Neuroimaging Biomarkers in Paediatric Sickle Cell Disease

Sickle Cell Disease (SCD) is a collection of genetic haemoglobinopathies, the most common and severe being homozygous sickle cell anaemia. In the UK, it has been estimated that 1 in 2000 children are born with SCD. The disease is characterised by chronic anaemia, recurrent pain crises and vascular occlusion. Neurologically, there is a high incidence of stroke in childhood, as well as cognitive dysfunction. Newborn screening programmes and preventative treatments have allowed a much longer lifespan; however recently, neurological research has shifted to characterising subtler aspects of brain development and functioning that may be critically important to the individual’s quality of life. This thesis overviews the neurological and neurocognitive complications of SCD, and how magnetic resonance imaging (MRI) can provide biomarkers for severity of disease. During the PhD, retrospective and prospective cognitive and MRI data were collected and analysed. Diagnostic clinical MRI sequences and advanced MRI sequences were applied, as well as a neuropsychological test battery aimed at intelligence and executive function. First, this thesis reviews the intelligence literature in SCD and includes previously unreported data, finding patients, regardless of abnormality seen on conventional MRI, have lowered full-scale intelligence quotient than controls. Then, to determine imaging biomarkers, volumetric differences and diffusion characteristics were identified. Patients were found to have decreased volumes of subcortical structures compared to controls, in groups corresponding to disease severity. Results from a three-year longitudinal clinical trial suggest evidence of atrophy in paediatric patients, with no apparent protective effect of treatment. Diffusion tensor imaging revealed reduced white matter integrity across the brain, correlating with recognised markers of disease severity (i.e. oxygen saturation and haemoglobin from a full blood count). Overall, the four experiments bridge a gap in the cognitive and neuroimaging literature of the extent of neurological injury in children with SCD

Intelligence quotient in paediatric sickle cell disease: a systematic review and meta-analysis

AIM: Sickle cell disease (SCD) is the commonest cause of childhood stroke worldwide. Magnetic resonance imaging (MRI) is routinely used to detect additional silent cerebral infarction (SCI), as IQ is lower in SCI as well as stroke. This review assesses the effect of infarction on IQ, and specifically whether, compared to healthy controls, IQ differences are seen in children with SCI with no apparent MRI abnormality. METHOD: A systematic review was conducted to include articles with an SCD paediatric population, MRI information, and Wechsler IQ. A meta-analysis of 19 articles was performed to compare IQ in three groups: stroke vs SCI; SCI vs no SCI; and no SCI vs healthy controls. RESULTS: Mean differences in IQ between all three groups were significant: stroke patients had lower IQ than patients with SCI by 10 points (six studies); patients with SCI had lower IQ than no patients with SCI by 6 points (17 studies); and no patients with SCI had lower IQ than healthy controls by 7 points (seven studies). INTERPRETATION: Children with SCD and no apparent MRI abnormality have significantly lower IQ than healthy controls. In this chronic condition, other biological, socioeconomic, and environmental factors must play a significant role in cognition

MRI detection of brain abnormality in sickle cell disease

Introduction: Over the past decades, neuroimaging studies have clarified that a significant proportion of patients with sickle cell disease (SCD) have functionally significant brain abnormalities. Clinically, structural magnetic resonance imaging (MRI) sequences (T2, FLAIR, diffusion-weighted imaging) have been used by radiologists to diagnose chronic and acute cerebral infarction (both overt and clinically silent), while magnetic resonance angiography and venography have been used to diagnose arteriopathy and venous thrombosis. In research settings, imaging scientists are increasingly applying quantitative techniques to shine further light on underlying mechanisms. Areas covered: From a June 2020 PubMed search of ‘magnetic’ or ‘MRI’ and ‘sickle’ over the previous 5 years, we selected manuscripts on T1-based morphometric analysis, diffusion tensor imaging, arterial spin labeling, T2-oximetry, quantitative susceptibility, and connectivity. Expert Opinion: Quantitative MRI techniques are identifying structural and hemodynamic biomarkers associated with risk of neurological and neurocognitive complications. A growing body of evidence suggests that these biomarkers are sensitive to change with treatments, such as blood transfusion and hydroxyurea, indicating that they may hold promise as endpoints in future randomized clinical trials of novel approaches including hemoglobin F upregulation, reduction of polymerization, and gene therapy. With further validation, such techniques may eventually also improve neurological and neurocognitive risk stratification in this vulnerable population

Vascular Instability and Neurological Morbidity in Sickle Cell Disease: An Integrative Framework

