Neurocognitive Outcomes Research Articles

Systemic Biological Mechanisms of Neurocognitive Dysfunction in Long-Term Survivors of Childhood Hodgkin Lymphoma.

Hodgkin lymphoma (HL) survivors experience neurocognitive impairment despite receiving no central nervous system-directed therapy, though little is known about the underlying mechanisms. HL survivors (n = 197) and age-, sex- and race/ethnicity frequency-matched community controls (n = 199) underwent standardized neurocognitive testing, and serum collection. Luminex multiplex or ELISA assays measured markers of inflammation and oxidative stress. Linear regression models compared biomarker concentrations between survivors and controls and with neurocognitive outcomes, adjusting for age, sex, race, body mass index, anti-inflammatory medication, and recent infections. HL survivors [mean (SD) current age 36 (8) years, 22 (8) years after diagnosis] demonstrated higher concentrations of interleukin-6 (IL6), high-sensitivity c-reactive protein (hs-CRP), oxidized low-density lipoprotein, and glutathione peroxidase (GPx), compared with controls (P's < 0.001). Among survivors, higher concentrations of IL6 were associated with worse visuomotor processing speed (P = 0.046). hs-CRP ≥3 mg/L was associated with worse attention, processing speed, memory, and executive function (P's < 0.05). Higher concentrations of malondialdehyde were associated with worse focused attention and visual processing speed (P's < 0.05). Homocysteine was associated with worse short-term recall (P = 0.008). None of these associations were statistically significant among controls. Among survivors, hs-CRP partially mediated associations between cardiovascular or endocrine conditions and visual processing speed, whereas IL6 partially mediated associations between pulmonary conditions and visuomotor processing speed. Neurocognitive function in long-term survivors of HL appears to be associated with inflammation and oxidative stress, both representing potential targets for future intervention trials.

Hypofractionated Stereotactic Radiosurgery in the Management of Brain Metastases.

Stereotactic radiosurgery (SRS) is an important weapon in the management of brain metastases. Single-fraction SRS is associated with local control rates ranging from approximately 70% to 100%, which are largely dependent on lesion and postoperative cavity size. The rates of local control and improved neurocognitive outcomes compared with conventional whole-brain radiation therapy have led to increased adoption of SRS in these settings. However, when treating larger targets and/or targets located in eloquent locations, the risk of normal tissue toxicity and adverse radiation effects within healthy brain tissue becomes significantly higher. Thus, hypofractionated SRS has become a widely adopted approach, which allows for the delivery of ablative doses of radiation while also minimizing the risk of toxicity. This approach has been studied in multiple retrospective reports in both the postoperative and intact settings. While there are no reported randomized data to date, there are trials underway evaluating this paradigm. In this article, we review the role of hypofractionated SRS in the management of brain metastases and emerging data that will serve to validate this treatment approach. Pertinent articles and references were obtained from a comprehensive search of PubMed/MEDLINE and clinicaltrials.gov .

Severe Sepsis During Treatment for Childhood Leukemia and Sequelae Among Adult Survivors

Children undergoing treatment for leukemia are at increased risk of severe sepsis, a dysregulated immune response to infection leading to acute organ dysfunction. As cancer survivors, they face a high burden of long-term adverse effects. The association between sepsis during anticancer therapy and long-term organ dysfunction in adult survivors of childhood cancer has not been examined. To determine whether severe sepsis during therapy for leukemia in childhood is associated with subsequent chronic health conditions in adult survivors. This cohort study included 644 adult survivors of childhood leukemia who were diagnosed between January 1, 1985, and July 19, 2010, and participated in the St Jude Lifetime Cohort Study. Participants were excluded if they received hematopoietic cell transplant or had relapsed leukemia. Data collection ended June 30, 2017. Data were analyzed from July 1, 2020, to January 5, 2024. Severe sepsis episodes, defined according to consensus criteria as septic shock, acute respiratory distress syndrome, or multiorgan dysfunction associated with infection occurring during anticancer therapy, were abstracted by medical record review for all participants. Common Terminology Criteria for Adverse Events-defined chronic health condition outcomes were independently abstracted. Associations between sepsis and cumulative incidence of chronic health conditions (eg, cardiovascular, pulmonary, kidney, neurological, and neurocognitive outcomes) were compared by adjusted hazard ratios from Cox proportional hazards logistic regression. Inverse propensity score weighting was used to adjust for potential confounders, including age, year of diagnosis, and leukemia type. The study sample consisted of 644 adult survivors of pediatric leukemia (329 women [51.1%] and 315 men [48.9%]; including 56 with a history of acute myeloid leukemia and 585 with a history of acute lymphoblastic leukemia) who were most recently evaluated at a median age of 24.7 (IQR, 21.2-28.3) years at a median time after leukemia diagnosis of 17.3 (IQR, 13.7-21.9) years. Severe sepsis during treatment of acute childhood leukemia occurred in 46 participants (7.1%). Participants who experienced severe sepsis during treatment were more likely to develop moderate to severe neurocognitive impairment (29 of 46 [63.0%] vs 310 of 598 [51.8%]; adjusted hazard ratio, 1.86 [95% CI, 1.61-2.16]; P < .001) significantly affecting attention, executive function, memory and visuospatial domains. Sepsis was not associated with long-term risk of cardiovascular, pulmonary, kidney, or neurological chronic health conditions. In this cohort study of long-term outcomes in survivors of pediatric leukemia, severe sepsis during anticancer therapy for leukemia was associated with a selectively increased risk for development of serious neurocognitive sequelae. Efforts to reduce the effects of anticancer therapy on long-term function and quality of life in survivors might include prevention of severe sepsis during therapy and early detection or amelioration of neurocognitive deficits in survivors of sepsis.

