Publications

Publication: International Journal of Behavioral Nutrition and Physical Activity

Lindsay T, Westgate K, Wijndaele K, Hollidge S, Kerrison N, Forouhi N, et al.

9 December 2019

Background Physical activity (PA) plays a role in the prevention of a range of diseases including obesity and cardiometabolic disorders. Large population-based descriptive studies of PA, incorporating precise measurement, are needed to understand the relative burden of insufficient PA levels and to inform the tailoring of interventions. Combined heart and movement sensing enables the study of physical activity energy expenditure (PAEE) and intensity distribution. We aimed to describe the sociodemographic correlates of PAEE and moderate-to-vigorous physical activity (MVPA) in UK adults.

Methods The Fenland study is a population-based cohort study of 12,435 adults aged 29–64 years-old in Cambridgeshire, UK. Following individual calibration (treadmill), participants wore a combined heart rate and movement sensor continuously for 6 days in free-living, from which we derived PAEE (kJ•day− 1•kg− 1) and time in MVPA (> 3 & > 4 METs) in bouts greater than 1 min and 10 min. Socio-demographic information was self-reported. Stratum-specific summary statistics and multivariable analyses were performed.

Results Women accumulated a mean (sd) 50(20) kJ•day− 1•kg− 1 of PAEE, and 83(67) and 33(39) minutes•day− 1 of 1-min bouted and 10-min bouted MVPA respectively. By contrast, men recorded 59(23) kJ•day− 1•kg− 1, 124(84) and 60(58) minutes•day− 1. Age and BMI were also important correlates of PA. Association with age was inverse in both sexes, more strongly so for PAEE than MVPA. Obese individuals accumulated less PA than their normal-weight counterparts, whether considering PAEE or allometrically-scaled PAEE (− 10 kJ•day− 1•kg− 1 or − 15 kJ•day− 1•kg-2/3 in men). Higher income and manual work were associated with higher PA; manual workers recorded 13–16 kJ•kg− 1•day− 1 more PAEE than sedentary counterparts. Overall, 86% of women and 96% of men accumulated a daily average of MVPA (> 3 METs) corresponding to 150 min per week. These values were 49 and 74% if only considering bouts > 10 min (15 and 31% for > 4 METs).

Conclusions PA varied by age, sex and BMI, and was higher in manual workers and those with higher incomes. Light physical activity was the main driver of PAEE; a component of PA that is currently not quantified as a target in UK guidelines.

Publication: Movement Disorders

Fraser S. Brown, James B. Rowe, Luca Passamonti, Timothy Rittman

6 December 2019

Despite falls being an almost universal clinical feature and central to the presentation and diagnostic criteria of progressive supranuclear palsy, our understanding of falls is surprisingly limited and there are few effective treatment options.

The researchers reviewed current understanding of the pathophysiology of falls, highlighting the roles of the indirect pathway and the pedunculopontine nucleus. They then identified shortcomings in commonly used assessments to measure falls, looked at medical and nonmedical fall prevention strategies, and finally discussed balancing falls risk against promoting independence.

Falls are central to progressive supranuclear palsy presentation and diagnosis. Indirect locomotor and pedunculopontine nucleus dysfunction are thought to be the neural substrate of falls in this condition. Attempts to measure and prevent falls, by medical and nonmedical means, are currently limited. A personalized approach is advocated in the management of falls.

Publication: Science

Tim H. H. Coorens, Taryn D. Treger, Reem Al-Saadi, Luiza Moore, Maxine G. B., Thomas J. Mitchell, Suzanne Tugnait, Christine Thevanesan, Matthew D. Young, Thomas R. W. Oliver, Minou Oostveen, Grace Collord, Patrick S. Tarpey, Alex Cagan, Yvette Hooks, Mark Brougham, Ben C. Reynolds, Giuseppe Barone, John Anderson, Mette Jorgensen, G. A. Amos Burke, Johannes Visser, James C. Nicholson, Naima Smeulders, Imran Mushtaq, Grant D. Stewart, Peter J. Campbell, David C. Wedge, Iñigo Martincorena, Dyanne Rampling, Liz Hook, Anne Y. Warren, Nicholas Coleman, Tanzina Chowdhury, Neil Sebire, Jarno Drost, Kourosh Saeb-Parsy, Michael R. Stratton, Karin Straathof, Kathy Pritchard-Jones, Sam Behjati

6 December 2019

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Summary:

Wilms tumour is the most common type of kidney cancer in childhood but it was not previously known how it arose in children’s kidneys. This research found out that both pediatric and adult kidney cancer arise in a similar way, from premalignant clonal expansions.