It is well-established that patients with sickle cell disease (SCD) are at substantial risk of neurological complications, including overt and silent stroke, microstructural injury, and cognitive difficulties. Yet the underlying mechanisms remain poorly understood, partly because findings have largely been considered in isolation. Here, we review mechanistic pathways for which there is accumulating evidence and propose an integrative systems-biology framework for understanding neurological risk. Drawing upon work from other vascular beds in SCD, as well as the wider stroke literature, we propose 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. We suggest that in this state, tissue oxygen supply is fragile and easily perturbed by changes in clinical condition, with the potential for stroke and/or microstructural injury if metabolic demand exceeds tissue oxygenation. This framework brings together recent developments in the field, highlights outstanding questions, and offers a first step toward a linking pathophysiological explanation of neurological risk that may help inform future screening and treatment strategies

Effectiveness of a Smartphone App (BioBase) for Reducing Anxiety and Increasing Mental Well-Being: Pilot Feasibility and Acceptability Study

This is the final version. Available on open access from JMIR Publications via the DOI in this recordBACKGROUND: The prevalence of workplace-related stress and anxiety is high, resulting in stress-related physical and mental illness. Digital self-guided interventions aimed at key areas of workplace design may be able to provide remote anxiolytic effects. OBJECTIVE: The aim of this feasibility study is to assess changes in anxiety and mental wellbeing after use of the BioBase programme, a mobile phone platform for psycho-educational modules, tools and real-time feedback of physiological data. METHODS: A four-week observational study was carried out in 55 healthy adults who were screened for stress with the Depression Anxiety Stress Scales (DASS) Stress subscale. Participants completed anxiety (6-item State-Trait Anxiety Inventory; STAI) and mental wellbeing (Warwick-Edinburgh Mental Wellbeing Scale; WEMWBS) questionnaires at baseline and at 4 weeks. Feedback questionnaires were administered after 4 weeks. RESULTS: After 4 weeks of using the programme and controlling for any effect of being paid to take part in the study, STAI significantly decreased (baseline mean= 45.52 ± 13.2, 4-weeks mean: 39.82 ± 11.2, t54 = -3.51, P < 0.001, CI: -8.88 - -2.52, Cohen's d = 0.96) and WEMWBS significantly increased (baseline mean = 48.12 ± 6.4, 4-weeks mean: 50.4 ± 6.9, t53 = 2.41, p = 0.019, CI: 0.44-4.23, Cohen's d = 0.66). Further, higher baseline stress was significantly associated with a greater decrease in STAI (t53 = -3.41, P = 0.001, CI: -8.10- -2.10, R2 = 0.180) and a greater increase in WEMWBS (t52 = 2.41, P = 0.019, CI: 0.38 - 4.11, R2 = 0.101). On feedback, participants found the programme easy to use navigate, with the content being acceptable and relevant to workplace-related stressors. 70% of participants would recommend the programme to a friend. CONCLUSIONS: The BioBase programme is a potentially effective intervention in decreasing anxiety and increasing mental wellbeing, with larger changes in those with higher baseline levels of stress. CLINICALTRIAL

Efficacy of the Digital Therapeutic Mobile App "BioBase" to Reduce Stress and Improve Mental Wellbeing Among University Students: a Randomized Controlled Trial.

This is the author accepted manuscript. The final version is available from JMIR Publications via the DOI in this record.BACKGROUND: UK university students are experiencing increasing levels of anxiety. A programme designed to increase awareness of one's present levels of wellbeing and suggest personalized health behaviours may reduce anxiety and improve mental wellbeing in students. The efficacy of a digital version of such a programme, providing biofeedback and therapeutic content based on personalized wellbeing metrics, is reported here. OBJECTIVE: The aim of this study was to test the efficacy and sustained effects of using a mobile app (BioBase) and paired wearable device (BioBeam), compared to a wait-list control group, on anxiety and wellbeing in university students with elevated levels of anxiety and stress. METHODS: The study employed a randomized, wait-list controlled, trial with assessments at baseline, 2-weeks, post-intervention (4 weeks), and at follow-up (6 weeks). Participants were eligible if they were current full-time undergraduate students and (1) at least 18 years of age, (2) scored >14 points on the DASS-21 stress subscale or > 7 points on the DASS-21 anxiety subscale, (3) owned an iOS smartphone, (4) did not have any previous psychiatric or neurological conditions, (6) were not pregnant at the time of testing, and (7) were able to read and understand English. Participants were encouraged to use BioBase daily and complete at least one course of therapeutic content. A p value ≤.05 was considered statistically significant. RESULTS: We found that a 4-weeks intervention with the BioBase programme significantly reduced anxiety and increased perceived wellbeing, with sustained effects at a 2-weeks follow-up. Furthermore, a significant reduction in depression levels was found following 4-weeks usage of Biobase. CONCLUSIONS: This study shows the efficacy of a biofeedback digital intervention in reducing self-reported anxiety and increasing perceived wellbeing in UK university students. Results suggest that digital mental health interventions could constitute a novel approach to treat stress and anxiety in students, which could be combined, or integrated with, existing therapeutic pathways. CLINICALTRIAL: https://osf.io/2w5sy/

