Background: Studies have suggested promising evidence that glial fibrillary acidic protein (GFAP) could be used as a blood biomarker to distinguish between ischemic stroke (IS) and intracerebral hemorrhage (ICH) in acute stage. Objective: To determine the available evidence for GFAP as a blood biomarker for differentiating ICH from IS and stroke mimics using a meta-analysis approach. Methods: Search terms were used for literature search: ("STROKE" [Mesh] OR "BIOMARKER" [Title/Abstract] OR "GFAP" [Title/Abstract])] OR "SPECIFICITY" OR "SENSTIVITY" at various search engines like PubMed, Google scholar, Trip database, clinicaltrial.gov for articles from 1990 through April 2019 using filter ‘human subjects’. Data were analysed using software STATA version 13. Results: A pooled analysis including 12 studies suggested that GFAP if used as a biomarker to differentiate between different types of strokes (ICH from IS and mimics) had a sensitivity of 78% (95% CI: 67% to 86%) and a specificity of 95% (95% CI: 88% to 98%). Positive likelihood ratio (LR) was 14.4 and negative LR was 0.23. SROC with prediction and confidence contours suggests promising area under the curve 0.93, 95% CI ranges from 0.90 to 0.95. Diagnostic odds ratio with 95% CI was observed 63 (31 to 125). Conclusion: Our meta-analysis suggests that GFAP has a promising diagnostic accuracy for the differentiation of ICH from IS and mimics. Further, phase II and phase III diagnostic test studies are required to validate the findings before using GFAP as a blood based biomarker for clinical use. Trial Registration: This study was registered in OSF registries 10.17605/OSF.IO/B9JP4

Alzheimer’s disease (AD) is the most common cause of dementia, and the gradual deterioration of brain function eventually leads to death. Almost all AD patients suffer from neuropsychiatric symptoms (NPS), the emergence of which correlates with dysfunctional serotonergic systems. Our aim is to generate hindbrain organoids containing serotonergic neurons using human induced Pluripotent Stem Cells (iPSCs). Work presented here is laying the groundwork for the application of hindbrain organoids to evaluate individual differences in disease progression, NPS development, and pharmacological treatment response. Human peripheral blood mononuclear cells (PBMCs) from healthy volunteers (n = 3), an AD patient without NPS (n = 1), and AD patients with NPS (n = 2) were reprogrammed into iPSCs and subsequently differentiated into hindbrain organoids. The presence of serotonergic neurons was confirmed by quantitative reverse transcription PCR, flow cytometry, immunocytochemistry, and detection of released serotonin (5-HT). We successfully reprogrammed PBMCs into 6 iPSC lines, and subsequently generated hindbrain organoids from 6 individuals to study inter-patient variability using a precision medicine approach. To assess patient-specific treatment effects, organoids were treated with different concentrations of escitalopram oxalate, commonly prescribed for NPS. Changes in 5-HT levels before and after treatment with escitalopram were dose-dependent and variable across patients. Organoids from different people responded differently to the application of escitalopram in vitro. We propose that this 3D platform might be effectively used for drug screening purposes to predict patients with NPS most likely to respond to treatment in vivo and to understand the heterogeneity of treatment responses.

Objective To undertake a genome-wide association study (GWAS) to identify genetic variants for stroke in an Indian population. Methods In a hospital-based case-control study, 8 teaching hospitals in India recruited 4,088 participants, including 1,609 stroke cases. Imputed genetic variants were tested for association with stroke subtypes using both single-marker and gene-based tests. Association with vascular risk factors was performed with logistic regression. Various databases were searched for replication, functional annotation, and association with related traits. Status of candidate genes previously reported in the Indian population was also checked. Results Associations of vascular risk factors with stroke were similar to previous reports and show modifiable risk factors such as hypertension, smoking, and alcohol consumption as having the highest effect. Single-marker–based association revealed 2 loci for cardioembolic stroke (1p21 and 16q24), 2 for small vessel disease stroke (3p26 and 16p13), and 4 for hemorrhagic stroke (3q24, 5q33, 6q13, and 19q13) at p < 5 × 10⁻⁸. The index single nucleotide polymorphism of 1p21 is an expression quantitative trait locus (p_lowest = 1.74 × 10⁻⁵⁸) for RWDD3 involved in SUMOylation and is associated with platelet distribution width (1.15 × 10⁻⁹) and 18-carbon fatty acid metabolism (p = 7.36 × 10⁻¹²). In gene-based analysis, we identified 3 genes (SLC17A2, FAM73A, and OR52L1) at p < 2.7 × 10⁻⁶. Eleven of 32 candidate gene loci studied in an Indian population replicated (p < 0.05), and 21 of 32 loci identified through previous GWAS replicated according to directionality of effect. Conclusions This GWAS of stroke in an Indian population identified novel loci and replicated previously known loci. Genetic variants in the SUMOylation pathway, which has been implicated in brain ischemia, were identified for association with stroke.

Studies on association between methylenetetrahydrofolate reductase gene (MTHFR) C677T gene polymorphism and ischemic stroke have shown conflicting results. We have conducted a meta-analysis to determine the precise association of the C677T polymorphism of MTHFR gene with risk of ischemic stroke. We searched electronic databases Medline, EMBASE, and Google Scholar (last search dated till August 2014). Pooled odds ratios (ORs) with 95% confidence intervals (CIs) from random or fixed-effects models were calculated. The methodological quality of included studies was determined by the quality assessment scale. Thirty eight case-control studies fulfilled our inclusion criteria comprising 6310 patients and 8297 controls. The significant associations between MTHFR C677T genetic polymorphism and risk of ischemic stroke were observed in dominant (OR, 1·09; 95% CI, 1·06-1·12, P-value < 0·001) and recessive (OR, 1·31; 95% CI, 1·19-1·44, P-value < 0·001) inheritance models. In an Asian population, significant association between the MTHFR polymorphism and ischemic stroke was observed (dominant model: OR 1·36, 95% CI 1·23-1·49 and under recessive model OR, 1·29; 95% CI, 1·15-1·45). In the Caucasian population borderline, non-significant association was observed under dominant model of inheritance (OR, 1·05; 95% CI, 0·99-1·10) but significant association was observed under the recessive model of inheritance (OR, 1·33; 95% CI, 1·13-1·58). The present study results suggest that MTHFR C677T genetic polymorphism is a probable risk of ischemic stroke.