Radiation-induced neuroinflammation – a potential protective role for PARP (poly ADP ribose polymerase) inhibitors?

Radiotherapy (RT) plays a fundamental role in the treatment of glioblastoma (GBM). GBM are notoriously invasive and harbour a subpopulation of cells with stem-like features which exhibit upregulation of the DNA damage response and are radioresistant. High radiation doses are therefore delivered to large brain volumes and are known to extend survival but also cause delayed toxicity with 50-90% of patients developing neurocognitive dysfunction. Emerging evidence identifies neuroinflammation as a critical mediator of the adverse effects of RT on cognitive function. In addition to its well-established role in promoting repair of radiation induced DNA damage, activation of poly(ADP-ribose) polymerase (PARP) can exacerbate neuroinflammation by promoting secretion of inflammatory mediators. Therefore, PARP represents an intriguing mechanistic link between radiation-induced activation of the DNA damage response and subsequent neuroinflammation. PARP inhibitors have emerged as promising new agents for GBM when given in combination with RT, with multiple preclinical studies demonstrating radiosensitizing effects and at least three compounds being evaluated in clinical trials. We propose that concomitant use of PARP inhibitors could reduce radiation-induced neuroinflammation and reduce the severity of radiation-induced cognitive dysfunction while at the same time improving tumour control by enhancing radiosensitivity.

Insufficient Sleep Following Pediatric Mild Traumatic Brain Injury Correlates With Neurocognitive Dysfunction

ObjectiveAnalyze the impact of sleep disturbance on neurocognitive function in children recovering from mild traumatic brain injury (mTBI).BackgroundSleep disturbance of any nature is reported in more than half of all mTBI patients. The pathophysiology of sleep disturbance following mTBI is associated with structural and functional disruptions of sleep circuitry and circadian rhythm. Specifically in the pediatric population, untreated sleep disturbance has been shown to delay mTBI recovery and compound other morbidities including neurocognitive dysfunction.Design/MethodsA retrospective chart review of 118 pediatric patients (mean age = 14.56 ± 2.03 years) recovering from mTBI was performed. Epworth Sleepiness Scale (SF-8) results were analyzed in relation to CNS Vital Signs (CNSVS) neurocognitive test outcomes. SF-8 is a subjective estimation of a patient's daytime sleepiness. CNSVS uses a multitude of domains to objectively evaluate the overall neurocognitive status of a patient. Pearson correlations were calculated using a type I error of p < 0.05 between variables.ResultsEpworth Sleepiness Scale (SF-8) results showed 28.82% of participants experienced excessive daytime sleepiness sufficient enough to recommend medical attention. Upon further analysis, there was a significant negative correlation between SF-8 and CNSVS neurocognitive test outcomes including complex attention (r = −0.37; p = 0.0004), cognitive flexibility (r = −0.24; p = 0.0151), executive function (r = −0.21; p = 0.0350), and simple attention (r = −0.36; p = 0.0003) scores. This means as SF-8 scores increased (participants defined as excessively sleepy), neurocognitive function scores in these domains decreased. There was not enough evidence to conclude a significant correlation between other CNSVS domains and SF-8 (all p > 0.05).ConclusionsOur findings support the concern of neurocognitive dysfunction among pediatric mTBI patients with sleep disturbance. Further analysis is needed to determine if mTBI is the primary source or an exacerbating factor of sleep disturbance within this population. Nonetheless, these findings suggest a need for thorough evaluation when treating sleep concerns, irrespective of a history of childhood mTBI.

