Antioxidant Capacity and Superoxide Dismutase Activity in Adrenoleukodystrophy

Importance  X-linked adrenoleukodystrophy (ALD) may switch phenotype to the fatal cerebral form (ie, cerebral ALD [cALD]), the cause of which is unknown. Determining differences in antioxidant capacity and superoxide dismutase (SOD) levels between phenotypes may allow for the generation of a clinical biomarker for predicting the onset of cALD, as well as initiating a more timely lifesaving therapy.

Objective  To identify variations in the levels of antioxidant capacity and SOD activity between ALD phenotypes in patients with cALD or adrenomyeloneuropathy (AMN), heterozygote female carriers, and healthy controls and, in addition, correlate antioxidant levels with clinical outcome scores to determine a possible predictive value.

Design, Setting, and Participants  Samples of monocytes and blood plasma were prospectively collected from healthy controls, heterozygote female carriers, and patients with AMN or cALD. We are counting each patient as 1 sample in our study. Because adrenoleukodystrophy is an X-linked disease, the affected group populations of cALD and AMN are all male. The heterozygote carriers are all female. The samples were assayed for total antioxidant capacity and SOD activity. The data were collected in an academic hospital setting. Eligibility criteria included patients who received a diagnosis of ALD and heterozygote female carriers, both of which groups were compared with age-matched controls. The prospective samples (n = 30) were collected between January 2015 to January 2016, and existing samples were collected from tissue storage banks at the Kennedy Krieger Institute (n = 30). The analyses were performed during the first 3 months of 2016.

Main Outcome and Measures  Commercially available total antioxidant capacity and SOD assays were performed on samples of monocytes and blood plasma and correlated with magnetic resonance imaging severity score.

Results  A reduction in antioxidant capacity was shown between the healthy controls (0.225 mmol trolox equivalent) and heterozygote carriers (0.181 mmol trolox equivalent), and significant reductions were seen between healthy controls and patients with AMN (0.102 mmol trolox equivalent; P < .01), as well as healthy controls and patients with cALD (0.042 mmol trolox equivalent; P < .01). Superoxide dismutase activity in human blood plasma mirrored these reductions between prospectively collected samples from healthy controls (2.66 units/mg protein) and samples from heterozygote female carriers (1.91 units/mg protein), patients with AMN (1.39 units/mg protein; P = .01), and patients with cALD (0.8 units/mg protein; P < .01). Further analysis of SOD activity in biobank samples showed significant reductions between patients with AMN (0.89 units/mg protein) and patients with cALD (0.18 units/mg protein) (P = .03). Plasma SOD levels from patients with cALD demonstrated an inverse correlation to brain magnetic resonance imaging severity score (R² = 0.75, P < .002). Longitudinal plasma SOD samples from the same patients (n = 4) showed decreased activity prior to and at the time of cerebral diagnosis over a period of 13 to 42 months (mean period, 24 months).

Conclusions and Relevance  Plasma SOD may serve as a potential biomarker for cerebral disease in ALD following future prospective studies.

JAMA Neurology 2017

Safety and efficacy of thrombectomy in acute ischaemic stroke (REVASCAT): 1-year follow-up of a randomised open-label trial

Summary

Background

The REVASCAT trial and other studies have shown that the neurovascular thrombectomy improves outcomes at 90 days post stroke. However, whether the observed benefit is sustained in the long term remains unknown. We report the results of the prespecified 12-month analysis of the REVASCAT trial.

Methods

Patients with acute ischaemic stroke who could be treated within 8 h of symptom onset were randomly assigned to medical therapy (including intravenous alteplase when eligible) and neurovascular thrombectomy with Solitaire FR or medical therapy alone. The main secondary outcome measure at 1 year follow-up was disability, measured using the modified Rankin Scale (mRS), ranging from 0 (no symptoms) to 6 (death) with categories 5 (severe disability) and 6 (death) collapsed into one category (severe disability or death), analysed as the distribution of the mRS. Additional prespecified secondary outcome measures included health-related quality of life measured with the EuroQol five dimensions questionnaire (EQ-5D) utility index (ranging from −0·3 to 1, higher values indicate better quality of life), the rate of functional independence (mRS 0–2), and cognitive function measured with the Trail Making Test (reported elsewhere). Treatment allocation was open label but endpoints at 12 months were assessed by masked investigators. The trial was registered at ClinicalTrials.gov, number NCT01692379.

