Roland Faigle

Signaling mechanisms regulating adult neural stem cells and neurogenesis

BACKGROUND Adult neurogenesis occurs throughout life in discrete regions of the mammalian brain and is tightly regulated via both extrinsic environmental influences and intrinsic genetic factors. In recent years, several crucial signaling pathways have been identified in regulating self-renewal, proliferation, and differentiation of neural stem cells, as well as migration and functional integration of developing neurons in the adult brain. SCOPE OF REVIEW Here we review our current understanding of signaling mechanisms, including Wnt, notch, sonic hedgehog, growth and neurotrophic factors, bone morphogenetic proteins, neurotransmitters, transcription factors, and epigenetic modulators, and crosstalk between these signaling pathways in the regulation of adult neurogenesis. We also highlight emerging principles in the vastly growing field of adult neural stem cell biology and neural plasticity. MAJOR CONCLUSIONS Recent methodological advances have enabled the field to identify signaling mechanisms that fine-tune and coordinate neurogenesis in the adult brain, leading to a better characterization of both cell-intrinsic and environmental cues defining the neurogenic niche. Significant questions related to niche cell identity and underlying regulatory mechanisms remain to be fully addressed and will be the focus of future studies. GENERAL SIGNIFICANCE A full understanding of the role and function of individual signaling pathways in regulating neural stem cells and generation and integration of newborn neurons in the adult brain may lead to targeted new therapies for neurological diseases in humans. This article is part of a Special Issue entitled Biochemistry of Stem Cells.

Predictors of critical care needs after IV thrombolysis for acute ischemic stroke.

Background and Purpose Intravenous (IV) tissue plasminogen activator (tPA) is the only Food and Drug Administration (FDA)-approved treatment for acute ischemic stroke. Post tPA patients are typically monitored in an intensive care unit (ICU) for at least 24 hours. However, rigorous evidence to support this practice is lacking. This study evaluates factors that predict ICU needs after IV thrombolysis. Methods A retrospective chart review was performed for 153 patients who received intravenous tPA for acute ischemic stroke. Data on stroke risk factors, physiologic parameters on presentation, and stroke severity were collected. The timing and nature of an intensive care intervention, if needed, was recorded. Using multivariable logistic regression, we determined factors associated with requiring ICU care. Results African American race (Odds Ratio [OR] 8.05, 95% Confidence Interval [CI] 2.65–24.48), systolic blood pressure, and National Institutes of Health Stroke Scale (NIHSS) (OR 1.20 per point increase, 95% CI 1.09–1.31) were predictors of utilization of ICU resources. Patients with an NIHSS≥10 had a 7.7 times higher risk of requiring ICU resources compared to patients who presented with an NIHSS<10 (p<0.001). Most patients with ICU needs developed them prior to the end of tPA infusion (81.0%, 95% CI 68.8–93.1). Only 7% of patients without ICU needs by the end of the tPA infusion went on to require ICU care later on. These patients were more likely to have diabetes mellitus and had significantly higher NIHSS compared to patients without further ICU needs (mean NIHSS 17.3, 95% CI 11.5–22.9 vs. 9.2, 95% CI 7.7–9.6). Conclusion Race, NIHSS, and systolic blood pressure predict ICU needs following tPA for acute ischemic stroke. We propose that patients without ICU needs by the end of the tPA infusion might be safely monitored in a non-ICU setting if NIHSS at presentation is low.

