Publications

Publication: European Journal of Applied Physiology

Veijalainen A, Haapala EA, Väistö J, Leppänen MH, Lintu N, Tompuri T, et al.

18 September 2019

The researchers looked at the associations of physical activity (PA), sedentary time (ST), and cardiorespiratory fitness (CRF) with heart rate variability (HRV) in children.

The participants were a population sample of 377 children aged 6–9 years (49% boys). ST, light PA (LPA), moderate PA (MPA), vigorous PA (VPA), and moderate-to-vigorous PA (MVPA), and PA energy expenditure (PAEE) were assessed using a combined heart rate and movement sensor, maximal power output per kilograms of lean body mass as a measure of CRF by maximal cycle ergometer exercise test, and HRV variables (SDNN, RMSSD, LF, and HF) using 5 min resting electrocardiography. Data were analysed by linear regression adjusted for years from peak height velocity.

In boys, ST was inversely associated and MVPA, VPA, PAEE, and CRF were directly associated with HRV variables. CRF was directly associated with all HRV variables and PAEE was directly associated with RMSSD after mutual adjustment for ST, PAEE, and CRF.

In girls, ST was inversely associated and LPA, MPA, VPA, MVPA, and PAEE were directly associated with HRV variables. After mutual adjustment for ST, PAEE, and CRF, only the inverse associations of ST with HRV variables remained statistically significant.

Higher ST and lower PA and CRF were associated with poorer cardiac autonomic nervous system function in children. Lower CRF in boys and higher ST in girls were the strongest correlates of poorer cardiac autonomic function.

Publication: Scientific Reports

Ottaviani JI, Fong R, Kimball J, Ensunsa JL, Gray N, Vogiatzoglou A, et al.

11 September 2019

Data from dietary intervention studies suggest that intake of (−)-epicatechin mediates beneficial vascular effects in humans. However, population-based investigations are required to evaluate associations between habitual intake and health and these studies rely on accurate estimates of intake, which nutritional biomarkers can provide.

Here, we evaluate a series of structurally related (−)-epicatechin metabolites (SREM), particularly (−)-epicatechin-3′-glucuronide, (−)-epicatechin-3′-sulfate and 3′-O-methyl-(−)-epicatechin-5-sulfate (SREMB), as flavan-3-ol and (−)-epicatechin intake. SREMB in urine proved to be a specific indicator of (−)-epicatechin intake, showing also a strong correlation with the amount of (−)-epicatechin ingested (R2: 0.86 (95% CI 0.8l; 0.92).

The median recovery of (−)-epicatechin as SREMB in 24 h urine was 10% (IQR 7–13%) and we found SREMB in the majority of participants of EPIC Norfolk (83% of 24,341) with a mean concentration of 2.4 ± 3.2 µmol/L.

Our results show that SREMB are suitable as biomarker of (−)-epicatechin intake. According to evaluation criteria from IARC and the Institute of Medicine, the results obtained support use of SREMB as a recovery biomarker to estimate actual intake of (−)-epicatechin.

Publication: Annals of Clinical and Translational Neurology

Nicolas Nicastro, Ajenthan Surendranathan, Elijah Mak, James B. Rowe, John T. O’Brien

10 September 2019

There is evidence of increased microglial activation in Parkinson’s disease (PD) as shown by in vivo PET ligand such as 11C‐PK11195. In addition, diffusion tensor imaging (DTI) imaging reveals widespread changes in PD, especially when the associated dementia develops.

The researchers studied five subjects with Parkinson’s disease dementia (PDD). Their findings suggest that while DTI metrics mirror cognitive severity, higher 11C‐PK11195 binding seems to be associated with a relative preservation of both white matter tracts and cognition.

Longitudinal studies are warranted to tackle the complex relationship between microglial activation and structural abnormalities in neurodegenerative conditions.

Publication: Brain Communications

Robin J Borchert, Timothy Rittman, Charlotte L Rae, Luca Passamonti, Simon P Jones, Deniz Vatansever, Patricia Vázquez Rodríguez, Zheng Ye, Cristina Nombela, Laura E Hughes, Trevor W Robbins, James B Rowe

6 September 2019

Parkinson’s disease has multiple detrimental effects on motor and cognitive systems in the brain. In contrast to motor deficits, cognitive impairments in Parkinson’s disease are usually not ameliorated, and can even be worsened, by dopaminergic treatments. Recent evidence has shown potential benefits from restoring other neurotransmitter deficits, including noradrenergic and serotonergic transmission.

The researchers studied global and regional brain network organization using task-free imaging (also known as resting-state), which minimizes performance confounds and the bias towards predetermined networks.

Thirty-three patients with idiopathic Parkinson’s disease were studied three times in a double-blinded, placebo-controlled counter-balanced crossover design, following placebo, 40 mg oral atomoxetine (selective noradrenaline reuptake inhibitor) or 30 mg oral citalopram (selective serotonin reuptake inhibitor).

