Exploring the mental health of adolescent parent families affected by HIV within the Eastern Cape province of South Africa: Addressing a critical evidence gap

Adolescent (10-19 years) pregnancy and poor adolescent mental health remain prominent global health issues. Sub-Saharan Africa has the highest rates of adolescent pregnancy globally and is the epicentre of the global HIV epidemic – both phenomena are associated with poor mental health. This thesis explores the potential synergistic impacts when adolescent pregnancy and HIV co-occur by examining i) prevalence and correlates of likely common mental disorder (CMD) among adolescent mothers, ii) the association between likely maternal CMD, HIV, and child cognitive development, iii) likely paternal CMD among the fathers of children born to adolescent mothers, and iv) whether fatherhood characteristics differ according to core maternal characteristics (e.g., HIV and mental health status). Cross-sectional data were drawn from two linked studies: the Adolescent HIV study (n=1059 adolescents living with HIV and a comparison group [n=467]), and the HEY BABY study (n=1046 young mothers and their child(ren)), undertaken between 2015-2019. Participants completed validated and study specific questionnaires including items on sociodemographic information, health and wellbeing, and parenting experience (within the HEY BABY study). Child development was assessed utilising the Mullen Scales of Early Learning (HEY BABY study). Likely CMD was measured utilising a battery of validated symptomology scales (depression, anxiety, posttraumatic stress, suicidality). Quantitative methodologies including regression modelling are utilised to explore data. Prevalence of likely CMD among adolescent mothers was 18.8% (Adolescent HIV) and 12.6% (HEY BABY). Compared to adolescent mothers not living with HIV, adolescent mothers living with HIV were more likely to report probable CMD (HEY BABY: 16.2% vs. 11.2%, X2=4.41, p=0.04). Identified risk factors (correlates) for likely CMD among adolescent mothers included violence exposure (verbal, physical or sexual abuse; OR=2.54 [95%CI:1.20-5.40], p=0.01]), exposure to community violence; (OR=2.09 [95%CI:1.33-3.27], p=0.001), and perceived lack of social support (OR=4.09 [95%CI:2.48-6.74], p=<0.0001). There was limited evidence of interactions, suggesting that the risk factors for likely CMD are similar among adolescent mothers living with and without HIV. When considering child cognitive development, maternal HIV was found to be associated with reduced child gross motor scores (B=-2.90 [95%CI:-5.35,-0.44], p=0.02), however, no associations were identified with either maternal likely CMD, nor maternal HIV status (inclusive of interaction terms). Prevalence of likely CMD among adolescent fathers was 12.5% (Adolescent HIV: n=8). Father involvement was low (HEY BABY: 19.5% were involved with their child at least once every two weeks). Adolescent mothers reporting probable CMD were less likely to be in a relationship with the father of their child (41.8% vs. 54.1%, X2=7.32, p=0.03), more likely to experience domestic violence perpetrated by the father of their child (8.2% vs. 3.3%, X2=6.07, p=0.01), and more likely to engage in arguments about finances with the father of their child (30.0% vs. 17.0%, X2=10.8, p=0.001). Findings highlight the commonality of mental health burden within the context of adolescent pregnancy and HIV, and the urgent need for effective evidence-based programming for adolescent parent families living with and affected by HIV within South Africa

Hypertension, antihypertensive use and the delayed onset of Huntington's Disease

Background: Hypertension is a modifiable cardiovascular risk factor implicated in neurodegeneration and dementia risk. In Huntington's disease, a monogenic neurodegenerative disease, autonomic and vascular abnormalities have been reported. This study's objective was to examine the relationship between hypertension and disease severity and progression in Huntington's disease. Methods: Using longitudinal data from the largest worldwide observational study of Huntington's disease (n = 14,534), we assessed the relationship between hypertension, disease severity, and rate of clinical progression in Huntington's disease mutation carriers. Propensity score matching was used to statistically match normotensive and hypertensive participants for age, sex, body mass index, ethnicity, and CAG length. Results: Huntington's disease patients had a lower prevalence of hypertension compared with age‐matched gene‐negative controls. Huntington's disease patients with hypertension had worse cognitive function, a higher depression score, and more marked motor progression over time compared with Huntington's disease patients without hypertension. However, hypertensive patients taking antihypertensive medication had less motor, cognitive, and functional impairment than Huntington's disease patients with untreated hypertension and a later age of clinical onset compared with untreated hypertensive patients and normotensive individuals with Huntington's disease. Conclusions: We report the novel finding that hypertension and antihypertensive medication use are associated with altered disease severity, progression, and clinical onset in patients with Huntington's disease. These findings have implications for the management of hypertension in Huntington's disease and suggest that prospective studies of the symptomatic or disease‐modifying potential of antihypertensives in neurodegenerative diseases are warranted

