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High levels of DNA damage in nerve cells can lead to dementia, researchers from the University of Sheffield have found.
Scientists from the world-leading Sheffield Institute for Translational Neuroscience (SITraN) have discovered a novel pathway contributing to dementia in individuals that lack the typical signs of Alzheimer’s disease in the brain. The research published now in the journal Neuropathology and Applied Neurobiology builds on previous work using brain tissue donated to the Medical Research Council Cognitive Function and Ageing Study (CFAS).
This population-based study shows that one in five of the elderly with documented dementia lack significant amounts of the classical hallmarks of Alzheimer’s disease in the brain, namely ß-amyloid plaques and neurofibrillary tangles. The Sheffield group have subsequently worked to investigate what else may be affecting brain function in this group of people.
The research team led by Steve Wharton, Professor of Neuropathology based at SITraN, focussed on this group of over 65 year olds with little or no classical signs of typical Alzheimer’s or dementia pathology. They isolated nerve cells from donated brain tissue and found that higher levels of DNA damage in nerve cells correlate with cognitive decline as documented in the donors’ medical records.
The scientists further examined the changes in cellular pathways in these dementia cases with high levels of DNA damage compared to healthy control samples. They found changes in genes associated with increased cholesterol biosynthesis, as well as impaired signalling pathways, which are essential for regulating the way that nerve cells respond to their environment, including insulin and Wnt signalling.
“As these changes are independent of established Alzheimer’s disease, they may underlie neuronal dysfunction in these cases and targeting them may provide another potential therapeutic approach to dementia,” said Professor Steve Wharton.
As life expectancy and with it the rate of dementia increases, there is a growing need to identify, prevent and effectively treat dementia. Most studies and clinical trials have focussed on tackling typical Alzheimer’s pathology – ß-amyloid plaques and neurofibrillary tangles in the brain. However, at present dementia remains incurable.
The Sheffield team which leads the neuropathology studies within CFAS has previously demonstrated that there is a significant overlap of what is seen as classical Alzheimer’s pathology between people with and without dementia, particularly in the very oldest.
Professor Wharton added: “Studies of the abnormal proteins deposited in Alzheimer’s, ß-amyloid and tau, are very important for understanding dementia and they are very important as targets for therapies, but it is important, given the very slow pace of development of such treatments, that our focus on the causes of dementia should not be too narrow.
“There is a compelling case to identify other cellular and molecular processes contributing to dementia in order to identify potential new therapeutic targets.”
Carol Brayne, Lead Investigator for the CFA study based at Cambridge University, said: “This work highlights the unique and enormous value of the contribution of individual CFAS participants, as brain tissue donors, and their families to understanding the complexity of dementia across the whole of the older population, compared with findings from groups selected by their contact with particular clinical services."
JE Simpson, PG Ince, T Minett, FE Matthews, PR Heath, PJ Shaw, E Goodall, CJ Garwood, LE Ratcliffe, C Brayne, M Rattray,SB Wharton (2015) Neuronal DNA damage response-associated dysregulation of signalling pathways and cholesterol metabolism at the earliest stages of Alzheimer-type pathology. Neuropathology and Applied Neurobiology; published online June 2015 http://onlinelibrary.wiley.com/doi/10.1111/nan.12252/abstract
JE Simpson, PG Ince, FE Matthews, PJ Shaw, PR Heath, C Brayne, C Garwood, A Higginbottom, SB. Wharton. (2015) A neuronal DNA damage response is detected at the earliest stages of Alzheimer’s neuropathology and correlates with cognitive impairment in the MRC-CFAS ageing brain cohort. Neuropathology and Applied Neurobiology 41(4):483-96. http://www.ncbi.nlm.nih.gov/pubmed/26095650
Researchers from the University of Sheffield‘s Institute for Translational Neuroscience are involved in an ambitious European research project aimed at finding a new treatment for motor neurone disease (MND).