A randomised, placebo-controlled, double blind, crossover trial on the effect of a 20:1 cannabidiol: Δ9-tetrahydrocannabinol medical cannabis product on neurocognition, attention, and mood

As cannabinoid-based medications gain popularity in the treatment of refractory medical conditions, it is crucial to examine the neurocognitive effects of commonly prescribed products to ensure associated safety profiles. The present study aims to investigate the acute effects of a standard 1 mL sublingual dose of CannEpil®, a medicinal cannabis oil containing 100 mg cannabidiol (CBD) and 5 mg Δ9-tetrahydrocannabinol (THC) on neurocognition, attention, and mood. A randomised, double-blind, placebo-controlled, within-subjects design assessed 31 healthy participants (16 female, 15 male), aged between 21 and 58 years, over a two-week experimental protocol. Neurocognitive performance outcomes were assessed using the Cambridge Neuropsychological Test Automated Battery, with the Profile of Mood States questionnaire, and the Bond-Lader Visual Analogue Scale used to assess subjective state and mood. CannEpil increased Total Errors in Spatial Span and Correct Latency (median) in Pattern Recognition Memory, while also increasing Efficiency Score (lower score indicates greater efficiency) relative to placebo (all p < .05). Subjective Contentedness (p < .01) and Amicability (p < .05) were also increased at around 2.5 h post dosing, relative to placebo. Drowsiness or sedative effect was reported by 23 % of participants between three to six hours post CannEpil administration. Plasma concentrations of CBD, THC, and their metabolites were not significantly correlated with any observed alterations in neurocognition, subjective state, or adverse event occurrence. An acute dose of CannEpil impairs select aspects of visuospatial working memory and delayed pattern recognition, while largely preserving mood states among healthy individuals. Intermittent reports of drowsiness and sedation underscore the inter-individual variability of medicinal cannabis effects on subjective state. (ANZCTR; ACTRN12619000932167; https://www.anzctr.org.au)

Neurocognitive outcome and associated factors in long-term, adult survivors of childhood acute lymphoblastic leukemia, treated without cranial radiation therapy.

There is limited research on neurocognitive outcome and associated risk factors in long-term, adult survivors of childhood acute lymphoblastic leukemia (ALL), without treatment of cranial radiation therapy. Moreover, the impact of fatigue severity and pain interference on neurocognition has received little attention. In this cross-sectional study, we examined neurocognitive outcome and associated factors in this population. Intellectual abilities, verbal learning/memory, processing speed, attention, and executive functions were compared to normative means/medians with one sample t tests or Wilcoxon signed-rank tests. Associations with risk factors, fatigue severity, and pain interference were analyzed with linear regressions. Long-term, adult survivors of childhood ALL (N = 53, 51% females, mean age = 24.4 years, SD = 4.4, mean = 14.7 years post-diagnosis, SD = 3.4) demonstrated above average intellectual abilities, but performed below average in attention, inhibition, processing speed, and shifting (p < 0.001). Executive functioning complaints were significantly higher than normative means, and positively associated with fatigue (p < 0.001). There was no interaction between sex and fatigue and no neurocognitive impairments were associated with pain interference, risk group, age at diagnosis, or sex. Long-term, adult survivors of ALL treated without cranial radiation therapy, demonstrate domain-specific performance-based neurocognitive impairments. However, continued research on the neurocognitive outcome in this population as they age will be important in the coming years. Executive functioning complaints were frequently in the clinical range, and often accompanied by fatigue. This suggests a need for cognitive rehabilitation programs.

Electroencephalographic guided propofol-remifentanil TCI anesthesia with and without dexmedetomidine in a geriatric population: electroencephalographic signatures and clinical evaluation.

