Publications

Publication: International Journal of Cancer

Olga E. Titova, Karl Michaëlsson, Mathew Vithayathil, Amy M. Mason, Siddhartha Kar, Stephen Burgess, Susanna C. Larsson

7 September 2020

Studies of sleep duration in relation to the risk of site‐specific cancers other than breast cancer are scarce. Furthermore, the available results are inconclusive and the causality remains unclear. In this study researchers aimed to investigate the potential causal associations of sleep duration with overall and site‐specific cancers using the Mendelian randomization (MR) design.

The researchers concluded that this MR study does not provide strong evidence to support causal associations of sleep duration with risk of overall and site‐specific cancers. The suggestive associations of short‐ or long‐sleep duration with certain cancers merit further investigation in other large MR studies.

Publication: Cell Reports Medicine

Petra Mlcochova, Dami Collier, Allyson Ritchie, Sonny M. Assennato, Myra Hosmillo, Neha Goel, Bo Meng, Krishna Chatterjee, Vivien Mendoza, Nigel Temperton, Leo Kiss, Leo C. James, Katarzyna A. Ciazynska, Xiaoli Xiong, John AG. Briggs, James A. Nathan, Federica Mescia, Laura Bergamaschi, Hongyi Zhang, Petros Barmpounakis, Nikos Demeris, Richard Skells, Paul A. Lyons, John Bradley, Steven Baker, Jean Pierre Allain, Kenneth GC. Smith, Rachel Bousfield, Michael Wilson, Dominic Sparkes, Glenn Amoroso, Effrosyni Gkrania-Klotsas, Susie Hardwick, Adrian Boyle, Ian Goodfellow, Ravindra K. Gupta 

1 September 2020

Summary

Testing patients for COVID-19 as soon as they arrive at hospital is essential to obtain a diagnosis and to make sure they receive the correct treatment as soon as possible.

In a recent Cambridge study, the use of the SAMBA II test reduced the amount of time patients spent on holding wards. Now Cambridge researchers wanted to go further to create a ‘gold-standard’ method of testing.

The most common form of testing is taking a swab of the nose and throat (known as PCR) to see if the virus is present. However, it can take as long as 14 days for an individual to show symptoms of COVID-19, by which time the virus may have moved from the nose and throat and into the lungs and other tissues and organs, making it harder to detect via a swab test. Another way to detect the virus is looking for antibodies (from blood samples) in individuals.

Cambridge researchers combined the two tests – PCR and the antibody test – to help identify who may have the virus. They found combining both tests was more effective to identify patients who had Covid than those who had just one of the tests. Read the full news story.

Publication: Brain A Journal of Neurology

Matthew J Betts, Evgeniya Kirilina, Maria C G Otaduy, Dimo Ivanov, Julio Acosta-Cabronero, Martina F Callaghan, Christian Lambert, Arturo Cardenas-Blanco, Kerrin Pine, Luca Passamonti, Clare Loane, Max C Keuken, Paula Trujillo, Falk Lüsebrink, Hendrik Mattern, Kathy Y Liu, Nikos Priovoulos, Klaus Fliessbach, Martin J Dahl, Anne Maaß, Christopher F Madelung, David Meder, Alexander J Ehrenberg, Oliver Speck, Nikolaus Weiskopf, Raymond Dolan, Ben Inglis, Duygu Tosun, Markus Morawski, Fabio A Zucca, Hartwig R Siebner, Mara Mather, Kamil Uludag, Helmut Heinsen, Benedikt A Poser, Robert Howard, Luigi Zecca, James B Rowe, Lea T Grinberg, Heidi I L Jacobs, Emrah Düzel, Dorothea Hämmerer

1 September 2020

Pathological alterations to the locus coeruleus, the major source of noradrenaline in the brain, are histologically evident in early stages of neurodegenerative diseases. Novel MRI approaches now provide an opportunity to quantify structural features of the locus coeruleus in vivo during disease progression.

In this article, the researchers present a consensus on how non-invasive in vivo assessment of locus coeruleus integrity can be used for clinical research in neurodegenerative diseases.