Cerebral Infarcts and Vasculopathy in Tanzanian Children With Sickle Cell Anemia

BACKGROUND: Cerebral infarcts and vasculopathy in neurologically asymptomatic children with sickle cell anemia (SCA) have received little attention in African settings. This study aimed to establish the prevalence of silent cerebral infarcts (SCI) and vasculopathy and determine associations with exposure to chronic hemolysis, anemia, and hypoxia. METHODS: We prospectively studied 224 children with SCA with transcranial Doppler (TCD), and magnetic resonance imaging (MRI) and magnetic resonance angiography (MRA). Regressions were undertaken with contemporaneous hemoglobin, reticulocyte count, mean prior hemoglobin, oxygen content, reticulocyte count, and indirect bilirubin. RESULTS: Prevalence of SCI was 27% (61 of 224); cerebral blood flow velocity was abnormal (>200 cm/s) in three and conditional (>170<200 cm/s) in one. Vasculopathy grades 2 (stenosis) and 3 (occlusion) occurred in 16 (7%) and two (1%), respectively; none had grade 4 (moyamoya). SCI was associated with vasculopathy on MRA (odds ratio 2.68; 95% confidence intervals [95% CI] 1.32 to 5.46; P = 0.007) and mean prior indirect bilirubin (odds ratio 1.02, 95% CI 1.00 to 1.03, P = 0.024; n = 83) but not age, sex, non-normal TCD, or contemporaneous hemoglobin. Vasculopathy was associated with mean prior values for hemoglobin (odds ratio 0.33, 95% CI 0.16 to 0.69, P = 0.003; n = 87), oxygen content (odds ratio 0.43, 95% CI 0.25 to 0.74, P = 0.003), reticulocytes (odds ratio 1.20, 95% CI 1.01-1.42, P = 0.041; n = 77), and indirect bilirubin (odds ratio 1.02, 95% CI 1.01 to 1.04, P = 0.009). CONCLUSIONS: SCI and vasculopathy on MRA are common in neurologically asymptomatic children with SCA living in Africa, even when TCD is normal. Children with vasculopathy on MRA are at increased risk of SCI. Longitudinal exposure to anemia, hypoxia, and hemolysis appear to be risk factors for vasculopathy

Development and Feasibility of a Digital Acceptance and Commitment Therapy-Based Intervention for Generalized Anxiety Disorder: Pilot Acceptability Study

This is the final version. Available on open access from JMIR Publications via the DOI in this recordBACKGROUND: Generalized anxiety disorder (GAD) is characterized by excessive worry that is difficult to control and has high comorbidity with mood disorders including depression. Individuals experience long wait times for diagnosis and often face accessibility barriers to treatment. There is a need for a digital solution that is accessible and acceptable to those with GAD. OBJECTIVE: This paper aims to describe the development of a digital intervention prototype of acceptance and commitment therapy (ACT) for GAD that sits within an existing well-being app platform, BioBase. A pilot feasibility study evaluating acceptability and usability is conducted in a sample of adults with a diagnosis of GAD, self-referred to the study. METHODS: Phase 1 applied the person-based approach (creation of guiding principles, intervention design objectives, and the key intervention features). In Phase 2 participants received the app-based therapeutic and paired wearable for 2 weeks. Self-report questionnaires were obtained at baseline and posttreatment. The primary outcome was psychological flexibility (Acceptance and Action Questionnaire-II [AAQ-II]) as this is the aim of ACT. Mental well-being (Warwick-Edinburgh Mental Well-being Scale [WEMWBS]) and symptoms of anxiety (7-item Generalized Anxiety Disorder Assessment [GAD-7]) and depression (9-item Patient Health Questionnaire [PHQ-9]) were also assessed. Posttreatment usability was assessed via self-report measures (System Usability Scale [SUS]) in addition to interviews that further explored feasibility of the digital intervention in this sample. RESULTS: The app-based therapeutic was well received. Of 13 participants, 10 (77%) completed the treatment. Results show a high usability rating (83.5). Participants found the digital intervention to be relevant, useful, and helpful in managing their anxiety. Participants had lower anxiety (d=0.69) and depression (d=0.84) scores at exit, and these differences were significantly different from baseline (P=.03 and .008 for GAD-7 and PHQ-9, respectively). Participants had higher psychological flexibility and well-being scores at exit, although these were not significantly different from baseline (P=.11 and .55 for AAQ-II and WEMWBS, respectively). CONCLUSIONS: This ACT prototype within BioBase is an acceptable and feasible digital intervention in reducing symptoms of anxiety and depression. This study suggests that this intervention warrants a larger feasibility study in adults with GAD.European Union Horizon 202

