Neurocognitive Outcomes Research Articles

Paternal, Maternal, and Familial Factors as Predictors of Sturge–Weber Syndrome Neurological Outcome

Objectives: To identify potential risk factors influencing Sturge–Weber Syndrome (SWS) and neurological outcomes in individuals with SWS and port-wine birthmarks from paternal, maternal, and familial factors. Methods: This study follows a retrospective cross-sectional design. Clinical visits took place at the Kennedy Krieger Institute, a tertiary care center. Participants were individuals with SWS or port-wine birthmarks. Results: Higher paternal age at conception was associated with a range of cognitive dysfunctions in offspring with SWS brain involvement. Indeed, paternal age was associated with low intelligence quotient (n = 25, P = .004), strokes or stroke-like episodes (n = 34, P = .030), gross and/or fine motor delay (n = 34, P = .036), delays in ability to perform activities of daily living (n = 30, P = .012), and delayed learning compared to peers (n = 31, P = .027). Furthermore, paternal age was correlated with worse cognitive outcomes, as measured by cognitive Neuroscore (r s = 0.575, P < .001, n = 32). When maternal thyroid disease and hypertension were present during pregnancy, offspring were more likely to experience low intelligence quotient (n = 30, P = .041) and regression of any abilities (n = 37, P = .045), respectively. Logistic regression confirmed the association between paternal age and severe cognitive Neuroscore (β = .580, P = .033, odds ratio: 1.79, 95% confidence interval: 1.05–3.04), even when controlling for the effects of seizures and strokes or stroke-like episodes. Conclusions: Prenatal factors were associated with neurological symptoms in subjects with SWS. Older paternal age, in particular, may predict worse neurocognitive outcomes. Further research is needed in larger cohorts to determine the value of the identified prenatal factors as prognostic tools. Likewise, animal models may be used to determine the impact of prenatal factors on the severity of outcome.

Intravenous ketamine versus electroconvulsive therapy for major depressive disorder or bipolar depression: A meta-analysis of randomized controlled trials.

Intravenous (IV) ketamine has been evaluated alongside electroconvulsive therapy (ECT) in addressing major depressive disorder (MDD) or bipolar depression (BD), though the comparative outcomes remain inconclusive. This meta-analysis aimed to provide a systematic assessment of the efficacy, safety, and tolerability of IV ketamine relative to ECT for treating MDD or BD. Randomized controlled trials (RCTs) comparing IV ketamine and ECT in terms of efficacy, safety, and tolerability for MDD or BD were identified and reviewed. Three independent investigators extracted relevant data, which was synthesized using RevMan 5.3 software under a random effects model. Five RCTs encompassing 664 patients diagnosed with MDD or BD were analyzed. At 24 h post-initial treatment, IV ketamine demonstrated a statistically greater reduction in depressive symptoms compared to ECT (standardized mean difference (SMD) = -0.53; 95 % CI = -1.03 to -0.04; P = 0.04; I2 = 80 %). However, no significant differences were observed between groups in terms of the study-defined response (risk ratio (RR) = 1.49; 95 % CI = 0.08 to 28.42; P = 0.79; I2 = 0 %) at 24 h. Similarly, no notable differences were found for depressive symptom improvement (SMD = -0.48; 95 % CI = -2.41 to 1.45; P = 0.63; I2 = 99 %), the study-defined response (RR: 0.96, 95 % CI: 0.70 to 1.31; P = 0.79; I2 = 75 %) or remission (RR: 0.91, 95 % CI: 0.45 to 1.82; P = 0.78; I2 = 90 %) at the end-of-treatment visit. Among the three RCTs (60 %) comparing the neurocognitive outcomes of IV ketamine and ECT through varying test batteries, results were inconsistent. IV ketamine was associated with marked increases in dissociation, blurred vision, dizziness, and diplopia, while ECT led to a significant rise in muscle pain (all Ps < 0.05). Discontinuation rates due to any cause were comparable between both groups (P > 0.05). IV ketamine demonstrates a faster onset of antidepressant effects compared to ECT, despite both treatments yielding comparable outcomes at the end-of-treatment visit for patients with MDD or BD. However, large-scale RCTs are required to thoroughly evaluate the long-term efficacy and safety of IV ketamine relative to ECT in these populations.

Shape Mediation Analysis in Alzheimer's Disease Studies.

As a crucial tool in neuroscience, mediation analysis has been developed and widely adopted to elucidate the role of intermediary variables derived from neuroimaging data. Typically, structural equation models (SEMs) are employed to investigate the influences of exposures on outcomes, with model coefficients being interpreted as causal effects. While existing SEMs have proven to be effective tools for mediation analysis involving various neuroimaging-related mediators, limited research has explored scenarios where these mediators are derived from the shape space. In addition, the linear relationship assumption adopted in existing SEMs may lead to substantial efficiency losses and decreased predictive accuracy in real-world applications. To address these challenges, we introduce a novel framework for shape mediation analysis, designed to explore the causal relationships between genetic exposures and clinical outcomes, whether mediated or unmediated by shape-related factors while accounting for potential confounding variables. Within our framework, we apply the square-root velocity function to extract elastic shape representations, which reside within the linear Hilbert space of square-integrable functions. Subsequently, we introduce a two-layer shape regression model to characterize the relationships among neurocognitive outcomes, elastic shape mediators, genetic exposures, and clinical confounders. Both estimation and inference procedures are established for unknown parameters along with the corresponding causal estimands. The asymptotic properties of estimated quantities are investigated as well. Both simulated studies and real-data analyses demonstrate the superior performance of our proposed method in terms of estimation accuracy and robustness when compared to existing approaches for estimating causal estimands.