In patients, atomoxetine improved fluency in proportion to plasma concentration, and improved response inhibition in proportion to increased hub Eigen centrality. Citalopram did not improve fluency or inhibitory control, but its influence on network integration and efficiency depended on disease severity: clustering, modularity and path length increased in patients with milder forms of Parkinson’s disease, but decreased in patients with more advanced disease.

This study supports the use of task-free imaging of brain networks in translational pharmacology of neurodegenerative disorders. The researchers propose that hub connectivity contributes to cognitive performance in Parkinson’s disease, and that noradrenergic treatment strategies can partially restore the neural systems supporting executive function.

Publication: Journal of Antimicrobial Chemotherapy

Pérez-Vázquez M, Sola Campoy PJ, Ortega A, Bautista V, Monzón S, Ruiz-Carrascoso G, Mingorance J, González-Barberá EM, Gimeno C, Aracil B, Sáez D, Lara N, Fernández S, González-López JJ, Campos J, Kingsley RA, Dougan G, Oteo-Iglesias J; Spanish NDM Study Group .  J Antimicrob Chemother.

3 September 2019

Publication: The Journal of the American Medical Association (JAMA)

Brian A. Ference, Deepak L. Bhatt, Alberico L. Catapano, Chris J. Packard, Ian Graham, Stephen Kaptoge, Thatcher B. Ference, Qi Guo, Ulrich Laufs, Christian T. Ruff, Arjen Cupido1, G. Kees Hovingh, John Danesh, Michael V. Holmes, George Davey Smith, Kausik K. Ray, Stephen J. Nicholls, Marc S. Sabatine

2 September 2019

Summary:

Most cardiovascular events can be prevented with sustained exposure to modestly lower combinations of lipoprotein cholesterol (LDL-C) and lower systolic blood pressure (SBP), according to research led by Cambridge researchers who carried out Mendelian randomization analyses involving 438,952 participants. Read the full story here.

Publication: Genome Biology

Ellington MJ, Heinz E, Wailan AM, Dorman MJ, de Goffau M, Cain AK, Henson SP, Gleadall N, Boinett CJ, Dougan G, Brown NM, Woodford N, Parkhill J, Török ME, Peacock SJ, Thomson NR.

2 September 2019

Publication: The Lancet Global Health

Stephen Kaptoge, Lisa Pennells, Dirk De Bacquer, Marie Therese Cooney, Maryam Kavousi, Oyere Onuma, Mark Woodward, Goodarz Danaei, Gregory Roth, Shanthi Mendis, Ian Graham, Cherian Varghese, Majid Ezzati, Rod Jackson, John Danesh & Emanuele Di Angelantonio

1 September 2019

Summary:

Cambridge-led researchers have updated World Health Organisation (WHO) cardiovascular disease (CVD) risk prediction charts to aid efforts to reduce the burden of CVD, one of the most common non-communicable diseases world-wide and responsible for an estimated 17.8 million deaths in 2017.

The research was funded by the National Institute for Health Research Cambridge Biomedical Research Centre, WHO, British Heart Foundation (BHF), BHF Cambridge Centre for Research Excellence and UK Medical Research Council.

The revised risk models will help particularly middle- to low-income countries in their efforts to prevent and control CVD. Full story here

Publication: Journal of Nutritional Science

Foster E, Lee C, Imamura F, Hollidge SE, Westgate KL, Venables MC, et al.

30 August 2019

Online self-reported 24-h dietary recall systems promise increased feasibility of dietary assessment. Comparison against interviewer-led recalls established their convergent validity; however, reliability and criterion-validity information is lacking.

The validity of energy intakes (EI) reported using Intake24, an online 24-h recall system, was assessed against concurrent measurement of total energy expenditure (TEE) using doubly labelled water in ninety-eight UK adults (40–65 years). Accuracy and precision of EI were assessed using correlation and Bland–Altman analysis. Test–retest reliability of energy and nutrient intakes was assessed using data from three further UK studies where participants (11–88 years) completed Intake24 at least four times; reliability was assessed using intra-class correlations (ICC).

Compared with TEE, participants under-reported EI by 25 % (95 % limits of agreement −73 % to +68 %) in the first recall, 22 % (−61 % to +41 %) for average of first two, and 25 % (−60 % to +28 %) for first three recalls. Correlations between EI and TEE were 0·31 (first), 0·47 (first two) and 0·39 (first three recalls), respectively. ICC for a single recall was 0·35 for EI and ranged from 0·31 for Fe to 0·43 for non-milk extrinsic sugars (NMES). Considering pairs of recalls (first two v. third and fourth recalls), ICC was 0·52 for EI and ranged from 0·37 for fat to 0·63 for NMES. EI reported with Intake24 was moderately correlated with objectively measured TEE and underestimated on average to the same extent as seen with interviewer-led 24-h recalls and estimated weight food diaries.