The collaboration between world-leading academic research groups aims to identify the therapeutic potential of a molecule (interleukin-2) that occurs naturally in our bodies and helps to regulate our immune system and the inflammation that contributes to motor neurone injury in MND.
Currently, a low dose of the molecule, interleukin-2 (IL-2), is being developed for the treatment of conditions affecting the immune system, including diabetes, arthritis, liver disease, and the complications of treating leukaemia and other cancers with stem cells.
While IL-2 has been used for many years at high dose to treat cancer, it is much safer – but still effective – when used at low doses in these immune disorders, as it can damp down harmful immune responses.
“Our main objective is to achieve a breakthrough in the treatment of MND by significantly slowing the progress of the disease through a low dose of IL-2,” said Dr Gilbert Bensimon, University Hospital, Nimes, France, who is project leader of Modifying Immune Response and Outcomes in Amyotrophic Lateral Sclerosis (MIROCALS).
To date, only one drug – riluzole – has been shown to slow the advance of MND, but its impact on the quality of life of people with the illness is marginal. Many other drugs have been tested but have failed.
Professor Nigel Leigh, co-lead and chief investigator for the clinical trial, of Brighton and Sussex Medical School, said:
“We are delighted to be collaborating with world-leading research groups in biomarker development, immunology, genetics and gene expression on this project. This collaboration will allow us to research a number of factors that may affect MND. Taken together, these analyses should allow us to ‘individualise’ responses to treatment that may be revealed during the study.”
In May, MIROCALS was awarded €5.98 million by the European Commission Directorate-General for Research and Innovation, under the EU Horizon 2020 Scheme. Additional support for the Clinical Centres has been awarded by the French Health Ministry Programme de Recherche Clinique (PHRC) in France and is under consideration by the MND Association in the UK.
Other novel features of the MIROCALS study include:
Project planning will start in September this year and researchers intend to recruit the first patients into the trial by September 2016. They aim to complete the study in 2019. In the meantime, the team is working on the essential groundwork for MIROCALS, including a small pilot study in France.
Professor Leigh adds:
“In addition to developing a new treatment for MND, MIROCALS aims to provide a new approach to clinical trials to break the impasse in developing new treatments for progressive disorders that include MND, dementia and Parkinson’s disease."
Professor Pamela Shaw, Director of SITraN and one of the principal investigators involved in this study, said:
“This is a very exciting experimental medicine study involving several leading European centres for MND research. Not only will we be able to investigate whether interleukin-2 slows the disease course in MND by modifying the inflammatory response within the nervous system, but we will also be investigating in the SITraN laboratories, in a work-package led by Dr Janine Kirby, biomarkers which will tell us at an early stage whether the treatment is beneficial and whether all patients or a particular subgroup develop a positive response.
We were very fortunate to receive funding support for this programme from the EU Horizon 2020 programme and the MND Association in a very stringent grant funding competition.”
First Year PhD Student Zahra Zahid who works in Professor Annalena Venneri’s Translational Neuropsychology Group has won a University of Sheffield Student Employee of the Year Award in the category “Off Campus Above and Beyond”. Moreover, Zahra has been chosen to go through to the Student Employer of the Year 2015 national level of the competition.
The Student Employee of the Year Awards is a national competition that aims to recognise and promote the outstanding contributions and achievements of students who combine part-time work with their study commitments. Employers are asked to nominate their exceptional students in three different categories; Above and Beyond, Step Up to Leadership and Commercial Impact, these can be either working on or off campus.
Zahra has won the regional award for her work as an A-level Biology Tutor at Oak Tree High School. Zahra said: "I am very grateful to be nominated. Teaching the children, I realised that I have a passion for it. This is something I wouldn’t have found out without taking this part-time job.”
The national award ceremony takes place on Thursday 2nd July in Liverpool – good luck to Zahra and all our University of Sheffield candidates at national level.
