Early-life origins of brain resilience to mental illness and cognitive impairment across the life-course

Lead Research Organisation: University of Aberdeen

Abstract

Research in children in North America using brain scanning has shown that the brain develops less well and has a smaller surface area in children of families with less income. This result was not found in a study from Norway, where there is greater socioeconomic equality. Our own research has shown that being poor as a child is associated with more brain abnormalities in later life, which are associated with depression and dementia. Countries such as India are experiencing a
rapid rise in what were considered "Western diseases", such as diabetes, combined with an increase in older people. In addition, there remain significant disparities in socioeconomic circumstance, access to education and healthcare.
Researchers in the UK, in Mysore and in Mumbai have established groups of normal people (cohorts) at different ages and from different socioeconomic circumstances that have already provided much evidence on the early life origins of later life
diseases, such as heart disease and diabetes. Here we will carry out work that will pave the way for a future large-scale study of mental health and thinking (cognitive) abilities in these groups. Concentrating on the Mysore groups in this application, we plan four projects that will help us design our future project to include people in Mysore and Mumbai.
1. We will invite a small number of the younger and older Mysore cohorts to have a brain scan first to find out how acceptable scanning is for them and secondly as a pilot study to test whether early life circumstances influence measurable changes on brain scans. We will investigate what factors in early life (such as your father's job, your birth weight) predict brain scan appearances.
2. By speaking with participants we will find out what people who are part of these informative cohorts think about volunteering for brain scans, blood tests and new computer tests of their thinking (cognitive) abilities. We will ask them how they view keeping information about them on a computer and their opinions of combining this information with other health and education information about them. We will also take account of local permissions, participants' and researchers' views
on creation of a future database that allows their information to be securely stored, transferred between institutions in India and anonymously available to future researchers. Such a collection of information would grow over time and allow future research to answer our question about the impact of early life environment on important mental health outcomes.
3. Provided participants agree, we will collect blood samples, cheek scrape samples, repeat tests of thinking abilities and depressive symptoms to add to existing research records and to allow us to calculate how many scans and tests would be needed in a future large-scale study to provide meaningful information. We will also take account of local permissions, participants' and researchers' views on creation of a future database that allows this information to be securely stored,
transferred between institutions in India and anonymously available to future researchers.
4. We will host a workshop at the University of Aberdeen for investigators from India and Aberdeen to discuss and plan analysis of the extensive information available in these participants and how we best design a data analysis plan, based on pilot data, existing expertise on "big data" approaches and meaningful statistical analysis for a future large-scale application
to address our research question.
The work we propose here will provide the preparatory work for a future study to discover what aspects of early life environment can be modified to reduce mental illness and cognitive decline in India. This addresses three of the Sustainable Development Goals: i) Goal 3-to ensure healthy lives and promote well-being for all at all ages; ii) Goal 4-to promote lifelong learning opportunities for all; iii) Goal 10-to reduce inequalities.

Technical Summary

Cortical surface area on Magnetic Resonance Imaging (MRI) from the Paediatric Imaging and NeuroGenetic dataset in North America varies with family income and this relationship is steepest at poorest incomes. This result was not found in Norway, where there is greater equality of socioeconomic circumstance (SEC). Our own research has shown that poorer childhood SEC predicts smaller hippocampi and more brain lesions in late life, which are linked to depressive symptoms and poorer cognition. Here we will extend research to cohorts in Mysore, India, with different SEC and culture, in whom rich life-course and risk factor data exist. We propose pilot work, public engagement and workshops to inform a large-scale future application to investigate hypotheses that early life factors influence risk of subsequent mental illness and cognitive decline. Concentrating on the Mysore groups here, we plan four activities that will inform design of a future project to include cohorts in Mysore and Mumbai. These are deliberately designed around data science, to enable work to be scaledup and to create a resource for future research:
Imaging - we will invite subsamples of young and older Mysore cohorts for brain MRI to assess feasibility, acceptability and to measure effect size to inform future power calculation.
Health informatics - using public engagement with participants we will determine their views on data linkage of pre-existing data, data to be collected and creation of a bio-resource.
Bioinformatics - we will collect new cognitive data, using a game that tests navigational ability, repeat previous cognitive and depression data, blood samples and buccal smears to obtain DNA and RNA for future analysis.
Computing science - we will host a workshop at the University of Aberdeen to which Indian and UK co-investigators will be invited to brainstorm "big data' management, analysis and machine learning methods to test in pilot data and apply to future large-scale work.

