques in adults without cognitive impairment versus cognitive impairment without dementia versus dementia before intracerebral haemorrhage, stratified by lobar and non-lobar intracerebral haemorrhage. In non-lobar intracerebral haemorrhage, severe cortical atrophy was less common in those without cognitive impairment (8/36, 22%) and cognitive impairment without dementia (0/9, 0%) versus dementia (5/9, 56%); P = 0.008. Irrespective of intracerebral haemorrhage location, adults without cognitive impairment had milder neurofibrillary tangle pathology measured by median Braak stage (lobar intracerebral haemorrhage: no cognitive impairment 2 [interquartile range, 2-3] versus cognitive impairment without dementia 4 [2-6] versus dementia 5.5 [4-6]; P = 0.004; non-lobar intracerebral haemorrhage: no cognitive impairment 2 [1-2] versus cognitive impairment without dementia 2 [1-2] versus dementia 5 [3-6]; P < 0.001). Irrespective of intracerebral haemorrhage location, adults without cognitive impairment had milder amyloid plaque pathology measured by median Thal stage (lobar intracerebral haemorrhage: no cognitive impairment 2 [1-2] versus cognitive impairment without dementia 2 [2-3] versus dementia 2.5 [2-3.5]; P = 0.033; non-lobar intracerebral haemorrhage: no cognitive impairment 1 [0-1] versus cognitive impairment without dementia 0 [0-2] versus dementia 3 [2-3]; P = 0.002). Our findings suggest that irrespective of intracerebral haemorrhage location, adults with cognitive impairment before an intracerebral haemorrhage have more Alzheimer's disease neuropathologic change.

Cerebral microbleeds is a predictor of recurrent small vessel cerebrovascular disease: Evaluation based on the recurrent stroke pattern

ObjectivesAn increased number of cerebral microbleeds (CMBs) is considered a predictive factor for recurrent small vessel cerebrovascular diseases, including lacunar infarction and non-lobar intracerebral hemorrhage (ICH). However, it is unclear which recurrent stroke pattern is mainly reflected in the number of CMBs. Materials and MethodsThis study enrolled 217 patients with their first stroke (148 deep lacunar infarctions and 69 non-lobar ICHs), between January 2009 and March 2015. The numbers of baseline and newly appearing CMBs in patients with recurrent stroke were compared with those in patients with non-recurrent stroke, and the dynamics of the number of CMBs was evaluated according to recurrent stroke patterns. ResultsFifty-nine patients with recurrent stroke were included in this study. A larger number of baseline and newly appearing CMBs was significantly associated with recurrent stroke (p = 0.04, p < 0.001, respectively). Recurrent stroke patterns were divided into four types: deep lacunar infarction/deep lacunar infarction (37 patients), deep lacunar infarction/non-lobar ICH (eight patients), non-lobar ICH/deep lacunar infarction (eight patients), and non-lobar ICH/non-lobar ICH (six patients). The number of newly appearing CMBs was significantly higher in patients with deep lacunar infarction/non-lobar ICH than in those with other recurrent stroke patterns (p = 0.04). ConclusionsThe number of CMBs is associated with recurrent stroke, including deep lacunar infarction and non-lobar ICH, and differs depending on the recurrent stroke patterns. The increase in the number of CMBs was strongly correlated with the deep lacunar infarction/non-lobar ICH recurrence pattern.

Bi-allelic NIT1 variants cause a brain small vessel disease characterized by movement disorders, massively dilated perivascular spaces, and intracerebral hemorrhage

PurposeTo describe a recessively inherited cerebral small vessel disease, caused by loss-of-function variants in Nitrilase1 (NIT1). MethodsWe performed exome sequencing, brain magnetic resonance imaging, neuropathology, electron microscopy, western blotting, and transcriptomic and metabolic analyses in 7 NIT1-small vessel disease patients from 5 unrelated pedigrees. ResultsThe first identified patients were 3 siblings, compound heterozygous for the NIT1 c.727C>T; (p.Arg243Trp) variant and the NIT1 c.198_199del; p.(Ala68∗) variant. The 4 additional patients were single cases from 4 unrelated pedigrees and were all homozygous for the NIT1 c.727C>T; p.(Arg243Trp) variant. Patients presented in mid-adulthood with movement disorders. All patients had striking abnormalities on brain magnetic resonance imaging, with numerous and massively dilated basal ganglia perivascular spaces. Three patients had non-lobar intracerebral hemorrhage between age 45 and 60, which was fatal in 2 cases. Western blotting on patient fibroblasts showed absence of NIT1 protein, and metabolic analysis in urine confirmed loss of NIT1 enzymatic function. Brain autopsy revealed large electron-dense deposits in the vessel walls of small and medium sized cerebral arteries. ConclusionNIT1-small vessel disease is a novel, autosomal recessively inherited cerebral small vessel disease characterized by a triad of movement disorders, massively dilated basal ganglia perivascular spaces, and intracerebral hemorrhage.