They outline the next steps for in vivo, post-mortem and clinical studies that can lay the groundwork to evaluate the potential of locus coeruleus imaging as a biomarker for neurodegenerative diseases.

Publication: Clinical Neuropathology

Melanie P Jensen, Olivera Spasic-Boskovic, James B Rowe, Clare Galton, Kieren S J Allinson

1 September 2020

The researchers presented the clinicopathological findings of a case of combined Fahr’s disease (FD) and dementia with Lewy bodies (DLB), associated with a novel pathogenic mutation. The patient presented with visual hallucinations, fluctuating confusion and parkinsonism, leading to a presumptive diagnosis of DLB. CT scan showed extensive bilateral parenchymal calcifications, suggestive of FD. DNA sequencing identified a novel missense variant (c.92A>T p.(Asn31Ile)) in the SLC20A2 gene, a gene known to be associated with FD. This change has not been previously recorded in genetic repositories, and in silico analyses classified it as likely to be disease-causing.

Neuropathological examination revealed, macroscopically and microscopically, extensive calcification in the striatum, globus and cerebellar white matter. There was also neuronal loss in the substantia nigra and residual neurones contained alpha-synuclein-positive Lewy bodies. The neuropathology was therefore consistent with DLB and FD.

A literature review identified 3 other cases of co-existing Fahr’s and Lewy body pathology, thus the frequency of dual pathology (44%) is higher than expected by random association. Further studies are needed to determine whether alpha-synucleinopathy is linked mechanistically to FD and/or represents a phenotypic subtype.

Publication: European Journal of Preventive Cardiology

Sangeeta Lachman, S Matthijs Boekholdt, Robert N Luben, Stephen J Sharp, Soren Brage, Kay-Tee Khaw, Ron JG Peters, Nicholas J Wareham

29 August 2020

Summary

Publication: Nature Medicine

Strain, T., Wijndaele, K., Dempsey, P., Sharp, S., Pearce, M., Jeon, J., Lindsay, T., Wareham, N. and Brage, S.

17 August 2020

Use of wearable devices that monitor physical activity is projected to increase more than fivefold per half-decade. In this study the researchers investigated how device-based physical activity energy expenditure (PAEE) and different intensity profiles were associated with all-cause mortality.

96,476 UK Biobank participants (mean age 62 years, 56% female) were studied and followed up for 3.1 years. The research showed that higher PAEE was associated with a lower hazard of all-cause mortality for a constant fraction of moderate-to-vigorous-intensity physical activity (MVPA).

The results show that higher volumes of PAEE are associated with reduced mortality rates, and achieving the same volume through higher-intensity activity is associated with greater reductions than through lower-intensity activity. The linkage of device-measured activity to energy expenditure creates a framework for using wearables for personalized prevention.

Publication: Nature Communications

Varun Warrier, David M. Greenberg, Elizabeth Weir  Clara Buckingham, Paula Smith, Meng-Chuan Lai,  Carrie Allison, Simon Baron-Cohen

7 August 2020

Summary:

Transgender and gender-diverse individuals are more likely to be autistic and report higher autistic traits

Researchers reviewed over 600,000 people and used five datasets where participants provided information such as gender identity and if they received a diagnosis of autism or other psychiatric conditions such as depression or schizophrenia. Participants also completed a measure of autistic traits.

Researchers found that transgender and gender-diverse adult individuals were between three and six times more likely to indicate that they were diagnosed as autistic compared to cisgender individuals. The study used data from adults who said they had received an autism diagnosis, however, it is likely there are more individuals on the autistic spectrum who are undiagnosed.

This research will help improve access to mental health care and support for transgender and gender-diverse individuals. Read the full news story.