QOL-24. NEUROLOGIC AND NEUROCOGNITIVE OUTCOMES AMONG SURVIVORS OF INFANT-TYPE HEMISPHERIC GLIOMA (IHG)

Abstract IHGs are large, hemorrhagic cerebral tumors associated with hydrocephalus, increased intracranial pressure, and herniation. Commonly diagnosed during early infancy, children with IHGs have an approximately 90% chance of overall survival when treated with surgery, chemotherapy, and, more recently, molecularly targeted therapies. However, there is limited understanding of long-term quality-of-life following treatment. Our study investigated long-term neurological and neurocognitive outcomes among IHG survivors. The medical database was reviewed for neurological sequelae and neurocognitive outcomes (intelligence [IQ], adaptive function, academic readiness) for 21 survivors. Median age of diagnosis and last follow-up were 0.8 (0.0-4.4) and 10.3 (4.8-17.6) years, respectively. Sixteen patients (76%) experienced atleast one neurological sequelae: 38% (8/21) had paresis/plegia; 24% (5/21) had spasticity, 26% (5/19) had abnormal speech, and 57% (12/21) had a long-term seizure disorder. Nine patients diagnosed with IHG at &amp;lt; 0.5 years had significantly higher rates of dysarthria (p = 0.019) and seizure disorders (p = 0.035) in follow-up in comparison to patients diagnosed at 0.5-1 year (n=4) and &amp;gt;1 year (n=8). Neurocognitive outcomes were available for 19 patients at a median of 6 years after diagnosis. Median IQ for the entire cohort was 68.0 (47.0-114.0), compared to normative expectations of 100 (SD = 15), with younger age at diagnosis associated with lower IQ (r = 0.36). Ten survivors experiencing seizures particularly had worse IQ scores (median 69.4 [47-101]). Survivors also had inferior outcomes in school readiness (median 46.0 [40.0-98.0]), compared to normative expectations of 100 (SD = 15), and adaptive function (median 48.0 [34.0-67.0]), compared to normative expectations of 50 (SD= 10), with younger age at diagnosis associated with lower performance for adaptive function (r = 0.45). CONCLUSION Children diagnosed with IHG have a high survival rate but experience substantial tumor-associated and treatment-related long-term morbidity. Future clinical trials should aim for better long-term quality of life for survivors through scientifically driven treatment modification.

CTNI-32. A MULTICENTER PHASE 1 TRIAL OF TUCATINIB, TRASTUZUMAB, AND CAPECITABINE WITH STEREOTACTIC RADIOSURGERY IN PATIENTS WITH BRAIN METASTASES FROM HER2 POSITIVE BREAST CANCER (TUTOR)

Abstract BACKGROUND Nearly 20-40% of HER2+ breast cancer patients develop brain metastases (BMs), where stereotactic radiosurgery (SRS) is standard-for-care for local control. Tucatinib, an oral HER2-selective TKI, is safe and efficacious in HER2+ breast cancer in combination with capecitabine and trastuzumab. Synergism between these 3 drugs (TCT) and radiation may enhance DNA damage. This phase 1 trial aims to evaluate TCT plus SRS for HER2+ breast cancer BMs (BCBM). METHODS TUTOR is a pre-registered (NCT05553522), single-arm, multicenter, ongoing, phase 1 trial that aims to determine the safety and efficacy of TCT+SRS in HER2+ BCBM patients. Patients with age 18-80 years, ECOG score 0-2, normal organ function, and ≤10 newly-diagnosed BMs are being enrolled at six US centers. Any number of prior systemic therapies are allowed, except tucatinib and capecitabine. Key exclusion criteria include leptomeningeal metastases, intra-tumoral or peri-tumoral hemorrhage, and BMs ≤5 mm of optic chiasm/nerve. Primary endpoint is maximum tolerated dose (MTD) of tucatinib, in this 3 + 3 de-escalation study starting at dose level (DL) 300 mg BID. DL-1 is 250 mg BID, and DL-2 is 200 mg BID. Secondary endpoints include efficacy as determined by response rate, intracranial progression-free survival (PFS), extracranial PFS, and overall survival. Neurocognitive outcomes are assessed using Hopkins Verbal Learning, Controlled Oral Word Association, Trail Making, and Grooved Pegboard Tests. Toxicities are assessed using CTCAE v5.0. Quality of life is assessed using Functional Assessment of Cancer Therapy with Brain Tumor module. Patients are administered tucatinib with SRS as per treating radiation oncologist, followed by tucatinib for two weeks, i.e. dose-limiting toxicity (DLT) period, followed by TCT until progression or intolerable toxicity. DLTs are defined by Grade 3 or 4 thrombocytopenia, grade 4 anemia, grade 4 neutropenia lasting &amp;gt;7 days, febrile neutropenia, and any non-hematologic toxicity of grade ≥3 (excluding alopecia). Cohort expansion at MTD to 40 patients is planned. Patient enrollment started in February 2023 and remains ongoing.