NCOG-35. THE LATE INTRACRANIAL ADVERSE EVENTS OCCUR MORE FREQUENTLY IN INTRACRANIAL GERMINOMAS TREATED WITH HIGH DOSE RADIOTHERAPY

OBJECTIVE The standard treatment for intracranial germinoma has been radiotherapy covering the whole ventricle together with chemotherapy. Radiotherapy is important, but it is a cause of the late brain damages. Therefore, the recent clinical trials have been planned to evaluate the reduced radiation dose. The aim of this study was to evaluate the intracranial adverse events in the patients with intracranial germinomas treated in our hospital. PATIENTS AND METHODS 65 patients were diagnosed as intracranial germinoma. Patients with hCG &gt; 100 IU/l and/or AFP &gt; 10 ng/ml were excluded. Patients, who were diagnosed as germinoma by imaging without histology, were included. RESULTS Follow-up time was from 2 to 467 months (median 136 months). Until 2005, 37 patients were treated with radiotherapy &gt;30 Gy alone or with chemotherapy. After then, 23 patients received whole-ventricle radiotherapy 24-30 Gy with chemotherapy. 2 patients were treated with chemotherapy alone, 3 were unknown. 10-year PFS was 82.05% in radiotherapy &gt;30 Gy alone, 86.36% in radiotherapy &gt;30 Gy with chemotherapy and 100% in radiotherapy 24-30 Gy with chemotherapy. The intracranial adverse events after the initial treatment were identified, such as pituitary dysfunction: 6 (9.2%), hearing disturbance: 2 (3.1%), neurocognitive dysfunction 6 (9.2%), microbleeds 10 (15.4%), cavernous angioma 6 (9.2%), brain tumor 1 (1.5%), cerebral artery stenosis 1 (1.5%). The frequency of late adverse brain events is higher in radiotherapy &gt;30 Gy with/without chemotherapy than 24-30 Gy (total events, 25 vs. 9, P&lt; 0.03). CONCLUSION Patients with intracranial germinoma obtain long-term survival but suffer from the late intracranial adverse events. The late intracranial adverse events occur more frequently in intracranial germinomas treated with radiotherapy &gt;30 Gy than 24-30 Gy. Long-term follow-up is important to promptly identify and deal with the late brain damages.

Concussion Incidence and Recovery Among Youth Athletes With ADHD Taking Stimulant-Based Therapy

Background: Attention deficit hyperactivity disorder (ADHD) may affect concussion risk and recovery in youth athletes. Purpose: To evaluate the association between incidence of concussion and postinjury recovery of symptoms and neurocognitive dysfunction among youth athletes with ADHD and differential stimulant use. Study Design: Cohort study; Level of evidence, 3. Methods: From 2009 to 2019, the authors administered the Immediate Post-concussion Assessment and Cognitive Testing (ImPACT) to youth athletes at the beginning of each season. Throughout the season, athletes with concussions were examined and readministered the ImPACT both postinjury and again 7 days after the postinjury administration. These athletes (N = 7453) were divided into those with ADHD on stimulant-based therapy (ADHD+meds; n = 167), those with ADHD not on stimulant-based therapy (ADHD-only; n = 354), and those with no ADHD (non-ADHD; n = 6932). Recovery of neurocognitive dysfunction at postinjury and follow-up was calculated using the ImPACT symptom score, verbal memory, visual memory, visual motor skills, and reaction time (calculated as standardized deviations from baseline). Univariate results were confirmed with multivariate analysis. Results: The ADHD+meds cohort had a lower incidence of concussion (37.3 concussions per 100 patient-years) compared with the ADHD-only group (57.0 concussions per 100 patient-years) (odds ratio [OR], 0.51 [95% CI, 0.37-0.71]; P < .0001) and non-ADHD group (52.8 concussions per 100 patient-years) (OR, 0.50 [95% CI, 0.37-0.67]; P < .0001). At postinjury, ImPACT scores were elevated from baseline to a similar extent in the ADHD+meds cohort compared with the other 2 groups. By follow-up, however, deviations from baseline were lower among the ADHD+meds group compared with the non-ADHD group in verbal memory (OR, 0.46 [95% CI, 0.28-0.76]; P = .002), visual memory (OR, 0.27 [95% CI, 0.10-0.66]; P = .005), and visual motor skills (OR, 0.58 [95% CI, 0.33-0.99]; P = .048). The deviation at follow-up was also lower among the ADHD+meds group compared with the ADHD-only group in visual memory (OR, 0.56 [95% CI, 0.33-0.96]; P = .04) and visual motor skills (OR, 0.42 [95% CI, 0.22-0.81]; P = .01). Conclusion: Stimulant use among youth athletes with ADHD was independently associated with reduced incidence for concussion and lower deviation from baseline in verbal memory, visual memory, and visual motor skills at 7 days postconcussion, suggesting lower neurocognitive impairment at follow-up in this group versus their peers.