Elderly and multimorbid patients are at high risk for developing unfavorable postoperative neurocognitive outcomes; however, well-adjusted and EEG-guided anesthesia may help titrate anesthesia and improve postoperative outcomes. Over the last decade, dexmedetomidine has been increasingly used as an adjunct in the perioperative setting. Its synergistic effect with propofol decreases the dose of propofol needed to induce and maintain general anesthesia. In this pilot study, we evaluate two highly standardized anesthetic regimens for their potential to prevent burst suppression and postoperative neurocognitive dysfunction in a high-risk population. Prospective, randomized clinical trial with non-blinded intervention. Operating room and post anesthesia care unit at Hospital Base San José, Osorno/Universidad Austral, Valdivia, Chile. 23 patients with scheduled non-neurologic, non-cardiac surgeries with age > 69years and a planned intervention time > 60min. Patients were randomly assigned to receive either a propofol-remifentanil based anesthesia or an anesthetic regimen with dexmedetomidine-propofol-remifentanil. All patients underwent a slow titrated induction, followed by a target controlled infusion (TCI) of propofol and remifentanil (n = 10) or propofol, remifentanil and continuous dexmedetomidine infusion (n = 13). We compared the perioperative EEG signatures, drug-induced changes, and neurocognitive outcomes between two anesthetic regimens in geriatric patients. We conducted a pre- and postoperative Montreal Cognitive Assessment (MoCa) test and measured the level of alertness postoperatively using a sedation agitation scale to assess neurocognitive status. During slow induction, maintenance, and emergence, burst suppression was not observed in either group; however, EEG signatures differed significantly between the two groups. In general, EEG activity in the propofol group was dominated by faster rhythms than in the dexmedetomidine group. Time to responsiveness was not significantly different between the two groups (p = 0.352). Finally, no significant differences were found in postoperative cognitive outcomes evaluated by the MoCa test nor sedation agitation scale up to one hour after extubation. This pilot study demonstrates that the two proposed anesthetic regimens can be safely used to slowly induce anesthesia and avoid EEG burst suppression patterns. Despite the patients being elderly and at high risk, we did not observe postoperative neurocognitive deficits. The reduced alpha power in the dexmedetomidine-treated group was not associated with adverse neurocognitive outcomes.

Reduced white matter maturation in the central auditory system of children living with HIV.

School-aged children experience crucial developmental changes in white matter (WM) in adolescence. The human immunodeficiency virus (HIV) affects neurodevelopment. Children living with perinatally acquired HIV (CPHIVs) demonstrate hearing and neurocognitive impairments when compared to their uninfected peers (CHUUs), but investigations into the central auditory system (CAS) WM integrity are lacking. The integration of the CAS and other brain areas is facilitated by WM fibers whose integrity may be affected in the presence of HIV, contributing to neurocognitive impairments. We used diffusion tensor imaging (DTI) tractography to map the microstructural integrity of WM between CAS regions, including the lateral lemniscus and acoustic radiation, as well as between CAS regions and non-auditory regions of 11-year-old CPHIVs. We further employed a DTI-based graph theoretical framework to investigate the nodal strength and efficiency of the CAS and other brain regions in the structural brain network of the same population. Finally, we investigated associations between WM microstructural integrity outcomes and neurocognitive outcomes related to auditory and language processing. We hypothesized that compared to the CHUU group, the CPHIV group would have lower microstructural in the CAS and related regions. Our analyses showed higher mean diffusivity (MD), a marker of axonal maturation, in the lateral lemniscus and acoustic radiations, as well as WM between the CAS and non-auditory regions predominantly in frontotemporal areas. Most affected WM connections also showed higher axial and radial diffusivity (AD and RD, respectively). There were no differences in the nodal properties of the CAS regions between groups. The MD of frontotemporal and subcortical WM-connected CAS regions, including the inferior longitudinal fasciculus, inferior fronto-occipital fasciculus, and internal capsule showed negative associations with sequential processing in the CPHIV group but not in the CHUU group. The current results point to reduced axonal maturation in WM, marked by higher MD, AD, and RD, within and from the CAS. Furthermore, alterations in WM integrity were associated with sequential processing, a neurocognitive marker of auditory working memory. Our results provide insights into the microstructural integrity of the CAS and related WM in the presence of HIV and link these alterations to auditory working memory.

Impact of trametinib on the neuropsychological profile of NF1 patients.

The use of trametinib in the treatment of pediatric low-grade gliomas (PLGG) and plexiform neurofibroma (PN) is being investigated in an ongoing multicenter phase II trial (NCT03363217). Preliminary data shows potential benefits with significant response in the majority of PLGG and PN and an overall good tolerance. Moreover, possible benefits of MEK inhibitor therapy on cognitive functioning in neurofibromatosis type 1 (NF1) were recently shown which supports the need for further evaluation. Thirty-six patients with NF1 (age range 3-19 years) enrolled in the phase II study of trametinib underwent a neurocognitive assessment at inclusion and at completion of the 72-week treatment. Age-appropriate Wechsler Intelligence Scales and the Trail Making Test (for children over 8 years old) were administered at each assessment. Paired t-tests and Reliable Change Index (RCI) analyses were performed to investigate change in neurocognitive outcomes. Regression analyses were used to investigate the contribution of age and baseline score in the prediction of change. Stable performance on neurocognitive tests was revealed at a group-level using paired t-tests. Clinically significant improvements were however found on specific indexes of the Wechsler intelligence scales and Trail Making Test, using RCI analyses. No significant impact of age on cognitive change was evidenced. However, lower initial cognitive performance was associated with increased odds of presenting clinically significant improvements on neurocognitive outcomes. These preliminary results show a potential positive effect of trametinib on cognition in patients with NF1. We observed significant improvements in processing speed, visuo-motor and verbal abilities. This study demonstrates the importance of including neuropsychological evaluations into clinical trial when using MEK inhibitors for patients with NF1.