Altered cerebrovascular response to acute exercise in patients with Huntington’s Disease

Objective. To determine whether a single session of exercise is sufficient to induce cerebral adaptations in individuals with Huntington’s disease, and explore the time dynamics of any acute cerebrovascular response. Methods. In this case-control study we employed arterial-spin labelling magnetic resonance imaging in 19 HD gene-positive participants (32-65 years old, 13 males) and 19 controls (29-63 years old, 10 males) matched for age, gender, body mass index and self-reported activity levels, to measure global and regional perfusion in response to 20-minutes of moderate intensity cycling. Cerebral perfusion was measured at baseline and 15-, 40- and 60-minutes after exercise cessation. Results. Relative to baseline, cerebral perfusion increased in HD patients yet was unchanged in control participants in the precentral gyrus, middle frontal gyrus and hippocampus 40 minutes after exercise cessation (+15 to +32.5% change in HD participants, -7.7 to 0.8% change in controls). CAG repeat length predicted the change in the precentral gyrus, and the intensity of the exercise intervention predicted hippocampal perfusion change in HD participants. In both groups, exercise increased hippocampal blood flow 60-minutes after exercise cessation. Conclusions. Here we demonstrate the utility of acute exercise as a clinically sensitive experimental paradigm to modulate the cerebrovasculature. Twenty minutes of aerobic exercise induced transient cerebrovascular adaptations in the hippocampus and cortex selectively in HD participants and likely represents latent neuropathology not evident at rest

Cerebral metabolic changes during visuomotor adaptation assessed using quantitative fMRI

The brain retains a lifelong ability to adapt through learning and in response to injury or disease-related damage, a process known as functional neuroplasticity. The neural energetics underlying functional brain plasticity have not been thoroughly investigated experimentally in the healthy human brain. A better understanding of the blood flow and metabolic changes that accompany motor skill acquisition, and which facilitate plasticity, is needed before subsequent translation to treatment interventions for recovery of function in disease. The aim of the current study was to characterize cerebral blood flow (CBF) and oxygen consumption (relative CMRO2) responses, using calibrated fMRI conducted in 20 healthy participants, during performance of a serial reaction time task which induces rapid motor adaptation. Regions of interest (ROIs) were defined from areas showing task-induced BOLD and CBF responses that decreased over time. BOLD, CBF and relative CMRO2 responses were calculated for each block of the task. Motor and somatosensory cortices and the cerebellum showed statistically significant positive responses to the task compared to baseline, but with decreasing amplitudes of BOLD, CBF, and CMRO2 response as the task progressed. In the cerebellum, there was a sustained positive BOLD response in the absence of a significant CMRO2 increase from baseline, for all but the first task blocks. This suggests that the brain may continue to elevate the supply energy even after CMRO2 has returned to near baseline levels. Relying on BOLD fMRI data alone in studies of plasticity may not reveal the nature of underlying metabolic responses and their changes over time. Calibrated fMRI approaches may offer a more complete picture of the energetic changes supporting plasticity and learning

Robust MR-based approaches to quantifying white matter structure and structure/function alterations in Huntington's disease