Novel Score Predicting Gastrostomy Tube Placement in Intracerebral Hemorrhage

Background and Purpose— Dysphagia after intracerebral hemorrhage (ICH) contributes significantly to morbidity, often necessitating placement of a percutaneous endoscopic gastrostomy (PEG) tube. This study describes a novel risk prediction score for PEG placement after ICH. Methods— We retrospectively analyzed data from 234 patients with ICH presenting during a 4-year period. One hundred eighty-nine patients met inclusion criteria. The sample was randomly divided into a development and a validation cohort. Logistic regression was used to develop a risk score by weighting predictors of PEG placement based on strength of association. Results— Age (odds ratio [OR], 1.64 per 10-year increase in age; 95% confidence interval [CI], 1.02–2.65), black race (OR, 3.26; 95% CI, 0.96–11.05), Glasgow Coma Scale (OR, 0.80; 95% CI, 0.62–1.03), and ICH volume (OR, 1.38 per 10-mL increase in ICH volume) were independent predictors of PEG placement. The final model for score development achieved an area under the curve of 0.7911 (95% CI, 0.6931–0.8892) in the validation group. The score was named the GRAVo score: Glasgow Coma Scale ⩽12 (2 points), Race (1 point for black), Age >50 years (2 points), and ICH Volume >30 mL (1 point). A score >4 was associated with ≈12× higher odds of PEG placement when compared with a score ⩽4 (OR, 11.81; 95% CI, 5.04–27.66), predicting PEG placement with 46.55% sensitivity and 93.13% specificity. Conclusions— The GRAVo score, combining information about Glasgow Coma Scale, race, age, and ICH volume, may be a useful predictor of PEG placement in ICH patients.

Racial and Socioeconomic Disparities in Gastrostomy Tube Placement After Intracerebral Hemorrhage in the United States

Background and Purpose— Percutaneous endoscopic gastrostomy (PEG) tubes are widely used for enteral feeding of patients after intracerebral hemorrhage (ICH). We sought to determine whether PEG placement after ICH differs by race and socioeconomic status. Methods— Patient discharges with ICH as the primary diagnosis from 2007 to 2011 were queried from the Nationwide Inpatient Sample. Logistic regression was used to evaluate the association between race, insurance status, and household income with PEG placement. Results— Of 49 946 included ICH admissions, a PEG was placed in 4464 (8.94%). Among PEG recipients, 47.2% were minorities and 15.6% were Medicaid enrollees, whereas 33.7% and 8.2% of patients without a PEG were of a race other than white and enrolled in Medicaid, respectively (P<0.001). Compared with whites, the odds of PEG were highest among Asians/Pacific Islanders (odds ratio [OR] 1.62, 95% confidence interval [CI] 1.32–1.99) and blacks (OR 1.42, 95% CI 1.28–1.59). Low household income (OR 1.25, 95% CI 1.09–1.44 in lowest compared with highest quartile) and enrollment in Medicaid (OR 1.36, 95% CI 1.17–1.59 compared with private insurance) were associated with PEG placement. Racial disparities (minorities versus whites) were most pronounced in small/medium-sized hospitals (OR 1.77, 95% CI 1.43–2.20 versus OR 1.31, 95% CI 1.17–1.47 in large hospitals; P value for interaction 0.011) and in hospitals with low ICH case volume (OR 1.58, 95% CI 1.38–1.81 versus OR 1.29, 95% CI 1.12–1.50 in hospitals with high ICH case volume; P value for interaction 0.007). Conclusions— Minority race, Medicaid enrollment, and low household income are associated with PEG placement after ICH.

Race‐Specific Predictors of Mortality in Intracerebral Hemorrhage: Differential Impacts of Intraventricular Hemorrhage and Age Among Blacks and Whites

Background Intracerebral hemorrhage (ICH) carries high risk for short‐term mortality. We sought to identify race‐specific predictors of mortality in ICH patients. Methods and Results We used 2 databases, the Johns Hopkins clinical stroke database and the Nationwide Inpatient Sample (NIS). We included 226 patients with the primary diagnosis of spontaneous ICH from our stroke database between 2010 and 2013; in the NIS, 42 077 patients met inclusion criteria. Logistic regression was used to assess differences in predictors of mortality in blacks compared to whites. In our clinical stroke database, Glasgow Coma Scale (GCS; P=0.016), ICH volume (P=0.013), intraventricular haemorrhage (IVH; P=0.023), and diabetes mellitus (P=0.037) were predictors of mortality in blacks, whereas GCS (P=0.007), ICH volume (P=0.005), age (P=0.002), chronic kidney disease (P=0.003), and smoking (P=0.010) predicted mortality in whites. Among patients with IVH, blacks had over 7 times higher odds of mortality compared to whites (odds ratio [OR], 7.27; P value for interaction, 0.017) and were more likely to present with hydrocephalus (OR, 2.76; P=0.026). In the NIS, black ICH patients had higher rates of external ventricular drain (EVD) placement compared to whites (9.7% vs 5.0%; P<0.001) and were more likely to develop hydrocephalus (OR, 1.32; 95% CI, 1.20–1.46). Comparison of a race‐specific ICH score to the original ICH score showed that the various ICH score components have differential relevance for ICH score performance by race. Conclusions IVH and age differentially predict mortality among blacks and whites. Blacks have higher rates of obstructive hydrocephalus and more frequently require EVD placement compared to their white counterparts.