Publication: PLoS ONE

Sagelv EH, Ekelund U, Pedersen S, Brage S, Hansen BH, Johansson J, et al.

3 December 2019

Introduction Surveillance of physical activity at the population level increases the knowledge on levels and trends of physical activity, which may support public health initiatives to promote physical activity. Physical activity assessed by accelerometry is challenged by varying data processing procedures, which influences the outcome. We aimed to describe the levels and prevalence estimates of physical activity, and to examine how triaxial and uniaxial accelerometry data influences these estimates, in a large population-based cohort of Norwegian adults.

Methods This cross-sectional study included 5918 women and men aged 40–84 years who participated in the seventh wave of the Tromsø Study (2015–16). The participants wore an ActiGraph wGT3X-BT accelerometer attached to the hip for 24 hours per day over seven consecutive days. Accelerometry variables were expressed as volume (counts·minute-1 and steps·day-1) and as minutes per day in sedentary, light physical activity and moderate and vigorous physical activity (MVPA).

Results From triaxial accelerometry data, 22% (95% confidence interval (CI): 21–23%) of the participants fulfilled the current global recommendations for physical activity (≥150 minutes of MVPA per week in ≥10-minute bouts), while 70% (95% CI: 69–71%) accumulated ≥150 minutes of non-bouted MVPA per week. When analysing uniaxial data, 18% fulfilled the current recommendations (i.e. 20% difference compared with triaxial data), and 55% (95% CI: 53–56%) accumulated ≥150 minutes of non-bouted MVPA per week. We observed approximately 100 less minutes of sedentary time and 90 minutes more of light physical activity from triaxial data compared with uniaxial data (p<0.001).

Conclusion The prevalence estimates of sufficiently active adults and elderly are more than three times higher (22% vs. 70%) when comparing triaxial bouted and non-bouted MVPA. Physical activity estimates are highly dependent on accelerometry data processing criteria and on different definitions of physical activity recommendations, which may influence prevalence estimates and tracking of physical activity patterns over time.

Publication: The Lancet Neurology

Katrina M Moore, Jennifer Nicholas, Prof Murray Grossman, Corey T McMillan, David J Irwin, Lauren Massimo, PhD et al

3 December 2019

Frontotemporal dementia is a heterogenous neurodegenerative disorder, with about a third of cases being genetic. Most of this genetic component is accounted for by mutations in GRN, MAPT, and C9orf72. In this study, the researchers aimed to complement previous phenotypic studies by doing an international study of age at symptom onset, age at death, and disease duration in individuals with mutations in GRN, MAPT, and C9orf72.

The study showed that age at symptom onset and at death of people with genetic frontotemporal dementia is influenced by genetic group and, particularly for MAPT mutations, by the specific mutation carried and by family membership.

Although estimation of age at onset will be an important factor in future pre-symptomatic therapeutic trials for all three genetic groups, this study suggests that data from other members of the family will be particularly helpful only for individuals with MAPT mutations. Further work in identifying both genetic and environmental factors that modify phenotype in all groups will be important to improve such estimates.

Publication: The Lancet Neurology

Emma L van der Ende, Lieke H Meeter, Jackie M Poos, Jessica L Panman, Lize C Jiskoot, Elise G P Dopper, Janne M Papma, Frank Jan de Jong, Inge M W Verberk, Prof Charlotte Teunissen, Prof Dimitris Rizopoulos, Carolin Heller, Rhian S Convery, Katrina M Moore, Martina Bocchetta, Mollie Neason, David M Cash, Barbara Borroni, Daniela Galimberti, Raquel Sanchez-Valle, Robert Laforce Jr, Fermin Moreno, Prof Matthis Synofzik, Prof Caroline Graff, Mario Masellis, Maria Carmela Tartaglia, Prof James B Rowe, et al

1 December 2019

Neurofilament light chain (NfL) is a promising blood biomarker in genetic frontotemporal dementia, with elevated concentrations in symptomatic carriers of mutations in GRN, C9orf72, and MAPT. A better understanding of NfL dynamics is essential for upcoming therapeutic trials. The research team aimed to study longitudinal NfL trajectories in people with presymptomatic and symptomatic genetic frontotemporal dementia.

Their findings show the value of blood NfL as a disease progression biomarker in genetic frontotemporal dementia and suggest that longitudinal NfL measurements could identify mutation carriers approaching symptom onset and capture rates of brain atrophy.

This is important because the characterisation of NfL over the course of disease provides valuable information for its use as a treatment effect marker.

