Tele-neuropsychological Assessment of Children and Young People: A Systematic Review

The coronavirus pandemic identified a clinical need for pediatric tele-neuropsychology (TeleNP) assessment. However, due to limited research, clinicians have had little information to develop, adapt, or select reliable pediatric assessments for TeleNP. This preliminary systematic review aimed to examine the feasibility of pediatric TeleNP assessment alongside (1) patient/family acceptability, (2) reliability, and (3) the quality of the literature. Between May 2021 and November 2022, manual searches of PubMed, PsycINFO, and Google Scholar were conducted using terms related to “pediatric” and “tele-neuropsychology.” After extracting relevant papers with samples aged 0–22 years, predefined exclusion criteria were applied. Quality assessment was completed using the AXIS appraisal tool (91% rater-agreement). Twenty-one studies were included in the review, with reported qualitative and quantitative data on the feasibility, reliability, and acceptability extracted. Across included studies, TeleNP was completed via telephone/video conference with participants either at home, in a local setting accompanied by an assistant, or in a different room but in the same building as the assessor. Pediatric TeleNP was generally reported to be feasible (e.g., minimal behavioral differences) and acceptable (e.g., positive feedback). Nineteen studies conducted some statistical analyses to assess reliability. Most observed no significant difference between in-person and TeleNP for most cognitive domains (i.e., IQ), with a minority finding variable reliability for some tests (e.g., attention, speech, visuo-spatial). Limited reporting of sex-assigned birth, racialized identity, and ethnicity reduced the quality and generalizability of the literature. To aid clinical interpretations, studies should assess underexamined cognitive domains (e.g., processing speed) with larger, more inclusive samples

Mind the gap: trajectory of cognitive development in young individuals with sickle cell disease: a cross-sectional study

STUDY OBJECTIVES: Compared to typically developing children and young adults (CYA-TD), those living with Sickle Cell Disease (CYA-SCD) experience more cognitive difficulties, particularly with executive function. Few studies have examined the relative importance of silent cerebral infarction (SCI), haemoglobin and arterial oxygen content on age-related cognitive changes using cross-sectional or longitudinal (developmental trajectory) data. This study presents cohort data from a single timepoint to inform studies with multiple timepoints. METHODS: We compared cross-sectional raw and scaled scores as age-related changes in cognition (trajectories) in CYA-SCD and age-and ethnicity-matched CYA-TD. We also compared cross-sectional age-related changes in cognition (trajectories) in CYA-SCD with and without SCI to CYA-TD. General cognitive abilities were assessed using Wechsler Intelligence Scales, including the Verbal Comprehension Index (VCI) and Perceptual Reasoning Index (PRI) underpinning IQ. Executive function was evaluated using the Delis-Kaplan Executive Function System (D-KEFS) Tower subtest and the Behaviour Rating Inventory of Executive Function (BRIEF) questionnaire. SCI were identified from contemporaneous 3 T MRI; participants with overt stroke were excluded. Recent haemoglobin was available and oxygen saturation (SpO2) was measured on the day of the MRI. RESULTS: Data were available for 120 CYA-SCD [62 male; age = 16.78 ± 4.79 years; 42 (35%) with SCI] and 53 CYA-TD (23 male; age = 17.36 ± 5.16). Compared with CYA-TD, CYA-SCD experienced a delayed onset in VCI and slower rate of development for BRIEF Global Executive Composite, Metacognition Index (MI), and Behaviour Regulation Index. The rate of executive function development for the BRIEF MI differed significantly between CYA-TD and CYA-SCD, with those with SCI showing a 26% delay compared with CYA-TD. For CYA-SCD with SCI, arterial oxygen content explained 22% of the variance in VCI and 37% in PRI, while haemoglobin explained 29% of the variance in PRI. CONCLUSION: Age-related cognitive trajectories of CYA-SCD may not be impaired but may progress more slowly. Longitudinal studies are required, using tests unaffected by practice. In addition to initiation of medical treatment, including measures to improve arterial oxygen content, early cognitive intervention, educational support, and delivery of extracurricular activities could support cognitive development for CYA-SCD.Graphical Abstract

Quantitative susceptibility mapping (QSM) and R2* of silent cerebral infarcts in sickle cell anemia