A Systematic Review of the Neurocognitive Effects of Psychedelics in Healthy Populations: Implications for Depressive Disorders and Post-Traumatic Stress Disorder.

This study aims to provide an overview of pharmacological trials that examine the neurocognitive effects of psychedelics among healthy individuals and patients with post-traumatic stress disorder (PTSD) or major depressive disorder (MDD). The Preferred Reporting Items for Systematic Reviews (PRISMA) was used as a guide to structure and report the findings for this review. A literature search included the MEDLINE database up until December 2022. We included randomized or open-label human studies of MDMA, psilocybin, mescaline, LSD, DMT, or cannabis reporting non-emotionally charged neurocognitive outcomes ("cold cognition") measured through validated neuropsychological tests. A total of 43 full-text papers on MDMA (15), cannabis (12), LSD (6), psilocybin (9), DMT/ayahuasca (1), and mescaline (0) were included, mostly on healthy subjects. A single article on MDMA's effects on cognition in subjects with PTSD was included; there were no studies on psychedelics and neurocognition in MDD. Most of the studies on healthy subjects reported detrimental or neutral effects on cognition during the peak effect of psychedelics with a few exceptions (e.g., MDMA improved psychomotor function). Performance on the type of neurocognitive dimension (e.g., attention, memory, executive function, psychomotor) varies by type of psychedelic, dosage, and cognitive testing. Small samples and a lack of uniformed methods across studies preclude unequivocal conclusions on whether psychedelics enhance, decrease, or have no significant effect on cognitive performance. It is foreseen that psychedelics will soon become an available treatment for various psychiatric disorders. The acute and long-term effects on cognition caused by psychedelics should be assessed in future studies.

Hypogonadism and neurocognitive outcomes among childhood cancer survivors.

Childhood cancer survivors are at risk for hypogonadism. The impact of hypogonadism on neurocognitive impairment and emotional distress in the non-cancer population has been shown; however, the relationship among the childhood cancer survivor population is unknown. We aimed to evaluate the contribution of hypogonadism to neurocognitive impairment and emotional distress among survivors. Cross-sectional study using retrospective cohort. In total, 3628 survivors who completed standard neurocognitive tests (six domains: processing speed, memory, executive function, attention, academics, and global cognition) and self-reported emotional distress were included in our study. Participants were stratified by sex and gonadal status. Outcomes were compared between hypogonadal and eugonadal groups by multivariable analysis, adjusting for established predictors, and mediation analyses to determine the direct/indirect effects of hypogonadism on outcomes. The hypogonadal group exhibited a higher prevalence of neurocognitive impairment across domains, but no difference in emotional distress. Hypogonadal females exhibited higher relative risk (1.7, 95% CI, 1.2-2.5) for impaired visual processing speed, compared to eugonadal females after adjusting for cancer-related variables. In mediation models, hypogonadism had a significant direct (P < .01) and indirect (from P < .01) impact on impairment in visual processing speed among females. Males demonstrated direct (P = .03) and indirect (P = .04) impact of hypogonadism on motor processing speed. Processing speed may be the most vulnerable neurocognitive domain associated with hypogonadism in survivors, while other domains were mainly impacted by cancer-related variables. Our findings support the need for further evaluation of the impact of sex hormone replacement therapy on neurocognitive function.

Neurocognitive outcomes and associated clinical factors 5 years after surgery in children with craniosynostosis.