Publication: Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring

Audrey Low, Elijah Mak, Maura Malpetti, Leonidas Chouliaras, Nicolas Nicastro, Li Sua, Negin Holland, Timothy Rittman, Patricia Vázquez Rodríguez, Luca Passamonti, W Richard Bevan-Jones, PP Simon Jones, James B.Rowe, John T.O’Brien

1 December 2019

Widespread cortical asymmetries have been identified in Alzheimer’s disease (AD), but thalamic asymmetries and their relevance to clinical severity in AD remain unclear.

This research discovered that although overall asymmetry of the thalamus did not differ between groups, greater leftward lateralization of atrophy in the ventral nuclei was demonstrated in AD, compared with controls and amyloid-positive mild cognitive impairment. Increased posterior ventrolateral and ventromedial nuclei asymmetry were associated with worse cognitive dysfunction, informant-reported neuropsychiatric symptoms, and functional ability.

Leftward ventral thalamic atrophy was associated with disease severity in AD. The findings suggest the clinically relevant involvement of thalamic nuclei in the pathophysiology of AD.

Publication: Diabetologia

Olov Rolandsson, Christiane S. Hampe, Nicholas J. Wareham et al

11 November 2019

Type 1 and type 2 diabetes differ with respect to pathophysiological factors such as beta cell function, insulin resistance and phenotypic appearance, but there may be overlap between the two forms of diabetes.

However, there are relatively few prospective studies that have characterised the relationship between autoimmunity and incident diabetes. The researchers investigated associations of antibodies against the 65 kDa isoform of GAD (GAD65) with type 1 diabetes and type 2 diabetes genetic risk scores and incident diabetes in adults in European Prospective Investigation into Cancer and Nutrition (EPIC)-InterAct, a case-cohort study nested in the EPIC cohort.

GAD65 antibodies were analysed in EPIC participants (over 40 years of age and free of known diabetes at baseline) by radioligand binding assay in a random subcohort (n = 15,802) and in incident diabetes cases (n = 11,981). Type 1 diabetes and type 2 diabetes genetic risk scores were calculated. Associations between GAD65 antibodies and incident diabetes were estimated using Prentice-weighted Cox regression.

GAD65 antibody positivity at baseline was associated with development of diabetes during a median follow-up time of 10.9 years (HR for GAD65 antibody positive vs negative 1.78; 95% CI 1.43, 2.20) after adjustment for sex, centre, physical activity, smoking status and education. The genetic risk score for type 1 diabetes but not type 2 diabetes was associated with GAD65 antibody positivity in both the subcohort (OR per SD genetic risk 1.24; 95% CI 1.03, 1.50) and incident cases (OR 1.97; 95% CI 1.72, 2.26) after adjusting for age and sex. The risk of incident diabetes in those in the top tertile of the type 1 diabetes genetic risk score who were also GAD65 antibody positive was 3.23 (95% CI 2.10, 4.97) compared with all other individuals, suggesting that 1.8% of incident diabetes in adults was attributable to this combination of risk factors.

This study indicates that incident diabetes in adults has an element of autoimmune aetiology. Thus, there might be a reason to re-evaluate the present subclassification of diabetes in adulthood.

Publication: QJM: An International Journal of Medicine

R El-Damanawi, M Lee, T Harris, L B Cowley, S Bond, H Pavey, R N Sandford, I B Wilkinson, F E Karet Frankl, T F Hiemstra

Publication: Neurology

Tamara P. Tavares, Derek G.V. Mitchell, Kristy Coleman, Christen Shoesmith, Robert Bartha, David M. Cash, Katrina M. Moore, John van Swieten, Barbara Borroni, Daniela Galimberti, Maria Carmela Tartaglia, James Rowe, Caroline Graff, Fabrizio Tagliavini, Giovanni Frisoni, Stefano Cappa, Robert Laforce, Alexandre de Mendonça, Sandro Sorbi, Garrick Wallstrom, Mario Masellis, Jonathan D. Rohrer, Elizabeth C. Finger

29 October 2019

The objective of this research was to characterize the time course of ventricular volume expansion in genetic frontotemporal dementia (FTD) and identify the onset time and rates of ventricular expansion in presymptomatic FTD mutation carriers. Participants included patients with a mutation in MAPT, PGRN, or C9orf72, or first-degree relatives of mutation carriers from the GENFI study with MRI scans at study baseline and at 1 year follow-up. The researchers aimed to identify identify differences in ventricular volume and in expansion rates as a function of time to expected disease onset between presymptomatic carriers and noncarriers.