Silent cerebral infarction (SCI) is the most commonly reported radiological abnormality in patients with sickle cell anemia (SCA) and is associated with future clinical stroke risk. To date, there have been few histological and quantitative MRI studies of SCI and multiple radiological definitions exist. As a result, the tissue characteristics and composition of SCI remain elusive. The objective of this work was therefore to investigate the composition of segmented SCI lesions using quantitative MRI for R 2 * and quantitative magnetic susceptibility mapping (QSM). 211 SCI lesions were segmented from 32 participants with SCA and 6 controls. SCI were segmented according to two definitions (FLAIR+/-T1w-based threshold) using a semi-automated pipeline. Magnetic susceptibility (χ) and R 2 * maps were calculated from a multi-echo gradient echo sequence and mean SCI values were compared to an equivalent region of interest in normal appearing white matter (NAWM). SCI χ and R 2 * were investigated as a function of SCI definition, patient demographics, anatomical location, and cognition. Compared to NAWM, SCI were significantly less diamagnetic (χ = -0.0067 ppm vs. -0.0153 ppm, p < 0.001) and had significantly lower R 2 * (16.7 s-1 vs. 19.2 s-1, p < 0.001). SCI definition had a significant effect on the mean SCI χ and R 2 * , with lesions becoming significantly less diamagnetic and having significantly lower R 2 * after the application of a more stringent T1w-based threshold. SCI-NAWM R 2 * decrease was significantly greater in patients with SCA compared with controls (-2.84 s-1 vs. -0.64 s-1, p < 0.0001). No significant association was observed between mean SCI-NAWM χ or R2* differences and subject age, lesion anatomical location, or cognition. The increased χ and decreased R 2 * in SCI relative to NAWM observed in both patients and controls is indicative of lower myelin or increased water content within the segmented lesions. The significant SCI-NAWM R 2 * differences observed between SCI in patients with SCA and controls suggests there may be differences in tissue composition relative to NAWM in SCI in the two populations. Quantitative MRI techniques such as QSM and R 2 * mapping can be used to enhance our understanding of the pathophysiology and composition of SCI in patients with SCA as well as controls

Exploring the relationship of sleep, cognition, and cortisol in sickle cell disease

Background: Neurocognitive impairment is common in people with Sickle Cell Disease (SCD) and evidence is accumulating that sleep disturbances play a role. The interaction between cortisol and sleep in the general population is associated with cognition as well as general wellbeing but there are few data in SCD. We aimed to understand the relationship between cortisol and sleep in individuals with SCD and explored associations with cognition. Methods: Forty-five participants of black heritage (SCD: N = 27, 9–29 years, 16 females; Controls: N = 18, 11–25 years, 13 females) were recruited from the community between 2018 - 2020. Participants completed standardized questionnaires about their sleep behaviour and wore actigraphy MotionWatch8 for 7 nights to assess nocturnal sleep patterns. Salivary cortisol samples were taken on wakening and 3 times after 14:00. Cognition was assessed using the Wechsler Intelligence Scales for children and adults. Results: People with SCD took longer to fall asleep and experienced greater wake bouts, mobile minutes and fragmented sleep compared to controls. Although non-significant, people with SCD experienced lower morning cortisol, with a flattened diurnal cortisol ratio compared to controls. Interestingly, SCD participants, but not controls, with low diurnal variation scored lowest on processing speed (PSI) and perceptual reasoning index (PRI). A moderator analysis revealed that the effect of morning cortisol and diurnal cortisol ratio on PRI by group health (i.e., SCD and healthy controls) depended on sleep quality. Discussion: Sleep and cortisol may play a crucial role in the expression of cognitive difficulties seen in SCD. This should be considered for the development of interventions to optimise cognitive functioning and sleep. This, in turn, could positively impact on secretion of cortisol and general health in SCD

A Comparison of MRI Quantitative Susceptibility Mapping and TRUST-Based Measures of Brain Venous Oxygen Saturation in Sickle Cell Anaemia

