The first blood samples for stem cell research from LBC1936 Wave 4.

The Disconnected Mind aims to understand

how changes in the brain’s white matter – its connectivity – contribute to age-related cognitive decline in humans.

Newsletter 29: March 2015 Welcome to the first Disconnected Mind newsletter of 2015. Yet again, just the few short months since the previous newsletter have seen many significant study developments. This issue includes news and reports from recent events, plus the regular contribution from our colleagues at Age UK. Get in touch for more information about anything in the newsletter, particularly if you have something you would like to be included in a future issue. Contact details are on the last page. LBC1936 Study Update Since Wave 4 of the LBC1936 study began in November last year, we have seen 90 participants at the Wellcome Trust Clinical Research Facility, completing cognitive and physical tests for a fourth time, at about age 79. So far, 49 have already completed a brain MRI scan, 71 have completed a Doppler ultrasound of their carotid arteries, and 70 have worn the activPAL activity monitor for over a week. An additional component of Wave 4 is to collect blood samples for induced Pluripotent Stem Cell (iPSC) lines. Dementias Platform UK funding enables us to create iPSCs from LBC participants’ white blood cells. These can then be used to create any type of cell in the body. For example, the iPSCs could be reprogrammed to become brain cells (neurons and glia), allowing us to learn more about how participants’ actual brain tissue responds to particular environmental challenges.

While these exciting new data are being collected, the team continue to publish outstanding research with the information gathered over the first three waves at ages 70, 73 and 76. Recent publications are listed at the end of the newsletter. Disconnected Mind in the News On the 16th January this year, the BBC aired their coverage of the start of Wave 4 testing as part of their week-long series on ageing. The film showed cohort members returning to Stenhouse School in Edinburgh where they originally sat the Moray House Test in 1947 at age 11. Professor James Goodwin from Age UK was on the sofa to discuss the study on BBC Breakfast.

View the video here: http://ow.ly/KbWS2

£1.3M imaging grant from Medical Research Council The Medical Research Council recently awarded £1.3M to the Disconnected Mind project to support the continued brain MRI and carotid artery ultrasound scans of participants at the Brain Research Imaging Centre at the University of Edinburgh. This will secure the 3rd wave of structural and diffusion brain imaging data, along with a 2nd wave of carotid ultrasound measures (separated by 6 years). This grant also provides two research fellow positions to analyse these highly valuable data, running until 2019. This is in addition to the multi-million pound PET-MRI scanner funding from the Dementias Platform UK. Professor Joanna Wardlaw, Director of Neuroimaging Sciences and of the Brain Research Imaging Centre, said, “the two grants combined will tell us much more about how the brain is affected during ageing, the impact of exercise, when new diseases are starting and help with testing new interventions.” £1M genetics grant from BBSRC The Biotechnology and Biological Sciences Research Council has awarded £1M to investigators at the Roslin Institute and the Disconnected Mind, which will enable whole-genome sequencing on every member of the Lothian Birth Cohort 1936. This is part of major investment in gene sequencing technology by the Universities of Edinburgh and Glasgow.

Professor David Hume, Director of The Roslin Institute, who led the application, said: “The rapid development of next sequencing technologies has revolutionised our ability to understand the relationship between genetic variation and phenotypes including complex traits like intelligence, cognition and disease risk. The funding of total genome sequencing of the Lothian Birth Cohort by BBSRC will support a unique resource for understanding the genetic control of the ageing process. It will also provide a bench mark against which we can compare other populations.” Staff news Later this month, Dr Erika Laukka from Karolinska Institutet and Stokholm University, Sweden will be visiting the Centre for Cognitive Ageing and Cognitive Epidemiology. She will be studying changes in mood and cognitive ability among the Lothian Birth Cohort members, in collaboration with Dr Dominika Dykiert and Dr Mike Allerhand, for one week from 23rd March. Multiple Awards for Professor Deary In our last newsletter, we announced that Professor Ian Deary was to receive the 2014 Lifetime Achievement Award from the International Society for Intelligence Research (ISIR). The award was presented in Graz, Austria in late December 2014. You can see his Distinguished Contributor Interview here: http://ow.ly/K0Ipb.

Prof. David Hume (centre) at the unveiling of the ‘Dolly Plaque’ at the Roslin Institute this February. With Norman Work of Edinburgh Council (left) and Dolly’s ‘inventor’, Prof. Sir Ian Wilmut (right).

A duo of Lifetime Achievement Awards for Prof. Ian Deary.

Ian is also to receive 3 other highly prestigious awards in 2015. The James McKeen Cattell Fellow Award for his lifetime contributions to the field of applied psychological science will be awarded to Ian at the 27th APS Annual Convention, to be held in May in New York. He will receive the Tenovus Medal for Outstanding Research in Biomedicine in September 2015, and the Distinguished Contribution Award from the International Society of Individual Differences (ISID) in July. The latter is only the 3rd time this award has been made in their 30+ year history. Many congratulations Ian!