Ventricular volume differences were observed 4 years prior to symptom disease onset for presymptomatic carriers compared to noncarriers. Annualized rates of ventricular volume expansion were greater in presymptomatic carriers relative to noncarriers. Importantly, time-intensive manually edited and fully automated ventricular volume resulted in similar findings.

Ventricular volume differences are detectable in presymptomatic genetic FTD. Concordance of results from time-intensive manual editing and fully automatic segmentation approaches support its value as a measure of disease onset and progression in future studies in both presymptomatic and symptomatic genetic FTD.

Publication: Molecular Psychiatry

Varun Warrier, Simon Baron-Cohen

29 October 2019

Summary:

People with a higher genetic likelihood of autism are more likely to report higher childhood maltreatment, self-harm and suicidal thoughts. Following on from a previous study, researchers looked at the genetic likelihood for autism in 100,000 people. They found those with a higher number of genetic varients associated with autism were more likely to report maltreatment and self-harm.

Publication: The Journal of Nutrition

Tong TYN, Koulman A, Griffin JL, Wareham NJ, Forouhi NG, Imamura F

26 October 2019

Cardiometabolic benefits of the Mediterranean diet have been recognized, but underlying mechanisms are not fully understood.

We aimed to investigate how the Mediterranean diet could influence circulating metabolites and how the metabolites could mediate the associations of the diet with cardiometabolic risk factors.

Publication: PLoS ONE

Yerrakalva D, Wijndaele K, Hajna S, Westgate K, Khaw K, Wareham N, et al.

25 October 2019

Compensatory behaviours may be one of the reasons for the limited success of sedentary time interventions in older adults, but this possibility remains unexplored.

Activity compensation is the idea that if we change activity levels at one time we compensate for them at a later time to maintain a set point. We aimed to assess, among adults aged ≥60 years, whether sedentary time and time spent in prolonged sedentary bouts (≥30 mins) on one day were associated with sedentary time and time spent in prolonged sedentary bouts (≥30 mins) on the following day. We also sought to determine whether these associations varied by sociodemographic and comorbid factors.

Sedentary time was assessed for seven days using hip-worn accelerometers (ActiGraph GT1M) for 3459 adults who participated in the EPIC-Norfolk Study between 2004 and 2011. We assessed day-to-day associations in total and prolonged bouts of sedentary time using multi-level regressions. We included interaction terms to determine whether associations varied by age, sex, smoking, body mass index, social class, retirement, education and comorbid factors (stroke, diabetes, myocardial infarction and cancer).

Participants (mean age = 70.3, SD = 6.8 years) accumulated 540 sedentary mins/day (SD = 80.1). On any given day, every 60 minutes spent in sedentary time was associated with 9.9 extra sedentary minutes on the following day (95% CI 9.0, 10.2). This association was greater in non-retired compared to retired participants (non-retired 2.57 extra minutes, p = 0.024) and in current compared to former and never-smokers (5.26 extra mins for current vs former; 5.52 extra mins for current vs never, p = 0.023 and 0.017, respectively). On any given day, every 60 minutes spent in prolonged bouts was associated with 7.8 extra minutes in these bouts the following day (95% CI 7.6, 8.4). This association was greater in older individuals (0.18 extra minutes/year of age, 95% CI 0.061, 0.29), and for retired versus non-retired (retired 2.74 extra minutes, 95% CI 0.21, 5.74).

Conclusion Older adults did not display day-to-day compensation. Instead, individuals demonstrate a large stable component of day-to-day time spent sedentary and in prolonged bouts with a small but important capacity for positive variation. Therefore older adults appear to be largely habitual in their sedentary behaviour. Strategies to augment these patterns may be possible, given they may differ by age, smoking, and working status.

Publication: Nature

Henry Lee-Six, Sigurgeir Olafsson, Peter Ellis, Robert J. Osborne, Mathijs A. Sanders, Luiza Moore, Nikitas Georgakopoulos, Franco Torrente, Ayesha Noorani, Martin Goddard, Philip Robinson, Tim H. H. Coorens, Laura O’Neill, Christopher Alder, Jingwei Wang, Rebecca C. Fitzgerald, Matthias Zilbauer, Nicholas Coleman, Kourosh Saeb-Parsy, Inigo Martincorena, Peter J. Campbell & Michael R. Stratton

23 October 2019

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This was a study of early changes in human colorectal tissue that could lead to adenomas/carconomas. These are rare outcomes even after a substantially increased mutational burden has been placed on the tissue, but it is important to study the earliest stages of colorectal carcinogenesis.