Craniosynostosis involves early closure of one or more sutures, which is known to limit normal cranium growth and interfere with normal brain development. Various surgical methods are used, ranging from minimally invasive strip craniectomy to more extensive whole-vault cranioplasty. This study aimed to evaluate neurocognitive outcomes 5 years after surgical treatment in children with craniosynostosis and to evaluate relevant clinical factors. After exclusion of genetically confirmed syndromic craniosynostosis patients, a retrospective review was conducted on 112 nonsyndromic craniosynostosis patients who underwent surgical treatment and follow-up neurocognitive assessment. Ninety-seven patients underwent strip craniectomy with postoperative orthotic helmet therapy, and 15 received other surgical treatment: 4 with distraction osteotomy and 11 with craniofacial reconstruction. Neurocognitive assessment using the Korean Wechsler Preschool and Primary Scale of Intelligence, Fourth Edition (K-WPPSI-IV), was performed 5 years postoperatively. Clinical factors were assessed regarding neurocognitive outcomes. The mean age at surgery was significantly younger in the strip craniectomy group (strip craniectomy 4.6 months vs other surgical treatment 18.6 months, p < 0.01). Patients with 2 or more sutures involved were more likely to receive more extensive surgical treatment (16.5% in the strip craniectomy group vs 53.8% in the other group, p < 0.01). Four (3.5%) patients who showed evidence of increased intracranial pressure (ICP) also underwent more extensive surgical treatment. Multivariable linear regression revealed a significant correlation of age at neurocognitive testing (-3.18, 95% CI -5.95 to -0.40, p = 0.02), increased ICP (-34.73, 95% CI -51.04 to -18.41, p < 0.01), and the level of maternal education (6.11, 95% CI 1.01-11.20, p = 0.02) with the Full-Scale Intelligence Quotient (FSIQ). Age at surgery, involvement of 2 or more sutures, and type of operation demonstrated no correlation with FSIQ. Among the 97 patients who underwent strip craniectomy, the FSIQ ranged from mean ± SD 100.2 ± 10.2 (bicoronal) to 110.1 ± 12.7 (lambdoid), and there was no significant difference between the suture groups (p = 0.41). The 5 index scores were all within average ranges based on their age norms. Age at neurocognitive assessment, increased ICP, and maternal education level showed significant correlations with the neurocognitive function of craniosynostosis patients. Although children with craniosynostosis exhibited favorable 5-year postoperative neurocognitive outcomes across various synostosis sutures, longer follow-up is needed to reveal the incidence of neurocognitive dysfunction in these patients.

Sleep Physiology and Neurocognition Among Adolescents With Attention-Deficit/Hyperactivity Disorder

Few studies have characterized the nature of sleep problems among adolescents with attention-deficit/hyperactivity disorder (ADHD) using polysomnography (PSG). Additionally, although adolescents with ADHD and adolescents with sleep disturbances display similar neurocognitive deficits, the role of sleep in contributing to neurocognitive impairment in adolescent ADHD is unknown. This study investigated differences in PSG-measured sleep among adolescents with ADHD compared with non-psychiatric controls and associations with neurocognition. Medication-free adolescents aged 13 to 17 (N = 62, n= 31 with ADHD; mean age= 15.3 years; 50% female) completed a diagnostic evaluation, 3 nights of ambulatory PSG, the Cambridge Neuropsychological Test Automated Battery, and subjective reports of sleep and executive functioning. Linear regressions covarying for age, sex, and pubertal status examined group differences in sleep indices, and partial Pearson correlations assessed relations between sleep and neurocognition. Although adolescents with ADHD did not exhibit differences in PSG-measured sleep duration, awakenings, or latency (ps > .05) compared with non-psychiatric controls, they displayed lower slow wave sleep percentage (β=-.40) and non-rapid eye movement (NREM) electroencephalogram (EEG) delta power (β=-.29). They also exhibited greater stage 2 percentage (β= .41), NREM EEG sigma power (β= .41), and elevated self-reported sleep disturbances (ps< .05). Lower NREM EEG delta power, increased high-frequency power, and slower decline in NREM EEG delta power overnight were associated with poorer neurocognition among adolescents with ADHD. Adolescents with ADHD reported more sleep disturbances than non-psychiatric controls and exhibited differences in sleep stage distribution and NREM sleep EEG frequency. Sleep-EEG spectral indices were associated with impaired neurocognition, suggesting that physiological sleep processes may underlie neurocognitive deficits in ADHD. Future studies may clarify whether sleep plays a causal role in neurocognitive impairments in adolescent ADHD and whether interventions normalizing sleep improve neurocognition. Sleep Dysfunction and Neurocognitive Outcomes in Adolescent ADHD; https://clinicaltrials.gov/; NCT02897362. We worked to ensure sex and gender balance in the recruitment of human participants. We worked to ensure race, ethnic, and/or other types of diversity in the recruitment of human participants. We worked to ensure that the study questionnaires were prepared in an inclusive way. One or more of the authors of this paper self-identifies as a member of one or more historically underrepresented sexual and/or gender groups in science. We actively worked to promote sex and gender balance in our author group. While citing references scientifically relevant for this work, we also actively worked to promote sex and gender balance in our reference list.

Characterization of brain development with neuroimaging in a female mouse model of chemotherapy treatment of acute lymphoblastic leukemia.