Benjamin Aribisala wins Young Investigator Award Many of you will remember Benjamin Aribisala from his time working on the brain imaging data of the LBC1936 participants. Last year, he moved to Lagos State University, Nigeria where he is Professor of Computer Science. We are delighted that Ben continues to collaborate with the team, and was recently awarded the Young Investigator Award from the Society for Brain Mapping and Therapeutics, in Los Angeles in early March. The award was presented at a black tie gala night by the Nigerian Ambassador to the US, Geoffrey Tenelaibe. Well done Benjamin!

News from Age UK What a great start to 2015 for The Disconnected Mind project! At Age UK, we’re delighted by the succession of excellent papers published since the start of the year and the world-wide media coverage that they’ve generated. Congratulations to all the authors. Cognitive ageing is increasingly ‘out there’ in the public consciousness. We plan to build on these foundations, continuing to promote the concept of healthy mental ageing alongside healthy physical ageing – both are priorities in Age UK’s work – as far as we possibly can. Head of Research, Professor James Goodwin, and Research Manager Libby Archer had that opportunity on 15 January. James was live ‘on the couch’ twice during BBC TV’s Breakfast talking about cognitive health as part of the show’s week-long series about ageing, while Libby did 12 back-to-back interviews for BBC local radio stations. As the LBC1936 studies continue to mature and extend, so does the potential for us to translate the findings for the benefit of older people. The potential extends across the Age UK Group, which includes our enterprise, retail and training products and services as well as charitable activities (for those new to Age UK, our commercial profits are 100% returned to support charitable work). In January, we held a landmark Disconnected Mind briefing at our office in London for 40 staff from across the Group. Lively talks by Ian, Simon and Stuart were followed by intensive break-out group discussions about where and how the project’s results relate to our work. Our Knowledge Manager, Phil Rossall, and Robin Morton will collaborate on building the outcomes of the day into the joint Knowledge Transfer plan.

Prof. Benjamin Aribisala (centre-right) received his award from Geoffrey Tenelaibe (centre-left) at the black tie gala in Los Angeles. With Dr Babak Kateb (SBMT founder; left) and Dr Harry Kloor (right).

Event feedback was excellent, for example from Nyree Guider, National Commercial Manager at Age UK Training. Nyree, who develops our courses for health and social care workers, said, “A huge thank you for the event. I had a fantastic day. To see the study’s progression so far was fascinating. I came away inspired and proud to work for Age UK.” January also saw the launch of Age UK’s new national campaign, No one should have no one. This simple statement is based on the unacceptable reality that 2.9 million older people in England have no one to turn to for advice and support (25% of people aged over 65). The campaign aims to provoke thought, raise awareness and encourage people to fundraise, volunteer and campaign for our cause. For example, we run a national telephone befriending service, Call in Time, which is a lifeline for many older people who receive regular calls from volunteer befrienders.

More on No one: http://www.ageuk.org.uk/no-one/

The wider network of local Age UKs and national partners – Age Scotland, Age Cymru and Age NI – offer a variety of services for older people who wouldn’t have anywhere else to turn to in times of need. No one should have no one is being promoted nationwide by town centre billboards, train panels, shop window posters and more. A parallel social media campaign, #NotByMySelfie, launched on 1 February to encourage people to show support by taking a selfie with someone who means something to them, whether older or younger, and uploading it to Twitter or Instagram.

Fancy joining in? More on #NotByMySelfie: http://www.ageuk.org.uk/no-one/notbymyselfie/ Fast Facts at Your Fingertips The Disconnected Mind study is highly complex. It has a compelling background. It has achieved a large number of highly noteworthy outputs for both scientific and lay audiences, has run across decades and multiple waves, and still has a huge amount of potential. Explaining all this to someone who has never heard of it before can be no mean feat. In order to make it easier to convey the scope of the study, we have developed a Fast Facts Card; a credit card-sized concertina leaflet containing study information over 12 panels, appropriate for interested scientists and lay-people.

If you would like copies of the Fast Facts Card to distribute at conferences or public engagement events, please get in touch using the contact details at the end of this newsletter. You can also obtain a pdf of the design by visiting: www.lothianbirthcohort.ed.ac.uk

Study finds first genes associated with general cognitive function (Molecular Psychiatry) A new paper led by Dr Gail Davies has identified genes associated with people’s general cognitive function. The research was published in Molecular Psychiatry and was also picked up by a variety of news outlets. An international team, led by the University of Edinburgh analysed data from 54,000 people aged 45 years and over, including information from the Lothian Birth Cohorts. They found significant small signals from four genetic

regions that were associated with having better thinking skills. These regions contained genes that have previously been associated with neurological and psychiatric states. After identifying these genes, further work is now required to understand their function in both body and brain. View the paper: PMID: 25644384 Watch the video here: http://ow.ly/K0Fng Genetic methylation predicts important life outcomes (Genome Biology and International Journal of Epidemiology) Two recent papers led by Dr Riccardo Marioni shed new light on the exciting new area of epigenetics. They concern the measurement of genetic methylation and its predictive power for late-life outcomes such as cognitive and physical fitness, and mortality. As we age, some genetic locations become increasingly methylated (an epigenetic mark that can be thought of as switching genes on or off). The degree to which certain genetic locations are methylated gives each participant a ‘methylation age’, akin to a biological clock. Published in the International Journal of Epidemiology (PMID: 25617346), the team found that those individuals whose methylation age was comparatively lower than their chronological age were cognitively and physically fitter. In addition, in a report in Genome Biology (PMID: 25633388), the team found that the difference between

