Publications

Publication: Journal of Clinical Endocrinology & Metabolism

Katherine Lawler, Isabel Huang-Doran, Takuhiro Sonoyama, Tinh-Hai Collet, Julia M Keogh, Elana Henning, Stephen O’Rahilly, Leonardo Bottolo, I Sadaf Farooqi

11 May 2020

Summary:

The hormone leptin is a key regulator of weight. Children who lack leptin (due to changes in the leptin gene) have a very large appetite and rapidly gain weight. After treatment with leptin injections, they can lose weight.

The researchers know that leptin works by reducing their appetite, but they wanted to find out if leptin can affect other metabolic processes around the body too.

They used a cutting-edge technique called metabolomics to simultaneously measure more than 600 metabolic reactions in a single blood sample taken from children and young adults before and after a short period of leptin treatment.

They found that leptin not only caused big shifts in how the body processes fats, but it affected amino acids (which make proteins), bile acids (which can act as cell signals) and steroids (involved in making hormones). These changes overlapped with the changes discovered previously in healthy adults after a period of fasting.

The research findings show that as well as affecting how much food we eat, leptin affects other aspects of our metabolism. This research paves the way for further research into leptin’s action on different cells in the human body.

Publication: Cell Metabolism

Marenne, G., Hendricks, A., Perdikari, A., Bounds, R., Payne, F., Keogh, J., Lelliott, C., Henning, E., Pathan, S., Ashford, S., Bochukova, E., Mistry, V., Daly, A., Hayward, C., Wareham, N., O’Rahilly, S., Langenberg, C., Wheeler, E., Zeggini, E., Farooqi, I. and Barroso, I.

2 June 2020

Obesity is genetically heterogeneous with monogenic and complex polygenic forms. Using exome and targeted sequencing in 2,737 severely obese cases and 6,704 controls, the researchers identified three genes (PHIP, DGKI, and ZMYM4) with an excess burden of very rare predicted deleterious variants in cases.

In cells, they showed that PHIP is involved in human energy homeostasis, which has potential diagnostic and therapeutic implications for patients with obesity and developmental delay.

Additionally, they found an excess burden of predicted deleterious variants involving genes nearest to loci from obesity genome-wide association studies.

Genes and gene sets influencing obesity with variable penetrance provide compelling evidence for a continuum of causality in the genetic architecture of obesity, and explain some of its missing heritability.

Publication: eLife

Lucy Rivett, Sushmita Sridhar, Dominic Sparkes, Matthew Routledge, Nick K. Jones, et al

12 May 2020

Summary:

Significant differences exist in the availability of healthcare worker (HCW) SARS-CoV-2 testing between countries, and existing programmes focus on screening symptomatic rather than asymptomatic staff. Over a 3-week period (April 2020), 1,032 asymptomatic HCWs were screened for SARS-CoV-2 in a large UK teaching hospital. Symptomatic staff and symptomatic household contacts were additionally tested. Real time RT-PCR was used to detect viral RNA from a throat+nose self-swab. 3% of HCWs in the asymptomatic screening group tested positive for SARS-CoV-2. 17/30 (57%) were truly asymptomatic/pauci-symptomatic. 30 (40%) had experienced symptoms compatible with coronavirus disease 2019 (COVID-19) >7 days prior to testing, most self-isolating, returning well. Clusters of HCW infection were discovered on two independent wards. Viral genome sequencing showed that the majority of HCWs had the dominant lineage B∙1. Our data demonstrates the utility of comprehensive screening of HCWs with minimal or no symptoms. This approach will be critical for protecting patients and hospital staff.

Publication: Brain

Maura Malpetti, Rogier A Kievit, Luca Passamonti, P Simon Jones, Kamen A Tsvetanov, Timothy Rittman, Elijah Mak, Nicolas Nicastro, W Richard Bevan-Jones, Li Su, Young T Hong, Tim D Fryer, Franklin I Aigbirhio, John T O’Brien, James B Rowe

07 May 2020

Summary:

Alzheimer’s disease is a condition associated with an ongoing decline of the brain functioning correctly. It can affect loss of memory, language and completing everyday tasks.

Researchers having been investigating the brains functionality, and whether they could help clinicians calculate how a patient will progress with their dementia.