Background: Huge advances have been made in understanding and addressing confounds in diffusion MRI data to quantify white matter microstructure. However, there has been a lag in applying these advances in clinical research. Some confounds are more pronounced in HD which impedes data quality and interpretability of patient-control differences. This study presents an optimised analysis pipeline and addresses specific confounds in a HD patient cohort. Method: 15 HD gene-positive and 13 matched control participants were scanned on a 3T MRI system with two diffusion MRI sequences. An optimised post processing pipeline included motion, eddy current and EPI correction, rotation of the B matrix, free water elimination ( FWE ) and tractography analysis using an algorithm capable of reconstructing crossing fibres. The corpus callosum was examined using both a region-of-interest and a deterministic tractography approach, using both conventional diffusion tensor imaging ( DTI )-based and spherical deconvolution analyses. Results: Correcting for CSF contamination significantly altered microstructural metrics and the detection of group differences. Reconstructing the corpus callosum using spherical deconvolution produced a more complete reconstruction with greater sensitivity to group differences, compared to DTI-based tractography. Tissue volume fraction ( TVF ) was reduced in HD participants and was more sensitive to disease burden compared to DTI metrics. Conclusion: Addressing confounds in diffusion MR data results in more valid, anatomically faithful white matter tract reconstructions with reduced within-group variance. TVF is recommended as a complementary metric, providing insight into the relationship with clinical symptoms in HD not fully captured by conventional DTI metrics

An epiblast stem cell-derived multipotent progenitor population for axial extension.

The caudal lateral epiblast of mammalian embryos harbours bipotent progenitors that contribute to the spinal cord and the paraxial mesoderm in concert with the body axis elongation. These progenitors, called neural mesodermal progenitors (NMPs), are identified as cells that co-express Sox2 and T/brachyury, a criterion used to derive NMP-like cells from embryonic stem cells in vitro However, unlike embryonic NMPs, these progenitors do not self-renew. Here, we find that the protocols that yield NMP-like cells in vitro initially produce a multipotent population that, in addition to NMPs, generates progenitors for the lateral plate and intermediate mesoderm. We show that epiblast stem cells (EpiSCs) are an effective source of these multipotent progenitors, which are further differentiated by a balance between BMP and Nodal signalling. Importantly, we show that NMP-like cells derived from EpiSCs exhibit limited self-renewal in vitro and a gene expression signature like their embryonic counterparts.Cambridge Trusts, Cambridge philosophical Societ

Parenting in Adversity: Effects of Older Caregivers, Biological Carers and Troubled Carers on Child Outcomes in High HIV-Affected Communities

Caregiving by older adults is a common phenomenon, enhanced in the era of HIV infection. This longitudinal study was set up to examine the effect of caregiver age, relationship and mental wellbeing on child (4-13 years) outcomes (psychosocial and cognitive) in a sample of 808 caregiver- child dyads in South Africa and Malawi. Respondents were drawn from consecutive attenders at Community Based Organisations (CBOs) and interviewed with standardised inventories at baseline and followed up 12-15 months later. Analysis focused on three separate aspects of the caregiver; age, relationship to the child, and mental wellbeing, results are stratified with regard to these factors. Results showed that compared to younger caregivers, over 50 years were carrying a heavy load of childcare, but caregiver age for the most part was not associated with child outcomes. Being biologically related to the child (such as biological grandparenting) was also not a significant factor in child outcomes measured. However, irrespective of age and relationship, caregiver mental health was associated with differences in child outcome - those children of caregivers with a greater mental health burden were found to report experiencing more physical and psychologically violent discipline. Over time, the use of violent discipline was found to reduce. These data suggest that older caregivers and grandparents are providing comparable care to younger caregivers, for young children in the face of the HIV epidemic and that interventions should focus on mental health support for all caregivers, irrespective of age or relationship to the child

The spatiotemporal dynamics of cerebral autoregulation in functional magnetic resonance imaging

The thigh-cuff release (TCR) maneuver is a physiological challenge that is widely used to assess dynamic cerebral autoregulation (dCA). It is often applied in conjunction with Transcranial Doppler ultrasound (TCD), which provides temporal information of the global flow response in the brain. This established method can only yield very limited insights into the regional variability of dCA, whereas functional MRI (fMRI) has the ability to reveal the spatial distribution of flow responses in the brain with high spatial resolution. The aim of this study was to use whole-brain blood-oxygenation-level-dependent (BOLD) fMRI to characterize the spatiotemporal dynamics of the flow response to the TCR challenge, and thus pave the way toward mapping dCA in the brain. We used a data driven approach to derive a novel basis set that was then used to provide a voxel-wise estimate of the TCR associated haemodynamic response function (HRFTCR). We found that the HRFTCR evolves with a specific spatiotemporal pattern, with gray and white matter showing an asynchronous response, which likely reflects the anatomical structure of cerebral blood supply. Thus, we propose that TCR challenge fMRI is a promising method for mapping spatial variability in dCA, which will likely prove to be clinically advantageous