Individual and System Contributions to Race and Sex Disparities in Thrombolysis Use for Stroke Patients in the United States

Background and Purpose— Intravenous thrombolysis (IVT) is underutilized in ethnic minorities and women. To disentangle individual and system-based factors determining disparities in IVT use, we investigated race/sex differences in IVT utilization among hospitals serving varying proportions of minority patients. Methods— Ischemic stroke admissions were identified from the Nationwide Inpatient Sample between 2007 and 2011. Hospitals were categorized based on the percentage of minority patients admitted with stroke (<25% minority patients [white hospitals], 25% to 50% minority patients [mixed hospitals], or >50% minority patients [minority hospitals]). Logistic regression was used to evaluate the association between race/sex and IVT use within and between the different hospital strata. Results— Among 337 201 stroke admissions, white men had the highest odds of IVT among all race/sex groups in any hospital strata, and the odds of IVT for white men did not differ by hospital strata. For white women and minority men, the odds of IVT were significantly lower in minority hospitals compared with white hospitals (odds ratio, 0.83; 95% confidence interval, 0.71–0.97, for white women; and odds ratio, 0.82; 95% confidence interval, 0.69–0.99, for minority men). Race disparities in IVT use among women were observed in white hospitals (odds ratio, 0.88; 95% confidence interval, 0.78–0.99, in minority compared with white women), but not in minority hospitals (odds ratio, 0.94, 95% confidence interval, 0.82–1.09). Sex disparities in IVT use were observed among whites but not among minorities. Conclusions— Minority men and white women have significantly lower odds of IVT in minority hospitals compared with white hospitals. IVT use in white men does not differ by hospital strata.

Troponin elevation predicts critical care needs and in-hospital mortality after thrombolysis in white but not black stroke patients

INTRODUCTION Stroke patients undergoing intravenous thrombolysis (IVT) are at increased risk for critical care interventions and mortality. Cardiac troponin elevation is common in stroke patients; however, its prognostic significance is unclear. The present study evaluates troponin elevation as a predictor of critical care needs and mortality in post-IVT patients and describes racial differences in its predictive accuracy. METHODS Logistic regression and receiver operating characteristics (ROC) analysis were used to determine racial differences in the predictive accuracy of troponin elevation for critical care needs and mortality in post-IVT patients. RESULTS Troponin elevation predicted critical care needs in white (odds ratio [OR] 29.40, 95% confidence interval [CI] 4.86-177.81) but not black patients (OR 0.50, 95% CI 0.14-1.78; P value for interaction < .001). Adding troponin elevation to a prediction model for critical care needs in whites improved the area under the curve from 0.670 to 0.844 (P = .006); however, addition of troponin elevation did not improve the model in blacks (area under the curve 0.843 vs 0.851, P = .54). Troponin elevation was associated with in-hospital mortality in whites (OR 21.94, 95% CI 3.51-137.11) but not blacks (OR 1.10, 95% CI 0.19-6.32, P value for interaction .022). CONCLUSION Troponin is a useful predictor of poor outcome in white but not black post-IVT stroke patients.

Comorbid Psychiatric Disease Is Associated With Lower Rates of Thrombolysis in Ischemic Stroke