Findings

From Nov 24, 2012, to Dec 12, 2014, 206 patients were randomly assigned to medical therapy plus endovascular treatment (n=103) or medical treatment alone (n=103), at four centres in Catalonia, Spain. At 12 months post randomisation, based on 205 of 206 outcomes available at 12 months, thrombectomy reduced disability over the range of the mRS (common adjusted odds ratio [aOR] 1·80, 95% CI 1·09–2·99), and improved functional independence (mRS=0–2; 45 [44%] of 103 patients vs 31 [30%] of 103 patients; aOR 1·86, 95% CI 1·01–3·44). Health-related quality of life was superior in the thrombectomy group (mean EQ-5D utility index score, 0·46 [SD 0·38] in the thrombectomy group vs 0·33 [0·33] in the control group, difference 0·12 [95% CI 0·03–0·22]; p=0·01). 1-year mortality was 23% (24 of 103 patients) in the thrombectomy group versus 24% (25 of 103 patients) in the control group.

Interpretation

At 12 months follow-up, neurovascular thrombectomy reduced post-stroke disability and improved health-related quality of life, indicating sustained benefit. These findings have important clinical and public health implications for evaluating the cost-effectiveness of the intervention in the long term.

Lancet Neurology 2017

Safety and efficacy of multipotent adult progenitor cells in acute ischaemic stroke (MASTERS): a randomised, double-blind, placebo-controlled, phase 2 trial

Summary

Background

Multipotent adult progenitor cells are a bone marrow-derived, allogeneic, cell therapy product that modulates the immune system, and represents a promising therapy for acute stroke. We aimed to identify the highest, well-tolerated, and safest single dose of multipotent adult progenitor cells, and if they were efficacious as a treatment for stroke recovery.

Methods

We did a phase 2, randomised, double-blind, placebo-controlled, dose-escalation trial of intravenous multipotent adult progenitor cells in 33 centres in the UK and the USA. We used a computer-generated randomisation sequence and interactive voice and web response system to assign patients aged 18–83 years with moderately severe acute ischaemic stroke and a National Institutes of Health Stroke Scale (NIHSS) score of 8–20 to treatment with intravenous multipotent adult progenitor cells (400 million or 1200 million cells) or placebo between 24 h and 48 h after symptom onset. Patients were ineligible if there was a change in NIHSS of four or more points during at least a 6 h period between screening and randomisation, had brainstem or lacunar infarct, a substantial comorbid disease, an inability to undergo an MRI scan, or had a history of splenectomy. In group 1, patients were enrolled and randomly assigned in a 3:1 ratio to receive 400 million cells or placebo and assessed for safety through 7 days. In group 2, patients were randomly assigned in a 3:1 ratio to receive 1200 million cells or placebo and assessed for safety through the first 7 days. In group 3, patients were enrolled, randomly assigned, and stratified by baseline NIHSS score to receive 1200 million cells or placebo in a 1:1 ratio within 24–48 h. Patients, investigators, and clinicians were masked to treatment assignment. The primary safety outcome was dose-limiting toxicity effects. The primary efficacy endpoint was global stroke recovery, which combines dichotomised results from the modified Rankin scale, change in NIHSS score from baseline, and Barthel index at day 90. Analysis was by intention to treat (ITT) including all patients in groups 2 and 3 who received the investigational agent or placebo. This study is registered with ClinicalTrials.gov, number NCT01436487.

