Dataset Information

Analysis of Early Stroke-induced Changes in Circulating Leukocyte Counts using Transcriptomic Deconvolution.

ABSTRACT: Growing evidence suggests that stroke alters the phenotype of the peripheral immune system; better characterization of this response could provide new insights into stroke pathophysiology. In this investigation, we employed a deconvolution approach to informatically infer the cellular composition of the circulating leukocyte pool at multiple timepoints following stroke onset based on whole blood mRNA expression. Microarray data generated from the peripheral blood of 23 cardiovascular disease controls and 23 ischemic stroke patients at 3, 5, and 24 hours post-symptom onset were obtained from a public repository. Transcriptomic deconvolution was used to estimate the relative counts of nine leukocyte populations based on the expression of cell-specific transcripts, and cell counts were compared between groups across timepoints. Inferred counts of lymphoid cell populations including B-cells, CD4+ T-cells, CD8+ T-cells, ?? T-cells, and NK-cells were significantly lower in stroke samples relative to control samples. With respect to myeloid cell populations, inferred counts of neutrophils and monocytes were significantly higher in stroke samples compared to control samples, however inferred counts of eosinophils and dendritic cells were significantly lower. These collective differences were most dramatic in samples collected at 5 and 24 hours post-symptom onset. Findings were subsequently confirmed in a second dataset generated from an independent population of 24 controls and 39 ischemic stroke patients. Collectively, these results offer a comprehensive picture of the early stroke-induced changes to the complexion of the circulating leukocyte pool, and provide some of the first evidence that stroke triggers an acute decrease in eosinophil counts.

SUBMITTER: O'Connell GC

PROVIDER: S-EPMC6294043 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Analysis of Early Stroke-induced Changes in Circulating Leukocyte Counts using Transcriptomic Deconvolution.

O'Connell Grant C GC Chang Julia H C JHC

Translational neuroscience 20181204

Growing evidence suggests that stroke alters the phenotype of the peripheral immune system; better characterization of this response could provide new insights into stroke pathophysiology. In this investigation, we employed a deconvolution approach to informatically infer the cellular composition of the circulating leukocyte pool at multiple timepoints following stroke onset based on whole blood mRNA expression. Microarray data generated from the peripheral blood of 23 cardiovascular disease con ...[more]

PMID: 30581599

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Project description:BackgroundNeuroinflammation plays an important role in the pathogenesis of acute ischemic stroke (AIS) and peripheral leukocyte counts have proved to be independent predictors of stroke severity and outcomes. Clinical significance of large vessel occlusion (LVO) in AIS is increasing, as these patients are potential candidates for endovascular thrombectomy and likely to have worse outcomes if not treated urgently. The aim of our study was to assess the relationship between on admission leukocyte counts and the presence of LVO in the early phase of AIS.MethodsWe have conducted a cross-sectional, observational study based on a registry of consecutive AIS patients admitted up to 4.5 h after stroke onset. Blood samples were taken at admission and leukocyte counts were measured immediately. The presence of LVO was verified based on the computed tomography angiography scan on admission.ResultsTotal white blood cell (WBC) and neutrophil counts were significantly higher in patients with LVO than those without LVO (P < 0.001 respectively). After adjustment for potential confounders total WBC counts (adjusted OR: 1.405 per 1 × 109/L increase, 95% CI: 1.209 to 1.632) and neutrophil counts (adjusted OR: 1.344 per 1 × 109/L increase, 95% CI: 1.155 to 1.564) were found to have the strongest associations with the presence of LVO. Total WBC and neutrophil counts had moderate ability to discriminate an LVO in AIS (AUC: 0.667 and 0.655 respectively). No differences were recorded in leukocyte counts according to the size of the occluded vessel and the status of collateral circulation in the anterior vascular territory. However, total WBC and neutrophil counts tended to be higher in patients with LVO in the posterior circulation (p = 0.005 and 0.010 respectively).ConclusionHigher admission total WBC and neutrophil counts are strongly associated with the presence of LVO and has moderate ability to discriminate an LVO in AIS. Detailed evaluation of stroke-evoked inflammatory mechanisms and changes according to the presence of LVO demands further investigation.