Current investigation of neurocognitive functioning in preschool children with cancer: A cross-sectional study from western China.

Cancer and its treatments may cause neurocognitive impairments in preschool children, but there is limited research on the neurocognitive outcomes of this population. This study, which assessed the neurocognitive function of preschool children with cancer and analyzed various influencing factors of neurocognitive functioning, is of significant importance. We aimed to investigate neurocognitive function and related risk factors in preschool children with cancer to inform preventive and intervention strategies. From September 2023 to May 2024, we recruited 100 preschool children with cancer. The Chinese version of the Ages & Stages Questionnaires, the Spence Preschool Anxiety Scale Chinese Version, and the Sleep Disturbance Scale for Children were used to collected data. Binary logistic stepwise regression analysis was used to explore the influencing factors of neurocognitive function in preschool children with cancer. 49% of the preschool children with cancer had abnormalities in at least one neurocognitive dimension. The majority of children had abnormalities in gross motor dimension, accounting for 30%, which was related to age and frequency of participation in neurocognitive activities. Communication dimension was related to father's education level, dietary habit, and frequency of participation in activities. Fine motor dimension was associated with age, sex, and father's education level. Problem-solving dimension was associated with age and dietary habit. Personal-social dimension was related to age and radiotherapy. Nearly half of preschool children with cancer experienced neurocognitive impairment. The Chinese version of the Ages & Stages Questionnaires is a simple and effective tool for screening children with possible neurocognitive impairment. It was found that children's neurocognitive function was significantly influenced by family environment, dietary habit, cognitive activities, and cancer treatment. Therefore, it is recommended to strengthen family and social support, and to formulate personalized intervention such as cognitive therapy and dietary adjustment based on children's age and family background, which are important for promoting neurocognitive recovery.

NCMP-19. IMPACT OF SUBVENTRICULAR ZONE INVASION ON PREOPERATIVE COGNITIVE DECLINE IN DIFFUSE GLIOMA PATIENTS

Abstract PURPOSE To determine the impact of subventricular zone (SVZ) invasion on neurocognitive dysfunction in diffuse glioma patients. MATERIALS AND METHODS We collected neuropsychological assessments of treatment-naïve WHO grade 2-4 diffuse glioma patients between 2017 to 2023. The Chi-square test determined the odds ratio (OR), and multiple linear regression identified factors related to cognitive deficits using Python 3.11.4. RESULTS Of the 129 patients, 64 exhibited SVZ invasion (SVZ+) while 65 were SVZ-. Groups were matched for WHO grading. SVZ+ was associated with more defective domains than SVZ- in both lower grade (WHO grade 2,3, 3.2 ± 2.1 vs. 2.1 ± 1.9, p=0.019) and high grade (WHO grade 4, 4.9 ± 1.6 vs. 3.6 ± 2.2, p=0.019) tumors. In lower grade gliomas, SVZ+ increased risks of language (OR 7.500, p&amp;lt;0.001) and visual learning impairments (OR 4.375, p=0.014). In high grade gliomas, SVZ+ rendered greater language (OR 8.556, p=0.003) and auditory learning vulnerability (OR 3.850, p=0.039). In right hemispheric tumors, SVZ+ lesions conferred worse executive (OR 6.667, p=0.006) and language function (OR 9.063, p=0.017); in left hemispheric tumors, SVZ+ lesions increased language (OR 3.125, p=0.012) and auditory learning (OR 2.889, p=0.024) impairment. Frontal horn of SVZ+ was related to working memory decline, and body part of SVZ+ was related to emotional deficits. Age and WHO grade 4 were associate with more defective domains in the SVZ+ group. In the SVZ- group, parietal lobe tumor was associate with more defective domains, while high education, temporal lobe, and WHO grade 2 were associate with fewer defective domains. CONCLUSION SVZ invasion impacts pre-operative neurocognitive function regardless of lesion laterality and WHO grade. Distinct SVZ sub-regions are linked to specific cognitive impairments. These findings highlight the need for precise tumor mapping involving the SVZ to evaluate neurocognitive outcomes and consider preventive or rehabilitative interventions.