Abstract TMP78: Disparities in Experiencing Major Adverse Cardiovascular Events Among Survivors of Spontaneous Intracerebral Hemorrhage by Hematoma Location

Background: Large studies evaluating the association of hematoma location with the risk of developing major adverse cardiovascular events (MACE) among survivors of intracerebral hemorrhage (ICH) in the United States are lacking. Methods: We identified adult (&gt;=18 years) ICH survivors from the state inpatient and the state emergency department databases of Florida, New York, Maryland, Washington, and Georgia (2016 - 2019). We fit a series of multivariable Fine-Gray sub-distribution hazard models, with the competing risk of death, and report the sub-distribution hazard ratio (SHR) and 95% confidence interval (CI) of the independent associations of hematoma location (lobar vs. non-lobar) with recurrent ICH (r-ICH), acute ischemic stroke (AIS), acute myocardial infarction (AMI), and MACE (any stroke, AMI, systemic embolism, or vascular death). Results: Among 10,652 ICH patients (median age [IQR]: 70 [58 - 80] years; 47.7% female; 43.2% lobar ICH), 3.3%, 3.1%, 0.5%, and 8.1%, respectively, experienced r-ICH, AIS, AMI, and MACE. Patients with lobar ICH (vs. non-lobar ICH) had a higher risk of r-ICH (SHR, CI: 1.67, 1.35 - 2.07) and MACE (1.28, 1.14 - 1.44). Blacks (vs. Whites) have a higher risk of AIS (1.64, 1.32 - 2.03) and MACE (1.42, 1.22 - 1.65). Also, privately insured patients (vs. Medicare) have a lower risk of r-ICH (0.45, 0.31 - 0.67), AIS (0.71, 0.53 - 0.95), and MACE (0.58, 0.47 - 0.71). Patients from low-income zip codes have a higher risk of AMI (1.83, 1.23 - 2.15) and MACE (1.16, 1.02 - 1.32). Patients with atrial fibrillation had a higher risk of AIS (1.47, 1.18 - 1.84) and MACE (1.26, 1.07 - 1.49). Patients with a high risk of metabolic syndrome (&gt;= 2 of the following: hypertension, diabetes, hyperlipidemia, or obesity) have a higher risk of AIS (1.37, 1.13 - 1.65), AMI (1.81, 1.19 - 2.75), and MACE (1.28, 1.13 - 1.44). Conclusions: Developing targeted secondary prevention strategies tailored to the specific sociodemographic and clinical profiles of ICH survivors is warranted.

Genetically predicted chronic rhinosinusitis and the risk of stroke: a two-sample Mendelian randomization study.

The causal association between chronic rhinosinusitis (CRS) and stroke remains uncertain due to the susceptibility of observational studies to confounding and the possibility of reverse causality. This study aims to examine the potential causal relationship between CRS and the risk of stroke, encompassing various subtypes. In this research, we utilized genome-wide association study (GWAS) data for CRS from FinnGen. We identified significant single-nucleotide polymorphisms (SNPs) associated with CRS and used them as instrumental variables (IVs). GWAS data for any ischemic stroke (AIS), ischemic stroke (IS), large-artery atherosclerotic stroke (LAS), small-vessel strokes (SVS), cardioembolic strokes (CES), intracerebral hemorrhage (ICH), lobar ICH, and non-lobar ICH came from multi-ancestry GWAS datasets. We conducted two-sample Mendelian randomization (MR) analyses using inverse variance weighting (IVW), weighted median, and MR-Egger regression methods to investigate potential causal relationships between CRS and stroke. Both heterogeneity and pleiotropy were evaluated by sensitivity analyses. The IVW analysis revealed no significant associations between CRS and AIS (OR = 0.99, 95% CI [0.93-1.05], p = 0.73), IS (OR = 0.97, 95% CI [0.81-1.17], p = 0.09), SVS (OR = 0.96, 95% CI [0.82-1.12], p = 0.58), LAS (OR = 0.91, 95% CI [0.77-1.08], p = 0.09), CES (OR = 0.97, 95% CI [0.81-1.17], p = 0.79), ICH (OR = 1.28, 95% CI [0.74-2.22], p = 0.28), lobar ICH (OR = 1.22, 95% CI [0.60-2.50], p = 0.28), and non-lobar ICH (OR = 1.25, 95% CI [0.65-2.40], p = 0.79). Sensitivity analysis found no evidence of horizontal pleiotropy. According to genetic evidence, this Mendelian randomization (MR) study does not indicate a causal relationship between CRS and stroke in European populations. However, further studies are necessary to comprehensively evaluate the potential association between CRS and stroke.

Deep Resequencing of the 1q22 Locus in Non-Lobar Intracerebral Hemorrhage.