Project description:ImportanceEmerging evidence implicates a role for neuroinflammation in Alzheimer disease (AD) pathogenesis, predominantly involving the innate immune system. Blood leukocyte counts are easily accessible markers of immune function; however, their association with the risk of AD is unknown.ObjectiveTo investigate the observational and genetic associations between types of blood leukocytes and risk of AD.Design, setting, and participantsIn a cohort study comprising observational and genetic analyses, the Copenhagen General Population Study prospective cohort (n = 101 582) was used for the observational analyses. For the genetic studies, nonlinearity was first evaluated for the association between leukocyte cell counts and AD risk using individual-level data from the UK Biobank (n = 365 913). Subsequently, a 2-sample mendelian randomization framework was applied using genetic instruments for blood leukocyte counts (n = 563 085); for AD, the European Alzheimer & Dementia Biobank was used, including 85 934 individuals with AD and 401 577 controls and the International Genomics of Alzheimer's Project, including 21 982 individuals with AD and 41 944 controls.ExposuresObservational and genetically determined types of blood leukocyte counts.Main outcomes and measuresHazard ratios (HRs) and 95% CIs for AD of cell count percentile groups in observational studies and odds ratios (ORs) and 95% CIs for AD per 1 SD genetically determined cell counts.ResultsThis cohort study included 101 582 participants (55 891 [55.0%] women) with a median age of 58 years (IQR, 48-67 years); of these, 1588 individuals developed AD. Multivariable-adjusted HRs for participants in the less than 5th vs the 25th to 75th (reference) percentile group were 1.24 (95% CI, 0.99-1.54) for blood monocytes and 1.25 for blood eosinophils (95% CI, 1.05-1.50). For participants in the greater than 95th vs the 25th to 75th percentile group, the HR was 1.30 (95% CI, 1.06-1.61) for blood neutrophils. Genetically, no evidence favored possible nonlinear associations. The ORs for AD per 1-SD decrease in genetically determined blood monocytes were 1.04 (95% CI, 1.00-1.10) in the European Alzheimer & Dementia Biobank consortium and 1.09 (95% CI, 1.01-1.17) in the International Genomics of Alzheimer's Project consortium. Using mendelian randomization, sensitivity analyses and multivariable analysis showed similar results.Conclusions and relevanceThe findings of this study suggest that low blood monocyte counts are associated with increased AD risk. These findings highlight a potential role of the innate immune system in AD pathogenesis.

Project description:PurposeDecreased peripheral lymphocyte counts are associated with survival after radiation therapy (RT) in several solid tumors, although they appear late during or after the radiation course and often correlate with other clinical factors. Here we investigate if absolute lymphocyte counts (ALCs) are independently associated with recurrence in pediatric medulloblastoma early during RT.Methods and materialsWe assessed 202 patients with medulloblastoma treated between 2000 and 2016 and analyzed ALC throughout therapy, focusing on both early markers (ALC during week 1 - ALCwk1; grade 3+ Lymphopenia during week 2 - Lymphopeniawk2) and late markers (ALC nadir). Uni- and multivariable regressions were used to assess association of clinical and treatment variables with ALC and of ALC with recurrence.ResultsThirty-six recurrences were observed, with a median time to recurrence of 1.6 years (range, 0.2-10.3) and 7.1 years median follow-up. ALC during RT was associated with induction chemotherapy (P < .001), concurrent carboplatin (P = .009), age (P = .01), and high-risk status (P = .05). On univariable analysis, high-risk disease (hazard ratio = 2.0 [1.06-3.9]; P = .03) and M stage≥1 (hazard ratio = 2.2 [1.1-4.4]) were associated with recurrence risk, as was lower ALC early during RT (ALCwk1, hazard ratio = 0.28 [0.12-0.65]; P = .003; Lymphopeniawk2, hazard ratio = 2.27 [1.1-4.6]; P = .02). Neither baseline ALC nor nadir correlated with outcome. These associations persisted when excluding carboplatin and pre-RT chemotherapy patients, and in the multivariable analysis accounting for confounders lymphocyte counts remained significant (ALCwk1, hazard-ratio = 0.23 [0.09-0.57]; P = .002; Lymphopeniawk2, hazard-ratio = 2.3 [1.1-4.8]; P = .03).ConclusionsALC during weeks 1 and 2 of RT was associated with recurrence, and low ALC is an independent prognostic factor in medulloblastoma. Strategies to mitigate the risk of radiation-induced lymphopenia should be considered.

Dataset Information

Analysis of Early Stroke-induced Changes in Circulating Leukocyte Counts using Transcriptomic Deconvolution.

Publications

Analysis of Early Stroke-induced Changes in Circulating Leukocyte Counts using Transcriptomic Deconvolution.

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