Microglial TLR4 Mediates White Matter Injury in a Combined Model of Diesel Exhaust Exposure and Cerebral Hypoperfusion.

BACKGROUND: Air pollution particulate matter exposure and chronic cerebral hypoperfusion (CCH) contribute to white matter toxicity through shared mechanisms of neuroinflammation, oxidative stress, and myelin breakdown. Prior studies showed that exposure of mice to joint particulate matter and CCH caused supra-additive injury to corpus callosum white matter. This study examines the role of TLR4 (toll-like receptor 4) signaling in mediating neurotoxicity and myelin damage observed in joint particulate matter and CCH exposures. METHODS: Experiments utilized a novel murine model of inducible monocyte/microglia-specific TLR4 knockout (i-mTLR4-ko). Bilateral carotid artery stenosis (BCAS) was induced surgically to model CCH. TLR4-intact (control) and i-mTLR4-ko mice were exposed to 8 weeks of either aerosolized diesel exhaust particulate (DEP) or filtered air (FA) in 8 experimental groups: (1) control/FA (n=10), (2) control/DEP (n=10), (3) control/FA+BCAS (n=9), (4) control/DEP+BCAS (n=10), (5) i-mTLR4-ko/FA (n=9), (6) i-mTLR4-ko/DEP (n=8), (7) i-mTLR4-ko/FA+BCAS (n=8), and (8) i-mTLR4-ko/DEP+BCAS (n=10). Corpus callosum levels of 4-hydroxynonenal, 8-Oxo-2'-deoxyguanosine, Iba-1 (ionized calcium-binding adapter molecule 1), and dMBP (degraded myelin basic protein) were assayed via immunofluorescence to measure oxidative stress, neuroinflammation, and myelin breakdown, respectively. RESULTS: Compared with control/FA mice, control/DEP+BCAS mice exhibited increased dMBP (41%; P<0.01), Iba-1 (51%; P<0.0001), 4-hydroxynonenal (100%; P<0.0001), and 8-Oxo-2'-deoxyguanosine (65%; P<0.05). I-mTLR4 knockout attenuated responses to DEP/BCAS for all markers. CONCLUSIONS: i-mTLR4-ko markedly reduced neuroinflammation and oxidative stress and attenuated white matter degradation following DEP and CCH exposures. This suggests a potential role for targeting TLR4 signaling in individuals with vascular cognitive impairment, particularly those exposed to substantial ambient air pollution.

Magnesium and Hematoma Expansion in Intracerebral Hemorrhage: A FAST-MAG Randomized Trial Analysis.

BACKGROUND: Observational studies suggest that magnesium may have hemostatic effects. FAST-MAG (Field Administration of Stroke Therapy-Magnesium) was a pragmatic clinical trial of magnesium sulfate administered prehospital for acute clinical stroke syndromes and included patients with intracerebral hemorrhage. Exploratory secondary analysis by the treatment group found no reduction in hematoma expansion (HE) associated with magnesium treatment in intracerebral hemorrhage but did not consider serum magnesium levels achieved. We analyzed FAST-MAG intracerebral hemorrhage data for associations between serum magnesium level, HE, and early neurological deterioration, accounting for groupwise biases. METHODS: HE was defined as hematoma volume increase ≥3 mL within 24 hours and early neurological deterioration as ≥1-point Glasgow Coma Scale decline from arrival to hospital day 4. Comparing treatment and placebo groups confirmed biased availability of neuroimaging data. Therefore, HE and neurological deterioration were analyzed and stratified by treatment and placebo groups using univariate tests and adjusted logistic regression. RESULTS: Spontaneous intracerebral hemorrhage was present in 381 patients. Placebo patients had fewer serial neuroimaging studies available (123 [65.4%] versus 145 [75.1%]; P=0.038). Necessary data were available in 104 magnesium- and 85 placebo-treated patients (age, 64.9 [13.0] years; 67.7% male). In the magnesium group, higher magnesium level was associated with less HE (adjusted odds ratio, 0.64 per mg/dL [95% CI, 0.42-0.93]) and less neurological deterioration (adjusted odds ratio, 0.54 per mg/dL [95% CI, 0.33-0.82]). In the placebo group, magnesium level was not associated with either HE or neurological deterioration. CONCLUSIONS: Magnesium may exhibit a hemostatic effect that was only observable in the FAST-MAG magnesium treatment group. Equipoise should be maintained, and specific trials are needed. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT00059332.

