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

Introduction: Total 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. Methods: In 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. Results: Total 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]). Conclusions: Total 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

Association of enlarged perivascular spaces and anticoagulant-related intracranial hemorrhage

Objective: To investigate whether enlarged perivascular spaces within the basal ganglia or deep cerebral white matter are risk factors for intracranial hemorrhage in patients taking oral anticoagulants (OAC), independent of established clinical and radiological risk factors, we conducted a post hoc analysis of CROMIS-2 (AF), a prospective inception cohort study. Methods: Patients with atrial fibrillation and recent TIA or ischaemic stroke underwent standardised MR imaging prior to starting OAC. We rated basal ganglia (BGPVS) and centrum semiovale (CSOPVS) perivascular spaces, cerebral microbleeds (CMBs), white matter hyperintensities and lacunes. We dichotomized the PVS rating using a threshold of >10 PVS in the relevant region of either cerebral hemisphere. The primary outcome was symptomatic intracranial hemorrhage (sICH). We identified risk factors for sICH using Cox regression. Results: 1386 participants with available clinical and imaging variables were followed up for a mean of 2.34 years. 14 sICH occurred (11 intracerebral). In univariable analysis, diabetes, CMB presence, lacune presence and >10 BGPVS, but not CSOPVS, were associated with sICH. In a multivariable model incorporating all variables with significant associations in univariable analysis, >10 BGPVS (HR 8.96, 95% CI 2.41 – 33.4, p = 0.001) and diabetes (HR 3.91, 95% CI 1.34 – 11.4) remained significant risk factors for sICH. Conclusion: Enlarged BGPVS might be a novel risk factor for OAC-related ICH. The strength of this association and potential use in predicting ICH in clinical practice should be investigated in larger cohorts

Clinical Associations and Prognostic Value of MRI-Visible Perivascular Spaces in Patients With Ischemic Stroke or TIA

BACKGROUND AND OBJECTIVES: Visible perivascular spaces are an MRI marker of cerebral small vessel disease and might predict future stroke. However, results from existing studies vary. We aimed to clarify this through a large collaborative multicenter analysis. METHODS: We pooled individual patient data from a consortium of prospective cohort studies. Participants had recent ischemic stroke or transient ischemic attack (TIA), underwent baseline MRI, and were followed up for ischemic stroke and symptomatic intracranial hemorrhage (ICH). Perivascular spaces in the basal ganglia (BGPVS) and perivascular spaces in the centrum semiovale (CSOPVS) were rated locally using a validated visual scale. We investigated clinical and radiologic associations cross-sectionally using multinomial logistic regression and prospective associations with ischemic stroke and ICH using Cox regression. RESULTS: We included 7,778 participants (mean age 70.6 years; 42.7% female) from 16 studies, followed up for a median of 1.44 years. Eighty ICH and 424 ischemic strokes occurred. BGPVS were associated with increasing age, hypertension, previous ischemic stroke, previous ICH, lacunes, cerebral microbleeds, and white matter hyperintensities. CSOPVS showed consistently weaker associations. Prospectively, after adjusting for potential confounders including cerebral microbleeds, increasing BGPVS burden was independently associated with future ischemic stroke (versus 0-10 BGPVS, 11-20 BGPVS: HR 1.19, 95% CI 0.93-1.53; 21+ BGPVS: HR 1.50, 95% CI 1.10-2.06; p = 0.040). Higher BGPVS burden was associated with increased ICH risk in univariable analysis, but not in adjusted analyses. CSOPVS were not significantly associated with either outcome. DISCUSSION: In patients with ischemic stroke or TIA, increasing BGPVS burden is associated with more severe cerebral small vessel disease and higher ischemic stroke risk. Neither BGPVS nor CSOPVS were independently associated with future ICH

Increased risk of recurrent stroke in patients with impaired kidney function: results of a pooled analysis of individual patient data from the MICON international collaboration