Role of Cardiovascular Risk in Associations of Brain-Derived Neurotrophic Factor with Longitudinal Brain and Cognitive Trajectories in Older Adults

ABSTRACT Background Higher levels of brain-derived neurotrophic factor (BDNF) have been associated with better neurocognitive outcomes. BDNF is present in cardiovascular tissue, and some evidence suggests it may benefit cardiovascular function. The current study assessed whether there is a mediating and/or moderating role of cardiovascular health in the relationship between BDNF and brain and cognitive outcomes. Method We examined longitudinal data from 397 older adults (aged 54–89;164 females, 233 males) enrolled in the Alzheimer’s Disease Neuroimaging Initiative with available plasma BDNF, medical, neuroimaging, and cognitive assessments. We used path analysis and linear regression to estimate the mediating and moderating roles of two measures of cardiovascular health, the Framingham Risk Score (FRS) and pulse pressure, in the relationships between BDNF and longitudinal changes in brain structure (white matter hyperintensity volume, hippocampal volume, and primary visual cortex volume) and cognitive function (executive function, episodic memory, and language). Results There was no significant association of plasma BDNF with FRS or pulse pressure (ps > 0.31), precluding mediation. There were no robust associations between BDNF and longitudinal change in any brain structural or cognitive measures (ps > .12). Higher FRS was significantly associated with greater increases in WMH volume (ps < .01). FRS and pulse pressure were not associated with any other brain structural or cognitive outcomes (ps > .07). Conclusion These results suggest that cardiovascular health may not play an important role in the influence of BDNF on neurocognitive health in older adults.

Long-term health outcomes of COVID-19 in ICU- and non-ICU-treated patients up to 2 years after hospitalization: a longitudinal cohort study (CO-FLOW)

BackgroundMany patients hospitalized for COVID-19 experience long-term health problems, but comprehensive longitudinal data up to 2 years remain limited. We aimed to (1) assess 2-year trajectories of health outcomes, including comparison between intensive care unit (ICU) treated and non-ICU-treated patients, and (2) identify risk factors for prominent health problems post-hospitalization for COVID-19.MethodsThe CO-FLOW multicenter prospective cohort study followed adults hospitalized for COVID-19 at 3, 6, 12, and 24 months post-discharge. Measurements included patient-reported outcomes (a.o., recovery, symptoms, fatigue, mental health, sleep quality, return to work, health-related quality of life [HRQoL]), and objective cognitive and physical tests. Additionally, routine follow-up data were collected.Results650 patients (median age 60.0 [IQR 53.0–67.0] years; 449/650 [69%] male) surviving hospitalization for COVID-19 were included, of whom 273/650 (42%) received ICU treatment. Overall, outcomes improved over time. Nonetheless, 73% (322/443) of patients had not completely recovered from COVID-19, with memory problems (274/443; 55%), concentration problems (259/443; 52%), and dyspnea (251/493; 51%) among most frequently reported symptoms at 2 years. Moreover, 61% (259/427) had poor sleep quality, 51% (222/433) fatigue, 23% (102/438) cognitive failures, and 30% (65/216) did not fully return to work. Objective outcome measures showed generally good physical recovery. Most outcomes were comparable between ICU- and non-ICU-treated patients at 2 years. However, ICU-treated patients tended to show slower recovery in neurocognitive symptoms, mental health outcomes, and resuming work than non-ICU-treated patients, while showing more improvements in physical outcomes. Particularly, female sex and/or pre-existing pulmonary disease were major risk factors for poorer outcomes.Conclusions73% (322/443) of patients had not completely recovered from COVID-19 by 2 years. Despite good physical recovery, long-term neurocognitive complaints, dyspnea, fatigue, and impaired sleep quality persisted. ICU-treated patients showed slower recovery in neurocognitive and mental health outcomes and resumption of work. Tailoring long-term COVID-19 aftercare to individual residual needs is essential. Follow-up is required to monitor further recovery.Trial registration: NL8710, registration date 12-06-2020.

Timing sensitivity of prenatal cortisol exposure and neurocognitive development.

Prenatal glucocorticoid exposure has been negatively associated with infant neurocognitive outcomes. However, questions about developmental timing effects across gestation remain. Participants were 253 mother-child dyads who participated in a prospective cohort study recruited in the first trimester of pregnancy. Diurnal cortisol was measured in maternal saliva samples collected across a single day within each trimester of pregnancy. Children (49.8% female) completed the Bayley Mental Development Scales, Third Edition at 6, 12, and 24 months and completed three observational executive function tasks at 24 months. Structural equation models adjusting for sociodemographic covariates were used to test study hypotheses. There was significant evidence for timing sensitivity. First-trimester diurnal cortisol (area under the curve) was negatively associated with cognitive and language development at 12 months and poorer inhibition at 24 months. Second-trimester cortisol exposure was negatively associated with language scores at 24 months. Third-trimester cortisol positively predicted performance in shifting between task rules (set shifting) at 24 months. Associations were not reliably moderated by child sex. Findings suggest that neurocognitive development is sensitive to prenatal glucocorticoid exposure as early as the first trimester and underscore the importance of assessing developmental timing in research on prenatal exposures for child health outcomes.

