Early prognostication of patient outcomes in intracerebral hemorrhage (ICH) is critical for patient care. We aim to investigate protein biomarkers' role in prognosticating outcomes in ICH patients. ...We assessed 22 protein biomarkers using targeted proteomics in serum samples obtained from the ICH patient dataset (N = 150). We defined poor outcomes as modified Rankin scale score of 3-6. We incorporated clinical variables and protein biomarkers in regression models and random forest-based machine learning algorithms to predict poor outcomes and mortality. We report Odds Ratio (OR) or Hazard Ratio (HR) with 95% Confidence Interval (CI). We used five-fold cross-validation and bootstrapping for internal validation of prediction models. We included 149 patients for 90-day and 144 patients with ICH for 180-day outcome analyses. In multivariable logistic regression, UCH-L1 (adjusted OR 9.23; 95%CI 2.41-35.33), alpha-2-macroglobulin (aOR 5.57; 95%CI 1.26-24.59), and Serpin-A11 (aOR 9.33; 95%CI 1.09-79.94) were independent predictors of 90-day poor outcome; MMP-2 (aOR 6.32; 95%CI 1.82-21.90) was independent predictor of 180-day poor outcome. In multivariable Cox regression models, IGFBP-3 (aHR 2.08; 95%CI 1.24-3.48) predicted 90-day and MMP-9 (aOR 1.98; 95%CI 1.19-3.32) predicted 180-day mortality. Machine learning identified additional predictors, including haptoglobin for poor outcomes and UCH-L1, APO-C1, and MMP-2 for mortality prediction. Overall, random forest models outperformed regression models for predicting 180-day poor outcomes (AUC 0.89), and 90-day (AUC 0.81) and 180-day mortality (AUC 0.81). Serum biomarkers independently predicted short-term poor outcomes and mortality after ICH. Further research utilizing a multi-omics platform and temporal profiling is needed to explore additional biomarkers and refine predictive models for ICH prognosis.
Background and purposes
Recent developments in high-throughput proteomic approach have shown the potential to discover biomarkers for diagnosing acute stroke and to elucidate the pathomechanisms ...specific to different stroke subtypes. We aimed to determine blood-based protein biomarkers to diagnose total stroke (IS+ICH) from healthy controls, ischemic stroke (IS) from healthy controls, and intracerebral hemorrhage (ICH) from healthy control subjects within 24 h using a discovery-based SWATH-MS proteomic approach.
Methods
In this discovery phase study, serum samples were collected within 24 h from acute stroke (IS & ICH) patients and healthy controls and were subjected to SWATH-MS-based untargeted proteomics. For protein identification, a high-pH fractionated peptide library for human serum proteins (obtained from SCIEX) comprising of 465 proteins was used. Significantly differentially expressed (SDE) proteins were selected using the following criteria: >1.5-fold change for upregulated, < 0.67 for downregulated,
p-
value < 0.05, and confirmed/tentative selection using Boruta random forest. Protein–protein interaction network analysis and the functional enrichment analysis were conducted using STRING 11 online tool, g:Profiler tool and Cytoscape 3.9.0 software. The statistical analyses were conducted in R version 3.6.2.
Results
Our study included 40 stroke cases (20 IS, 20 ICH) within 24 h and 40 age-, sex-, hypertension-, and diabetes-matched healthy controls. We quantified 375 proteins between the stroke cases and control groups through SWATH-MS analysis. We observed 31 SDE proteins between total stroke and controls, 16 SDE proteins between IS and controls, and 41 SDE proteins between ICH and controls within 24 h. Four proteins ceruloplasmin, alpha-1-antitrypsin (SERPINA1), von Willebrand factor (vWF), and coagulation factor XIII B chain (F13B) commonly differentiated total stroke, IS, and ICH from healthy control subjects. The most common significant pathways in stroke cases involved complement and coagulation cascades, platelet degranulation, immune-related processes, acute phase response, lipid-related processes, and pathways related to extracellular space and matrix.
Conclusion
Our discovery phase study identified potential protein biomarker candidates for the diagnosis of acute stroke and highlighted significant pathways associated with different stroke subtypes. These potential biomarker candidates warrant further validation in future studies with a large cohort of stroke patients to investigate their diagnostic performance.
Ischemic stroke (IS) is a complex and devastating vascular disease that has become one of the leading causes of disability and mortality worldwide. Several studies have shown the association between ...matrix metalloproteinase (MMP) family gene polymorphisms and IS. However, the results have been indecisive.