Background and Purpose— Intravenous thrombolysis (IVT) improves outcomes after acute ischemic stroke but is underused in certain patient populations. Mental illness is pervasive in the United States, and patients with comorbid psychiatric disease experience inequities in treatment for a range of conditions. We aimed to determine whether comorbid psychiatric disease is associated with differences in IVT use in acute ischemic stroke. Methods— Acute ischemic stroke admissions between 2007 and 2011 were identified in the Nationwide Inpatient Sample. Psychiatric disease was defined by International Classification of Diseases, Ninth Revision, Clinical Modification codes for secondary diagnoses of schizophrenia or other psychoses, bipolar disorder, depression, or anxiety. Using logistic regression, we tested the association between IVT and psychiatric disease, controlling for demographic, clinical, and hospital factors. Results— Of the 325 009 ischemic stroke cases meeting inclusion criteria, 12.8% had any of the specified psychiatric comorbidities. IVT was used in 3.6% of those with, and 4.4% of those without, psychiatric disease (P<0.001). Presence of any psychiatric disease was associated with lower odds of receiving IVT (adjusted odds ratio, 0.80; 95% confidence interval, 0.76–0.85). When psychiatric diagnoses were analyzed separately individuals with schizophrenia or other psychoses, anxiety, or depression each had significantly lower odds of IVT compared to individuals without psychiatric disease. Conclusions— Acute ischemic stroke patients with comorbid psychiatric disease have significantly lower odds of IVT. Understanding barriers to IVT use in such patients may help in developing interventions to increase access to evidence-based stroke care.

Safety of intravenous alteplase within 4.5 hours for patients awakening with stroke symptoms

Background Up to 25% of acute stroke patients first note symptoms upon awakening. We hypothesized that patients awaking with stroke symptoms may be safely treated with intravenous alteplase (IV tPA) using non-contrast head CT (NCHCT), if they meet all other standard criteria. Methods The SAfety of Intravenous thromboLytics in stroke ON awakening (SAIL ON) was a prospective, open-label, single treatment arm, pilot safety trial of standard dose IV tPA in patients who presented with stroke symptoms within 0–4.5 hours of awakening. From January 30, 2013, to September 1, 2015, twenty consecutive wakeup stroke patients selected by NCHCT were enrolled. The primary outcome was symptomatic intracerebral hemorrhage (sICH) in the first 36 hours. Secondary outcomes included NIH stroke scale (NIHSS) at 24 hours; and modified Rankin Score (mRS), NIHSS, and Barthel index at 90 days. Results The average age was 65 years (range 47–83); 40% were women; 50% were African American. The average NIHSS was 6 (range 4–11). The average time from wake-up to IV tPA was 205 minutes (range 114–270). The average time from last known well to IV tPA was 580 minutes (range 353–876). The median mRS at 90 days was 1 (range 0–5). No patients had sICH; two of 20 (10%) had asymptomatic ICH on routine post IV tPA brain imaging. Conclusions Administration of IV tPA was feasible and may be safe in wakeup stroke patients presenting within 4.5 hours from awakening, screened with NCHCT. An adequately powered randomized clinical trial is needed. Clinical trial registration ClinicalTrials.gov NCT01643902.

Minority race and male sex as risk factors for non-beneficial gastrostomy tube placements after stroke

Background Percutaneous endoscopic gastrostomy (PEG) tubes are widely used for enteral feeding after stroke; however, PEG tubes placed in patients in whom death is imminent are considered non-beneficial. Aim We sought to determine whether placement of non-beneficial PEG tubes differs by race and sex. Design and setting/participants In this retrospective cohort study, inpatient admissions for stroke patients who underwent palliative/withdrawal of care, were discharged to hospice, or died during the hospitalization, were identified from the Nationwide Inpatient Sample between 2007 and 2011. Logistic regression was used to evaluate the association between race and sex with PEG placement. Results Of 36,109 stroke admissions who underwent palliative/withdrawal of care, were discharge to hospice, or experienced in-hospital death, a PEG was placed in 2,258 (6.3%). Among PEG recipients 41.1% were of a race other than white, while only 22.0% of patients without PEG were of a minority race (p<0.001). The proportion of men was higher among those with compared to without a PEG tube (50.0% vs. 39.2%, p<0.001). Minority race was associated with PEG placement compared to whites (OR 1.75, 95% CI 1.57–1.96), and men had 1.27 times higher odds of PEG compared to women (95% CI 1.16–1.40). Racial differences were most pronounced among women: ethnic/racial minority women had over 2-fold higher odds of a PEG compared to their white counterparts (OR 2.09, 95% CI 1.81–2.41), while male ethnic/racial minority patients had 1.44 increased odds of a PEG when compared to white men (95% CI 1.24–1.67, p-value for interaction <0.001). Conclusion Minority race and male sex are risk factors for non-beneficial PEG tube placements after stroke.