Effect of Air Pollution Particulate Matter on Ischemic and Hemorrhagic Stroke: A Scoping Review.

Air pollution particulate matter (PM) exposure has been established as a risk factor for stroke. However, few studies have investigated the effects of PM exposure on stroke subtypes (ischemic and hemorrhagic stroke). Ischemic (IS) and hemorrhagic strokes (HS) involve distinctive pathophysiological pathways and may be differentially influenced by PM exposure. This review aims to characterize the effects of PM exposure on ischemic and hemorrhagic strokes. It also identifies subpopulations that may be uniquely vulnerable to PM toxicity. Pubmed was queried from 2000 to 2023 to identify clinical and epidemiological studies examining the association between PM exposure and stroke subtypes (ischemic and hemorrhagic stroke). Inclusion criteria were: 1) articles written in English 2) clinical and epidemiological studies 3) studies with a clear definition of stroke, IS, HS, and air pollution 4) studies reporting the effects of PM and 5) studies that included distinct analyses per stroke subtype. Two independent reviewers screened the literature for applicable studies. A total of 50 articles were included in this review. Overall, PM exposure increases ischemic stroke risk in both lightly and heavily polluted countries. The association between PM exposure and hemorrhagic stroke is variable and may be influenced by a country's ambient air pollution levels. A stronger association between PM exposure and stroke is demonstrated in older individuals and those with pre-existing diabetes. There is no clear effect of sex or hypertension on PM-associated stroke risk. Current literature suggests PM exposure increases ischemic stroke risk, with an unclear effect on hemorrhagic stroke risk. Older patients and those with pre-existing diabetes may be the most vulnerable to PM toxicity. Future investigations are needed to characterize the influence of sex and hypertension on PM-associated stroke risk.

Circadian variation in stroke onset: Differences between ischemic and hemorrhagic stroke and weekdays versus weekends.

OBJECTIVES: To delineate diurnal variation onset distinguishing ischemic from hemorrhagic stroke, wake from sleep onset, and weekdays from weekends/holidays. MATERIALS AND METHODS: We analyzed patients enrolled in the FAST-MAG trial of field-initiated neuroprotective agent in patients with hyperacute stroke within 2h of symptoms onset. Stroke onset times were analyzed in 1h, 4h, and 12h time blocks throughout the 24h day-night cycle. Patient demographic, clinical features, stroke severity, and prehospital workflow were evaluated for association with onset times. RESULTS: Among 1615 acute cerebrovascular disease patients, final diagnoses were acute cerebral ischemia in 76.5% and Intracerebral hemorrhage in 23.5%. Considering all acute cerebrovascular disease patients, frequency of wake onset times showed a bimodal pattern, with peaks on onsets at 09:00-13:59 and 17:00-18:59 and early morning (00:00-05:59) onset in only 3.8%. Circadian rhythmicity differed among stroke subtypes: in acute cerebral ischemia, a single broad plateau of elevated incidences was seen from 10:00-21:59; in Intracerebral hemorrhage, bimodal peaks occurred at 09:00 and 19:00. The ratio of Intracerebral hemorrhage to acute cerebral ischemia occurrence was highest in early morning, 02:00-06:59. Marked weekday vs weekends pattern variation was noted for acute cerebral ischemia, with a broad plateau between 09:00 and 21:59 on weekdays but a unimodal peak at 14:00-15:59 on weekends. CONCLUSIONS: Wake onset of acute cerebrovascular disease showed a marked circadian variation, with distinctive patterns of a broad elevated plateau among acute cerebral ischemia patients; a bimodal peak among intracerebral hemorrhage patients; and a weekend change in acute cerebral ischemia pattern to a unimodal peak.

Neurologic Improvement in Acute Cerebral Ischemia: Frequency, Magnitude, Predictors, and Clinical Outcomes.