In recent years, interest has grown in the potential for magnetic resonance imaging (MRI) measures of venous oxygen saturation (Yv) to improve neurological risk prediction. T2-relaxation-under-spin-tagging (TRUST) is an MRI technique which has revealed changes in Yv in patients with sickle cell anemia (SCA). However, prior studies comparing Yv in patients with SCA relative to healthy controls have reported opposing results depending on whether the calibration model, developed to convert blood T2 to Yv, is based on healthy human hemoglobin (HbA), bovine hemoglobin (HbBV) or sickle hemoglobin (HbS). MRI Quantitative Susceptibility Mapping (QSM) is an alternative technique that may hold promise for estimating Yv in SCA as blood magnetic susceptibility is linearly dependent upon Yv, and no significant difference has been found between the magnetic susceptibility of HbA and HbS. Therefore, the aim of this study was to compare estimates of Yv using QSM and TRUST with five published calibration models in healthy controls and patients with SCA. 17 patients with SCA and 13 healthy controls underwent MRI. Susceptibility maps were calculated from a multi-parametric mapping acquisition and Yv was calculated from the mean susceptibility in a region of interest in the superior sagittal sinus. TRUST estimates of T2, within a similar but much smaller region, were converted to Yv using five different calibration models. Correlation and Bland-Altman analyses were performed to compare estimates of Yv between TRUST and QSM methods. For each method, t-tests were also used to explore group-wise differences between patients with SCA and healthy controls. In healthy controls, significant correlations were observed between QSM and TRUST measures of Yv, while in SCA, there were no such correlations. The magnitude and direction of group-wise differences in Yv varied with method. The TRUST-HbBV and QSM methods suggested decreased Yv in SCA relative to healthy controls, while the TRUST-HbS (p < 0.01) and TRUST-HbA models suggested increased Yv in SCA as in previous studies. Further validation of all MRI measures of Yv, relative to ground truth measures such as O15 PET and jugular vein catheterization, is required in SCA before QSM or TRUST methods can be considered for neurological risk prediction

Effects of regional brain volumes on cognition in sickle cell anemia: A developmental perspective

BACKGROUND AND OBJECTIVES: Cognitive difficulties in people with sickle cell anemia (SCA) are related to lower processing speed index (PSI) and working memory index (WMI). However, risk factors are poorly understood so preventative strategies have not been explored. Brain volumes, specifically white matter volumes (WMV) which increases through early adulthood, have been associated with better cognition in healthy typically developing individuals. In patients with SCA, the reduced WMV and total subcortical volumes noted could explain cognitive deficits. We therefore examined developmental trajectories for regional brain volumes and cognitive endpoints in patients with SCA. METHODS: Data from two cohorts, the Sleep and Asthma Cohort and Prevention of Morbidity in SCA, were available. MRI data included T1-weighted axial images, pre-processed before regional volumes were extracted using Free-surfer. PSI and WMI from the Weschler scales of intelligence were used to test neurocognitive performance. Hemoglobin, oxygen saturation, hydroxyurea treatment and socioeconomic status from education deciles were available. RESULTS: One hundred and twenty nine patients (66 male) and 50 controls (21 male) aged 8-64 years were included. Brain volumes did not significantly differ between patients and controls. Compared with controls, PSI and WMI were significantly lower in patients with SCA, predicted by increasing age and male sex, with lower hemoglobin in the model for PSI but no effect of hydroxyurea treatment. In male patients with SCA only, WMV, age and socioeconomic status predicted PSI, while total subcortical volumes predicted WMI. Age positively and significantly predicted WMV in the whole group (patients + controls). There was a trend for age to negatively predict PSI in the whole group. For total subcortical volume and WMI, age predicted decrease only in the patient group. Developmental trajectory analysis revealed that PSI only was significantly delayed in patients at 8 years of age; the rate of development for the cognitive and brain volume data did not differ significantly from controls. DISCUSSION: Increasing age and male sex negatively impact cognition in SCA, with processing speed, also predicted by hemoglobin, delayed by mid childhood. Associations with brain volumes were seen in males with SCA. Brain endpoints, calibrated against large control datasets, should be considered for randomized treatment trials

Brain volume in Tanzanian children with sickle cell anaemia: A neuroimaging study

Brain injury is a common complication of sickle cell anaemia (SCA). White matter (WM) and cortical and subcortical grey matter (GM), structures may have reduced volume in patients with SCA. This study focuses on whether silent cerebral infarction (SCI), vasculopathy or anaemia affects WM and regional GM volumes in children living in Africa. Children with SCA (n = 144; aged 5-20 years; 74 male) and sibling controls (n = 53; aged 5-17 years; 29 male) underwent magnetic resonance imaging. Effects of SCI (n = 37), vasculopathy (n = 15), and haemoglobin were assessed. Compared with controls, after adjusting for age, sex and intracranial volume, patients with SCA had smaller volumes for WM and cortical, subcortical and total GM, as well as bilateral cerebellar cortex, globus pallidus, amygdala and right thalamus. Left globus pallidus volume was further reduced in patients with vasculopathy. Putamen and hippocampus volumes were larger in patients with SCA without SCI or vasculopathy than in controls. Significant positive effects of haemoglobin on regional GM volumes were confined to the controls. Patients with SCA generally have reduced GM volumes compared with controls, although some subcortical regions may be spared. SCI and vasculopathy may affect the trajectory of change in subcortical GM and WM volume. Brain volume in non-SCA children may be vulnerable to contemporaneous anaemia