Venous cerebral blood flow quantification and cognition in patients with sickle cell anemia

Prior studies have described high venous signal qualitatively using arterial spin labelling (ASL) in patients with sickle cell anemia (SCA), consistent with arteriovenous shunting. We aimed to quantify the effect and explored cross-sectional associations with arterial oxygen content (CaO2), disease-modifying treatments, silent cerebral infarction (SCI), and cognitive performance. 94 patients with SCA and 42 controls underwent cognitive assessment and MRI with single- and multi- inflow time (TI) ASL sequences. Cerebral blood flow (CBF) and bolus arrival time (BAT) were examined across gray and white matter and high-signal regions of the sagittal sinus. Across gray and white matter, increases in CBF and reductions in BAT were observed in association with reduced CaO2 in patients, irrespective of sequence. Across high-signal sagittal sinus regions, CBF was also increased in association with reduced CaO2 using both sequences. However, BAT was increased rather than reduced in patients across these regions, with no association with CaO2. Using the multiTI sequence in patients, increases in CBF across white matter and high-signal sagittal sinus regions were associated with poorer cognitive performance. These novel findings highlight the utility of multiTI ASL in illuminating, and identifying objectively quantifiable and functionally significant markers of, regional hemodynamic stress in patients with SCA

Study of montelukast in children with sickle cell disease (SMILES): a study protocol for a randomised controlled trial

BACKGROUND: Young children with sickle cell anaemia (SCA) often have slowed processing speed associated with reduced brain white matter integrity, low oxygen saturation, and sleep-disordered breathing (SDB), related in part to enlarged adenoids and tonsils. Common treatments for SDB include adenotonsillectomy and nocturnal continuous positive airway pressure (CPAP), but adenotonsillectomy is an invasive surgical procedure, and CPAP is rarely well-tolerated. Further, there is no current consensus on the ability of these treatments to improve cognitive function. Several double-blind, randomised controlled trials (RCTs) have demonstrated the efficacy of montelukast, a safe, well-tolerated anti-inflammatory agent, as a treatment for airway obstruction and reducing adenoid size for children who do not have SCA. However, we do not yet know whether montelukast reduces adenoid size and improves cognition function in young children with SCA. METHODS: The Study of Montelukast In Children with Sickle Cell Disease (SMILES) is a 12-week multicentre, double-blind, RCT. SMILES aims to recruit 200 paediatric patients with SCA and SDB aged 3-7.99 years to assess the extent to which montelukast can improve cognitive function (i.e. processing speed) and sleep and reduce adenoidal size and white matter damage compared to placebo. Patients will be randomised to either montelukast or placebo for 12 weeks. The primary objective of the SMILES trial is to assess the effect of montelukast on processing speed in young children with SCA. At baseline and post-treatment, we will administer a cognitive evaluation; caregivers will complete questionnaires (e.g. sleep, pain) and measures of demographics. Laboratory values will be obtained from medical records collected as part of standard care. If a family agrees, patients will undergo brain MRIs for adenoid size and other structural and haemodynamic quantitative measures at baseline and post-treatment, and we will obtain overnight oximetry. DISCUSSION: Findings from this study will increase our understanding of whether montelukast is an effective treatment for young children with SCA. Using cognitive testing and MRI, the SMILES trial hopes to gain critical knowledge to help develop targeted interventions to improve the outcomes of young children with SCA. TRIAL REGISTRATION: ClinicalTrials.gov NCT04351698 . Registered on April 17, 2020. European Clinical Trials Database (EudraCT No. 2017-004539-36). Registered on May 19, 2020