Comparing the Neurocognitive Effects of Right-Unilateral Ultra-Brief Pulse Electroconvulsive Therapy and Magnetic Seizure Therapy for the Treatment of Major Depressive Episode

Magnetic seizure therapy (MST) is under investigation as a treatment for adults with major depression. Prior research suggested that MST has comparable antidepressant efficacy with electroconvulsive therapy (ECT), but with greater cognitive safety. The objective of the study was to compare the neurocognitive outcomes of patients receiving an acute course of MST with those receiving ECT for the treatment of major depressive episode. This was a between-subject, double-masked, randomized, multi-center clinical trial. Seventy-three participants with a severe major depressive episode were enrolled and randomly assigned to treatment with MST (N = 38) or ultra-brief pulse right unilateral ECT (N = 35). The main outcomes were change in performance from baseline to end of acute treatment on multiple neurocognitive measures. Patients receiving MST, relative to those receiving ECT, had superior cognitive outcomes up to 72-hours post-treatment. Specifically, following MST treatment, there was significant improvement in fine motor dexterity (p=0.017) and no significant change in cognitive domains of attention, verbal fluency, executive function, and verbal learning and memory. In contrast, following treatment with ECT, patients demonstrated significantly worsened performance on measures of verbal fluency (p<0.001), executive function (p=0.038), and verbal memory retention (p<0.001). Autobiographical memory consistency significantly decreased following treatment with both ECT (p<0.001) and MST, though the magnitude of change was greater for ECT. The study findings confirm prior work and provide new evidence supporting the enhanced cognitive safety of MST relative to ECT. Future research is warranted on MST to optimize its application in individuals across the lifespan with neuropsychiatric illnesses. ClinicalTrials.gov identifier: NCT00488748.

Neuroprotective effects of GLP-1 receptor agonists in neurodegenerative Disorders: A Large-Scale Propensity-Matched cohort study

BackgroundGLP-1 receptor agonists, traditionally used for treating type 2 diabetes mellitus and obesity, have demonstrated anti-inflammatory properties. However, their potential neuroprotective effects in neurodegenerative disorders remain unclear. ObjectiveTo evaluate the impact of GLP-1 receptor agonists on the risk of developing various neurodegenerative conditions in obese patients. MethodsThis comprehensive retrospective cohort study analyzed data from 5,307,845 obese adult patients across 73 healthcare organizations in 17 countries. Propensity score matching was performed, resulting in 102,935 patients in each cohort. We compared the risk of developing neurodegenerative disorders between obese patients receiving GLP-1 receptor agonist therapy and those who were not. ResultsObese patients treated with GLP-1 receptor agonists showed significantly lower risks of developing Alzheimer’s disease (RR = 0.627, 95 %CI = 0.481–0.817), Lewy body dementia (RR = 0.590, 95 %CI = 0.462–0.753), and vascular dementia (RR = 0.438, 95 %CI = 0.327–0.588). The risk reduction for Parkinson’s disease was not statistically significant overall (RR = 0.784, 95 %CI = 0.580–1.058) but was significant for semaglutide users (RR = 0.574, 95 %CI = 0.369–0.893). Semaglutide consistently showed the most pronounced protective effects across all disorders. Additionally, a significant reduction in all-cause mortality was observed (HR = 0.525, 95 %CI = 0.493–0.558). ConclusionThis study provides evidence that the effects of GLP-1 receptor agonists may extend beyond their known metabolic and cardioprotective benefits to include neuroprotection, associated with a decreased risk of developing various neurodegenerative disorders. These findings suggest the potential for expanding the therapeutic applications of GLP-1 receptor agonists to improve neurocognitive outcomes. Further research is warranted to elucidate the mechanisms underlying these neuroprotective effects and to explore their clinical applications in neurodegenerative disease prevention and treatment.

Study protocol: Cerebral autoregulation, brain perfusion, and neurocognitive outcomes after traumatic brain injury -CAPCOG-TBI.

Moderate-severe traumatic brain injury (msTBI) stands as a prominent etiology of adult disability, with increased risk for cognitive impairment and dementia. Although some recovery often occurs within the first year post-injury, predicting long-term cognitive outcomes remains challenging, partly due to the significant pathophysiological heterogeneity of TBI, including acute cerebrovascular injury. The primary aim of our recently funded study, cerebral autoregulation, brain perfusion, and neurocognitive outcomes after traumatic brain injury (CAPCOG-TBI), is to determine if acute cerebrovascular dysfunction after msTBI measured using multimodal non-invasive neuromonitoring is associated with cognitive outcome at 1-year post-injury. This longitudinal observational study will be conducted at two Level 1 trauma centers in Texas, USA, and will include adult patients with msTBI, and/or mild TBI with neuroimaging abnormalities. Multimodal cerebral vascular assessment using transcranial Doppler and cerebral near-infrared spectroscopy (NIRS) will be conducted within 7-days of onset of TBI. Longitudinal outcomes, including cognitive/functional assessments (Glasgow Outcome Scale and Patient-Reported Outcomes Measurement Information System), cerebral vascular assessment, and imaging will be performed at follow-ups 3-, 6-, and 12-months post-injury. We aim to recruit 100 subjects with msTBI along with 30 orthopedic trauma controls (OTC). This study is funded by National Institute of Neurological Disease and Stroke (NINDS) and is registered on Clinicaltrial.org (NCT06480838). We anticipate that msTBI patients will exhibit impaired cerebrovascular function in the acute phase compared to the OTC group. The severity of cerebrovascular dysfunction during this stage is expected to inversely correlate with cognitive and functional outcomes at 1-year post-injury. Additionally, recovery from cerebrovascular dysfunction is expected to be linked to cognitive recovery. The results of this study could help to understand the contribution of cerebrovascular dysfunction to cognitive outcomes after TBI and pave the way for innovative vascular-focused interventions aimed at enhancing cognitive recovery and mitigating neurodegeneration following msTB. In addition, its focus toward personalized medicine to aid in the management and prognosis of TBI patients.