Genome-wide association studies have identified 1q22 as a susceptibility locus for cerebral small vessel diseases, including non-lobar intracerebral hemorrhage (ICH) and lacunar stroke. In the present study, we performed targeted high-depth sequencing of 1q22 in ICH cases and controls to further characterize this locus and prioritize potential causal mechanisms, which remain unknown. A total of 95,000 base pairs spanning 1q22, including SEMA4A, SLC25A44, and PMF1/PMF1-BGLAP were sequenced in 1,055 spontaneous ICH cases (534 lobar and 521 non-lobar) and 1,078 controls. Firth regression and Rare Variant Influential Filtering Tool analysis were used to analyze common and rare variants, respectively. Chromatin interaction analyses were performed using Hi-C, chromatin immunoprecipitation followed by sequencing, and chromatin interaction analysis with paired-end tag databases. Multivariable Mendelian randomization assessed whether alterations in gene-specific expression relative to regionally co-expressed genes at 1q22 could be causally related to ICH risk. Common and rare variant analyses prioritized variants in SEMA4A 5'-UTR and PMF1 intronic regions, overlapping with active promoter and enhancer regions based on ENCODE annotation. Hi-C data analysis determined that 1q22 is spatially organized in a single chromatin loop, and that the genes therein belong to the same topologically associating domain. Chromatin immunoprecipitation followed by sequencing and chromatin interaction analysis with paired-end tag data analysis highlighted the presence of long-range interactions between the SEMA4A-promoter and PMF1-enhancer regions prioritized by association testing. Multivariable Mendelian randomization analyses demonstrated that PMF1 overexpression could be causally related to non-lobar ICH risk. Altered promoter-enhancer interactions leading to PMF1 overexpression, potentially dysregulating polyamine catabolism, could explain demonstrated associations with non-lobar ICH risk at 1q22, offering a potential new target for prevention of ICH and cerebral small vessel disease. ANN NEUROL 2024;95:325-337.

Exploring the Causality of Type 1 Diabetes and Stroke Risk: A Mendelian Randomization Study and Meta-analysis.

Type II diabetes was causally related to stroke, which is a risk factor for stroke. However, the causal relationship between type I diabetes(T1D) and stroke, especially its subtypes, remains unclear. To determine whether T1D has a genetic causal link to stroke and its subtypes, we undertook this mendelian randomization (MR) study. The genome-wide association studies (GWAS) of T1D was the source of exposure. The outcomes were strokes and their subtypes, including ischemic stroke (IS), small vessel stroke (SVS), cardioembolic stroke (CES), large artery atherosclerosis stroke (LAS), intracerebral hemorrhage (ICH), lobar intracerebral hemorrhage (LICH), and non-lobar intracerebral hemorrhage (NLICH). We used outcome GWAS conducted by ISGC consortium for the initial phase and GWAS from MEGASTROKE consortium as the data for the replication phase to confirm the causal association. Besides, we conducted a meta-analysis of the causal association from ISGC and MEGASTROKE databases to confirm robust causality. Inverse-variance weighting (IVW) was utilized as the primary method to estimate the causality between T1D and stroke. The Cochran's Q test and the MR-PRESSO global test were used to examine the sensitivity. We discovered the causal relationship between T1D and SVS (OR = 1.17, 95% CI: 1.07-1.28, p = 6.0 × 10- 4), CES (OR = 1.11, 95%CI: 1.03-1.21, p = 0.0080) in initial stage. The replication phase validated T1D has a causal relationship with SVS (OR = 1.12, 95% CI: 1.06-1.18, p = 4.0 × 10- 5), but not with stroke and other subtypes. The meta-analysis of initial and replication stage again supported the causal link between T1D and SVS (OR = 1.13, 95% CI: 1.08-1.18, p < 0.05). However, no causal relationship was found between T1D and other stroke subtypes. The sensitivity analysis also supported the robust of these results. In conclusion, T1D was causally associated with SVS, but not with other subtypes of stroke. More investigation is needed to understand the underlying biology mechanism.

Mendelian randomization study and meta-analysis exploring the causality of age at menarche and the risk of intracerebral hemorrhage and ischemic stroke.