Online 24-h recall systems may offer low-cost, low-burden alternatives for collecting dietary information.

Publication: EMBO Molecular Medicine

Blohmke CJ, Muller J, Gibani MM, Dobinson H, Shrestha S, Perinparajah S, Jin C, Hughes H, Blackwell L, Dongol S, Karkey A, Schreiber F, Pickard D, Basnyat B, Dougan G, Baker S, Pollard AJ, Darton TC.

30 August 2019

Publication: Cell

Ramakrishnan L, Roca Soler FJ, Whitworth L, Redmond S, Jones AA.

29 August 2019

Publication: PLOS ONE

Cullerton K, Adams J, Francis O, Forouhi N, White M.

22 August 2019

Key to scientific integrity is ensuring that research findings are considered credible by scientific peers, practitioners, policymakers and the public.

Industry sponsorship of nutritional research can result in bias and raises significant professional, public and media concern. Yet, there is no international consensus on how to prevent or manage conflicts of interest for researchers considering engaging with the food industry.

This study aimed to determine internationally agreed principles to guide interactions between population health researchers and the food industry to prevent or manage conflicts of interest. We used a two-stage, online Delphi study for researchers, and an online survey for stakeholders. High levels of agreement on principles were achieved for both groups (researchers 68%; stakeholders 65%). Highest levels of agreement were with principles concerning research methods and governance.

More contentious were principles that required values-based decision-making, such as determining which elements of the commercial sector are acceptable to interact with. These results provide the basis for developing internationally-agreed guidelines for population health researchers governing interactions with the food industry.

Publication: Nature Genetics

Kumar N, Browne HP, Viciani E, Forster SC, Clare S, Harcourt K, Stares MD, Dougan G, Fairley DJ, Roberts P, Pirmohamed M, Clokie MRJ, Jensen MBF, Hargreaves KR, Ip M, Wieler LH, Seyboldt C, Norén T, Riley TV, Kuijper EJ, Wren BW, Lawley TD.

12 August 2019

Publication: Diagnostics

Jeremy M. Brown, Julie Wiggins, Kate Dawson, Timothy Rittman, James B. Rowe

12 August 2019

This research paper summarises the current status of two novel short cognitive tests (SCT), known as Test Your Memory (TYM) and Test Your Memory for Mild Cognitive Impairment (TYM-MCI). The history of and recent research on the TYM and TYM-MCI are summarised in applications for Alzheimer’s and non-Alzheimer’s dementia and mild cognitive impairment.

In this NIHR Cambridge-BRC funded research, the researchers found out that the TYM test can be used in a general neurology clinic and can help distinguish patients with Alzheimer’s disease (AD) from those with no neurological cause for their memory complaints. An adapted tele-TYM test administered by telephone to patients produces scores which correlate strongly with the clinic-administered Addenbrooke’s Cognitive Examination revised (ACE-R) test and can identify patients with dementia.

This is important because the team showed that patients with AD decline on the TYM test at a rate of 3.6–4.1 points/year.

Publication: Nature Biotechnology

Johannes Bargehr, Lay Ping Ong, Maria Colzani, Hongorzul Davaapil, Peter Hofsteen, Shiv Bhandari, Laure Gambardella, Nicolas Le Novère, Dharini Iyer, Fotios Sampaziotis, Florian Weinberger, Alessandro Bertero, Andrea Leonard, William G. Bernard, Amy Martinson, Nichola Figg, Michael Regnier, Martin R. Bennett, Charles E. Murry & Sanjay Sinha

2 August 2019

Summary:

Transplanting an area of damaged tissue with a combination of both heart and muscle cells and supportive cells taken from the outer layer of the heart wall, may be able to help the organs recover from the damage caused by a heart attack. Part funded by the BHF and NIHR and supported by the NIHR Cambridge BRC, researchers have used supportive epicardial cells developed from human stem cells to help transplanted heart cells live longer. Full story here

Publication: Aging Research Reviews

Audrey Low, Elijah Mak, James B.Rowe, Hugh S.Markus, John T. O’Brien

1 August 2019

Inflammation is increasingly implicated as a risk factor for dementia, stroke, and small vessel disease (SVD). However, the underlying mechanisms and causative pathways remain unclear. The researchers systematically reviewed the existing literature on the associations between markers of inflammation and SVD (i.e., white matter hyperintensities (WMH), lacunes, enlarged perivascular spaces (EPVS), cerebral microbleeds (CMB)) in cohorts of older people with good health, cerebrovascular disease, or cognitive impairment.