Mitochondrial DNA copy number and neurocognitive outcomes in children.

Low mitochondria DNA copy number (mtDNAcn) has been linked to cognitive decline. However, the role of mtDNAcn in healthy cognitive development is unclear. We hypothesized early-life mtDNAcn would be associated with children's learning and memory. We quantified mtDNAcn in umbilical cord blood and child blood at ages 5-7 from participants in a prospective birth cohort. We administered the Children's Memory Scale (CMS) at ages 9-14 (N = 342) and the Wechsler Intelligence Scale for Children (WISC-IV) at ages 7 and 9 (N = 457). Associations between mtDNAcn tertiles and CMS and WISC were evaluated with linear regression and linear mixed-effects models, respectively. We examined non-linear associations using generalized additive mixed models. Relative to the middle tertile of mtDNAcn, lower childhood mtDNAcn was associated with lower WISC Working Memory (β = -2.65, 95% CI [-5.24, -0.06]) and Full-Scale IQ (β = -3.71 [-6.42, -1.00]), and higher CMS Visual Memory (β = 4.70 [0.47, 8.93]). Higher childhood mtDNAcn was linked to higher CMS Verbal Memory (β = 7.75 [2.50, 13.01]). In non-linear models, higher childhood mtDNAcn was associated with lower WISC Verbal Comprehension. Our study provides novel evidence that mtDNAcn measured in childhood is associated with children's neurocognitive performance. mtDNAcn may be a marker of healthy child development. Mitochondrial DNA copy number (mtDNAcn) may serve as a biomarker for early-life neurocognitive performances in the children's population. Both low and high mtDNAcn may contribute to poorer neurocognition, reflected through learning and memory abilities. This research elucidated the importance of investigating mitochondrial biomarkers in healthy populations and facilitated advancements of future studies to better understand the associations between mitochondrial markers and adverse children's health outcomes.

Systemic Inflammatory Effect of Hypobaria During Aeromedical Evacuation after Porcine Traumatic Brain Injury.

Traumatic brain injury (TBI)-related morbidity is caused largely by secondary injury resulting from hypoxia, excessive sympathetic drive, and uncontrolled inflammation. Aeromedical evacuation (AE) is used by the military for transport of wounded soldiers to higher levels of care. We hypothesized that the hypobaric, hypoxic conditions of AE may exacerbate uncontrolled inflammation after TBI that could contribute to more severe TBI-related secondary injury. Thirty-six female pigs were used to test TBI vs Sham TBI, hypoxia vs normoxia, and hypobaria vs ground conditions. TBI was induced by controlled cortical injury, hypobaric conditions of 12,000 ft were established in an altitude chamber, and hypoxic exposure was titrated to 85% SpO 2 while at altitude. Serum cytokines, ubiquitin C-terminal hydrolase L1, and TBI biomarkers were analyzed via ELISA. Gross analysis and staining of cortex and hippocampus tissue was completed for glial fibrillary acidic protein and phosphorylated tau. Serum interleukin-1β, interleukin-6, and tumor necrosis factor-α were significantly elevated after TBI in pigs exposed to altitude-induced hypobaria/hypoxia, as well as hypobaria alone, compared with ground level/normoxia. No difference in TBI biomarkers after TBI or hypobaric, hypoxic exposure was noted. No difference in brain tissue glial fibrillary acidic protein or phosphorylated tau when comparing the most different conditions of Sham TBI + ground or normoxia with the TBI + hypobaria/hypoxia group was noted. The hypobaric environment of AE induces systemic inflammation after TBI. Severe inflammation may play a role in exacerbating secondary injury associated with TBI and contribute to worse neurocognitive outcomes. Measures should be taken to minimize barometric and oxygenation changes during AE after TBI.