Publications

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Title Bioimaging and bioinformatics 
Description This award enabled pilot and feasibility work, public engagement and workshop activities, described in events/workshop section and here: Vignette 1. Bioimaging: Pilot collection of brain magnetic resonance imaging (MRI) in subsamples of the Mysore Parthenon Cohort (current age 20-21, N~500) and Mysore Birth Records Cohort (current age 51-83, N~750). • Following visits to different MRI scanners during the November 2017 visit, a decision was made to use the 1.5 T scanner at the Narayana Multispeciality Hospital in Mysore. This is supported by trained technicians, engineers and radiologists, led by Dr Shailesh Pene. Alison Murray, Gordon Waiter along with KN Kiran set-up and tested the Aberdeen brain MRI imaging protocol on the Mysore scanner during a visit in April 2018, with acquisition of two volunteer datasets, one of whom was Dr Waiter. These datasets were reviewed in Aberdeen, compared with prior brain MRI data for Dr Waiter, and are of excellent quality. Standard operating procedures have been written. • We have applied for and received ethics approval to carry out the data collection from the University of Aberdeen College Ethics Review Board (CERB) and the local Indian ethics permissions from CSI Holdsworth Memorial Hospital (where participants are recruited and tested) and Narayana Hospital, Mysore (where MRI is conducted). There was a delay in commencing MRI because ethics approvals in India took longer than expected. However, since approval was obtained, we have recruited steadily. • So far 65 Mysore participants have successfully undergone brain MRI using the Aberdeen protocol at Narayana Hospital. Image data have been successfully transferred and uploaded into XNAT in the Safe Haven, Aberdeen Data Centre for storage and data analysis. Image quality has been reviewed and is excellent. There was one early protocol breach when an MRI technician, who was unaware of the project, altered the number of slices acquired (as they would usually do when customising an imaging protocol for an individual patient but which is not desirable when applying a research protocol). This change was quickly detected on receipt of data in Aberdeen, feedback given and the reasons for consistency explained. This was a useful learning exercise for staff at both sites. Since then the correct protocol has been applied consistently. Data analysis will proceed once imaging data collection is complete. We explored the feasibility of using XNAT in Mysore as an analysis and distribution platform for brain imaging and meta-data collected as part of Vignette No.1. Following feasibility visit and discussion with colleagues in Mysore, we decided that the optimal solution, at this stage of joint working, was to host a secure XNAT database within the Grampian DaSH Data Safe Haven - a secure hosting facility to enable robust data management, sharing, and analysis by the research team. This has been set up and secure data flows established and quality checked. As part of this activity, Co-Is and staff (G Waiter, C Black, K Wilde, J Williams, D Chapko, A Murray) visited the team in Mumbai for a similar infrastructure assessment and to establish new collaborative links for our future grant application. Vignette 3. Bioinformatics: We collected new data using existing tests of cognitive ability and depressive symptoms and investigated feasibility, with cohort participants and Mysore research staff, of collecting new navigation ability data using the Sea Hero Quest game on iPads. New bio-samples were collected from Mysore cohort participants. • 10/66 Cognitive Testing (~15 minutes), this was carried out after brain MRI in the participants from the Mysore Birth Records Cohort. • WAIS IV Cognitive Battery (~90 minutes), this was carried out before or after brain MRI in participants from the Parthenon Cohort. • Spatial Navigation Abilities (Sea Hero Quest) on iPad (20-30 min), before or after brain MRI i. A clinical version of the game has been installed on two iPads; Dorota Chapko prepared the SHQ study manual in collaboration Michael Hornberger and Gillian Coughlan (UEA) and trained the research staff in Mysore (Kiran KN, Santosh N, Ramya MC) on how to administer SHQ to assess spatial navigation abilities among the cohort members. ii. Following initial technical difficulties (the version of the game initially supplied would not run and an updated version of the software was required before successfully implementing). So far 16 participants have played the game as part of the research visit and the data have been successfully collected, transferred to XNAT for storage and analysis. • Our initial aim in Vignette 3 had been to collect both buccal samples and blood samples. However, it became clear during team discussions and review of data already held, that some samples already existed in CCMB Hyderabad, under curation by Dr G Chandak. For consistency and in order to increase numbers of samples for future analyses we decided to continue with blood sampling. One blood sample was obtained per participant, to undertake selected candidate gene analyses during this grant, and to store blood for future RNA analyses. 
Type Of Material Physiological assessment or outcome measure 
Year Produced 2015 
Provided To Others? No  
Impact The Aberdeen MRI protocol has been refined and tested during previous Wellcome Trust award, Stratifying Resilience and Depression Longitudinally. It has now been applied in India, Taiwan and Uruguay. 
 