Findings

The study was done between Oct 24, 2011, and Dec 7, 2015. After safety assessments in eight patients in group 1, 129 patients were randomly assigned (67 to receive multipotent adult progenitor cells and 62 to receive placebo) in groups 2 and 3 (1200 million cells). The ITT populations consisted of 65 patients who received multipotent adult progenitor cells and 61 patients who received placebo. There were no dose-limiting toxicity events in either group. There were no infusional or allergic reactions and no difference in treatment-emergent adverse events between the groups (64 [99%] of 65 patients in the multipotent adult progenitor cell group vs 59 [97%] of 61 in the placebo group). There was no difference between the multipotent adult progenitor cell group and placebo groups in global stroke recovery at day 90 (odds ratio 1·08 [95% CI 0·55–2·09], p=0·83).

Interpretation

Administration of multipotent adult progenitor cells was safe and well tolerated in patients with acute ischaemic stroke. Although no significant improvement was observed at 90 days in neurological outcomes with multipotent adult progenitor cells treatment, further clinical trials evaluating the efficacy of the intervention in an earlier time window after stroke (<36 h) are planned

Lancet Neurology 2017

Limited role for extended maintenance temozolomide for newly diagnosed glioblastoma

ABSTRACT

Objective: To explore an association with survival of modifying the current standard of care for patients with newly diagnosed glioblastoma of surgery followed by radiotherapy plus concurrent and 6 cycles of maintenance temozolomide chemotherapy (TMZ/RT → TMZ) by extending TMZ beyond 6 cycles.

Methods: The German Glioma Network cohort was screened for patients with newly diagnosed glioblastoma who received TMZ/RT → TMZ and completed ≥6 cycles of maintenance chemotherapy without progression. Associations of clinical patient characteristics, molecular markers, and residual tumor determined by magnetic resonance imaging after 6 cycles of TMZ with progression-free survival (PFS) and overall survival (OS) were analyzed with the log-rank test. Multivariate analyses using the Cox proportional hazards model were performed to assess associations of prolonged TMZ use with outcome.

Results: Sixty-one of 142 identified patients received at least 7 maintenance TMZ cycles (median 11, range 7–20). Patients with extended maintenance TMZ treatment had better PFS (20.5 months, 95% confidence interval [CI] 17.7–23.3, vs 17.2 months, 95% CI 10.2–24.2, p = 0.035) but not OS (32.6 months, 95% CI 28.9–36.4, vs 33.2 months, 95% CI 25.3–41.0, p = 0.126). However, there was no significant association of prolonged TMZ chemotherapy with PFS (hazard ratio [HR] = 0.8, 95% CI 0.4–1.6, p = 0.559) or OS (HR = 1.6, 95% CI 0.8–3.3, p = 0.218) adjusted for age, extent of resection, Karnofsky performance score, presence of residual tumor, O⁶-methylguanine DNA methyltransferase (MGMT) promoter methylation status, or isocitrate dehydrogenase (IDH) mutation status.

Conclusion: These data may not support the practice of prolonging maintenance TMZ chemotherapy beyond 6 cycles.

Classification of evidence: This study provides Class III evidence that in patients with newly diagnosed glioblastoma, prolonged TMZ chemotherapy does not significantly increase PFS or OS.

Neurology 2017

Diverging white matter trajectories in children after traumatic brain injury The RAPBI study

ABSTRACT

Objective: To examine longitudinal trajectories of white matter organization in pediatric moderate/severe traumatic brain injury (msTBI) over a 12-month period.

Methods: We studied 21 children (16 M/5 F) with msTBI, assessed 2–5 months postinjury and again 13–19 months postinjury, as well as 20 well-matched healthy control children. We assessed corpus callosum function through interhemispheric transfer time (IHTT), measured using event-related potentials, and related this to diffusion-weighted MRI measures of white matter (WM) microstructure. At the first time point, half of the patients with TBI had significantly slower IHTT (TBI-slow-IHTT, n = 11) and half were in the normal range (TBI-normal-IHTT, n = 10).

Results: The TBI-normal-IHTT group did not differ significantly from healthy controls, either in WM organization in the chronic phase or in the longitudinal trajectory of WM organization between the 2 evaluations. In contrast, the WM organization of the TBI-slow-IHTT group was significantly lower than in healthy controls across a large portion of the WM. Longitudinal analyses showed that the TBI-slow-IHTT group experienced a progressive decline between the 2 evaluations in WM organization throughout the brain.

