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We aimed to investigate whether mitochondrial dysfunction in extracellular cerebrospinal fluid (CSF), which is associated with autophagy and mitophagy, might be involved in neurological outcomes in adult patients with hemorrhagic moyamoya disease (MMD) whose pathogenesis related to poor outcomes is not well-known. CSF samples were collected from 43 adult MMD patients and analyzed according to outcomes at 3 months. Fluorescence-activated cell sorter analysis (FACS) and the JC-1 red/green ratio were used to assess mitochondrial cells and intact mitochondrial membrane potential (MMP). We performed quantitative real-time polymerase chain reaction and Western blotting analyses of autophagy and mitophagy-related markers, including HIF1α, ATG5, pBECN1, BECN1, BAX, BNIP3L, DAPK1, and PINK1. Finally, FACS analysis with specific fluorescence-conjugated antibodies was performed to evaluate the potential cellular origin of CSF mitochondrial cells. Twenty-seven females (62.8%) with a mean age of 47.4 ± 9.7 years were included in the study. Among 43 patients with hemorrhagic MMD, 23 (53.5%) had poor outcomes. The difference in MMP was evident between the two groups (2.4 ± 0.2 in patients with poor outcome vs. 3.5 ± 0.4 in patients with good outcome; p = 0.02). A significantly higher expression (2–ΔCt) of HIF1α, ATG5, DAPK1 followed by BAX and BNIP3L mRNA and protein was also observed in poor-outcome patients compared to those with good outcomes. Higher percentage of vWF-positive mitochondria, suggesting endothelial cell origins, was observed in patients with good outcome compared with those with poor outcome (25.0 ± 1.4% in patients with good outcome vs. 17.5 ± 1.5% in those with poor outcome; p < 0.01). We observed the association between increased mitochondrial dysfunction concomitant with autophagy and mitophagy in CSF cells and neurological outcomes in adult patients with hemorrhagic MMD. Further prospective multicenter studies are needed to determine whether it has a diagnostic value for risk prediction. [ABSTRACT FROM AUTHOR]

Object. We aimed to investigate the association of Haptoglobin (Hp) phenotypes with perihematomal edema (PHE) and neurological outcomes after intracerebral hemorrhage (ICH). Methods. This prospective multicenter study enrolled patients that suffered ICH from March 2017 to February 2020. Hp phenotypes were determined using Western blotting; relative α1 intensity was calculated in patients with Hp2-1. A multivariable logistic regression analysis was then conducted to identify risk factors for increased relative PHE at 96 h and 3-month poor outcomes. Results. In total, 120 patients were ultimately enrolled: Hp1-1 (n = 15, 12.5%); Hp2-1 (n = 51, 42.5%); and Hp2-2 (n = 54, 45.0%). Hp phenotype was significantly associated with PHE (p = 0.028). With Hp1-1 as a reference value, Hp2-2 significantly increased the likelihood of increased rPHE (OR = 6.294, 95% CI: 1.283–30.881), while Hp2-1 did not (OR = 2.843, 95% CI: 0.566–14.284). Poor outcomes were found to be closely associated with hematoma volume at admission (OR = 1.057, 95% CI: 1.015–1.101) and surgical treatment (OR = 5.340, 95% CI: 1.665–17.122) but not Hp phenotypes (p = 0.190). Further, a high level of relative α1 intensity was identified to be significantly associated with decreased rPHE (OR = 0.020, 95% CI: 0.001–0.358). However, the relative α1 intensity was not associated with poor outcomes (OR = 0.057, 95% CI: 0.001–11.790). Conclusions: ICH patients with Hp2-2 exhibited a higher likelihood of increased rPHE than those with Hp1-1. Higher relative α1 intensities were identified to be closely associated with rPHE in patients with Hp2-1. [ABSTRACT FROM AUTHOR]