BACKGROUND: Patients with chronic kidney disease are at increased risk of stroke and frequently have cerebral microbleeds. Whether such patients also encounter an increased risk of recurrent stroke has not been firmly established. We aimed to determine whether impaired kidney function is associated with the risk of recurrent stroke, and microbleed presence, distribution and severity. METHODS: We used pooled data from the Microbleeds International Collaborate Network to investigate associations of impaired kidney function, defined as estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2. Our primary outcome was a composite of recurrent ischaemic stroke (IS) and intracranial haemorrhage (ICrH). Secondary outcomes included: (1) individual components of the primary outcome; (2) modification of the primary outcome by microbleed presence or anticoagulant use and (3) microbleed presence, distribution and severity. RESULTS: 11 175 patients (mean age 70.7±12.6, 42% female) were included, of which 2815 (25.2%) had impaired kidney function. Compared with eGFR ≥60, eGFR <60 was associated with a higher risk of the primary outcome (adjusted HR, aHR 1.33 (95% CI 1.14 to 1.56), p<0.001) and higher rates of the recurrent IS (aHR 1.33 (95% CI 1.12 to 1.58)). Reduced eGFR was not associated with ICrH risk (aHR 1.07 (95% CI 0.70 to 1.60)). eGFR was also associated with microbleed presence (adjusted OR, aOR 1.14 (95% CI 1.03 to 1.26)) and severity (aOR 1.17 (95% CI 1.06 to 1.29)). Compared with having no microbleeds, eGFR was lower in those with strictly lobar microbleeds (adjusted mean difference (aMD) -2.10 mL/min/1.73 cm2 (95% CI -3.39 to -0.81)) and mixed microbleeds (aMD -2.42 (95% CI -3.70 to -1.15)), but not strictly deep microbleeds (aMD -0.67 (95% CI -1.85 to 0.51)). CONCLUSIONS: In patients with IS or transient ischaemic attack, impaired kidney function was associated with a higher risk of recurrent stroke and higher microbleeds burden, compared with those with normal kidney function. Further research is needed to investigate potential additional measures for secondary prevention in this high-risk group

Impact of Cerebral Microbleeds in Stroke Patients with Atrial Fibrillation

OBJECTIVES: Cerebral microbleeds are associated with the risks of ischemic stroke and intracranial hemorrhage, causing clinical dilemmas for antithrombotic treatment decisions. We aimed to evaluate the risks of intracranial hemorrhage and ischemic stroke associated with microbleeds in patients with atrial fibrillation treated with Vitamin K antagonists, direct oral anticoagulants, antiplatelets, and combination therapy (i.e. concurrent oral anticoagulant and antiplatelet) METHODS: We included patients with documented atrial fibrillation from the pooled individual patient data analysis by the Microbleeds International Collaborative Network. Risks of subsequent intracranial hemorrhage and ischemic stroke were compared between patients with and without microbleeds, stratified by antithrombotic use. RESULTS: A total of 7,839 patients were included. The presence of microbleeds was associated with an increased relative risk of intracranial hemorrhage (aHR 2.74, 95% confidence interval 1.76 - 4.26) and ischemic stroke (aHR 1.29, 95% confidence interval 1.04 - 1.59). For the entire cohort, the absolute incidence of ischemic stroke was higher than intracranial hemorrhage regardless of microbleeds burden. However, for the subgroup of patients taking combination of anticoagulant and antiplatelet therapy, the absolute risk of intracranial hemorrhage exceeded that of ischemic stroke in those with 2-4 microbleeds (25 vs 12 per 1,000 patient-years) and ≥11 microbleeds (94 vs 48 per 1,000 patient-years). INTERPRETATION: Patients with atrial fibrillation and high burden of microbleeds receiving combination therapy have a tendency of higher rate of intracranial hemorrhage than ischemic stroke, with potential for net harm. Further studies are needed to help optimize stroke preventive strategies in this high-risk group. This article is protected by copyright. All rights reserved

Reprogrammed Lipid Metabolism and the Lipid-Associated Hallmarks of Colorectal Cancer