Using an imaging machine called PET (positron emission tomography) they were able to take brain scans and detect the build-up of ‘junk proteins’ in the brain alongside brain inflammation and shrinkage. It could help predict how fast or slow and individual will progress with their dementia.

The PET scans could predict faster cognitive decline in patients and they were more accurate predictors than MRI measures of brain shrinkage.

Publication: Brain A Journal of Neurology

Maura Malpetti, Rogier A Kievit, Luca Passamonti, P Simon Jones, Kamen A Tsvetanov, Timothy Rittman, Elijah Mak, Nicolas Nicastro, W Richard Bevan-Jones, Li Su, Young T Hong, Tim D Fryer, Franklin I Aigbirhio, John T O’Brien, James B Rowe

7 May 2020

Tau pathology, neuroinflammation, and neurodegeneration are key aspects of Alzheimer’s disease. Understanding whether these features predict cognitive decline, alone or in combination, is crucial to develop new prognostic measures and enhanced stratification for clinical trials. Here, the researchers studied how baseline assessments of in vivo tau pathology (measured by 18F-AV-1451 PET), neuroinflammation (measured by 11C-PK11195 PET) and brain atrophy (derived from structural MRI) predicted longitudinal cognitive changes in patients with Alzheimer’s disease pathology.

In patients, both stepwise backward elimination and Bayesian model selection revealed an optimal predictive model that included both components of 18F-AV-1451 and the first (i.e. anterior temporal) component for 11C-PK11195. However, the MRI-derived atrophy component and demographic variables were excluded from the optimal predictive model of cognitive decline.

The researchers conclude that temporo-parietal tau pathology and anterior temporal neuroinflammation predict cognitive decline in patients with symptomatic Alzheimer’s disease pathology. This indicates the added value of PET biomarkers in predicting cognitive decline in Alzheimer’s disease, over and above MRI measures of brain atrophy and demographic data. The findings also support the strategy for targeting tau and neuroinflammation in disease-modifying therapy against Alzheimer’s disease.

Publication: Nature

James E. D. Thaventhiran, Hana Lango Allen, Kenneth G. C. Smith 

06 May 2020

Summary:

Cambridge researchers sequenced the entire genetic code of 974 people with PID. The team were able to identify variations in genes already known to cause PID. To help identify genetic causes for the remaining participants and other patients with PID, the team used a statistical program known as BeviMed. BeviMed can be used to predict genes that may cause PID, by comparing the genomes of cases and controls. Using this technique, the team were able to identify new genes that cause PID. Full press release here

Publication: Nature Microbiology

Francesca Gaccioli, Susanne Lager, Marcus C. de Goffau, Ulla Sovio, Justyna Dopierala, Sungsam Gong, Emma Cook, Andrew Sharkey, Ashley Moffett, Wai Kwong Lee, Christian Delles, Cristina Venturini, Judith Breuer, Julian Parkhill, Sharon J. Peacock, D. Stephen Charnock-Jones & Gordon C. S. Smith

4 May 2020

Summary: 

The placenta is the interface between the mum and the fetus and supports the growth of the baby in the womb. Abnormal function of the placenta is associated with poor pregnancy outcome, including maternal and infant diseases and deaths. In turn, placental dysfunction could be due to viral infections, which are known to cause organ failure. We investigated whether viral infection of the placenta is associated with diseases of human pregnancy related to poor placental function, such as pre-eclampsia (hypertensive disorder in the mother) and fetal growth restriction (impaired growth of the fetus during pregnancy).

Using samples from more than 5,000 pregnancies and data available in the literature, we demonstrated that the presence of inherited human herpesvirus 6 (HHV-6) DNA in the feto-placental unit is associated with an increased risk of the mother to develop pre-eclampsia. The virus can be passed to the fetus and the placenta from both the mother and the father. Importantly, our study did not identify any other viral associations with the 2 studied conditions. HHV-6 was the only clear viral signal observed in a large number of placental samples from pathological and normal pregnancies.