Publication: JCO Clinical Cancer Informatics

Mireia Crispin-Ortuzar, Marcel Gehrung, Stephan Ursprung, Andrew B. Gill, Anne Y. Warren, Lucian Beer, Ferdia A. Gallagher, Thomas J. Mitchell, Iosif A. Mendichovszky, Andrew N. Priest, Grant D. Stewart, Evis Sala, Florian Markowetz

August 2020

Summary

Cancer is a highly heterogeneous disease. Different parts of a single tumour often look different in medical images; they sometimes even carry different genetic information. This complexity may be key to understanding why some tumours respond better to therapy than others. Once the tumour has been removed through surgery, researchers can obtain tissue samples that allow them to study its spatial composition. However, matching these data to the images that were obtained before surgery is challenging.

The research team developed a computational methodology that relies on 3D printing to automatically design and create tumour moulds that help to match images and tissue accurately without disrupting clinical practice.

Their work provides a robust and automated interface between imaging and tissue, enabling the development of clinical studies to probe tumor heterogeneity on multiple spatial scales. Understanding this heterogeneity may be key to understand why some tumours respond better to therapy than others.

Publication: Journal of Neurology, Neurosurgery and Psychiatry

Tamara Paulo Tavares, Derek G V Mitchell, Kristy KL Coleman, Brenda L Coleman, Christen L Shoesmith, Christopher R Butler, Isabel Santana, Adrian Danek, Alexander Gerhard, Alexandre de Mendonca, Barbara Borroni, Maria Carmela Tartaglia, Caroline Graff, Daniela Galimberti, Fabrizio Tagliavini, Fermin Moreno, Giovanni Frisoni, James Benedict Rowe, Johannes Levin, John Cornelis Van Swieten, Markus Otto, Matthis Synofzik, Raquel Sanchez-Valle, Rik Vandenbergh, Robert Jr Laforce, Roberta Ghidoni, Sandro Sorbi, Simon Ducharme, Mario Masellis, Jonathan Rohrer, Elizabeth Finger

7 August 2020

The clinical heterogeneity of frontotemporal dementia (FTD) complicates identification of biomarkers for clinical trials that may be sensitive during the prediagnostic stage. It is not known whether cognitive or behavioural changes during the preclinical period are predictive of genetic status or conversion to clinical FTD.

The first objective was to evaluate the most frequent initial symptoms in patients with genetic FTD. The second objective was to evaluate whether preclinical mutation carriers demonstrate unique FTD-related symptoms relative to familial mutation non-carriers

The most frequently endorsed initial symptoms among symptomatic patients were apathy (23%), disinhibition (18%), memory impairments (12%), decreased fluency (8%) and impaired articulation (5%). Predominant first symptoms were usually discordant between family members. Relative to biologically related non-carriers, preclinical MAPT carriers endorsed worse mood and sleep symptoms, and C9orf72 carriers endorsed marginally greater abnormal behaviours. Preclinical GRN carriers endorsed less mood symptoms compared with non-carriers, and worse everyday skills.

Preclinical mutation carriers exhibited neuropsychiatric symptoms compared with non-carriers that may be considered as future clinical trial outcomes. Given the heterogeneity in symptoms, the detection of clinical transition to symptomatic FTD may be best captured by composite indices integrating the most common initial symptoms for each genetic group.

Publication: Neurobiology of Aging

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

1 August 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. The researchers tested the hypothesis that Tau pathology is associated with functional organization of widespread neurophysiological networks.

They found that 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.

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: The Lancet

Prof Rebecca C Fitzgerald, Massimiliano di Pietro, Maria O’Donovan, Roberta Maroni, Beth Muldrew, Irene Debiram-Beecham, Marcel Gehrung,  Judith Offman, Monika Tripathi, Samuel G Smith, Benoit Aigret, Fiona M Walter, Prof Greg Rubin, on behalf of theBEST3 Trial team † Prof Peter Sasieni

31 July 2020

Summary:

Barrett’s oesophagus is a condition that can lead to oesophageal cancer in a small number of people. It’s usually diagnosed in hospital by endoscopy (passing a camera down into the stomach). Samples of cells from any areas that don’t look normal are then collected, but an endoscopy can be uncomfortable and does have some risks.