Survivors of pediatric acute lymphoblastic leukemia (ALL) exhibit abnormal neurocognitive outcomes that are possibly due to exposures to neurotoxic chemotherapy agents. This study aimed to determine the feasibility of characterizing long-term neuroanatomical changes with in vivo neuroimaging in a preclinical model of treatment for ALL. Female mice (C57BL/6) were randomly assigned to a saline control group (n=10) or a treatment group (n=10) that received intrathecal methotrexate and oral dexamethasone (IT-MTX + DEX). Mice were subsequently scanned three times on a 7T MRI at ages 3, 6, and 12 months (T1, T2, and T3, respectively), which corresponds with human age-equivalents spanning early to late adulthood. Regional brain volumes were automatically segmented, and volume change between timepoints (i.e., T1 to T2; and T2 to T3) were compared between groups (i.e., saline vs. IT-MTX + DEX). Five mice in the IT-MTX + DEX group, and seven mice in the saline group completed all three scans. Between T1 and T2, volumetric change was significantly different between groups in total gray matter [estimate =2.06, 95% confidence interval (CI): 0.27-3.84], the cerebrum (estimate =1.62, 95% CI: 0.14-3.09), claustrum (estimate =0.06, 95% CI: 0.02-0.09), amygdala (estimate =0.16, 95% CI: 0.03-0.29), and striatum (estimate =0.18, 95% CI: 0.01-0.35), with the IT-MTX + DEX group exhibiting a more robust increase in volume than the saline-treated group. Between T2 and T3, group differences in structural brain development were evident for total white matter (estimate =-0.14, 95% CI: -0.27 to -0.01), and the corpus callosum (estimate =-0.09, 95% CI: -0.19 to 0.00) and amygdala (estimate =-0.05, 95% CI: -0.10 to 0.00). In contrast to the rapid brain growth observed earlier in development (i.e., T1 to T2), the IT-MTX + DEX group exhibited an attenuated increase in volume relative to the saline-treated group between T2 and T3. The results demonstrate feasibility of modeling pediatric ALL treatment in a preclinical model and highlight the potential of using preclinical neuroimaging models to gain insight into brain development throughout survivorship.

Influence of maternal folate depletion on Art3 DNA methylation in the murine adult brain; potential consequences for brain and neurocognitive health.

The developmental origins of health and disease hypothesis suggest early-life environment impacts health outcomes throughout the life course. In particular, epigenetic marks, including DNA methylation, are thought to be key mechanisms through which environmental exposures programme later-life health. Adequate maternal folate status before and during pregnancy is essential in the protection against neural tube defects, but data are emerging that suggest early-life folate exposures may also influence neurocognitive outcomes in childhood and, potentially, thereafter. Since folate is key to the supply of methyl donors for DNA methylation, we hypothesize that DNA methylation may be a mediating mechanism through which maternal folate influences neurocognitive outcomes. Using bisulphite sequencing, we measured DNA methylation of five genes (Art3, Rsp16, Tspo, Wnt16, and Pcdhb6) in the brain tissue of adult offspring of dams who were depleted of folate (n = 5, 0.4 mg folic acid/kg diet) during pregnancy (~19-21 days) and lactation (mean 22 days) compared with controls (n = 6, 2 mg folic acid/kg diet). Genes were selected as methylation of their promoters had previously been found to be altered by maternal folate intake in mice and humans across the life course, and because they have potential associations with neurocognitive outcomes. Maternal folate depletion was significantly associated with Art3 gene hypomethylation in subcortical brain tissue of adult mice at 28 weeks of age (mean decrease 6.2%, P = .03). For the other genes, no statistically significant differences were found between folate depleted and control groups. Given its association with neurocognitive outcomes, we suggest Art3 warrants further study in the context of lifecourse brain health. We have uncovered a potential biomarker that, once validated in accessible biospecimens and human context, may be useful to track the impact of early-life folate exposure on later-life neurocognitive health, and potentially be used to develop and monitor the effects of interventions.

Persistent neurocognitive deficits in cognitively impaired survivors of sepsis are explained by reductions in working memory capacity.

Sepsis is defined as life-threatening organ dysfunction caused by a dysregulated host response to infection. Mounting evidence suggests that many cognitively impaired sepsis survivors show long-term neurocognitive deficits in neuropsychological tasks. To date, the underlying mechanisms of these deficits are insufficiently understood. Based on previous evaluations we hypothesized that visual attention and working memory may be affected in a sample of cognitively impaired sepsis survivors. We utilized psychophysical whole-and partial-report paradigms based on the computational theory of visual attention (TVA) to determine (i) whether sepsis survivors show changes in basic parameters of visual attention and working memory, (ii) whether the affected parameters are related to neuropsychological test results in a standard battery in sepsis survivors and matched healthy control participants, (iii) whether between-group differences in these basic parameters of visual attention could account for underperformance of sepsis survivors in neuropsychological tests when adjusting for potentially relevant clinical variables. We showed that, in sepsis survivors, the maximum number of elements consciously maintained in an instant, i.e. the working memory storage capacity K, is reduced (sepsis survivors: M = 3.0; healthy controls: M = 3.4). Moreover, K explained variance in neurocognitive outcomes -17% in attentional and 16 % in executive functions - in a standard neuropsychological battery. The association remained stable when adjusting for clinical variables. Thus, in our sample of cognitively impaired sepsis survivors, a reduction in working memory capacity seems to be a critical determinant of the neurocognitive sequelae. It should be the subject of future work on mechanisms but may also serve as surrogate outcome measure in interventional studies.