Pre-eclampsia is a condition characterized by high maternal blood pressure and protein levels in the urine in the second half of pregnancy. It represents a major determinant of the global burden of disease. Although pre-eclamspia is known to be associated with poor development and function of the placenta, the causes of placental insufficiency are not fully understood. Identifying those will help us to understand and treat this condition, which affects 5-8% of all pregnant women and is responsible for over 75,000 maternal deaths and 500,000 fetal deaths worldwide every year. Our work demonstates that viral infection of the placenta is not a major cause of pre-eclampsia and that a small proportion of cases is likely to be due to the presence of HHV-6 in the feto-placental unit.

Publication: Cortex

Thomas E. Cope, Yury Shtyrov, Lucy J. MacGregor, Rachel Holland, Friedemann Pulvermüller, James B. Rowe, Karalyn Patterson

1 May 2020

In the healthy human brain, the processing of language is strongly lateralised, usually to the left hemisphere, while the processing of complex non-linguistic sounds recruits brain regions bilaterally. Here the researchers asked whether the anterior temporal lobes, strongly implicated in semantic processing, are critical to this special treatment of spoken words. Nine patients with semantic dementia (SD) and fourteen age-matched controls underwent magnetoencephalography and structural MRI.

Source reconstructions confirmed recruitment of right-sided analogues of language regions in SD: atrophy of anterior temporal lobes was associated with increased activity in right temporal pole, middle temporal gyrus, inferior frontal gyrus and supramarginal gyrus.

Overall, the results indicate that anterior temporal lobes are necessary for normal and efficient lateralised processing of word identity by the language network.

Publication: Brain A Journal of Neurology

Alexander G Murley, Ian Coyle-Gilchrist, Matthew A Rouse, P Simon Jones, Win Li, Julie Wiggins, Claire Lansdall, Patricia Vázquez Rodríguez, Alicia Wilcox, Kamen A Tsvetanov, Karalyn Patterson, Matthew A Lambon Ralph, James B Rowe

1 May 2020

The syndromes caused by frontotemporal lobar degeneration have highly heterogeneous and overlapping clinical features. There has been great progress in the refinement of clinical diagnostic criteria in the past decade, but the researchers propose that a better understanding of aetiology, pathophysiology and symptomatic treatments can arise from a transdiagnostic approach to clinical phenotype and brain morphometry. In a cross-sectional epidemiological study, they examined 310 patients with a syndrome likely to be caused by frontotemporal lobar degeneration, including behavioural variant frontotemporal dementia, non-fluent, and semantic variants of primary progressive aphasia (PPA), progressive supranuclear palsy and corticobasal syndrome. They included patients with logopenic PPA and those who met criteria for PPA but not a specific subtype.

The results show that syndromes associated with frontotemporal lobar degeneration do not form discrete mutually exclusive categories from their clinical features or structural brain changes, but instead exist in a multidimensional spectrum. Patients often manifest diagnostic features of multiple disorders while deficits in behaviour, movement and language domains are not confined to specific diagnostic groups.

It is important to recognize individual differences in clinical phenotype, both for clinical management and to understand pathogenic mechanisms. The researchers suggest that a transdiagnostic approach to the spectrum of frontotemporal lobar degeneration syndromes provides a useful framework with which to understand disease aetiology, progression, and heterogeneity and to target future treatments to a higher proportion of patients.

Publication: Brain Communications

Marta M Correia, Timothy Rittman, Christopher L Barnes, Ian T Coyle-Gilchrist, Boyd Ghosh, Laura E Hughes, James B Rowe

27 April 2020

The early and accurate differential diagnosis of parkinsonian disorders is still a significant challenge for clinicians. In recent years, a number of studies have used magnetic resonance imaging data combined with machine learning and statistical classifiers to successfully differentiate between different forms of Parkinsonism. However, several questions and methodological issues remain, to minimize bias and artefact-driven classification. In this study, the researchers compared different approaches for feature selection, as well as different magnetic resonance imaging modalities, with well-matched patient groups and tightly controlling for data quality issues related to patient motion.

Their cross-validation results suggest that using principal components analysis for feature extraction provides higher classification accuracies when compared to a region-of-interest based approach. However, the differences between the two feature extraction methods were significantly reduced when an independent sample was used for validation, suggesting that the principal components analysis approach may be more vulnerable to overfitting with cross-validation. Both T1-weighted and diffusion magnetic resonance imaging data could be used to successfully differentiate between subject groups, with neither modality outperforming the other across all pairwise comparisons in the cross-validation analysis. However, features obtained from diffusion magnetic resonance imaging data resulted in significantly higher classification accuracies when an independent validation cohort was used.