Quantification of Silent Cerebral Infarction on High-Resolution FLAIR and Cognition in Sickle Cell Anemia

Research in sickle cell anemia (SCA) has used, with limited race-matched control data, binary categorization of patients according to the presence or absence of silent cerebral infarction (SCI). SCI have primarily been identified using low-resolution MRI, with radiological definitions varying in lesion length and the requirement for abnormality on both fluid attenuated inversion recovery (FLAIR) and T1-weighted images. We aimed to assess the effect of published SCI definitions on global, regional, and lobar lesion metrics and their value in predicting cognition. One hundred and six patients with SCA and 48 controls aged 8-30 years underwent 3T MRI with a high-resolution FLAIR sequence and Wechsler cognitive assessment. Prevalence, number, and volume of lesions were calculated using a semi-automated pipeline for SCI defined as: (1) Liberal: any length (L-SCI); (2) Traditional: >3 mm in greatest dimension (T-SCI); (3) Restrictive; >3 mm in greatest dimension with a corresponding T1-weighted hypo-intensity (R-SCI). Globally, as hypothesized, there were large effects of SCI definition on lesion metrics in patients and controls, with prevalence varying from 24-42% in patients, and 4-23% in controls. However, contrary to hypotheses, there was no effect of any global metric on cognition. Regionally, there was a consistent distribution of SCI in frontal and parietal deep and juxta-cortical regions across definitions and metrics in patients, but no consistent distribution in controls. Effects of regional SCI metrics on cognitive performance were of small magnitude; some were paradoxical. These findings expose the challenges associated with the widespread use of SCI presence as a biomarker of white-matter injury and cognitive dysfunction in cross-sectional high-resolution MRI studies in patients with SCA. The findings indicate that with high-resolution MRI: (1) radiological definitions have a large effect on resulting lesion groups, numbers, and volumes; (2) there is a non-negligible prevalence of lesions in young healthy controls; and (3) at the group-level, there is no cross-sectional association between global lesion metrics and general cognitive impairment irrespective of lesion definition and metric. With high-resolution multi-modal MRI, the dichotomy of presence or absence of SCI does not appear to be a sensitive biomarker for the detection of functionally significant pathology; the search for appropriate endpoints for clinical treatment trials should continue

Vascular Instability and Neurological Morbidity in Sickle Cell Disease

It is well-established that patients with sickle cell disease (SCD) are at substantial risk of neurological complications, including overt stroke, silent cerebral infarction, microstructural tissue injury, and cognitive impairment. Yet the underlying mechanisms remain poorly understood, partly because findings have largely been considered in isolation. This thesis reviews mechanistic pathways for which there is accumulating evidence and proposes an integrative systems-biology framework for understanding neurological risk. The framework proposes that macro-circulatory hyper-perfusion, regions of relative micro- circulatory hypo-perfusion, and an exhaustion of cerebral reserve mechanisms, together lead to a state of cerebral vascular instability. In this state, tissue oxygen supply is fragile and easily perturbed by changes in clinical condition, with the potential for stroke, SCI, and/or microstructural tissue injury if metabolic demand exceeds tissue oxygenation; all of which may increase the risk of cognitive impairment. The thesis then describes three original cross- sectional research studies in which quantitative MRI methods are used to identify potential biomarkers that may serve to indirectly interrogate parts of the proposed framework. The first study explores silent cerebral infarction, with a comprehensive analysis of the effects of published radiological definitions on quantitative lesion metrics, and explores the value of global, regional, and lobar lesion metrics based on different definitions for prediction of cognitive outcome. The second study focuses on microstructural tissue injury, employing novel diffusion and multiparametric mapping techniques to explore tissue changes both in normal appearing white matter and silent cerebral infarction, as well as any relationships between them. The third study employs arterial spin labeling techniques to identify potential quantitative biomarkers of regional haemodynamic stress, and explores associations with exposure to hypoxia, structural tissue injury (i.e. SCI and white matter integrity reductions), and cognitive outcome. Findings are considered in the context of the proposed framework, and suggestions for future research to further refine the framework are provided