BACKGROUND AND OBJECTIVES: Investigations of rapid neurologic improvement (RNI) in patients with acute cerebral ischemia (ACI) have focused on RNI occurring after hospital arrival. However, with stroke routing decisions and interventions increasingly migrating to the prehospital setting, there is a need to delineate the frequency, magnitude, predictors, and clinical outcomes of patients with ACI with ultra-early RNI (U-RNI) in the prehospital and early postarrival period. METHODS: We analyzed prospectively collected data of the prehospital Field Administration of Stroke Therapy-Magnesium (FAST-MAG) randomized clinical trial. Any U-RNI was defined as improvement by 2 or more points on the Los Angeles Motor Scale (LAMS) score between the prehospital and early post-emergency department (ED) arrival examinations and classified as moderate (2-3 point) or dramatic (4-5 point) improvement. Outcome measures included excellent recovery (modified Rankin Scale [mRS] score 0-1) and death by 90 days. RESULTS: Among the 1,245 patients with ACI, the mean age was 70.9 years (SD 13.2); 45% were women; the median prehospital LAMS was 4 (interquartile range [IQR] 3-5); the median last known well to ED-LAMS time was 59 minutes (IQR 46-80 minutes), and the median prehospital LAMS to ED-LAMS time was 33 minutes (IQR 28-39 minutes). Overall, any U-RNI occurred in 31%, moderate U-RNI in 23%, and dramatic U-RNI in 8%. Any U-RNI was associated with improved outcomes, including excellent recovery (mRS score 0-1) at 90 days 65.1% (246/378) vs 35.4% (302/852), p < 0.0001; decreased mortality by 90 days 3.7% (14/378) vs 16.4% (140/852), p < 0.0001; decreased symptomatic intracranial hemorrhage 1.6% (6/384) vs 4.6% (40/861), p = 0.0112; and increased likelihood of being discharged home 56.8% (218/384) vs 30.2% (260/861), p < 0.0001. DISCUSSION: U-RNI occurs in nearly 1 in 3 ambulance-transported patients with ACI and is associated with excellent recovery and decreased mortality at 90 days. Accounting for U-RNI may be useful for routing decisions and future prehospital interventions. TRIAL REGISTRATION INFORMATION: clinicaltrials.gov. Unique identifier: NCT00059332.

Effect of Magnesium on Deterioration and Symptomatic Hemorrhagic Transformation in Cerebral Ischemia: An Ancillary Analysis of the FAST-MAG Trial.

BACKGROUND: Magnesium (Mg) is a neuroprotectant in preclinical models. Lower serum Mg levels have been associated with symptomatic hemorrhagic transformation (HT) in patients with ischemic stroke. Early treatment of acute ischemic stroke with Mg may reduce rates of symptomatic HT. METHODS: In this post hoc study of the Field Administration of Stroke Therapy Magnesium (FAST-MAG) trial, 1,245 participants with a diagnosis of cerebral ischemia received 20 g of Mg or placebo initiated in the prehospital setting. Posttreatment serum Mg level was measured for 809 participants. Cases of clinical deterioration, defined as worsening by ≥4 points on the National Institute of Health Stroke Scale (NIHSS), were imaged and evaluated for etiology. Symptomatic HT was defined as deterioration with imaging showing new hemorrhage. RESULTS: Clinical deterioration occurred in 187 and symptomatic HT in 46 of 1,245 cases of cerebral ischemia. Rates of deterioration and symptomatic HT were not significantly lower in those who received Mg (15.7% vs. 14.4%, p = 0.591; 2.8% vs. 4.6%, p = 0.281). In cases where serum Mg level was obtained posttreatment, lower serum Mg level (<1.7 mg/dL) was associated with significantly higher rates of deterioration and symptomatic HT (27.5% vs. 15.5%, p = 0.0261; 11.6% vs. 3.65%, p = 0.00819). CONCLUSIONS: Treatment with Mg did not significantly reduce rates of clinical deterioration or symptomatic HT. Future analysis should address whether treatment with Mg could have influenced the subgroup with low serum Mg at baseline.

Particulate matter exposure and chronic cerebral hypoperfusion promote oxidative stress and induce neuronal and oligodendrocyte apoptosis in male mice.

Chronic cerebral hypoperfusion (CCH) may amplify the neurotoxicity of nanoscale particulate matter (nPM), resulting in white matter injury. This study characterized the joint effects of nPM (diameter ≤ 200 nm) and CCH secondary to bilateral carotid artery stenosis (BCAS) exposure on neuronal and white matter injury in a murine model. nPM was collected near a highway and re-aerosolized for exposure. Ten-week-old C57BL/6 male mice were randomized into four groups: filtered air (FA), nPM, FA + BCAS, and nPM + BCAS. Mice were exposed to FA or nPM for 10 weeks. BCAS surgeries were performed. Markers of inflammation, oxidative stress, and apoptosis were examined. nPM + BCAS exposure increased brain hemisphere TNFα protein compared to FA. iNOS and HNE immunofluorescence were increased in the corpus callosum and cerebral cortex of nPM + BCAS mice compared to FA. While nPM exposure alone did not decrease cortical neuronal cell count, nPM decreased corpus callosum oligodendrocyte cell count. nPM exposure decreased mature oligodendrocyte cell count and increased oligodendrocyte precursor cell count in the corpus callosum. nPM + BCAS mice exhibited a 200% increase in cortical neuronal TUNEL staining and a 700% increase in corpus callosum oligodendrocyte TUNEL staining compared to FA. There was a supra-additive interaction between nPM and BCAS on cortical neuronal TUNEL staining (2.6× the additive effects of nPM + BCAS). nPM + BCAS exposure increased apoptosis, neuroinflammation, and oxidative stress in the cerebral cortex and corpus callosum. nPM + BCAS exposure increased neuronal apoptosis above the separate responses to each exposure. However, oligodendrocytes in the corpus callosum demonstrated a greater susceptibility to the combined neurotoxic effects of nPM + BCAS exposure.