To find out more about the Student Employee of the Year Awards visit: http://careersservice.blogspot.co.uk/ and watch the video to hear what this year’s winners had to say https://www.youtube.com/watch?t=102&v=q3OWGVDWCb4
A study conducted by researchers at the University of Sheffield has revealed blood types play a role in the development of the nervous system and may cause a higher risk of developing cognitive decline.
The research, carried out in collaboration with the IRCCS San Camillo Hospital Foundation in Venice, shows that people with an ‘O’ blood type have more grey matter in their brain, which helps to protect against diseases such as Alzheimer’s, than those with ‘A’, ‘B’ or ‘AB’ blood types.
Research fellow Matteo De Marco and Professor Annalena Venneri, from the University’s Department of Neuroscience, made the discovery after analysing the results of 189 Magnetic Resonance Imaging (MRI) scans from healthy volunteers.
The researchers calculated the volumes of grey matter within the brain and explored the differences between different blood types.
The results, published in The Brain Research Bulletin, show that individuals with an ‘O’ blood type have more grey matter in the posterior proportion of the cerebellum.
In comparison, those with ‘A’, ‘B’ or ‘AB’ blood types had smaller grey matter volumes in temporal and limbic regions of the brain, including the left hippocampus, which is one of the earliest part of the brain damaged by Alzheimer’s disease.
These findings indicate that smaller volumes of grey matter are associated with non-‘O’ blood types.
As we age a reduction of grey matter volumes is normally seen in the brain, but later in life this grey matter difference between blood types will intensify as a consequence of ageing.
“The findings seem to indicate that people who have an ‘O’ blood type are more protected against the diseases in which volumetric reduction is seen in temporal and mediotemporal regions of the brain like with Alzheimer’s disease for instance,” said Matteo DeMarco.
“However additional tests and further research are required as other biological mechanisms might be involved.”
Professor Annalena Venneri added: “What we know today is that a significant difference in volumes exists, and our findings confirm established clinical observations. In all likelihood the biology of blood types influences the development of the nervous system. We now have to understand how and why this occurs.”
Matteo De Marco, Annalena Venneri: O’ blood type is associated with larger grey-matter volumes in the cerebellum. Brain Research Bulletin Vol 116, doi:10.1016/j.brainresbull.2015.05.005
Researchers from around the UK, led by a team at the University of Sheffield’s Institute for Translational Neuroscience (SITraN), have found new evidence to support early nutrition management in motor neuron disease (MND).
The first UK wide study into tube feeding in MND (ProGas) has found that MND patients benefited most from enteral feeding when they had lost less than 10 per cent of their body weight before the intervention. In contrast, significant weight loss at the onset of enteral feeding was associated with shorter survival.
Based on the results of the study, published in the journal The Lancet Neurology, the investigators recommend enteral feeding for MND patients as early as possible at five per cent weight loss from MND diagnosis.
Chief Investigator Dr Chris McDermott, Reader in Neurology at SITraN and Consultant Neurologist at the MND Care and Research Centre at the Sheffield Teaching Hospitals Foundation Trust, said: “These findings will help health care professionals and patients to make informed decisions about the choice of gastrostomy method and timing.”
The prospective multi-centre evaluation of gastrostomy in patients with MND (ProGas) included data from 24 centres in the UK. A total of 330 patients in the study underwent gastrostomy which entails the insertion of a tube in the stomach to facilitate enteral feeding and were followed up for 12 months. The study aimed to provide evidence on the benefits and timing of gastrostomy feeding, as well as the optimum tube insertion method in terms of safety and clinical outcome.
Study author Dr Theocharis Stavroulakis, Research Associate at SITraN, who analysed the UK wide data said: “Although recommended by both the American Academy of Neurologists and European Federation of Neurological Societies, there was little evidence for the optimum method and timing for gastrostomy. Decisions in clinical practice are currently largely based on consensus and expert opinion. The aim of our study was to provide evidence for the available treatment options and establish guidelines for best clinical practice to improve care for MND patients.”