Lipids have diverse structures, with multifarious regulatory functions in membrane homeostasis and bioenergetic metabolism, in mediating functional protein-lipid and protein-protein interactions, as in cell signalling and proliferation. An increasing body of evidence supports the notion that aberrant lipid metabolism involving remodelling of cellular membrane structure and changes in energy homeostasis and signalling within cancer-associated pathways play a pivotal role in the onset, progression, and maintenance of colorectal cancer (CRC) and their tumorigenic properties. Recent advances in analytical lipidome analysis technologies have enabled the comprehensive identification and structural characterization of lipids and, consequently, our understanding of the role they play in tumour progression. However, despite progress in our understanding of cancer cell metabolism and lipidomics, the key lipid-associated changes in CRC have yet not been explicitly associated with the well-established 'hallmarks of cancer' defined by Hanahan and Weinberg. In this review, we summarize recent findings that highlight the role of reprogrammed lipid metabolism in CRC and use this growing body of evidence to propose eight lipid metabolism-associated hallmarks of colorectal cancer, and to emphasize their importance and linkages to the established cancer hallmarks

Effect of Expression of Human Glucosylceramidase 2 Isoforms on Lipid Profiles in COS-7 Cells

Glucosylceramide (GlcCer) is a major membrane lipid and the precursor of gangliosides. GlcCer is mainly degraded by two enzymes, lysosomal acid β-glucosidase (GBA) and nonlysosomal β-glucosidase (GBA2), which may have different isoforms because of alternative splicing. To understand which GBA2 isoforms are active and how they affect glycosphingolipid levels in cells, we expressed nine human GBA2 isoforms in COS-7 cells, confirmed their expression by qRT-PCR and Western blotting, and assayed their activity to hydrolyze 4-methylumbelliferyl-β-D-glucopyranoside (4MUG) in cell extracts. Human GBA2 isoform 1 showed high activity, while the other isoforms had activity similar to the background. Comparison of sphingolipid levels by ultra-high resolution/accurate mass spectrometry (UHRAMS) analysis showed that isoform 1 overexpression increased ceramide and decreased hexosylceramide levels. Comparison of ratios of glucosylceramides to the corresponding ceramides in the extracts indicated that GBA2 isoform 1 has broad specificity for the lipid component of glucosylceramide, suggesting that only one GBA2 isoform 1 is active and affects sphingolipid levels in the cell. Our study provides new insights into how increased breakdown of GlcCer affects cellular lipid metabolic networks

A Novel Function of Sphingosine Kinase 2 in the Metabolism of Sphinga-4,14-Diene Lipids

The number, position, and configuration of double bonds in lipids affect membrane fluidity and the recruitment of signaling proteins. Studies on mammalian sphingolipids have focused on those with a saturated sphinganine or mono-unsaturated sphingosine long chain base. Using high-resolution liquid chromatography-tandem mass spectrometry (LC-MS/MS), we observed a marked accumulation of lipids containing a di-unsaturated sphingadiene base in the hippocampus of mice lacking the metabolic enzyme sphingosine kinase 2 (SphK2). The double bonds were localized to positions C4-C5 and C14-C15 of sphingadiene using ultraviolet photodissociation-tandem mass spectrometry (UVPD-MS/MS). Phosphorylation of sphingoid bases by sphingosine kinase 1 (SphK1) or SphK2 forms the penultimate step in the lysosomal catabolism of all sphingolipids. Both SphK1 and SphK2 phosphorylated sphinga-4,14-diene as efficiently as sphingosine, however deuterated tracer experiments in an oligodendrocyte cell line demonstrated that ceramides with a sphingosine base are more rapidly metabolized than those with a sphingadiene base. Since SphK2 is the dominant sphingosine kinase in brain, we propose that the accumulation of sphingadiene-based lipids in SphK2-deficient brains results from the slower catabolism of these lipids, combined with a bottleneck in the catabolic pathway created by the absence of SphK2. We have therefore uncovered a previously unappreciated role for SphK2 in lipid quality control

Extracellular vesicular lipids as biomarkers for the diagnosis of Alzheimer’s disease

An increasing number of studies have revealed that dysregulated lipid homeostasis is associated with the pathological processes that lead to Alzheimer’s disease (AD). If changes in key lipid species could be detected in the periphery, it would advance our understanding of the disease and facilitate biomarker discovery. Global lipidomic profiling of sera/blood however has proved challenging with limited disease or tissue specificity. Small extracellular vesicles (EV) in the central nervous system, can pass the blood-brain barrier and enter the periphery, carrying a subset of lipids that could reflect lipid homeostasis in brain. This makes EVs uniquely suited for peripheral biomarker exploration