Association Between Hyperacute Blood Pressure Variability and Hematoma Expansion After Intracerebral Hemorrhage: Secondary Analysis of the FAST-MAG Database.

BACKGROUND: Blood pressure variability (BPV) has emerged as a significant factor associated with clinical outcomes after intracerebral hemorrhage (ICH). Although hematoma expansion (HE) is associated with clinical outcomes, the relationship between BPV that encompasses prehospital data and HE is unknown. We hypothesized that BPV was positively associated with HE. METHODS: We analyzed 268 patients with primary ICH enrolled in the National Institutes of Health-funded Field Administration of Stroke Therapy-Magnesium (FAST-MAG) study who received head computed tomography or magnetic resonance imaging on arrival to the emergency department (ED) and repeat imaging within 6-48 h. BPV was calculated by standard deviation (SD) and coefficient of variation (CV) from prehospital data as well as systolic blood pressure (SBP) measurements taken on ED arrival, 15 min post antihypertensive infusion start, 1 h post maintenance infusion start, and 4 h after ED arrival. HE was defined by hematoma volume expansion increase > 6 mL or by 33%. Univariate logistic regression was used for presence of HE in quintiles of SD and CV of SBP for demographics and clinical characteristics. RESULTS: Of the 268 patients analyzed from the FAST-MAG study, 116 (43%) had HE. Proportions of patients with HE were not statistically significant in the higher quintiles of the SD and CV of SBP for either the hyperacute or the acute period. Presence of HE was significantly more common in patients on anticoagulation. CONCLUSIONS: Higher BPV was not found to be associated with occurrence of HE in the hyperacute or the acute period of spontaneous ICH. Further study is needed to determine the relationship.

Neurotoxicity of Diesel Exhaust Particles.

BACKGROUND: Air pollution particulate matter (PM) is strongly associated with risks of accelerated cognitive decline, dementia and Alzheimer's disease. Ambient PM batches have variable neurotoxicity by collection site and season, which limits replicability of findings within and between research groups for analysis of mechanisms and interventions. Diesel exhaust particles (DEP) offer a replicable model that we define in further detail. OBJECTIVE: Define dose- and time course neurotoxic responses of mice to DEP from the National Institute of Science and Technology (NIST) for neurotoxic responses shared by DEP and ambient PM. METHODS: For dose-response, adult C57BL/6 male mice were exposed to 0, 25, 50, and 100µg/m3 of re-aerosolized DEP (NIST SRM 2975) for 5 h. Then, mice were exposed to 100µg/m3 DEP for 5, 100, and 200 h and assayed for amyloid-ß peptides, inflammation, oxidative damage, and microglial activity and morphology. RESULTS: DEP exposure at 100µg/m3 for 5 h, but not lower doses, caused oxidative damage, complement and microglia activation in cerebral cortex and corpus callosum. Longer DEP exposure for 8 weeks/200 h caused further oxidative damage, increased soluble Aß, white matter injury, and microglial soma enlargement that differed by cortical layer. CONCLUSION: Exposure to 100µg/m3 DEP NIST SRM 2975 caused robust neurotoxic responses that are shared with prior studies using DEP or ambient PM0.2. DEP provides a replicable model to study neurotoxic mechanisms of ambient PM and interventions relevant to cognitive decline and dementia.

Magnesium Sulfate and Hematoma Expansion: An Ancillary Analysis of the FAST-MAG Randomized Trial.