The relationship between the age at menarche (AAM) and the risk of intracerebral hemorrhage (ICH) and ischemic stroke (IS) is still up for debate. The purpose of this study was to investigate potential causal connections between them. Genome-wide association analysis (GWAS) of AAM conducted by the MRC-IEU consortium was utilized for association analyses of ICH and IS by two-sample Mendelian randomization (MR) study. AAM data of the within-family GWAS consortium were used as replication phase data to verify the causal relationship between each other. Inverse variance weighting (IVW) method was the primary method used in this MR study. For additional proof, the weighted median estimation, MR-Egger regression, MR-PRESSO test, and MR-Robust Adjusted Profile Score evaluation were performed. The Cochran's Q test and the MR-PRESSO global test were used, respectively, to examine the sensitivity and pleiotropy. Random effects meta-analysis was utilized to analyze the causal data from the two consortiums to further explore the causality between AAM and ICH, IS. We found that the AAM was causally linked with the risk of ICH (OR = 0.48, 95% CI: 0.28-0.80, p = 0.006). On the contrary, the causal effect from AAM to IS (OR = 0.98, 95% CI: 0.91-1.06, p = 0.64) has not been confirmed. For all subtypes of ICH, we found that nonlobar intracerebral hemorrhage (NLICH, OR = 0.41, 95% CI: 0.23-0.75, p = 0.004) but not lobar intracerebral hemorrhage (LICH, OR = 0.65, 95% CI: 0.34-1.24, p = 0.19) was associated with AAM without surprise. Similarly, we used the within-family GWAS consortium data to explore causality and found that AAM may reduce the risk of ICH (OR = 0.78, 95% CI: 0.72-0.86, p = 9.5 × 10-8 ) and NLICH (OR = 0.68, 95% CI: 0.61-0.75, p = 3.4 × 10-13 ) by IVW methods, but is not related to IS (OR = 0.97, 95% CI: 0.93-1.02, p = 0.26). These findings are further supported by the meta-analysis. Both Cochran's Q test and the MR-PRESSO global test failed to detect the presence of sensitivity. AAM and ICH, particularly NLICH, are causally related, but not LICH, IS, or its subtypes in European population.

Major Cardiovascular Events After Spontaneous Intracerebral Hemorrhage by Hematoma Location

Survivors of spontaneous (ie, nontraumatic and with no known structural cause) intracerebral hemorrhage (ICH) have an increased risk of major cardiovascular events (MACEs), including recurrent ICH, ischemic stroke (IS), and myocardial infarction (MI). Only limited data are available from large, unselected population studies assessing the risk of MACEs according to index hematoma location. To examine the risk of MACEs (ie, the composite of ICH, IS, spontaneous intracranial extra-axial hemorrhage, MI, systemic embolism, or vascular death) after ICH based on ICH location (lobar vs nonlobar). This cohort study identified 2819 patients in southern Denmark (population of 1.2 million) 50 years or older hospitalized with first-ever spontaneous ICH from January 1, 2009, to December 31, 2018. Intracerebral hemorrhage was categorized as lobar or nonlobar, and the cohorts were linked to registry data until the end of 2018 to identify the occurrence of MACEs and separately recurrent ICH, IS, and MI. Outcome events were validated using medical records. Associations were adjusted for potential confounders using inverse probability weighting. Location of ICH (lobar vs nonlobar). The main outcomes were MACEs and separately recurrent ICH, IS, and MI. Crude absolute event rates per 100 person-years and adjusted hazard ratios (aHRs) with 95% CIs were calculated. Data were analyzed from February to September 2022. Compared with patients with nonlobar ICH (n = 1255; 680 [54.2%] men and 575 [45.8%] women; mean [SD] age, 73.5 [11.4] years), those with lobar ICH (n = 1034; 495 [47.9%] men and 539 [52.1%] women, mean [SD] age, 75.2 [10.7] years) had higher rates of MACEs per 100 person-years (10.84 [95% CI, 9.51-12.37] vs 7.91 [95% CI, 6.93-9.03]; aHR, 1.26; 95% CI, 1.10-1.44) and recurrent ICH (3.74 [95% CI, 3.01-4.66] vs 1.24 [95% CI, 0.89-1.73]; aHR, 2.63; 95% CI, 1.97-3.49) but not IS (1.45 [95% CI, 1.02-2.06] vs 1.77 [95% CI, 1.34-2.34]; aHR, 0.81; 95% CI, 0.60-1.10) or MI (0.42 [95% CI, 0.22-0.81] vs 0.64 [95% CI, 0.40-1.01]; aHR, 0.64; 95% CI, 0.38-1.09). In this cohort study, spontaneous lobar ICH was associated with a higher rate of subsequent MACEs than nonlobar ICH, primarily due to a higher rate of recurrent ICH. This study highlights the importance of secondary ICH prevention strategies in patients with lobar ICH.

A Genomic Risk Score Identifies Individuals at High Risk for Intracerebral Hemorrhage.