Safety and efficacy of iron supplementation with 3 months of daily ferrous sulphate in children living with HIV and mild-to-moderate anaemia in Uganda: a double-blind, randomised, placebo-controlled trial

Iron deficiency is the most common nutritional deficiency in the world, but iron supplementation can increase risk of opportunistic infections, especially in children living with HIV. We aimed to assess the effect of supplemental iron on haemoglobin concentration in children living with HIV and mild-to-moderate anaemia in Uganda. We did a double-blind, randomised, placebo-controlled trial of iron supplementation in children aged 6 months to 12 years living with HIV at two sites (ie, Kampala and Fort Portal, Uganda). Inclusion criteria were confirmed diagnosis of HIV and stable treatment with antiretroviral therapy for at least 6 months. Exclusion criteria were already taking iron supplementation, acute illness, current opportunistic infection, fever, known sickle cell disease, severe undernutrition, or any chronic illness requiring medical attention. Children were randomly assigned (1:1) via simple randomisation to an 84-day course of either ferrous sulphate or identical placebo tablets once per day. Randomisation codes were computer-generated and stratified by age (ie, 6-23 months or 24 months and older) by the Toronto Institute of Pharmaceutical Technology, the tablet manufacturer. Participants and all individuals giving the interventions, assessing outcomes, and analysing data were masked to group assignment. Children aged 6-23 months received tablets of 12·5 mg ferrous sulphate or identical placebo; children aged 24 months or older received tablets of 30·0 mg ferrous sulphate or identical placebo. Caregivers were instructed to give the supplement after a meal, preferably after an evening meal. The primary outcome was mean haemoglobin concentration at day 84. All analyses were intention to treat. This trial is registered at ClinicalTrials.gov (NCT03596996). Between May 5, 2018, and Nov 6, 2019, 973 children living with HIV were screened, of whom 200 (20%) met all inclusion criteria and were enrolled. 102 (51%) were randomly assigned to receive iron and 98 (49%) to receive placebo. In the iron group, 57 (56%) of 102 children were male and 45 (44%) were female. In the placebo group, 44 (45%) of 98 children were male and 54 (55%) were female. Iron supplementation was associated with improvement in haemoglobin in unadjusted analysis (p=0·029), but not adjusted analysis (p=0·10), and with improvement in ferritin and hepcidin in both adjusted (p=0·0046; p=0·0079) and unadjusted (p<0·0001; p<0·0001) analyses at day 84. There were four hospital admissions, all for children in the iron group; none were fatal: two children were admitted to hospital with pneumonia, one with severe malaria, and one with hepatitis. Frequency of admissions was not significantly different between groups (p=0·12). Iron could have haematological benefit and improve iron status in children living with HIV in Uganda. Future studies powered for morbidity outcomes with longer follow-up are needed, as are those that evaluate the effects of iron supplementation on neurocognitive outcomes. Minnesota Masonic Charities, the Department of Pediatrics at the University of Minnesota, the Hennepin Healthcare Research Institute, and the US National Institutes of Health.

12566 Adult Growth Hormone Deficiency, Replacement Therapy Use, and IGF1 Levels in Association with Physical, Psychosocial, and Neurocognitive Outcomes Among Childhood Cancer Survivors

Abstract Disclosure: T. Yoshida: None. J.L. Baedke: None. H. Wang: None. C.H. Yu: None. C.L. Wilson: None. D.A. Mulrooney: None. S.B. Dixon: None. I. Huang: None. T.M. Brinkman: None. K.R. Krull: None. S. Mostoufi-Moab: None. J. Miguel Martínez: None. K.K. Ness: None. M.M. Hudson: None. Y. Yasui: None. A. Delaney: None. Background: Adult growth hormone deficiency (aGHD) is a common and often untreated late effect among childhood cancer survivors. Untreated aGHD likely adds to the burden of health outcomes in survivors already experiencing cancer treatment related late toxicities. As comprehensive data on the consequences of untreated aGHD in survivors are scarce, we assessed the clinical impact of untreated aGHD among survivors, together with socioeconomic factors as potential contributing factors, utilizing a large, clinically characterized cohort of childhood cancer survivors. Methods: 3902 five-year survivors ≥ 18 years old [median (25th-75th percentile) age, 31.7y (25.2-40.0); age at cancer diagnosis 8.1y (3.5-13.6); 47.5% female] were examined. We assessed the: 1) proportion of survivors with aGHD on GH therapy (GHT); 2) association between GHT and socioeconomic factors (e.g., household income, area deprivation index) by multivariable logistic regression; and 3) associations between age- and sex-adjusted insulin-like growth factor 1 (IGF1) z-score and prevalence of clinically-assessed (i.e., body composition, metabolic/cardiovascular factors, neurocognitive function) and self-reported [i.e., quality of life (QoL), emotional symptom] outcomes by multivariable logistic regression with trend test, adjusting for potential confounders (e.g., radiation to the hypothalamic-pituitary region). Results: aGHD was observed in 9.1% (354/3902) of survivors; among them, 9.0% (32/354) were on GHT. Survivors on GHT were more likely to have higher household income, hold health insurance, and reside in less socioeconomically disadvantaged neighborhoods, compared to survivors with untreated aGHD. Socioeconomic factors had significant independent associations with GHT use in multivariable analysis [e.g., annual household income &amp;lt;$40,000 vs. ≥$80,000, adjusted odds ratio (aOR) of GHT use, 0.28; 95% confidence interval (CI), 0.08-0.86]. Lower IGF1 z-score (IGF1 z-score ≤ -2, vs. IGF1 z-score &amp;gt;0) was associated with a higher prevalence of various outcomes (aOR, 95% CI), such as abdominal obesity (2.56, 1.98-5.26), weak handgrip strength (2.49, 1.65-3.73), hypertension (1.47, 1.06-2.04), abnormal glucose metabolism (2.07, 1.49-2.86), impaired health-related QoL (e.g., physical functioning, 1.97, 1.35-2.86), depression (1.58, 1.06-2.33), and impairment in multiple neurocognitive functions (e.g., verbal reasoning, a global measure of intelligence, 2.22, 1.49-3.30) with a dose-response relationship. Conclusions: Our data support a negative impact of untreated aGHD on physical, psychosocial, and neurocognitive outcomes among survivors and suggest the potential of GHT to improve QoL of survivors with aGHD. As lower socioeconomic status may affect survivors’ access to GHT, this disparity should be considered in interventions evaluating GHT for survivors with aGHD. Presentation: 6/3/2024