BACKGROUND: Intracerebral hemorrhage (ICH) is the deadliest form of stroke. In observational studies, lower serum magnesium has been linked to more hematoma expansion (HE) and intracranial hemorrhage, implying that supplemental magnesium sulfate is a potential acute treatment for patients with ICH and could reduce HE. FAST-MAG (Field Administration of Stroke Therapy - Magnesium) was a clinical trial of magnesium sulfate started prehospital in patients with acute stroke within 2 hours of last known well enrolled. CT was not required prior to enrollment, and several hundred patients with acute ICH were enrolled. In this ancillary analysis, we assessed the effect of magnesium sulfate treatment upon HE in patients with acute ICH. METHODS: We retrospectively analyzed data that were prospectively collected in the FAST-MAG study. Patients received intravenous magnesium sulfate or matched placebo within 2 hours of onset. We compared HE among patients allocated to intravenous magnesium sulfate or placebo with a Mann-Whitney U. We used the same method to compare neurological deficit severity (National Institutes of Health Stroke Scale) and global disability (modified Rankin Scale) at 3 months. RESULTS: Among 268 patients with ICH meeting study entry criteria, mean 65.4±13/4 years, 33% were female, and 211 (79%) had a history of hypertension. Initial deficit severities were median (interquartile range) of 4 (3-5) on the Los Angeles Motor Scale in the field and National Institutes of Health Stroke Scale score of 16 (9.5-25.5) early after hospital arrival. Follow-up brain imaging was performed a median of 17.1 (11.3-22.7) hours after first scan. The magnesium and placebo groups did not statistically differ in hematoma volume on arrival, 10.1 (5.6-28.7) versus 12.4 (5.6-28.7) mL (P=0.6), or HE, 2.0 (0.1-7.4) versus 1.5 (-0.2 to 8) mL (P=0.5). There was no difference in functional outcomes (modified Rankin Scale score of 3-6), 59% versus 50% (P=0.5). CONCLUSIONS: Magnesium sulfate did not reduce HE or improve functional outcomes at 90 days. A benefit for patients with initial hypomagnesemia was not addressed. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT00059332.

National Institutes of Health Stroke Scale Correlates Well with Initial Intracerebral Hemorrhage Volume.

OBJECTIVES: The US Centers for Medicare and Medicaid Services (CMS) currently publicly reports hospital-quality, risk-adjusted mortality measure for ischemic stroke but not intracerebral hemorrhage (ICH). The NIHSS, which is captured in CMS administrative claims data, is a candidate metric for use in ICH risk adjustment and has been shown to predict clinical outcome with accuracy similar to the ICH Score. Correlation between early NIHSS and initial ICH volume would further support use of the NIHSS for ICH risk adjustment. MATERIALS AND METHODS: Among 372 ICH patients enrolled in a large multicenter trial (FAST-MAG), the relation between early NIHSS and early ICH volume was assessed with correlation and linear trend analysis. RESULTS: Overall, there was strong correlation between NIHSS and ICH volume, r = 0.77 (p < 0.001), and for every 10cc increase in ICH the NIHSS increased by 4.5 points. Correlation coefficients were comparable in all subgroups, but magnitude of NIHSS increase with ICH unit volume increase was greater with left than right hemispheric ICH, with presence rather than absence of IVH, with imaging done within the first hour than second hour after last known well, with men than women, and with younger than older patients. CONCLUSION: Early NIHSS neurologic deficit severity values correlate strongly with initial ICH hematoma volume. As with ischemic stroke, lesion volume increases produce greater NIHSS change in the left than right hemisphere, reflecting greater NIHSS sensitivity to left hemisphere function. These findings provide further support for the use of NIHSS in risk-adjusted mortality measures for intracerebral hemorrhage.

Tobacco Use Is Associated With Increased 90-Day Readmission Among Patients Undergoing Surgery for Degenerative Spine Disease.

STUDY DESIGN: Retrospective database study. OBJECTIVE: Tobacco use is associated with complications after surgical procedures, including poor wound healing, surgical site infections, and cardiovascular events. We used the Nationwide Readmissions Database (NRD) to determine if tobacco use is associated with increased 30- and 90-day readmission among patients undergoing surgery for degenerative spine disorders. METHODS: Patients who underwent elective spine surgery were identified in the NRD from 2010 to 2014. The study population included patients with degenerative spine disorders treated with discectomy, fusion, or decompression. Descriptive and multivariate logistic regression analyses were performed to identify patient and hospital factors associated with 30- and 90-day readmission, with significance set at P value <.001. RESULTS: Within 30 days, 4.8% of patients were readmitted at a median time of 9 days. The most common reasons for 30-day readmission were postoperative infection (12.5%), septicemia (3.5%), and postoperative pain (3.0%). Within 90 days, 7.3% were readmitted at a median time of 18 days. The most common reasons for 90-day readmission were postoperative infection (9.6%), septicemia (3.5%), and pneumonia (2.3%). After adjustment for patient and hospital characteristics, tobacco use was independently associated with readmission at 90 days (odds ratio 1.05, 95% confidence interval 1.03-1.07, P < .0001) but not 30 days (odds ratio 1.02, 95% confidence interval 1.00-1.05, P = .045). CONCLUSIONS: Tobacco use is associated with readmission within 90 days after cervical and thoracolumbar spine surgery for degenerative disease. Tobacco use is a known risk factor for adverse health events and therefore should be considered when selecting patients for spine surgery.