Intracerebral hemorrhage (ICH) has an estimated heritability of 29%. We developed a genomic risk score for ICH and determined its predictive power in comparison to standard clinical risk factors. We combined genome-wide association data from individuals of European ancestry for ICH and related traits in a meta-genomic risk score ([metaGRS]; 2.6 million variants). We tested associations with ICH and its predictive performance in addition to clinical risk factors in a held-out validation dataset (842 cases and 796 controls). We tested associations with risk of incident ICH in the population-based UK Biobank cohort (486 784 individuals, 1526 events, median follow-up 11.3 years). One SD increment in the metaGRS was significantly associated with 31% higher odds for ICH (95% CI, 1.16-1.48) in age-, sex- and clinical risk factor-adjusted models. The metaGRS identified individuals with almost 5-fold higher odds for ICH in the top score percentile (odds ratio, 4.83 [95% CI, 1.56-21.2]). Predictive models for ICH incorporating the metaGRS in addition to clinical predictors showed superior performance compared to the clinical risk factors alone (c-index, 0.695 versus 0.686). The metaGRS showed similar associations for lobar and nonlobar ICH, independent of the known APOE risk locus for lobar ICH. In the UK Biobank, the metaGRS was associated with higher risk of incident ICH (hazard ratio, 1.15 [95% CI, 1.09-1.21]). The associations were significant within both a relatively high-risk population of antithrombotic medications users, as well as among a relatively low-risk population with a good control of vascular risk factors and no use of anticoagulants. We developed and validated a genomic risk score that predicts lifetime risk of ICH beyond established clinical risk factors among individuals of European ancestry. Whether implementation of the score in risk prognostication models for high-risk populations, such as patients under antithrombotic treatment, could improve clinical decision making should be explored in future studies.

Association Between Statin Use and Intracerebral Hemorrhage Location: A Nested Case-Control Registry Study.

A causal relationship between statin use and intracerebral hemorrhage (ICH) is uncertain. We hypothesized that an association between long-term statin exposure and ICH risk might vary for different ICH locations. We conducted this analysis using linked Danish nationwide registries. Within the Southern Denmark Region (population 1.2 million), we identified all first-ever cases of ICH between 2009 and 2018 in persons aged ≥55 years. Patients with medical record-verified diagnoses were classified as having a lobar or nonlobar ICH and matched for age, sex, and calendar year to general population controls. We used a nationwide prescription registry to ascertain prior statin and other medication use that we classified for recency, duration, and intensity. Using conditional logistic regression adjusted for potential confounders, we calculated adjusted ORs (aORs) and corresponding 95% CIs for the risk of lobar and nonlobar ICH. We identified 989 patients with lobar ICH (52.2% women, mean age 76.3 years) who we matched to 39,500 controls and 1,175 patients with nonlobar ICH (46.5% women, mean age 75.1 years) who we matched to 46,755 controls. Current statin use was associated with a lower risk of lobar (aOR 0.83; 95% CI, 0.70-0.98) and nonlobar ICH (aOR 0.84; 95% CI, 0.72-0.98). Longer duration of statin use was also associated with a lower risk of lobar (<1 year: aOR 0.89; 95% CI, 0.69-1.14; ≥1 year to <5 years aOR 0.89; 95% CI 0.73-1.09; ≥5 years aOR 0.67; 95% CI, 0.51-0.87; p for trend 0.040) and nonlobar ICH (<1 year: aOR 1.00; 95% CI, 0.80-1.25; ≥1 year to <5 years aOR 0.88; 95% CI 0.73-1.06; ≥5 years aOR 0.62; 95% CI, 0.48-0.80; p for trend <0.001). Estimates stratified by statin intensity were similar to the main estimates for low-medium intensity therapy (lobar aOR 0.82; nonlobar aOR 0.84); the association with high-intensity therapy was neutral. We found that statin use was associated with a lower risk of ICH, particularly with longer treatment duration. This association did not vary by hematoma location.

Cerebral Amyloid Angiopathy and the Risk of Hematoma Expansion.

We assessed whether hematoma expansion (HE) and favorable outcome differ according to type of intracerebral hemorrhage (ICH). Among participants with ICH enrolled in the TICH-2 (Tranexamic Acid for Hyperacute Primary Intracerebral Haemorrhage) trial, we assessed baseline scans for hematoma location and presence of cerebral amyloid angiopathy (CAA) using computed tomography (CT, simplified Edinburgh criteria) and magnetic resonance imaging (MRI; Boston criteria) and categorized ICH as lobar CAA, lobar non-CAA, and nonlobar. The main outcomes were HE and favorable functional outcome. We constructed multivariate regression models and assessed treatment effects using interaction terms. A total of 2,298 out of 2,325 participants were included with available CT (98.8%; median age=71 years, interquartile range=60-80 years; 1,014 female). Additional MRI was available in 219 patients (9.5%). Overall, 1,637 participants (71.2%) had nonlobar ICH; the remaining 661 participants (28.8%) had lobar ICH, of whom 202 patients had lobar CAA-ICH (8.8%, 173 participants according to Edinburgh and 29 participants according to Boston criteria) and 459 did not (lobar non-CAA, 20.0%). For HE, we found a significant interaction of lobar CAA ICH with time from onset to randomization (increasing risk with time, pinteraction < 0.001) and baseline ICH volume (constant risk regardless of volume, pinteraction < 0.001) but no association between type of ICH and risk of HE or favorable outcome. Tranexamic acid significantly reduced the risk of HE (adjusted odds ratio=0.7, 95% confidence interval=0.6-1.0, p= 0.020) without statistically significant interaction with type of ICH (pinteraction = 0.058). Tranexamic acid was not associated with favorable outcome. Risk of HE in patients with lobar CAA-ICH was not independently increased but seems to have different dynamics compared to other types of ICH. The time window for treatment of CAA-ICH to prevent HE may be longer. ANN NEUROL 2022;92:921-930.