Description Mysore - Aberdeen Health Data Research 
Organisation University of Aberdeen
Country United Kingdom 
Sector Academic/University 
PI Contribution PI and 6 CoIs. Wrote grant application, co-ordinated research and research visits.Expertise on brain imaging, analysis, health data research, data linkage, public engagement and mental health.
Collaborator Contribution Provision of access to Mysore Parthenon and Mysore Birth Records cohorts and many years expertise in high quality epidemiology research with these participants.
Impact Brain imaging Public health Health data research Genetics/epigenetics Mental health Social science Computing science
Start Year 2017
 
Description Data Science and Data Analysis Workshop University of Aberdeen 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Vignette 4 Data Science and Data Analysis workshop: We hosted a two-day Workshop (19-20 September 2018) at the University of Aberdeen for Indian Co-Investigators, UK co-investigators from the University of Southampton and University of East Anglia. The workshop included presentations from UK and Indian co-Is, visits to the Aberdeen Centre for Health Data Science, the Department of Computing Science, the Data Centre (where data from the University of Aberdeen and Robert Gordon University and those in Safe Haven are securely stored).
• We established trust and shared goals as part of this and future projects
• We established data governance pathways and defined the shared data safe haven model whereby each of the cohort collaborators retains full governance control of their data and provide expert guidance in terms of coordinating research access and disclosure control assessments
• We debated hypothesis driven and data-driven methods of analysis
• We described data available and tried out new ways of collecting data (such as language free tools on a tablet)
• Importantly, we developed Aims and Objectives and Table 1 (existing data and new data to be collected in the three Indian cohorts and existing data in the Aberdeen Children of the 1950s) in the LINEAGE application under review.
Year(s) Of Engagement Activity 2018
 
Description Participant engagement activities Mysore and Mumbai 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Study participants or study members
Results and Impact Vignette 2. Health Informatics: We aimed to develop awareness of health informatics through public engagement with participants and researchers in Mysore. Two large public engagement events were held with participants and their families of the Parthenon cohort (30 families) and with participants of the Mysore Birth Records Cohort (30 families) in Mysore during June 2018. A third, funded by the Scottish Universities Life Sciences Alliance, with the families and children of SARAS kids (40 families and 50 health workers), in Mumbai in June 2018. Dorota Chapko, RF employed on this confidence award organised these three events with colleagues in India (see output in section 5, engagement). Our main aims included seeking participants' views on the information given to them for the consenting process, how they would like results to be fed back, and their views on continuing to participate in future studies. Their views were overwhelmingly positive with highly pertinent suggestions for future study design, the benefits of participating and future policy change.
Team visits to Centre for Studies of Social Change, Mumbai, and Holdsworth Memorial Hospital, Mysore took place in April 2018.
Participant engagement activities were held with the Parthenon cohort and their families Mysore, June 2018.
Year(s) Of Engagement Activity 2018