Air Pollution Particulate Matter Amplifies White Matter Vascular Pathology and Demyelination Caused by Hypoperfusion.

Cerebrovascular pathologies are commonly associated with dementia. Because air pollution increases arterial disease in humans and rodent models, we hypothesized that air pollution would also contribute to brain vascular dysfunction. We examined the effects of exposing mice to nanoparticulate matter (nPM; aerodynamic diameter ≤200 nm) from urban traffic and interactions with cerebral hypoperfusion. C57BL/6 mice were exposed to filtered air or nPM with and without bilateral carotid artery stenosis (BCAS) and analyzed by multiparametric MRI and histochemistry. Exposure to nPM alone did not alter regional cerebral blood flow (CBF) or blood brain barrier (BBB) integrity. However, nPM worsened the white matter hypoperfusion (decreased CBF on DSC-MRI) and exacerbated the BBB permeability (extravascular IgG deposits) resulting from BCAS. White matter MRI diffusion metrics were abnormal in mice subjected to cerebral hypoperfusion and worsened by combined nPM+BCAS. Axonal density was reduced equally in the BCAS cohorts regardless of nPM status, whereas nPM exposure caused demyelination in the white matter with or without cerebral hypoperfusion. In summary, air pollution nPM exacerbates cerebrovascular pathology and demyelination in the setting of cerebral hypoperfusion, suggesting that air pollution exposure can augment underlying cerebrovascular contributions to cognitive loss and dementia in susceptible elderly populations.

Air Pollution Particulate Matter Exposure and Chronic Cerebral Hypoperfusion and Measures of White Matter Injury in a Murine Model.

BACKGROUND: Exposure to ambient air pollution particulate matter (PM) is associated with increased risk of dementia and accelerated cognitive loss. Vascular contributions to cognitive impairment are well recognized. Chronic cerebral hypoperfusion (CCH) promotes neuroinflammation and blood-brain barrier weakening, which may augment neurotoxic effects of PM. OBJECTIVES: This study examined interactions of nanoscale particulate matter (nPM; fine particulate matter with aerodynamic diameter ≤200 nm) and CCH secondary to bilateral carotid artery stenosis (BCAS) in a murine model to produce white matter injury. Based on other air pollution interactions, we predicted synergies of nPM with BCAS. METHODS: nPM was collected using a particle sampler near a Los Angeles, California, freeway. Mice were exposed to 10 wk of reaerosolized nPM or filtered air (FA) for 150 h. CCH was induced by BCAS surgery. Mice (C57BL/6J males) were randomized to four exposure paradigms: a) FA, b) nPM, c) FA + BCAS, and d) nPM + BCAS. Behavioral outcomes, white matter injury, glial cell activation, inflammation, and oxidative stress were assessed. RESULTS: The joint nPM + BCAS group exhibited synergistic effects on white matter injury (2.3× the additive nPM and FA + BCAS scores) with greater loss of corpus callosum volume on T2 magnetic resonance imaging (MRI) (30% smaller than FA group). Histochemical analyses suggested potential microglial-specific inflammatory responses with synergistic effects on corpus callosum C5 immunofluorescent density and whole brain nitrate concentrations (2.1× and 3.9× the additive nPM and FA + BCAS effects, respectively) in the joint exposure group. Transcriptomic responses (RNA-Seq) showed greater impact of nPM + BCAS than individual additive effects, consistent with changes in proinflammatory pathways. Although nPM exposure alone did not alter working memory, the nPM + BCAS cohort demonstrated impaired working memory when compared to the FA + BCAS group. DISCUSSION: Our data suggest that nPM and CCH contribute to white matter injury in a synergistic manner in a mouse model. Adverse neurological effects may be aggravated in a susceptible population exposed to air pollution. https://doi.org/10.1289/EHP8792.