Polygenic risk scores (PRSs) have an important relevance to approaches for clinical usage in intracranial aneurysm (IA) patients. Hence, we aimed to develop IA-predicting PRS models including the genetic basis shared with acute ischemic stroke (AIS) in Korean populations. We applied a weighted PRS (wPRS) model based on a previous genome-wide association study (GWAS) of 250 IA patients in a hospital-based multicenter cohort, 222 AIS patients in a validation study, and 296 shared controls. Risk predictability was analyzed by the area under the receiver operating characteristic curve (AUROC). The best-fitting risk models based on wPRSs were stratified into tertiles representing the lowest, middle, and highest risk groups. The weighted PRS, which included 29 GWASs (p < 5×10−8) and two reported genetic variants (p < 0.01), showed a high predictability in IA patients (AUROC = 0.949, 95% CI: 0.933–0.966). This wPRS was significantly validated in AIS patients (AUROC = 0.842, 95% CI: 0.808–0.876; p < 0.001). Two-stage risk models stratified into tertiles showed an increased risk for IA (OR = 691.25, 95% CI: 241.77–1976.35; p = 3.1×10−34; sensitivity/specificity = 0.728/0.963), which was replicated in AIS development (OR = 39.76, 95% CI: 16.91–93.49; p = 3.1×10−17; sensitivity/specificity = 0.284/0.963). A higher wPRS for IA may be associated with an increased risk of AIS in the Korean population. These findings suggest that IA and AIS may have a shared genetic architecture and should be studied further to generate a precision medicine model for use in personalized diagnosis and treatment. [ABSTRACT FROM AUTHOR]

In addition to conventional genome-wide association studies (GWAS), a fine-mapping analysis is increasingly used to identify the genetic function of variants associated with disease susceptibilities. Here, we used a fine-mapping approach to evaluate candidate variants based on a previous GWAS involving patients with intracranial aneurysm (IA). A fine-mapping analysis was conducted based on the chromosomal data provided by a GWAS of 250 patients diagnosed with IA and 296 controls using posterior inclusion probability (PIP) and log10 transformed Bayes factor (log10BF). The narrow sense of heritability (h2) explained by each candidate variant was estimated. Subsequent gene expression and functional network analyses of candidate genes were used to calculate transcripts per million (TPM) values. Twenty single-nucleotide polymorphisms (SNPs) surpassed a genome-wide significance threshold for creditable evidence (log10BF > 6.1). Among them, four SNPs, rs75822236 (GBA; log10BF = 15.06), rs112859779 (TCF24; log10BF = 12.12), rs79134766 (OLFML2A; log10BF = 14.92), and rs371331393 (ARHGAP32; log10BF = 20.88) showed a completed PIP value in each chromosomal region, suggesting a higher probability of functional candidate variants associated with IA. On the contrary, these associations were not shown clearly under different replication sets. Our fine-mapping analysis suggested that four functional candidate variants of GBA, TCF24, OLFML2A, and ARHGAP32 were linked to IA susceptibility and pathogenesis. However, this approach could not completely replace replication sets based on large-scale data. Thus, caution is required when interpreting results of fine-mapping analysis. [ABSTRACT FROM AUTHOR]

Decreased mitochondrial membrane potential in cerebrospinal fluid (CSF) was observed in patients with subarachnoid hemorrhage (SAH) accompanied by delayed cerebral ischemia (DCI). However, whether abnormal mechanisms of mitochondria are associated with the development of DCI has not been reported yet. Under cerebral ischemia, mitochondria can transfer into the extracellular space. Mitochondrial dysfunction can aggravate neurologic complications. The objective of this study was to evaluate whether mitochondrial dysfunction might be associated with autophagy and mitophagy in CSF cells to provide possible insight into DCI pathogenesis. CSF samples were collected from 56 SAH patients (DCI, n = 21; and non-DCI, n = 35). We analyzed CSF cells using autophagy and mitophagy markers (DAPK1, BNIP3L, BAX, PINK1, ULK1, and NDP52) via qRT-PCR and western blotting of proteins (BECN1, LC3, and p62). Confocal microscopy and immunogold staining were performed to demonstrate the differentially expression of markers within dysfunctional mitochondria. Significant induction of autophagic flux with accumulation of autophagic vacuoles, increased expression of BECN1, LC3-II, and p62 degradation were observed during DCI. Compared to non-DCI patients, DCI patients showed significantly increased mRNA expression levels (2−ΔCt) of DAPK1, BNIP3L, and PINK1, but not BAX, ULK1, or NDP52. Multivariable logistic regression analysis revealed that Hunt and Hess grade ≥ IV (p = 0.023), DAPK1 (p = 0.003), and BNIP3L (p = 0.039) were related to DCI. Increased mitochondrial dysfunction associated with autophagy and mitophagy could play an important role in DCI pathogenesis. [ABSTRACT FROM AUTHOR]