Overall, the results support the use of statistical classification approaches for differential diagnosis of parkinsonian disorders. However, classification accuracy can be affected by group size, age, sex and movement artefacts. With appropriate controls and out-of-sample cross validation, diagnostic biomarker evaluation including magnetic resonance imaging based classifiers may be an important adjunct to clinical evaluation.

Publication: Nature

Luiza Moore, Daniel Leongamornlert, Tim H. H. Coorens, Mathijs A. Sanders, Peter Ellis, Stefan Dentro, Kevin Dawson, Tim Butler, Raheleh Rahbari, Thomas J Mitchell, Francesco Maura, Jyoti Nangalia, Patrick S. Tarpey, Simon F. Brunner, Henry Lee-Six, Yvette Hooks, Sarah Moody, Krishnaa Mahbubani, Mercedes Jimenez-Linan, Jan J. Brosens, Christine A. Iacobuzio-Donahue, Inigo Martincorena, Kourosh Saeb-Parsy, Peter J. Campbell, Michael R. Stratton

22 April 2020

Summary: 

This paper looks at somatic mutation (changes in the DNA) in healthy human tissue in the endometrium (womb lining) and provides insights into the earliest stages of uterine cancer development, which is the fourth most common cancer in women in the UK.

Many cells in the inner lining of the uterus carry ‘cancer-driving’ mutations that frequently arise early in life. Using whole-genome sequencing to better understand the genetic changes in healthy endometrial tissue, the researchers found that a high proportion of cells carry driver mutations, even though they appear completely normal under the microscope. Furthermore the team found that many of these driver mutations appear to have arisen early in life, in many cases during childhood.

Publication: BMC Medicine

Lois Kim, Nicholas Boxall, Anne George, Keith Burling, Pete Acher, Jonathan Aning, Stuart McCracken, Toby Page and Vincent J. Gnanapragasam

17 April 2020

Summary: 

At the moment if a man is referred for suspected prostate cancer he has to undergo an MRI scan and perhaps a prostate biopsy to find out if he has the disease. This costs a lot of money and means many hospital visits and potentially dangerous side effects (bleeding or infections from the biopsy). In this study researchers wanted to test if using a new biomarker blood test called PHI (Prostate Health Index) could reduce the number of unnecessary investigations for suspected prostate cancer. To do this they measured the PHI levels in over 500 men from 5 hospitals and tested how effective it was at selecting men for further investigations.

They found that if the PHI test was used to decide who should go onto have MRI and biopsies, doctors would reduce the number of scans needed by 25% and the number of biopsies needed by 40%, but still find the same number of prostate cancers. Moreover, using this test and pathway would save the NHS a lot of money as it is much cheaper than the current pathway.

Hospital visits and appointments could also be drastically reduced, which is particularly important in these days of shielding and social distancing to help with the COVID crisis.

Publication: Journal of Neurology

Alexander G. Murley, P. Simon Jones, Ian Coyle Gilchrist, Lucy Bowns, Julie Wiggins, Kamen A. Tsvetanov & James B. Rowe

10 April 2020

Widespread metabolic changes are seen in neurodegenerative disease and could be used as biomarkers for diagnosis and disease monitoring. They may also reveal disease mechanisms that could be a target for therapy. In this study the researchers looked for blood-based biomarkers in syndromes associated with frontotemporal lobar degeneration (FTLD).

Forty-nine of 842 metabolites were significantly altered in frontotemporal lobar degeneration syndromes (after false-discovery rate correction for multiple comparisons). These were distributed across a wide range of metabolic pathways including amino acids, energy and carbohydrate, cofactor and vitamin, lipid and nucleotide pathways. The metabolomic profile supported classification between frontotemporal lobar degeneration syndromes and controls with high accuracy (88.1–96.6%) while classification accuracy was lower between the frontotemporal lobar degeneration syndromes (72.1–83.3%). One metabolic profile, comprising a range of different pathways, was consistently identified as a feature of each disease versus controls: the degree to which a patient expressed this metabolomic profile was associated with their subsequent survival (hazard ratio 0.74 [0.59–0.93], p = 0.0018).