The Cytosponge test allows the patient to swallow a small capsule with a sponge inside, which is attached to a piece of string. The capsule dissolves after a few minutes, and the sponge inside is released. A nurse then gently pulls the string to remove the sponge. On the way out the sponge collects cells from the lining of the oesophagus. The sample is then taken for analysis using a new laboratory marker called TFF3.

Researchers studied 13,222 participants who were randomly allocated to being offered the sponge test or being looked after by the GP in the usual way. Over the course of a year, the odds of detecting Barrett’s were ten times higher in those who were offered the Cytosponge with 140 cases diagnosed compared to 13 in usual care. In addition, the Cytosponge diagnosed five cases of early cancer (stage 1 and 2), whereas only one case of early cancer was detected in the usual care group.

Alongside better detection, the test means cancer patients can benefit from kinder treatment options if their cancer is caught at a much earlier stage. Read the full news article.

Publication: Cell Reports

Michael C. Lee, Michael S. Nahorski, James R.F. Hockley, Frank Reimann, Ewan St. John Smith, C. Geoffrey Woods

21 July 2020; DOI: 10.1016/j.celrep.2020.107941

Summary:

Women who don’t need pain relief during childbirth may have a key genetic variant that acts as a natural epidural. Supported by the NIHR Cambridge BRC, researchers investigated why some women experience different levels of pain during childbirth.

Women who did not require any pain relief during the birth of their first child took part in a study to understand their pain threshold. This included applying heat and pressure to their arms and putting their hands in icy water. They were then measured against a control group of women were who were given pain relief during childbirth.

They found the group the women who didn’t need any pain relief had a high pain threshold than those of the control group. Their genetic cold was then sequenced and found these women had a higher-than-expected prevalence of a rare variant of the gene KCNG4. This gene acts as a gate, controlling the electric signal that flows along our nerve cells. This could be the reason why these women did not require pain relief during childbirth. Read the full news article

Publication: Journal of Magnetic Resonance Imaging

Dimitri A. Kessler, James W. MacKay, Scott McDonald, Stephen McDonnell, Andrew J. Grainger, Alexandra R. Roberts, Robert L. Janiczek, Martin J. Graves, Joshua D. Kaggie, Fiona J. Gilbert

The researchers wanted to further understanding of the biomechanical properties of articular cartilage in our knee joints. By combining quantitative magnetic resonance imaging (MRI) and sophisticated 3D surface analysis methods of articular cartilage they were able to determine changes in cartilage microstructure following a mild, 5-minute stepping exercise in young, healthy individuals.

The team determined that our quantitative MRI methods are sensitive to changes of different compositional characteristics of articular cartilage such as changes in its water content or macromolecular structure following the stepping exercise. While previous studies have shown that changes in cartilage morphology (thickness, volume) recovers almost fully in about 45–90 minutes, they showed that the compositional changes induced by the exercise do not recover within an hour following cessation.

This is important because measuring the responses of cartilage to dynamic joint loading may present a way of determining cartilage health state as well as differences in healthy and diseased cartilage. With the exercise performed in this study being short and of limited duration, it could be extended for use in patients with early‐stage knee joint disease and minimal accompanying pain. As exercise is recommended as a form of conservative management of joint disease-related symptoms, the study provides an initial interpretation of short-term changes that occur in cartilage microstructure in response to exercise.

Publication: Journal of Neurology, Neurosurgery and Psychiatry

Jonathan Tay, Robin G Morris, Anil M Tuladhar, Masud Husain, Frank-Erik de Leeuw, Hugh S Markus

July 2020

Summary:

Cerebral small vessel disease (SVD) is the leading vascular cause of dementia and plays a major role in cognitive decline and mortality.

This research aimed to determine whether apathy or depression predicts all-cause dementia in SVD patients.

Using two prospective cohort studies of SVD, the researchers looked at changes in apathy and depression in 104 patients to predict dementia.

The research indicated that while increasing apathy was associated with dementia, baseline depression and change in depression did not predict dementia.

The researchers concluded that apathy, but not depression, may be an early sign of dementia in SVD, and that this may be useful in identifying at-risk individuals.