Genetically-Proxied Levels of Vitamin D and Risk of Intracerebral Hemorrhage.

BackgroundThe evidence linking vitamin D (VitD) levels and spontaneous intracerebral hemorrhage (ICH) remains inconclusive. We tested the hypothesis that lower genetically determined VitD levels are associated with higher risk of ICH.Methods and ResultsWe conducted a 2 sample Mendelian Randomization (MR) study using publicly available summary statistics from published genome‐wide association studies of VitD levels (417 580 study participants) and ICH (1545 ICH cases and 1481 matched controls). We used the inverse‐variance weighted approach to generate causal estimates and the MR Pleiotropy Residual Sum and Outlier and MR‐Egger approaches to assess for horizontal pleiotropy. To account for known differences in their underlying mechanism, we implemented stratified analysis based on the location of the hemorrhage within the brain (lobar or nonlobar). Our primary analysis indicated that each SD decrease in genetically instrumented VitD levels was associated with a 60% increased risk of ICH (odds ratio [OR], 1.60; [95% CI, 1.05–2.43]; P=0.029). We found no evidence of horizontal pleiotropy (MR‐Egger intercept and MR Pleiotropy Residual Sum and Outlier global test with P>0.05). Stratified analyses indicated that the association was stronger for nonlobar ICH (OR, 1.87; [95% CI, 1.18–2.97]; P=0.007) compared with lobar ICH (OR, 1.43; [95% CI, 0.86–2.38]; P=0.17).ConclusionsLower levels of genetically proxied VitD levels are associated with higher ICH risk. These results provide evidence for a causal role of VitD metabolism in ICH.

Genetics and Epigenetics of Spontaneous Intracerebral Hemorrhage.

Intracerebral hemorrhage (ICH) is a complex and heterogeneous disease, and there is no effective treatment. Spontaneous ICH represents the final manifestation of different types of cerebral small vessel disease, usually categorized as: lobar (mostly related to cerebral amyloid angiopathy) and nonlobar (hypertension-related vasculopathy) ICH. Accurate phenotyping aims to reflect these biological differences in the underlying mechanisms and has been demonstrated to be crucial to the success of genetic studies in this field. This review summarizes how current knowledge on genetics and epigenetics of this devastating stroke subtype are contributing to improve the understanding of ICH pathophysiology and their potential role in developing therapeutic strategies.

Higher Cerebral Small Vessel Disease Burden in Patients With Small Intracerebral Hemorrhage.

ObjectiveTo investigate the association between cerebral small vessel disease (SVD) and hematoma volume in primary intracerebral hemorrhage (ICH).MethodsPatients from a prospective ICH cohort were enrolled. Admission and follow-up CT scan within 72 h after onset were reviewed to calculate the final hematoma volume. We evaluated cortical superficial siderosis and the global SVD score, including white matter hyperintensities, lacunes, enlarged perivascular space, and cerebral microbleeds on MRI. We conducted the multivariate logistic regression analyses to explore the association between SVD markers and small ICH, as well as hematoma volume. Hematoma location was stratified into lobar and non-lobar for subgroup analysis.ResultsA total of 187 patients with primary ICH (mean age 62.4 ± 13.4 years, 67.9% male) were enrolled. 94 (50.2%) patients had small ICH. The multivariate logistic regression analysis showed an association between global SVD score and small ICH [adjusted odds ratio (aOR) 1.27, 95% CI 1.03–1.57, p = 0.027] and a trend of higher global SVD score towards non-lobar small ICH (aOR 1.23, 95% CI 0.95–1.58, p = 0.122). In the multivariate linear regression analysis, global SVD score was inversely related to hematoma volume of all ICH (β = −0.084, 95% CI −0.142 to −0.025, p = 0.005) and non-lobar ICH (β = −0.112, 95% CI −0.186 to −0.037, p = 0.004). Lacune (β = −0.245, 95% CI −0.487 to −0.004, p = 0.046) was associated with lower non-lobar ICH volume.ConclusionGlobal SVD score is associated with small ICH and inversely correlated with hematoma volume. This finding predominantly exists in non-lobar ICH.