Evidence from 82 articles revealed relatively robust associations between SVD and markers of vascular inflammation, especially amongst stroke patients, suggesting that alterations to the endothelium and blood-brain barrier may be a driving force behind SVD.

These findings have important implications on interventions, suggesting the potential utility of treatments targeting the brain endothelium and blood brain barrier to combat SVD and associated neurodegenerative diseases.

Publication: Nature

Publication: Psychopharmacology

Lim TV, Cardinal RN, Savulich GJ, Moustafa AA, Robbins TW, Ersche KD

1 August 2019

Drug addiction has been suggested to develop through drug-induced changes in learning and memory processes. Whilst the initiation of drug use is typically goal-directed and hedonically motivated, over time, drug-taking may develop into a stimulus-driven habit, characterised by persistent use of the drug irrespective of the consequences.

Converging lines of evidence suggest that stimulant drugs facilitate the transition of goal-directed into habitual drug-taking, but their contribution to goal-directed learning is less clear.

Computational modelling may provide an elegant means for elucidating changes during instrumental learning that may explain enhanced habit formation.

The research team used formal reinforcement learning algorithms to deconstruct the process of appetitive instrumental learning and to explore potential associations between goal-directed and habitual actions in patients with cocaine use disorder (CUD).

They re-analysed appetitive instrumental learning data in 55 healthy control volunteers and 70 CUD patients by applying a reinforcement learning model within a hierarchical Bayesian framework. They used a regression model to determine the influence of learning parameters and variations in brain structure on subsequent habit formation.

The research showed that poor instrumental learning performance in CUD patients was largely determined by difficulties with learning from feedback, as reflected by a significantly reduced learning rate.

Subsequent formation of habitual response patterns was partly explained by group status and individual variation in reinforcement sensitivity. White matter integrity within goal-directed networks was only associated with performance parameters in controls but not in CUD patients.

The data indicate that impairments in reinforcement learning are insufficient to account for enhanced habitual responding in CUD.

Publication: Psychopharmacology

Kanen JW, Ersche KD, Fineberg NA, Robbins TW, Cardinal RN

20 July 2019

Disorders of compulsivity such as stimulant use disorder (SUD) and obsessive-compulsive disorder (OCD) are characterised by deficits in behavioural flexibility, some of which have been captured using probabilistic reversal learning (PRL) paradigms.

This study used computational modelling to characterise the reinforcement learning processes underlying patterns of PRL behaviour observed in SUD and OCD and to show how the dopamine D2/3 receptor agonist pramipexole and the D2/3 antagonist amisulpride affected these responses.

The researchers applied a hierarchical Bayesian method to PRL data across three groups: individuals with SUD, OCD, and healthy controls. Participants completed three sessions where they received placebo, pramipexole, and amisulpride, in a double-blind placebo-controlled, randomised design.

The researchers compared seven models using a bridge sampling estimate of the marginal likelihood.

The results showed that stimulus-bound perseveration, a measure of the degree to which participants responded to the same stimulus as before irrespective of outcome, was significantly increased in SUD, but decreased in OCD, compared to controls (on placebo).

Individuals with SUD also exhibited reduced reward-driven learning, whilst both the SUD and OCD groups showed increased learning from punishment (nonreward).

Pramipexole and amisulpride had similar effects on the control and OCD groups; both increased punishment-driven learning. These D2/3-modulating drugs affected the SUD group differently, remediating reward-driven learning and reducing aspects of perseverative behaviour, amongst other effects.

The research showed how perseverative tendencies and reward- and punishment-driven learning differentially contribute to PRL in SUD and OCD.

D2/3 agents modulated these processes and remediated deficits in SUD in particular, which may inform therapeutic effects.

Publication: The Journal of Neuroscience

L. Passamonti, K.A. Tsvetanov, P.S. Jones, W.R. Bevan-Jones, R. Arnold, R.J. Borchert, E. Mak, L. Su, J.T. O’Brien and J.B. Rowe

18 July 2019

Neuroinflammation is a key part of the etio-pathogenesis of Alzheimer’s disease. The researchers tested the relationship between neuroinflammation and the disruption of functional connectivity in large-scale networks, and their joint influence on cognitive impairment.

Patients showed significantly higher [11C]PK11195 binding relative to controls, in a distributed spatial pattern including the hippocampus, medial, and inferior temporal cortex. Patients with enhanced loading on this [11C]PK11195 binding distribution displayed diffuse abnormal functional connectivity. The expression of a stronger association between such abnormal connectivity and higher levels of neuroinflammation correlated with worse cognitive deficits.

This study suggests that neuroinflammation relates to the pathophysiological changes in network function that underlie cognitive deficits in Alzheimer’s disease. Neuroinflammation, and its association with functionally-relevant reorganisation of brain networks, is proposed as a target for emerging immuno-therapeutic strategies aimed at preventing or slowing the emergence of dementia.