Publication: Nature Communications

Andrea I. Luppi1, Michael M. Craig, Ioannis Pappas, Paola Finoia, Guy B. Williams, Judith Allanson, John D. Pickard, Adrian M. Owen, Lorina Naci, David K. Menon & Emmanuel A. Stamatakis 

10 October 2019

Summary:

Researchers used functional Magnetic Resonance Imaging (fMRI) to scan the brains of healthy volunteers and brain injured patients who had been awake but no signs of awareness or in a minimally conscious state, to understand what happens to the brain when consciousness is lost.

Publication: Journal of the American Geriatrics Society

Bielemann RM, LaCroix AZ, Bertoldi AD, Tomasi E, Demarco FF, Gonzalez MC, et al.

8 October 2019

Use of objectively measured physical activity (PA) in older adults to assess relationship between PA and risk of all-causes mortality is scarce. This study evaluated the associations of PA based on accelerometry and a questionnaire with the risk of mortality among older adults from a city in Southern Brazil.

Overall physical activity (mg), light physical activity (LPA), and moderate to vigorous physical activity (MVPA) were estimated by raw accelerometer data. The International Physical Activity Questionnaire estimated leisure time and commuting PA. Hazard ratios (excluding deaths in the first 6 mo) stratified by sex were estimated by Cox regression analysis considering adjustment for confounders.

From the 1451 older adults interviewed in 2014, 145 died (10%) after a follow-up of an average 2.6 years. Men and women in the highest tertile of overall PA had on average a 77% and 92% lower risk of mortality than their less active counterparts. The highest tertile of LPA was also related to a lower risk of mortality in individuals of both sexes. MVPA statistically reduced the risk of mortality only among women. Self-reported leisure-time PA was statistically associated with a lower risk of mortality only among men. Women in the highest tertiles of commuting PA showed a lower risk of mortality than those in the reference group.

CONCLUSION Accelerometry-based PA was associated with a lower risk of mortality among Brazilian older adults. Older individuals should practice any type of PA.

Publication: Nature Metabolism

Jack L. Martin, Ana S. H. Costa, Anja V. Gruszczyk, Timothy E. Beach, Fay M. Allen, Hiran A. Prag, Elizabeth C. Hinchy, Krishnaa Mahbubani, Mazin Hamed, Laura Tronci, Efterpi Nikitopoulou, Andrew M. James, Thomas Krieg, Alan J. Robinson, Margaret M. Huang, Stuart T. Caldwell, Angela Logan, Laura Pala, Richard C. Hartley, Christian Frezza, Kourosh Saeb-Parsy, Michael P. Murphy

30 September 2019

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Summary:

During retrieval of kidneys for transplant, there is inevitably a period of time when the organ is without blood flow but still warm (warm ischaemia). A human kidney cannot sustain this for long. During warm ischaemia, a metabolite called succinate builds up. When blood flow is restored, then counter-intuitively, the kidney tissue is damaged with the arrival of oxygenated blood. A drug was tested that ameliorates this damage. This research shows how the function and life span of a transplanted organ can be improved.

Publication: J Neurology Neurosurgery Psychiatry

Denis HL, Lamontagne-Proulx J, St-Amour I, Mason SL, Rowley JW, Cloutier N, et al.

2019 Mar;90(3):272-283

Publication: Nature

Bashford-Rogers, R.J.M., Bergamaschi, L., McKinney, E.F., Pombal, D.C., Mescia, F., Lee, J.C., Thomas, D.C., Flint, S.M., Kellam, P., Jayne, D.R.W., Lyons P.A. and Smith, K.G.C.

25 September 2019

Publication: Metabolomics

Furse S, Billing G, Snowden SG, Smith J, Goldberg G, Koulman A.

25 September 2019

This study was motivated by the report that infant development correlates with particular lipids in infant plasma.

The hypothesis was that the abundance of these candidate biomarkers is influenced by the dietary intake of the infant.

A cohort of 30 exclusively-breastfeeding mother–infant pairs from a small region of West Africa was used for this observational study. Plasma and milk from the mother and plasma from her infant were collected within 24 h, 3 months post partum. The lipid, sterol and glyceride composition was surveyed using direct infusion MS in positive and negative ion modes. Analysis employed a combination of univariate and multivariate tests.

The lipid profiles of mother and infant plasma samples are similar but distinguishable, and both are distinct from milk. Phosphatidylcholines (PC), cholesteryl esters (CEs) and cholesterol were more abundant in mothers with respect to their infants. A latent structure model showed that four lipids in infant plasma previously shown to be biomarkers clustered with cholesteryl esters in the maternal circulation.

This study found evidence that the abundance of individual lipid isoforms associated with infant development are associated with the abundance of individual molecular species in the mother’s circulation.