The metabolic changes in FTLD are promising diagnostic and prognostic biomarkers. Further work is required to replicate these findings, examine longitudinal change, and test their utility in differentiating between FTLD syndromes that are pathologically distinct but phenotypically similar.

Publication: Nutrients

Silvia Pastorino, Tom Bishop, Stephen J. Sharp, Matthew Pearce, Tasnime Akbaraly, Natalia B. Barbieri, Maira Bes-Rastrollo, Joline W. J. Beulens, Zhengming Chen, Huaidong Du, Bruce B. Duncan, Atsushi Goto, Tommi Härkänen, Maryam Hashemian, Daan Kromhout, Ritva Järvinen, Mika Kivimaki, Paul Knekt, Xu Lin, Eiliv Lund, Dianna J. Magliano, Reza Malekzadeh, Miguel Ángel Martínez-González, Gráinne O’Donoghue, Donal O’Gorman, Hossein Poustchi, Charlotta Rylander, Norie Sawada, Jonathan E. Shaw, Maria Schmidt, Sabita S. Soedamah-Muthu, Liang Sun, Wanqing Wen, Alicja Wolk, Xiao-Ou Shu, Wei Zheng, Nicholas J. Wareham, and Nita G. Forouhi

7 April 2020

Summary

Eating fish is generally considered part of a healthy diet. This is based on previous evidence from research that found benefits of consuming fish for heart disease. That is why there are various dietary guidelines that recommend that people should consume fish regularly.

Whether fish consumption also has a role in the prevention of type 2 diabetes is not clear. In previous research it was reported that the relationship between eating fish and developing type 2 diabetes may vary in different parts of the world.

To understand this better, we undertook research including data from studies in several world regions.  The InterConnect project enabled us to analyse data from nearly one million people from 28 studies across the world, among whom 48,000 people developed type 2 diabetes over time. Researchers analysed data on different types of fish, including shellfish, fatty fish, lean fish and fried fish.

Publication: Frontiers in Neuroscience

Audrey Low, Elijah Mak, James D. Stefaniak, Maura Malpetti, Nicolas Nicastro, George Savulich, Leonidas Chouliaras, Hugh S. Markus, James B. Rowe and John T. O’Brien

19 March 2020

The peak width of skeletonized mean diffusivity (PSMD) has been proposed as a fully automated imaging marker of relevance to cerebral small vessel disease (SVD). The researchers assessed PSMD in relation to conventional SVD markers, global measures of neurodegeneration, and cognition.

PSMD was associated with global and regional SVD measures, especially WMH and microbleeds. Dominance analysis demonstrated that among SVD markers, WMH was the strongest predictor of PSMD. Furthermore, PSMD was more closely associated to WMH than with GM and WM volumes.

This new measure appears to be a marker of diffuse brain injury, largely due to vascular pathology, and may be a useful and convenient metric of overall cerebrovascular burden.

Publication: International Journal of Epidemiology

Brage S, Lindsay T, Venables M, Wijndaele K, Westgate K, Collins D, et al.

19 March 2020

This is the first nationally representative study of human energy expenditure, covering the UK in the period 2008-2015.

Key messages:

• Total energy expenditure (MJ/day) increases steadily with age throughout childhood and adolescence, peaks in the 3rd decade of life in women and 4th decade of life in men, before decreasing gradually in old age.
• Physical activity energy expenditure (kJ/day/kg or kJ/day/kg fat-free mass) declines steadily with age from childhood to old age, more steeply so in males.
• Body-fat percentage is strongly inversely associated with physical activity energy expenditure.
• We found little evidence that energy expenditure varied by geographical region, over time, or by dietary macronutrient composition.

Publication: Neurobiology of Aging

Ece Kocagoncuae, Andrew Quinn, Azadeh Firouzi, Elisa Cooper, Andrea Greve, Roger Gunn, Gary Green, Mark W. Woolrich, Richard N. Henson, Simon Lovestone, James B. Rowe

17 March 2020

Understanding the role of Tau protein aggregation in the pathogenesis of Alzheimer’s disease is critical for the development of new Tau-based therapeutic strategies to slow or prevent dementia.