Publication: Movement Disorders

Negin Holland, P. Simon Jones, George Savulich, Julie K. Wiggins, Young T. Hong, Tim D. Fryer, Roido Manavaki, Selena Milicevic Sephton, Istvan Boros, Maura Malpetti, Frank H. Hezemans, Franklin I. Aigbirhio, Jonathan P. Coles, John O’Brien, James B. Rowe

11 July 2020

In this study the researchers tested the hypothesis that synaptic density is reduced in the primary tauopathies of progressive supranuclear palsy (PSP) (Richardson’s syndrome) and amyloid‐negative corticobasal syndrome (CBS).

Nine CBS patients had negative amyloid biomarkers determined by [11C]PiB PET and hence were deemed likely to have corticobasal degeneration (CBD). Patients with PSP‐Richardson’s syndrome and amyloid‐negative CBS were impaired in executive, memory, and visuospatial tasks. [11C]UCB‐J binding was reduced across frontal, temporal, parietal, and occipital lobes, cingulate, hippocampus, insula, amygdala, and subcortical structures in both PSP and CBD patients compared to controls (P < 0.01), with median reductions up to 50%, consistent with postmortem data. Reductions of 20% to 30% were widespread even in areas of the brain with minimal atrophy. There was a negative correlation between global [11C]UCB‐J binding and the PSP and CBD rating scales (R = –0.61, P < 0.002; R = –0.72, P < 0.001, respectively) and a positive correlation with the revised Addenbrooke’s Cognitive Examination (R = 0.52; P = 0.01).

The researchers confirm severe synaptic loss in PSP and CBD in proportion to disease severity, providing critical insight into the pathophysiology of primary degenerative tauopathies. [11C]UCB‐J may facilitate treatment strategies for disease‐modification, synaptic maintenance, or restoration.

Publication: Movement Disorders

Negin Holland, P. Simon Jones, George Savulich, Julie K. Wiggins, Young T. Hong, Tim D. Fryer, Roido Manavaki, Selena Milicevic Sephton, Istvan Boros, Maura Malpetti, Frank H. Hezemans, Franklin I. Aigbirhio, Jonathan P. Coles, John O’Brien, James B. Rowe

11 July 2020

Summary

In this study researchers looked at the loss of synapses in two tau-related neurodegenerative diseases (progressive supranuclear palsy and corticobasal syndrome) and the effect of this loss on cognition. The research was done using a novel PET radioligand, [11C]UCB-J.

They found a profound loss of synapses in all areas of the brain, beyond the effect of volume loss. This synaptic loss negatively correlated with disease severity and positively witih cognition.

These findings are key in identifying early steps in the pathology of neurodegeneration, and offer therapeutic targets for future clinical trials.

Publication: Journal of Alzheimer's Disease

Nicolasa Nicastro, Maura Malpetti, Thomas Cope, William Richard Bevan-Jones, Elijah Mak, Luca Passamonti, James B. Rowe, John T. O’Brien

30 June 2020

The changes of cortical structure in Alzheimer’s disease (AD) and frontotemporal dementia (FTD) are usually described in terms of atrophy. However, neurodegenerative diseases may also affect the complexity of cortical shape, such as the fractal dimension of the brain surface.

In this study, the researchers assessed the regional patterns of cortical thickness and fractal dimension changes in a cross-sectional cohort of patients with AD and FTD.

In addition to the well-established pattern of cortical thinning encompassing temporoparietal regions in AD and frontotemporal areas in FTD, they observed reductions of fractal dimension encompassing cingulate areas and insula for both conditions, but specifically involving orbitofrontal cortex and paracentral gyrus for FTD (FDR p < 0.05). Correlational analyses between fractal dimension and cognition showed that these regions were particularly vulnerable with regards to memory and language impairment, especially in FTD.

While the present study demonstrates globally similar patterns of fractal dimension changes in AD and FTD, the researchers observed distinct cortical complexity correlates of cognitive domains impairment. Further studies are required to assess cortical complexity measures at earlier disease stages (e.g., in prodromal/asymptomatic carriers of FTD-related gene mutations) and determine whether fractal dimension represents a sensitive imaging marker for prevention and diagnostic strategies.