"Navigating moyamoya: bridging gaps in neurocognitive outcomes through STA-ACA bypass".

With its bimodal age distribution, higher prevalence in Far East Asian populations, and significant risk of ischemic stroke, Moyamoya disease (MMD) poses a distinctive clinical challenge. In a recently published study by Sho Tsunoda et al., the neurocognitive results of patients with MMD undergoing revascularization surgery were assessed, highlighting the potential advantages of superficial temporal artery to anterior cerebral artery (STA-ACA) direct bypass in ameliorating neuropsychological impairment. Despite its propitious findings, the study's limitations-including a small sample size, single-center design, and lack of long-term follow-up-underscore the need for further research. Future multicenter, prospective trials with larger patient cohorts and comprehensive neurocognitive assessments are essential to validate these results and enhance the generalizability of the findings. This letter emphasizes the importance of robust study designs in advancing our understanding of MMD treatment and ensuring better patient outcomes.

Assessment of Adaptive Functioning and the Impact ofSeizures in KBG Syndrome.

This study aimed to examine the adaptive functioning status and the impact of epileptic seizures on neurocognitive outcomes in KBG syndrome, a rare genetic neurodevelopmental disorder characterized by pathogenic variants in ANKRD11. A single clinician interviewed individuals and families with genetically confirmed cases of KBG syndrome. Trained professionals also conducted assessments using the Vineland-3 Adaptive Behavior Scales. The assessment covered the domains of communication, daily living skills, socialization, and maladaptive behaviors, and then compared individuals with and without epilepsy. Further comparisons were made with data from interviews and participants' medical records. Thirty-nine individuals (22 males, 17 females) with KBG syndrome, confirmed through genetic analysis, were interviewed via videoconferencing, followed by Vineland-3 assessment by trained raters. Individuals with KBG syndrome came from 36 unique families spanning 11 countries. While the KBG cohort displayed lower overall adaptive behavior composite scores compared with the average population, several members displayed standard scores at or higher than average, as well as higher scores compared with those with the neurodevelopmental disorder Ogden syndrome. Within the KBG cohort, males consistently scored lower than females across all domains, but none of these categories reached statistical significance. While the group with epilepsy exhibited overall lower scores than the nonseizure group in every category, statistical significance was only reached in the written communication subdomain. Our research provides insights that can aid in epilepsy screening and inform assessment strategies for neurocognitive functioning in those with this condition. The cohort performed overall higher than expected, with outliers existing in both directions. Although our results suggest that seizures might influence the trajectory of KBG syndrome, the approaching but overall absence of statistical significance between study groups underscores the need for a more extensive cohort to discern subtle variations in functioning.

Perinatal risk factors and neurocognitive outcomes in children and adolescents with sickle cell disease.

The literature on cognitive and academic outcomes for children with sickle cell disease (SCD) who experience perinatal risk factors is limited. We aimed to evaluate if low birthweight (LBW), gestational age, and history of neonatal intensive care unit (NICU) admission were associated with neurocognitive functioning, grade retention, or receipt of early intervention or formal educational support in children with SCD. This prospective birth cohort study included 336 participants, ages 8-18, with SCD, who received cognitive testing as part of standard of care and whose caregivers completed behavioral rating scales. Multivariable generalized linear regression models were used to examine associations between perinatal risks and outcome variables, after adjusting for demographic and medical covariates. The prevalence of NICU admission and LBW were 12.03% and 13.50%, respectively. Lower birthweight, earlier gestational age, and NICU admission were associated with worse working memory performance and receipt of early intervention services. Lower birthweight and NICU admission were also associated with slower processing speed. History of NICU admission was associated with caregiver ratings of hyperactivity and emotional dysregulation. The effects of perinatal risk factors on neurocognitive, academic, or educational outcomes were not dependent on SCD genotype. History of LBW or NICU admission was associated with worse cognitive outcomes and increased use of early intervention services among children with SCD. Early identification of perinatal risk factors will help identify children who will benefit from formal developmental or neuropsychological evaluations to manage the comorbidity of SCD and perinatal risks and facilitate increased intervention.