Core outcome measurement set for research and clinical practice in post-COVID-19 condition (long COVID) in children and young people: an international Delphi consensus study "PC-COS Children".

The coronavirus disease 2019 (COVID-19) pandemic substantially impacted different age groups, with children and young people not exempted. Many have experienced enduring health consequences. Presently, there is no consensus on the health outcomes to assess in children and young people with post-COVID-19 condition. Furthermore, it is unclear which measurement instruments are appropriate for use in research and clinical management of children and young people with post-COVID-19. To address these unmet needs, we conducted a consensus study, aiming to develop a core outcome set (COS) and an associated core outcome measurement set (COMS) for evaluating post-COVID-19 condition in children and young people. Our methodology comprised of two phases. In phase 1 (to create a COS), we performed an extensive literature review and categorisation of outcomes, and prioritised those outcomes in a two-round online modified Delphi process followed by a consensus meeting. In phase 2 (to create the COMS), we performed another modified Delphi consensus process to evaluate measurement instruments for previously defined core outcomes from phase 1, followed by an online consensus workshop to finalise recommendations regarding the most appropriate instruments for each core outcome. In phase 1, 214 participants from 37 countries participated, with 154 (72%) contributing to both Delphi rounds. The subsequent online consensus meeting resulted in a final COS which encompassed seven critical outcomes: fatigue; post-exertion symptoms; work/occupational and study changes; as well as functional changes, symptoms, and conditions relating to cardiovascular, neuro-cognitive, gastrointestinal and physical outcomes. In phase 2, 11 international experts were involved in a modified Delphi process, selecting measurement instruments for a subsequent online consensus workshop where 30 voting participants discussed and independently scored the selected instruments. As a result of this consensus process, four instruments met a priori consensus criteria for inclusion: PedsQL multidimensional fatigue scale for "fatigue"; PedsQL gastrointestinal symptom scales for "gastrointestinal"; PedsQL cognitive functioning scale for "neurocognitive" and EQ-5D for "physical functioning". Despite proposing outcome measurement instruments for the remaining three core outcomes ("cardiovascular", "post-exertional malaise", "work/occupational and study changes"), a consensus was not achieved. Our international, consensus-based initiative presents a robust framework for evaluating post-COVID-19 condition in children and young people in research and clinical practice via a rigorously defined COS and associated COMS. It will aid in the uniform measurement and reporting of relevant health outcomes worldwide.

Screening for obstructive sleep apnea (OSA) in children and adolescents with obesity: A scoping review of national and international pediatric obesity and pediatric OSA management guidelines.

Obstructive sleep apnea (OSA) is a prevalent complication that affects up to 60% of children and adolescents with obesity. It is associated with poorer cardiometabolic outcomes and neurocognitive deficits. Appropriate screening and intervention for OSA are crucial in the management of children with obesity. We performed a scoping review of international and national pediatric obesity (n = 30) and pediatric OSA (n = 10) management guidelines to evaluate the recommendations on OSA screening in pediatric obesity. Sixteen (53%) of the pediatric obesity guidelines had incorporated OSA screening to varying extents, with no consistent recommendations on when and how to screen for OSA, and subsequent management of OSA in children with obesity. We provide our recommendations that are based on the strength and certainty of evidence presented. These include a clinical-based screening for OSA in all children with body mass index (BMI) ≥ 85th percentile or those with rapid BMI gain (upward crossing of 2 BMI percentiles) and the use of overnight polysomnography to confirm the diagnosis of OSA in those with high clinical suspicion. We discuss further management of OSA unique to children with obesity. An appropriate screening strategy for OSA would facilitate timely intervention that has been shown to improve cardiometabolic and neurocognitive outcomes.

Long-Term Neuropsychiatric, Neurocognitive, and Functional Outcomes of Patients Receiving ECMO: A Systematic Review and Meta-Analysis