Conclusions: We present preliminary evidence suggesting a potential biomarker that identifies a subset of patients with impaired callosal organization in the first months postinjury who subsequently experience widespread continuing and progressive degeneration in the first year postinjury.

• Neurology 2017

Systematic model of peripheral inflammation after subarachnoid hemorrhage

ABSTRACT

Objective: To investigate inflammatory processes after aneurysmal subarachnoid hemorrhage (aSAH) with network models.

Methods: This is a retrospective observational study of serum samples from 45 participants with aSAH analyzed at multiple predetermined time points: <24 hours, 24 to 48 hours, 3 to 5 days, and 6 to 8 days after aSAH. Concentrations of cytokines were measured with a 41-plex human immunoassay kit, and the Pearson correlation coefficients between all possible cytokine pairs were computed. Systematic network models were constructed on the basis of correlations between cytokine pairs for all participants and across injury severity. Trends of individual cytokines and correlations between them were examined simultaneously.

Results: Network models revealed that systematic inflammatory activity peaks at 24 to 48 hours after the bleed. Individual cytokine levels changed significantly over time, exhibiting increasing, decreasing, and peaking trends. Platelet-derived growth factor (PDGF)-AA, PDGF-AB/BB, soluble CD40 ligand, and tumor necrosis factor-α (TNF-α) increased over time. Colony-stimulating factor (CSF) 3, interleukin (IL)-13, and FMS-like tyrosine kinase 3 ligand decreased over time. IL-6, IL-5, and IL-15 peaked and decreased. Some cytokines with insignificant trends show high correlations with other cytokines and vice versa. Many correlated cytokine clusters, including a platelet-derived factor cluster and an endothelial growth factor cluster, were observed at all times. Participants with higher clinical severity at admission had elevated levels of several proinflammatory and anti-inflammatory cytokines, including IL-6, CCL2, CCL11, CSF3, IL-8, IL-10, CX3CL1, and TNF-α, compared to those with lower clinical severity.

Conclusions: Combining reductionist and systematic techniques may lead to a better understanding of the underlying complexities of the inflammatory reaction after aSAH.

Neurology 2017

Epidemiology and prognosis of mild traumatic brain injury in returning soldiers A cohort study

ABSTRACT

Objective: Mild traumatic brain injury (mTBI; concussion) is common in returning service members yet limited definitive evidence exists on its prognosis.

Methods: Almost 25,000 non–medically evacuated soldiers returning from Afghanistan or Iraq to 2 military bases between 2009 and 2014 were screened for mTBI. We invited a random sample to participate in the present study, oversampling those screening positive, resulting in 557 mTBI cases and 1,010 controls, of whom 366 cases and 599 controls completed 3-month follow-up evaluations. The criterion measure of screened mTBI was the Ohio State University Traumatic Brain Injury Identification Method. Postconcussive symptoms (PCS) were measured at follow-up with the Neurobehavioral Symptom Inventory. Symptoms reported at a severe or very severe level were considered clinically relevant.

Results: About half (47%) of soldiers who had sustained an mTBI during this latest deployment reported PCS at 3-month follow-up vs 25% of controls: adjusted odds ratio 2.4 (1.8–3.2). The most commonly reported symptoms (cases vs controls) were sleep problems (30% vs 14%), forgetfulness (21% vs 9%), irritability (17% vs 8%), and headaches (15% vs 5%). mTBI cases were about twice as likely as controls to report receiving rehabilitative services and fair or poor health. Other predictors of PCS included posttraumatic stress, combat exposure, and noncephalic pain. A majority of both cases and controls reported traumatic brain injuries predating this latest deployment.

Conclusions: In this nonclinical population of recently deployed soldiers, a substantial proportion of those who had sustained an mTBI were symptomatic 3 months postdeployment. Future studies need to include longer follow-up to measure symptom resolution.

Neurology 2017