Higher Tau burden in early Alzheimer’s disease was associated with a shift away from the optimal small-world organization and a more fragmented network in the beta and gamma bands, whereby parieto-occipital areas were disconnected from the anterior parts of the network. Similarly, higher Tau burden was associated with decreases in both local and global efficiency, especially in the gamma band.

The results support the translational development of neurophysiological “signatures” of Alzheimer’s disease, to understand disease mechanisms in humans and facilitate experimental medicine studies.

Publication: Nature Medicine

Ulla Sovio, Neil Goulding, Nancy McBride, Emma Cook, Francesca Gaccioli, D. Stephen Charnock-Jones, Debbie A. Lawlor & Gordon C. S. Smith

11 March 2020

Summary: 

Fetal growth restriction (FGR) means that the fetus fails to grow according to its growth potential. The condition is a major cause of stillbirth, neonatal illness and death. Maternal risk factors and ultrasound measurements alone are not effective in screening for fetal growth restriction. Biomarkers in the pregnant woman’s blood could possibly improve screening for FGR.

Using serial maternal serum samples from the Pregnancy Outcome Prediction (POP) study, the research team identified metabolites that were predictive of FGR at term. These were used to calculate a ratio that clearly improves the prediction of FGR over currently known risk factors. They successfully validated the finding in plasma samples from a demographically different Born in Bradford (BiB) study.

Together with ultrasound measurements, the metabolite ratio could possibly be used to improve late pregnancy screening for fetal growth restriction. Screen-positive women could be offered enhanced monitoring and targeted induction of labour to prevent adverse effects associated with FGR.

Publication: PLoS Med

Hardeman W, Mitchell J, Pears S, Van Emmenis M, Theil F, Gc VS, et al.

6 March 2020

The majority of people do not achieve recommended levels of physical activity. There is a need for effective, scalable interventions to promote activity. Self-monitoring by pedometer is a potentially suitable strategy. We assessed the effectiveness and cost-effectiveness of a very brief (5-minute) pedometer-based intervention (‘Step It Up’) delivered as part of National Health Service (NHS) Health Checks in primary care.

The Very Brief Intervention (VBI) Trial was a two parallel-group, randomised controlled trial (RCT) with 3-month follow-up, conducted in 23 primary care practices in the East of England.

Participants were 1,007 healthy adults aged 40 to 74 years eligible for an NHS Health Check. They were randomly allocated to either intervention (505) or control group (502), stratified by primary care practice. Control participants received the NHS Health Check only. Intervention participants additionally received Step It Up: a 5-minute face-to-face discussion, written materials, pedometer, and step chart. The primary outcome was accelerometer-based physical activity volume at 3-month follow-up adjusted for sex, 5-year age group, and general practice.

Conclusions

In this large well-conducted trial, we found no evidence of effect of a plausible very brief pedometer intervention embedded in NHS Health Checks on objectively measured activity at 3-month follow-up.

Publication: Scientific Reports

T. D. Turmezei, G. M. Treece, A. H. Gee, S. Sigurdsson, H. Jonsson, T. Aspelund, V. Gudnason & K. E. S. Poole

March 2020

Summary

Hip osteoarthritis is a very common condition that will affect up to 25% of the population in their lifetime. There is no cure for this painful and debilitating disease, with the mainstay of treatment currently being surgical replacement of the joint once it has become too stiff or painful to use. Research trials trying to find effective therapies for osteoarthritis currently rely on x-ray radiograph imaging to test if there have been any meaningful changes in the structure of the joint for a new therapy, but this method suffers from being unable to detect small changes reliably and from only being able to see the joint in 2D.

We developed the joint space mapping (JSM) technique in a collaboration between the Departments of Medicine and Engineering at the University of Cambridge and have since taken it to test on patient data from the widely regarded AGES-Reykjavik patient cohort of healthy older Icelandic adults.

Our research showed that JSM can identify structurally relevant disease features related to the important outcome of joint replacement in hip osteoarthritis better than the current clinical trial 2D imaging gold standards. This means that JSM could be a significantly better way of identifying who might be at high risk from getting hip osteoarthritis, those in whom the disease might be progressing rapidly, and whether any new therapy is effective at stopping the joint destruction that ultimately leads to joint failure. These results have been achieved by using an existing and readily available clinical imaging technique to look at the hip joint in 3D.