To investigate the association between Matrix Metalloproteinase gene polymorphisms and risk of IS.
A literature search for eligible candidate gene studies published before, 28 June 2017, was conducted in the PubMed, EMBASE, Cochrane and Google Scholar databases. The following combinations of main keywords were used: (‘Matrix Metalloproteinase’ or ‘MMP’ or ‘Stromelysin-1’ or ‘Gelatinase b’) AND (‘ischemic stroke’ or ‘IS’) AND (‘single nucleotide polymorphism’ or ‘gene polymorphism’ or ‘SNP’). Fixed or random effects models were used to estimate the Pooled Odds ratio (OR) and 95% confidence interval (CI). Statistical analysis was carried out by using STATA version 13.0 software.
Total 29 studies were included in our meta-analysis. A significant association was observed for MMP-9 (−1562C/T) (OR 1.27; 95% CI 1.06 to 1.53; p value = 0.01) and MMP-12 (−1082 A/G) (OR 2.55; 95% CI 1.75 to 3.71; p value<0.001) gene polymorphisms and risk of IS. No significant association was found for any of the MMP-1(−1607 1G/2G), MMP-2 (−1306C/T) & (−735C/T) and MMP-3 (−1612 5A/6A) gene polymorphisms with the risk of IS.
Our meta-analysis suggests that MMP-9 (−1562C/T) and MMP-12 (−1082 A/G) gene polymorphisms could be a risk factor for IS while MMP-1 (−1607 1G/2G), MMP-2 (−1306C/T) & (−735C/T) and MMP-3 (−1612 5A/6A) have no association with the risk of causing IS. However, large prospective studies with sufficient power are required to validate our findings.
•Significant association observed for MMP-9 (−1562C/T) (OR 1.27; 95% CI 1.06 to 1.53) gene polymorphism and risk of IS•Significant association observed for MMP-12 (−1082 A/G) (OR 2.55; 95% CI 1.75 to 3.71) gene polymorphism and risk of IS•MMP-9 (-1562C/T) gene polymorphism found to be a risk factor for Asian population in all the three models of inheritance.
Neurological involvement in sarcoidosis is termed as neurosarcoidosis. It usually leads to cranial neuropathies, although it can involve any part of the neuroaxis. Although sarcoidosis is a ...proinflammatory state, there is an associated anergic state demonstrable by a feeble tuberculin response. Lymphocytic sequestration in granulomas can be associated with peripheral CD4 lymphocytopenia (40% of patients with sarcoidosis) predisposing to opportunistic infections. Here we have described a young, otherwise immunocompetent male presenting with subacute onset right hemiparesis with motor aphasia, who was diagnosed to have progressive multifocal leukoencephalopathy (PML) secondary to pulmonary sarcoidosis. We want to emphasize that PML should be considered as a differential in all cases of secondary demyelination (even apparently immunocompetent individuals) as early diagnosis and treatment of the underlying cause is likely to yield better outcomes.
•Sarcoidosis can predispose to Progressive multifocal leukoencephalopathy (PML) in an otherwise immunocompetent adult.•PML should be ruled out in all cases of suspected secondary demyelination.•An ill-defined hyperintense edge and hypointense core on DWI is typical of PML.•Although sarcoidosis associated PML portends poor prognosis, early diagnosis and treatment is likely to result in better outcomes.
Background
Correct diagnosis of stroke and its subtypes is pivotal in early stages for optimum treatment.
Aims
The aim of this systematic review and meta-analysis is to summarize the published ...evidence on the potential of blood biomarkers in the diagnosis and differentiation of stroke subtypes.
Methods
A literature search was conducted for papers published until 20 April 2020 in PubMed, EMBASE, Cochrane Library, TRIP, and Google Scholar databases to search for eligible studies investigating the role of blood biomarkers in diagnosing stroke. Quality assessment was done using modified Quality Assessment of Diagnostic Accuracy Studies questionnaire. Pooled standardized mean difference and 95% confidence intervals were calculated. Presence of heterogeneity among the included studies was investigated using the Cochran's Q statistic and I2 metric tests. If I2 was < 50% then a fixed-effect model was applied else a random-effect model was applied. Risk of bias was assessed using funnel plots and between-study heterogeneity was assessed using meta-regression and sensitivity analyses. Entire statistical analysis was conducted in STATA version 13.0.