Magnetic resonance imaging-based scores of small vessel diseases: Associations with intracerebral haemorrhage location

IntroductionTotal small vessel disease (SVD) score and cerebral amyloid angiopathy (CAA) score are magnetic resonance imaging-based composite scores built to preferentially capture deep perforator arteriopathy-related and CAA-related SVD burden, respectively. Non-lobar intracerebral haemorrhage (ICH) is related to deep perforator arteriopathy, while lobar ICH can be associated with deep perforator arteriopathy or CAA; however, the associations between ICH location and these scores are not established. MethodsIn this post-hoc analysis from a prospective cohort study, we included 153 spontaneous non-cerebellar ICH patients. Wald test, univariable and multivariable logistic regression analysis were performed to investigate the association between each score (and individual score components) and ICH location. ResultsTotal SVD score was associated with non-lobar ICH location (Wald test: unadjusted, p = 0.017; adjusted, p = 0.003); however, no individual component of total SVD score was significantly associated with non-lobar ICH. CAA score was not significantly associated with lobar location (Wald test: unadjusted, p = 0.056; adjusted, p = 0.126); cortical superficial siderosis (OR 8.85 [95%CI 1.23–63.65], p = 0.030) and ≥ 2 strictly lobar microbleeds (OR 1.63 [95%CI 1.04–2.55], p = 0.035) were related with lobar ICH location, while white matter hyperintensities showed an inverse relation (OR 0.53 [95%CI 0.26–1.08; p = 0.081]). ConclusionsTotal SVD score was associated with non-lobar ICH location. The lack of significant association between CAA score and lobar ICH may in part be due to the mixed aetiology of lobar ICH, and to the inclusion of white matter hyperintensities, a non-specific marker of SVD type, in the CAA score.

Differences in cerebral small vessel disease magnetic resonance imaging markers between lacunar stroke and non-Lobar intracerebral hemorrhage.

IntroductionIt is unclear why cerebral small vessel disease (SVD) leads to lacunar stroke in some and to non–lobar intracerebral hemorrhage (ICH) in others. We investigated differences in MRI markers of SVD in patients with lacunar stroke or non–lobar ICH.Patients and methodsWe included patients from two prospective cohort studies with either lacunar stroke (RUN DMC) or non–lobar ICH (FETCH). Differences in SVD markers (white matter hyperintensities [WMH], lacunes, cerebral microbleeds [CMB]) between groups were investigated with univariable tests; multivariable logistic regression analysis, adjusted for age, sex, and vascular risk factors; spatial correlation analysis and voxel–wise lesion symptom mapping.ResultsWe included 82 patients with lacunar stroke (median age 63, IQR 57–72) and 54 with non-lobar ICH (66, 59–75). WMH volumes and distribution were not different between groups. Lacunes were more frequent in patients with a lacunar stroke (44% vs. 17%, adjusted odds ratio [aOR] 5.69, 95% CI [1.66–22.75]) compared to patients with a non–lobar ICH. CMB were more frequent in patients with a non–lobar ICH (71% vs. 23%, aOR for lacunar stroke vs non–lobar ICH 0.08 95% CI [0.02–0.26]), and more often located in non–lobar regions compared to CMB in lacunar stroke.DiscussionAlthough we obserd different types of MRI markers of SVD within the same patient, ischemic markers of SVD were more frequent in the ischemic type of lacunar stroke, and hemorrhagic markers were more prevalent in the hemorrhagic phenotype of non-lobar ICH.ConclusionThere are differences between MRI markers of SVD between patients with a lacunar stroke and those with a non-lobar ICH.

Ethnic and Racial Variation in Intracerebral Hemorrhage Risk Factors and Risk Factor Burden

Black and Hispanic individuals have an increased risk of intracerebral hemorrhage (ICH) compared with their White counterparts, but no large studies of ICH have been conducted in these disproportionately affected populations. To examine the prevalence, odds, and population attributable risk (PAR) percentage for established and novel risk factors for ICH, stratified by ICH location and racial/ethnic group. The Ethnic/Racial Variations of Intracerebral Hemorrhage Study was a case-control study of ICH among 3000 Black, Hispanic, and White individuals who experienced spontaneous ICH (1000 cases in each group). Recruitment was conducted between September 2009 and July 2016 at 19 US sites comprising 42 hospitals. Control participants were identified through random digit dialing and were matched to case participants by age (±5 years), sex, race/ethnicity, and geographic area. Data analyses were conducted from January 2019 to May 2020. Case and control participants underwent a standardized interview, physical measurement for body mass index, and genotyping for the ɛ2 and ɛ4 alleles of APOE, the gene encoding apolipoprotein E. Prevalence, multivariable adjusted odds ratio (OR), and PAR percentage were calculated for each risk factor in the entire ICH population and stratified by racial/ethnic group and by lobar or nonlobar location. There were 1000 Black patients (median [interquartile range (IQR)] age, 57 [50-65] years, 425 [42.5%] women), 1000 Hispanic patients (median [IQR] age, 58 [49-69] years; 373 [37.3%] women), and 1000 White patients (median [IQR] age, 71 [59-80] years; 437 [43.7%] women). The mean (SD) age of patients with ICH was significantly lower among Black and Hispanic patients compared with White patients (eg, lobar ICH: Black, 62.2 [15.2] years; Hispanic, 62.5 [15.7] years; White, 71.0 [13.3] years). More than half of all ICH in Black and Hispanic patients was associated with treated or untreated hypertension (PAR for treated hypertension, Black patients: 53.6%; 95% CI, 46.4%-59.8%; Hispanic patients: 46.5%; 95% CI, 40.6%-51.8%; untreated hypertension, Black patients: 45.5%; 95% CI, 39.%-51.1%; Hispanic patients: 42.7%; 95% CI, 37.6%-47.3%). Lack of health insurance also had a disproportionate association with the PAR percentage for ICH in Black and Hispanic patients (Black patients: 21.7%; 95% CI, 17.5%-25.7%; Hispanic patients: 30.2%; 95% CI, 26.1%-34.1%; White patients: 5.8%; 95% CI, 3.3%-8.2%). A high sleep apnea risk score was associated with both lobar (OR, 1.68; 95% CI, 1.36-2.06) and nonlobar (OR, 1.62; 95% CI, 1.37-1.91) ICH, and high cholesterol was inversely associated only with nonlobar ICH (OR, 0.60; 95% CI, 0.52-0.70); both had no interactions with race and ethnicity. In contrast to the association between the ɛ2 and ɛ4 alleles of APOE and ICH in White individuals (eg, presence of APOE ɛ2 allele: OR, 1.84; 95% CI, 1.34-2.52), APOE alleles were not associated with lobar ICH among Black or Hispanic individuals. This study found sleep apnea as a novel risk factor for ICH. The results suggest a strong contribution from inadequately treated hypertension and lack of health insurance to the disproportionate burden and earlier onset of ICH in Black and Hispanic populations. These findings emphasize the importance of addressing modifiable risk factors and the social determinants of health to reduce health disparities.