methylation age and chronological age was predictive of all-cause mortality, beyond other well-known mortality predictors. Daily Express: http://ow.ly/KdamQ The Independent: http://ow.ly/KdbMH Watch the video here: http://ow.ly/K0Fng Cigarette smoking linked to thinner brain cortex In a report recently published in Molecular Psychiatry in collaboration with Sherif Karama and colleagues from the Montreal Neurological Institute (PMID: 25666755), data from the LBC1936 showed a clear association between cigarette smoking and having a thinner cerebral cortex (the outer layer of the brain). When the effects of quitting were examined, it appeared that it took around 25 years for complete recovery in affected areas to take place. These findings therefore suggest that smoking is associated with accelerated cortical thinning (which may be linked to age-related cognitive decline), and that partial recovery – while possible – could be a long process. The story was covered in the Independent (http://ow.ly/Kd8AJ), The Times, The Sun and The Metro, as well as various international newspapers.

Newly ‘in press’ Clarke, T.-K., 20 authors, Deary, I. J., &

McIntosh, A. M. (in press). Common polygenic risk for autism spectrum disorders (ASD) is associated with cognitive ability in the general population. Molecular Psychiatry.

Hansell, N. K., 23 authors, Deary, I. J., &

Wright, M. J. (in press). Genetic basis of a cognitive complexity metric. PLoS One.

Ibrahim Verbaas, C. A., 118 authors,

Deary, I. J., 5 authors, & Mosley, T. H. (in press). GWAS for executive function and processing speed suggest involvement of the CADM2 gene. Molecular Psychiatry.

Karama, S., Ducharme, S., Corley, J.,

Choinard-Decorte, Starr, J. M., Wardlaw, J. M., Bastin, M., & Deary, I. J. (in press). Cigarette smoking and thinning of the brain’s cortex. Molecular Psychiatry.

Lopez, L. M., 20 authors, Deary, I. J., &

Wardlaw, J. M. (in press). Genes from a translational analysis support a multifactorial nature of white matter hyperintensities. Stroke.

Marioni, R. E., Shah, S., McRae, A. F.,

Ricthie, S. J., Muniz-Terrera, G., Harris, S. E., Gibson, J., Redmond, P., Cox, S. R., Pattie, A., Corley, J., Taylor, A., Murphy, L., Starr, J. M., Horvath, S., Visscher, P. M., Wray, N. R., & Deary, I. J. (in press). The epigenetic clock is associated with physical and cognitive fitness in the Lothian Birth Cohort 1936. International Journal of Epidemiology.

Ritchie, S. J., Bates, T. C., & Deary, I. J.

(in press). Testing how education influences cognitive development: improvements in general ability or

specific skills? Developmental Psychology.

Shenkin, S. D., Laidlaw, K., Allerhand, M.,

Mead, G. E., Starr, J. M., & Deary, I. J. (in press). Life course influences of physical and cognitive function and personality on attitudes to aging in the Lothian Birth Cohort 1936. International Psychogeriatrics / IPA.

Taylor, A. M., MacGillivray, T. J.,

Henderson, R. D., Ilzina, L., Dhillon, B., Starr, J. M., & Deary, I. J. (in press). Retinal vascular fractal dimension, childhood IQ, and cognitive ability in old age: The Lothian Birth Cohort Study 1936. PLoS One.

Newly ‘in print’ Booth, T., Royle, N. A., Corley, J., Gow,

A. J., Valdes Hernandez, M. A., Maniega, S. M., Ritchie, S. J., Bastin, M. E., Starr, J. M., Wardlaw, J. M., & Deary, I. J. (2015). Association of allostatic load with brain structure and cognitive ability in later life. Neurobiology of Aging, 36, 1390-13909.

Davies, G., 126 authors, Deary, I.J. (2015).

Genetic contributions to variation in general cognitive function: a meta-analysis of genome-wide association studies in the CHARGE consortium (N =53949). Molecular Psychiatry, 20, 183-192.

Marioni, R.E., 9 authors, Deary, I.J.

(2015). DNA methylation age of blood predicts all-cause mortality in later life. Genome Biology, 16:25

You can stay up to date on the most recent DM research by checking the regularly-updated list of publications at: www.lothianbirthcohort.ed.ac.uk. Those requiring a PDF version of anything listed should get in touch with Paul Redmond (lbc1936@ed.ac.uk) in the first instance. Do also keep Paul updated about your ‘in press’ or recently published papers too. They’ll be added to the website to ensure everyone can see these as soon as possible, and may be profiled in a future newsletter. Contact Please get in touch with any items for inclusion in future newsletters.

Simon Cox

Simon.Cox@ed.ac.uk March 2015

www.lothianbirthcohort.ed.ac.uk