Cerebral Oximetry Measurements Results Depending on a Preclinical Skull Phantom Model

It is more common to perform non-invasive examination during general anaesthesia to ensure effective perioperative patient care. To achieve these results, researchers and clinicians are seeking out different technologies and developing new equipment. One such apparatus is a cerebral oximeter, which is used during cardiac surgery with cardiopulmonary bypass for neuroprotection management for reducing risk of postoperative neurological injury (cerebral stroke, neurocognitive dysfunction, and cerebral haemorrhage). A cerebral oximeter performs non-invasive transcutaneous measurements using near infrared radiation to assess the oxygenation of tissues. The objective of the study was to determine if the angle and thickness of a patient’s skull affects measurements. Intralipid water solution, gelatine, and ink were used to make six phantoms with skull thickness ranging from 6 to 11 mm. All phantoms were bent froma0to20 degrees angle. The cerebral oximeter SOMETICS INVOS 5100C was used to perform regional oximetry measurements. For skull thickness of 11 mm, the rSO2 was 45.8% (SD 0.96); for skull thickness of 10 mm, the rSO2 was 45.25% (SD 2.22); for skull thickness of 9 mm, the rSO2 was 32% (SD 1.63); for skull thickness of 8 mm, the rSO2 was 17% (SD 1.83); for skull thickness of 7 mm, the rSO2 was 15% (SD 0); for skull thickness of 6 mm, the rSO2 was 15% (SD 0). No significant changes were observed regarding the angle of the skull phantom. The thickness of the bone layer of the skull phantom affected the regional oximetry results, whereas the angle of the skull did not affect it.

Donor bone marrow-derived macrophage MHC II drives neuroinflammation and altered behaviour during chronic GVHD in mice

Graft-versus-host disease (GVHD) remains the leading cause of non-relapse mortality after allogeneic stem cell transplantation for haematological malignancies. Manifestations of GVHD in the central nervous system (CNS) present as neurocognitive dysfunction in up to 60% of patients, however, the mechanisms driving chronic GVHD in the CNS are yet to be elucidated. Our studies of murine chronic GVHD revealed behavioural deficits associated with broad neuroinflammation and persistent Ifng upregulation. By flow cytometry, we observed a proportional shift in the donor-derived T-cell population in the chronic GVHD brain from early CD8 dominance to later CD4 sequestration. RNA sequencing of the hippocampus identified perturbations to structural and functional synapse-related gene expression, together with the upregulation of genes associated with IFN-γ responses and antigen presentation. Neuroinflammation in the cortex of mice and humans during acute GVHD was recently shown to be mediated by resident microglia-derived TNF. In contrast, infiltration of pro-inflammatory MHC class II+ donor bone marrow-derived macrophages (BMDM) was identified as a distinguishing feature of chronic CNS GVHD. Donor BMDM, which comprised up to 50% of the CNS myeloid population, exhibited a transcriptional signature distinct from resident microglia. Recipients of MHC class II knockout bone marrow grafts exhibited attenuated neuroinflammation and behaviour comparable to controls, suggestive of a critical role of donor BMDM MHC class II expression in CNS chronic GVHD. Our identification of disease mediators distinct from those in the acute phase indicates the necessity to pursue alternative therapeutic targets for late-stage neurological manifestations.