Results
A total of 40 studies including patients with 5001 ischemic strokes, 756 intracerebral hemorrhage, 554 stroke mimics, and 1774 healthy control subjects analyzing 25 biomarkers (within 24 h after symptoms onset/after the event) were included in our meta-analysis; 67.5% of studies had moderate evidence of quality. Brain natriuretic peptide, matrix metalloproteinase-9, and D-dimer significantly differentiated ischemic stroke from intracerebral hemorrhage, stroke mimics, and health control subjects (p < 0.05). Glial fibrillary acidic protein successfully differentiated ischemic stroke from intracerebral hemorrhage (standardized mean difference −1.04; 95% confidence interval −1.46 to −0.63) within 6 h. No studies were found to conduct a meta-analysis of blood biomarkers differentiating transient ischemic attack from healthy controls and stroke mimics.
Conclusion
This meta-analysis highlights the potential of brain natriuretic peptide, matrix metalloproteinase-9, D-dimer, and glial fibrillary acidic protein as diagnostic biomarkers for stroke within 24 h. Results of our meta-analysis might serve as a platform for conducting further targeted proteomics studies and phase-III clinical trials.
PROSPERO Registration ID: CRD42019139659.
Abstract
Primary CNS Vasculitis (PCNSV) is a rare inflammatory disorder affecting the blood vessels of the central nervous system. Patients present with a combination of headaches, seizures, and ...focal neurological deficits. There is usually a diagnostic delay. Treatment is based on observational studies and expert opinion. Our objective was to identify clinical, laboratory, neuroimaging, pathologic or management-related associations with 2 year outcome in patients with primary CNS vasculitis. We conducted a cohort study at a single tertiary care referral centre of prospectively (2018-2019) and retrospectively (2010-2018) identified individuals with primary CNS vasculitis (diagnosis was proven by either brain biopsy or cerebral digital subtraction angiography). Clinical, imaging and histopathologic findings, treatment, and functional outcomes were recorded. Univariate and stepwise multiple logistic regression were applied. P-value<0.05 was considered statistically significant. The main outcome measures were documentation of clinical improvement or worsening (defined by mRS scores) and identification of independent predictors of good functional outcome (mRS 0-2) at 2 years. We enrolled eighty-two biopsy and/or angiographically proven PCNSV cases. The median age at presentation was 34 years with a male predilection and a median diagnostic delay of 23 months. Most patients presented with seizures (70.7%). All patients had haemorrhages on MRI. Histologically lymphocytic subtype was the commonest. Corticosteroids with cyclophosphamide was the commonest medication used. The median mRS at follow-up of 2 years was 2 (0-3), and 65.2% of patients achieved a good functional outcome. Myelitis and longer duration of illness before diagnosis were associated with poorer outcomes. The presence of hemorrhages on SWI sequence of MRI might be a sensitive imaging marker. Treatment with steroids and another immunosuppressant probably reduced relapse rates in our cohort. We have described the third largest PCNSV cohort and multi-centre randomised controlled trials are required to study the relative efficacy of various immunosuppressants.
Study registration:
CTRI/2018/03/012721.
Primary CNS Vasculitis (PCNSV) is a rare, diverse, and polymorphic CNS blood vessel inflammatory condition. Due to its rarity, clinical variability, heterogeneous imaging results, and lack of ...definitive laboratory markers, PCNSV diagnosis is challenging. This retrospective cohort analysis identified patients with histological diagnosis of PCNSV. Demographic data, clinical presentation, neuroimaging studies, and histopathologic findings were recorded. We enrolled 56 patients with a positive biopsy of CNS vasculitis. Most patients had cerebral hemisphere or brainstem symptoms. Most brain MRI lesions were bilateral, diffuse discrete to confluent white matter lesions. Frontal lobe lesions predominated, followed by inferior cerebellar lesions. Susceptibility-weighted imaging (SWI) hemorrhages in 96.4% (54/56) of patients, either solitary microhemorrhages or a combination of micro and macrohemorrhages. Contrast-enhanced T1-WIs revealed parenchymal enhancement in 96.3% (52/54 patients). The most prevalent pattern of enhancement observed was dot-linear (87%), followed by nodular (61.1%), perivascular (25.9%), and patchy (16.7%). Venulitis was found in 19 of 20 individuals in cerebral DSA. Hemorrhages in SWI and dot-linear enhancement pattern should be incorporated as MINOR diagnostic criteria to diagnose PCNSV accurately within an appropriate clinical context. Microhemorrhages in SWI and venulitis in DSA, should be regarded as a potential marker for PCNSV.