Publication: Neurobiology of Aging

Nicolas Nicastro, Maura Malpetti, Elijah Mak, Guy B. Williams, W. Richard Bevan-Jones, Stephen F. Carter, Luca Passamonti, Tim D. Fryer, Young T. Hong, Franklin I. Aigbirhiod, James B. Rowe, John T. O’Brien

17 June 2020

Neuroinflammation is increasingly recognized as playing a key pathogenetic role in Alzheimer’s disease (AD). Here the researchers examined the relationship between in vivo neuroinflammation and gray matter (GM) changes.

AD/mild cognitive impairment participants exhibited GM atrophy and cortical thinning in AD-related temporoparietal regions (false discovery rate–corrected p < 0.05). Patients also showed increased microglial activation in temporal cortices. Higher 11C-PK11195 binding in these regions was associated with reduced volume and cortical thickness in parietal, occipital, and cingulate areas (false discovery rate p < 0.05). Hippocampal GM atrophy and parahippocampal cortical thinning were related to worse cognition (p < 0.05), but these effects were not mediated by microglial activation.

This study demonstrates an association between in vivo microglial activation and markers of GM damage in AD, positioning neuroinflammation as a potential target for immunotherapeutic strategies.

Publication: Journal of Clinical Urology

Vincent J Gnanapragasam, Kelly Leonard, Michal Sut, Cristian Ilie, Jonathan Ord, Jacques Roux, Maria Consuelo Hart Prieto, Anne Warren, Priya Tamer

June 2020

Prostate cancer is the commonest male cancer and more than one million rectal biopsies for suspected prostate cancer are carried out each year. However, a significant number of men undergoing rectal biopsies develop infection and sepsis.

This study showed that the CamPROBE, a device developed by Cambridge researchers that can be used under local anaesthetic, is just as good at diagnosing prostate cancer as rectal biopsies – with less infection risk.

Led by Cambridge University Hospitals (CUH), the study recruited 40 patients across six sites. CUH developed a user training course and disseminated the method to the other sites, which then offered the Cambridge Prostate Biopsy Device (CamPROBE), as an alternative to transrectal ultrasound guided biopsy to men due for a biopsy as part of their clinical management.

There were no infections, device deficiencies or safety issues reported, and the CamPROBE appears non-inferior in terms of cancer detection rates. The study also showed that the procedure is well tolerated by patients, suited to the local anaesthetic outpatient setting and can be readily disseminated and adopted.

Future clinical investigation trials will aim at confirming the veracity of the findings, develop head-to-head comparisons with other biopsy methods and explore comparative health economic and cost benefit analysis.

Publication: medRxiv

Dami A Collier, Sonny M Assennato, Nyarie Sithole, Katherine Sharrocks, Allyson Ritchie, Pooja Ravji, Matt Routledge, Dominic Sparkes, Jordan Skittrall, Ben Warne, Anna Smielewska, Isobel Ramsey, Neha Goel, Martin Curran, David Enoch, Rhys Tassell, Michelle Lineham, Devan Vaghela, Clare Leong, Hoi Ping Mok, John Bradley, Kenneth Gc Smith, Vivien Mendoza, Nikos Demiris, Martin Besser, Gordon Dougan, Paul J Lehner, Hongyi Zhang, Claire Waddington, Helen Lee,  Ravindra K Gupta

03 June 2020

Summary:

SAMBA II machines were deployed in the ED and holding wards at Addenbrooke’s hospital to help detect COVID-19 in patients as part of a research trial called COVIDx.

Researchers investigated whether using the new machines could accurately provide a faster diagnosis than standard testing practices and review how it would affect patient waiting times.

After collecting nose and throat swabs from over 140 patients, the samples were processed using the SAMBA II machine. Researchers found they were able to provide an accurate diagnostic result within 90 minutes, compared to the standard 24-48-hour lab waiting time. Read the full story.