Despite the common occurrence of neurologic complications during extracorporeal membrane oxygenation (ECMO) support, data on long-term neuropsychiatric, neurocognitive, and functional outcomes are sparse. We aimed to determine the prevalence of long-term neuropsychiatric symptoms, neurocognitive and functional impairment, and favorable neurologic outcomes in adult patients who receive ECMO. PubMed, Embase, Cochrane, Web of Science, and Scopus were searched for text related to ECMO and neuropsychiatric, neurocognitive, and functional outcomes from inception to May 3, 2023. Our primary outcome was the prevalence of neuropsychiatric symptoms (pain/discomfort, anxiety, depression, posttraumatic stress disorder [PTSD], and sleep disturbance) at long-term (≥6 months) follow-up. Our secondary outcomes were the prevalence of neurocognitive impairment (memory, attention, and reasoning), functional impairment (daily activities, physical activity/mobility, and personal/self-care), and favorable neurologic outcomes (Cerebral Performance Category ≤2, modified Rankin scale ≤3, or Glasgow Outcome Scale ≥4). This study was registered in PROSPERO (CRD42023420565). We included 59 studies with 3,280 patients (median age 54 years, 69% male). The cohort consisted of 86% venoarterial (VA)-ECMO (n = 2,819) and 14% venovenous (VV)-ECMO (n = 461) patients. More than 10 tools were used to assess neuropsychiatric and neurocognitive outcomes, indicating a lack of standardization in assessment methodologies. The overall prevalence of neuropsychiatric symptoms was 41% (95% CI 33%-49%): pain/discomfort (52%, 95% CI 42%-63%), sleep disturbance (37%, 95% CI 0%-98%), anxiety (36%, 95% CI 27%-46%), depression (31%, 95% CI 22%-40%), and PTSD (18%, 95% CI 9%-29%). The prevalence of neurocognitive impairment was 38% (95% CI 13%-65%). The prevalence of functional impairment was 52% (95% CI 40%-64%): daily activities (54%, 95% CI 41%-66%), mobility (41%, 95% CI 28%-54%), and self-care (21%, 95% CI 13%-31%). The prevalence of neuropsychiatric symptoms in VV-ECMO patients was higher than that in VA-ECMO patients (55% [95% CI 34%-75%] vs 32% [95% CI 23%-41%], p = 0.01), though the prevalence of neurocognitive and functional impairment was not different between the groups. The prevalence of favorable neurologic outcomes was not different at various follow-ups: 3 months (23%, 95% CI 12%-36%), 6 months (25%, 95% CI 16%-35%), and ≥1 year (28%, 95% CI 21%-36%, p = 0.68). A substantial proportion of ECMO patients seemed to experience neuropsychiatric symptoms and neurocognitive and functional impairments at long-term follow-up. Considerable heterogeneity in methodology for gauging these outcomes exists, warranting the need for standardization. Multicenter prospective observational studies are indicated to further investigate risk factors for these outcomes in ECMO-supported patients.

20-year neurocognitive development following a schizophrenia spectrum disorder and associations with symptom severity and functional outcomes.

Cognitive deficits are a core feature of schizophrenia and are closely associated with poor functional outcomes. It remains unclear if cognitive deficits progress over time or remain stable. Determining patients at increased risk of progressive worsening might help targeted neurocognitive remediation approaches. This 20-year follow-up study examined neurocognitive outcomes of 156 participants from the OPUS I trial. Neurocognition was assessed using the brief assessment of cognition in schizophrenia at the 10- and 20-year follow-up, allowing us to examine changes in neurocognition over ten years. We found that 30.5% of patients had a declining course of neurocognition, 49.2% had a stable course of neurocognition and 20.3% experienced improvements in neurocognition. Good cognitive functioning at the 20-year follow-up was significantly associated with higher levels of social functioning (B 6.86, CI 4.71-9.02, p < 0.001) while increasing experiential negative symptoms were significantly correlated to cognitive worsening (PC-0.231, p = 0.029). Younger age at inclusion (B: 0.23 per 10-years, CI 0.00-0.045, p = 0.047) and low level of education (below ten years) (mean difference: -0.346, CI -0.616 to -0.076, p = 0.012) predicted declining neurocognition. Our findings support the notion of different schizophrenia subtypes with varying trajectories. Neurocognitive impairment at the 20-year follow-up was associated with other poor outcomes, highlighting the importance of treatments aimed at improving neurocognition in patients with schizophrenia spectrum disorders.

Understanding the association between fatigue and neurocognitive functioning in patients with glioma: A cross-sectional multinational study.

Fatigue and neurocognitive impairment are highly prevalent in patients with glioma, significantly impacting health-related quality of life. Despite the presumed association between these two factors, evidence remains sparse. Therefore, we aimed to investigate this relationship using multinational data. We analyzed data on self-reported fatigue and neurocognitive outcomes from postoperative patients with glioma from the University of California San Francisco (n = 100, UCSF) and Amsterdam University Medical Center (n = 127, Amsterdam UMC). We used multiple linear regression models to assess associations between fatigue and seven (sub)domains of neurocognitive functioning and latent profile analysis to identify distinct patterns of fatigue and neurocognitive functioning. UCSF patients were older (median age 49 vs. 43 years, P = .002), had a higher proportion of grade 4 tumors (32% vs. 18%, P = .03), and had more neurocognitive deficits (P = .01). While the number of clinically fatigued patients was similar between sites (64% vs. 58%, P = .12), fatigue and the number of impaired neurocognitive domains were not correlated (P = .16-.72). At UCSF, neurocognitive domains were not related to fatigue, and at Amsterdam UMC attention and semantic fluency explained only 4-7% of variance in fatigue. Across institutions, we identified four distinct patterns of neurocognitive functioning, which were not consistently associated with fatigue. Although individual patients might experience both fatigue and neurocognitive impairment, the relationship between the two is weak. Consequently, both fatigue and neurocognitive functioning should be independently assessed and treated with targeted therapies.