HOPE (National Institute for Health and Care Research Global Health Research Group on Homelessness and Mental Health in Africa) aims to develop and evaluate interventions that address the unmet needs of people who are homeless and have severe mental illness (SMI) living in three African countries in ways that are rights-based, contextually grounded, scalable and sustainable.

We will work in the capital city (Addis Ababa) in Ethiopia, a regional city (Tamale) in Ghana, and the capital city (Nairobi) and a rural county (Makueni) in Kenya to understand different approaches to intervention needed across varied settings.

We will be guided by the MRC/NIHR framework on complex interventions and implementation frameworks and emphasise co-production. Formative work will include synthesis of global evidence (systematic review, including grey literature, and a Delphi consensus exercise) on interventions and approaches to homelessness and SMI. We will map contexts; conduct focused ethnography to understand lived experiences of homelessness and SMI; carry out a cross-sectional survey of people who are homeless (n = 750 Ghana/Ethiopia; n = 350 Kenya) to estimate prevalence of SMI and identify prioritised needs; and conduct in-depth interviews and focus group discussions with key stakeholders to understand experiences, challenges and opportunities for intervention. This global and local evidence will feed into Theory of Change (ToC) workshops with stakeholders to establish agreement about valued primary outcomes, map pathways to impact and inform selection and implementation of interventions. Intervention packages to address prioritised needs will be co-produced, piloted and optimised for feasibility and acceptability using participatory action research. We will use rights-based approaches and focus on community-based care to ensure sustainability. Realist approaches will be employed to analyse how contextual variation affects mechanisms and outcomes to inform methods for a subsequent evaluation of larger scale implementation. Extensive capacity-strengthening activities will focus on equipping early career researchers and peer researchers. People with lived experience of SMI and policymakers are an integral part of the research team. Community engagement is supported by working closely with multisectoral Community Advisory Groups.

HOPE will develop evidence to support action to respond to the needs and preferences of people experiencing homelessness and SMI in diverse settings in Africa. We are creating a new partnership of researchers, policymakers, community members and people with lived experience of SMI and homelessness to enable African-led solutions. Key outputs will include contextually relevant practice and policy guidance that supports achievement of inclusive development.

The discovery of potential disease-modifying therapies in a neurodegenerative condition like Huntington's disease depends on the availability of sensitive biomarkers that reflect decline across disease stages and that are functionally and clinically relevant.

To quantify macrostructural and microstructural changes in participants with premanifest and symptomatic Huntington's disease over 30 months, and to establish their functional and clinical relevance.

Multimodal magnetic resonance imaging study measuring changes in macrostructural (volume) and microstructural (diffusivity) measures in 40 patients with premanifest Huntington's disease, 36 patients with symptomatic Huntington's disease and 36 healthy control participants over three testing sessions spanning 30 months.

Relative to controls, there was greater longitudinal atrophy in participants with symptomatic Huntington's disease in whole brain, grey matter, caudate and putamen, as well as increased caudate fractional anisotropy; caudate volume loss was the only measure to differ between premanifest Huntington's disease and control groups. Changes in caudate volume and fractional anisotropy correlated with each other and neurocognitive decline; caudate volume loss also correlated with clinical and disease severity.

Caudate neurodegeneration, especially atrophy, may be the most suitable candidate surrogate biomarker for consideration in the development of upcoming clinical trials.