Association of early glycemic change with short-term mortality in lobar and non-lobar intracerebral hemorrhage

The association between early glycemic change and short-term mortality in non-diabetic patients with acute intracerebral hemorrhage (ICH) is unclear. We retrospectively investigated non-diabetic patients with lobar (n = 262) and non-lobar ICH (n = 370). Each patient had a random serum glucose test on hospital admission and a fasting serum glucose test within the following 48 h. Hyperglycemia was defined as serum glucose ≥ 7.8 mmol/l. Four patterns were determined: no hyperglycemia (reference category), persistent hyperglycemia, delayed hyperglycemia, and decreasing hyperglycemia. Associations with 30-day mortality were estimated using Cox models adjusted for major features of ICH severity. Persistent hyperglycemia was associated with 30-day mortality in both lobar (HR 3.00; 95% CI 1.28–7.02) and non-lobar ICH (HR 4.95; 95% CI 2.20–11.09). In lobar ICH, 30-day mortality was also associated with delayed (HR 4.10; 95% CI 1.77–9.49) and decreasing hyperglycemia (HR 2.01, 95% CI 1.09–3.70). These findings were confirmed in Cox models using glycemic change (fasting minus random serum glucose) as a continuous variable. Our study shows that, in non-diabetic patients with ICH, early persistent hyperglycemia is an independent predictor of short-term mortality regardless of hematoma location. Moreover, in non-diabetic patients with lobar ICH, both a positive and a negative glycemic change are associated with short-term mortality.

Rare Missense Functional Variants at COL4A1 and COL4A2 in Sporadic Intracerebral Hemorrhage.

ObjectiveTo test the genetic contribution of rare missense variants in COL4A1 and COL4A2 in which common variants are genetically associated with sporadic intracerebral hemorrhage (ICH), we performed rare variant analysis in multiple sequencing data for the risk for sporadic ICH.MethodsWe performed sequencing across 559 Kbp at 13q34 including COL4A1 and COL4A2 among 2,133 individuals (1,055 ICH cases; 1,078 controls) in United States–based and 1,381 individuals (192 ICH cases; 1,189 controls) from Scotland-based cohorts, followed by sequence annotation, functional impact prediction, genetic association testing, and in silico thermodynamic modeling.ResultsWe identified 107 rare nonsynonymous variants in sporadic ICH, of which 2 missense variants, rs138269346 (COL4A1I110T) and rs201716258 (COL4A2H203L), were predicted to be highly functional and occurred in multiple ICH cases but not in controls from the United States–based cohort. The minor allele of rs201716258 was also present in Scottish patients with ICH, and rs138269346 was observed in 2 ICH-free controls with a history of hypertension and myocardial infarction. Rs138269346 was nominally associated with nonlobar ICH risk (p = 0.05), but not with lobar ICH (p = 0.08), while associations between rs201716258 and ICH subtypes were nonsignificant (p > 0.12). Both variants were considered pathogenic based on minor allele frequency (<0.00035 in European populations), predicted functional impact (deleterious or probably damaging), and in silico modeling studies (substantially altered physical length and thermal stability of collagen).ConclusionsWe identified rare missense variants in COL4A1/A2 in association with sporadic ICH. Our annotation and simulation studies suggest that these variants are highly functional and may represent targets for translational follow-up.