Nanoparticulate matter exposure results in white matter damage and an inflammatory microglial response in an experimental murine model.

Exposure to ambient air pollution has been associated with white matter damage and neurocognitive decline. However, the mechanisms of this injury are not well understood and remain largely uncharacterized in experimental models. Prior studies have shown that exposure to particulate matter (PM), a sub-fraction of air pollution, results in neuroinflammation, specifically the upregulation of inflammatory microglia. This study examines white matter and axonal injury, and characterizes microglial reactivity in the corpus callosum of mice exposed to 10 weeks (150 hours) of PM. Nanoscale particulate matter (nPM, aerodynamic diameter ≤200 nm) consisting primarily of traffic-related emissions was collected from an urban area in Los Angeles. Male C57BL/6J mice were exposed to either re-aerosolized nPM or filtered air for 5 hours/day, 3 days/week, for 10 weeks (150 hours; n = 18/group). Microglia were characterized by immunohistochemical double staining of ionized calcium-binding protein-1 (Iba-1) with inducible nitric oxide synthase (iNOS) to identify pro-inflammatory cells, and Iba-1 with arginase-1 (Arg) to identify anti-inflammatory/ homeostatic cells. Myelin injury was assessed by degraded myelin basic protein (dMBP). Oligodendrocyte cell counts were evaluated by oligodendrocyte transcription factor 2 (Olig2). Axonal injury was assessed by axonal neurofilament marker SMI-312. iNOS-expressing microglia were significantly increased in the corpus callosum of mice exposed to nPM when compared to those exposed to filtered air (2.2 fold increase; p<0.05). This was accompanied by an increase in dMBP (1.4 fold increase; p<0.05) immunofluorescent density, a decrease in oligodendrocyte cell counts (1.16 fold decrease; p<0.05), and a decrease in neurofilament SMI-312 (1.13 fold decrease; p<0.05) immunofluorescent density. Exposure to nPM results in increased inflammatory microglia, white matter injury, and axonal degradation in the corpus callosum of adult male mice. iNOS-expressing microglia release cytokines and reactive oxygen/ nitrogen species which may further contribute to the white matter damage observed in this model.

Urban Air Pollution Nanoparticles from Los Angeles: Recently Decreased Neurotoxicity.

BACKGROUND: Air pollution is widely associated with accelerated cognitive decline at later ages and risk of Alzheimer's disease (AD). Correspondingly, rodent models demonstrate the neurotoxicity of ambient air pollution and its components. Our studies with nano-sized particulate matter (nPM) from urban Los Angeles collected since 2009 have shown pro-amyloidogenic and pro-inflammatory responses. However, recent batches of nPM have diminished induction of the glutamate receptor GluA1 subunit, Iba1, TNFα, Aß42 peptide, and white matter damage. The same methods, materials, and mouse genotypes were used throughout. OBJECTIVE: Expand the nPM batch comparisons and evaluate archived brain samples to identify the earliest change in nPM potency. METHODS: Batches of nPM were analyzed by in vitro cell assays for NF-κB and Nrf2 induction for comparison with in vivo responses of mouse brain regions from mice exposed to these batches, analyzed by PCR and western blot. RESULTS: Five older nPM batches (2009-2017) and four recent nPM batches (2018, 2019) for NF-κB and Nrf2 induction showed declines in nPM potency after 2017 that paralleled declines of in vivo activity from independent exposures in different years. CONCLUSION: Transcription-based in vitro assays of nPM corresponded to the loss of in vivo potency for inflammatory and oxidative responses. These recent decreases of nPM neurotoxicity give a rationale for evaluating possible benefits to the risk of dementia and stroke in Los Angeles populations.

Tobacco Use Is Associated with Readmission within 90 Days after Craniotomy.

OBJECTIVE: Tobacco use increases morbidity and mortality following craniotomy. Readmission is an important hospital metric of patient outcomes and has been used to inform reimbursement. This study aims to determine if tobacco use is associated with readmission within 90 days of hospital discharge among patients undergoing elective craniotomy. METHODS: The Nationwide Readmissions Database (NRD), a population-based, nationally representative database, was queried from 2010-2014. Patients undergoing craniotomy for benign or malignant tumors, vascular pathologies, and epilepsy were identified. Readmissions within 90 days of index hospitalization were characterized by admitting diagnoses. Tobacco use was defined by ICD-9 coding for active or prior use. Descriptive and multivariable regression analyses evaluated patient and hospital factors associated with readmission. RESULTS: The study population included 77,903 patients treated with craniotomy. Of these, 17,674 (22.6%) were readmitted within 90 days. The most common reasons for readmission were post-operative infection (5.8%), septicemia (4.2%), pulmonary embolism (3.9%), and pneumonia (2.9%). Tobacco use was associated with a 7% increased likelihood of 90-day readmission (OR 1.07, 95% CI 1.03-1.11, p = 0.0008) after accounting for other patient-, disease-, and hospital-level factors in multivariate analysis. CONCLUSIONS: Tobacco use was associated with increased 90-day readmission in patients undergoing craniotomy. Recognizing tobacco use as a modifiable risk factor of readmission presents an opportunity to identify susceptible patients.

The Effect of Early Treatment with Intravenous Magnesium Sulfate on the Incidence of Cardiac Comorbidities in Hospitalized Stroke Patients.

BACKGROUND: Cardiac adverse events are common among patients presenting with acute stroke and contribute to overall morbidity and mortality. Prophylactic measures for the reduction of cardiac adverse events in hospitalized stroke patients have not been well understood. We sought to investigate the effect of early initiation of high-dose intravenous magnesium sulfate on cardiac adverse events in stroke patients. METHODS: This is a secondary analysis of the prehospital Field Administration of Stroke Therapy-Magnesium (FAST-MAG) randomized phase-3 clinical trial, conducted from 2005-2013. Consecutive patients with suspected acute stroke and a serum magnesium level within 72 hours of enrollment were selected. Twenty grams of magnesium sulfate or placebo was administered in the ambulance starting with a 15-minute loading dose intravenous infusion followed by a 24-hour maintenance infusion in the hospital. RESULTS: Among 1126 patients included in the analysis of this study, 809 (71.8%) patients had ischemic stroke, 277 (24.6%) had hemorrhagic stroke, and 39 (3.5%) with stroke mimics. The mean age was 69.5 (SD13.4) and 42% were female. 565 (50.2%) received magnesium treatment, and 561 (49.8%) received placebo. 254 (22.6%) patients achieved the target, and 872 (77.4%) did not achieve the target, regardless of their treatment group. Among 1126 patients, 159 (14.1%) had at least one CAE. Treatment with magnesium was not associated with fewer cardiac adverse events. A multivariate binary logistic regression for predictors of CAEs showed a positive association of older age and frequency of CAEs (R = 1.04, 95% CI 1.03-1.06, p < 0.0001). Measures of early and 90-day outcomes did not differ significantly between the magnesium and placebo groups among patients who had CAEs. CONCLUSION: Treatment of acute stroke patients with magnesium did not result in a reduction in the number or severity of cardiac serious adverse events.

A Prehospital Acute Stroke Trial has Only Modest Impact on Enrollment in Concurrent, Post-arrival-Recruiting Stroke Trials.

BACKGROUND: Because "time is brain," acute stroke trials are migrating to the prehospital setting. The impact upon enrollment in post-arrival trials of earlier recruitment in a prehospital trial requires delineation. METHODS: We analyzed all patients recruited into acute and prevention stroke trials during an 8-year period when an academic medical center (AMC) was participating in a prehospital treatment trial - the NIH Field Administration of Stroke Treatment - Magnesium (FAST-MAG) study. RESULTS: During the study period, in addition to FAST-MAG, the AMC participated in 33 post-arrival stroke trials: 27 for acute cerebral ischemia, one for intracerebral hemorrhage, and 5 secondary prevention trials. Throughout the study period, the AMC was recruiting for at least 3 concurrent post-arrival acute trials. Among 199 patients enrolled in acute stroke trials, 98 (49%) were in FAST-MAG and 101 (51%) in concurrent, post-arrival acute trials. Among FAST-MAG patients, 67% were not eligible for any concurrent acute, post-arrival trial. Of 134 patients eligible for post-arrival acute trials, 101 (76%) were enrolled in post-arrival trials and 32 (24%) in FAST-MAG. Leading reasons FAST-MAG patients were ineligible for post-arrival acute trials were: NIHSS too low (23.4%), intracranial hemorrhage (17.9%), IV tPA used in standard management (9.0%), NIHSS too high (7.1%), and age too high (5.2%). CONCLUSIONS: A prehospital hyperacute stroke trial with wide entry criteria reduced only modestly, by one-fourth, enrollment into concurrently active, post-arrival stroke trials. Simultaneous performance of prehospital and post-arrival acute and secondary prevention stroke trials in research networks is feasible.