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Neuroscience research in the West of Scotland consists of clinical and basic scientists working together to translate an understanding of basic mechanisms of damage in the nervous system and the role of genetic susceptibility into treatments for acute brain injury (stroke and head injury) and chronic neurological disease (demyelination, Alzheimer’s Disease, infection and malignancy)
Brain damage after a stroke or head injury is a key clinical problem. Cerebrovascular disease ranks third as the cause of death in Western Europe and results in much disability in the adult population. Head injury is a leading cause of death from accidents in young adults.
· Alzheimer’s Disease
· Parkinson’s Disease
· Triplet Repeat Disorders (Myotonic Dystrophy and Huntington’s Disease)
· Multiple Sclerosis
· Brain Injury and Ischaemia (mechanical injury and stroke)
· Neuropathy · Schizophrenia
· Depression and Mental Health · Pain
· Spinal Cord/Sensory Function
· Neuroinflammation · Genetic Studies
· Functional Neuropharmacology
· Behavioural Neuropharmacology · Neuroimaging
· Functional Genomics
Alzheimer’s disease is a progressive degenerative disease that is the most common form of dementia, mostly affecting people over the age of 65. Diagnosis can be difficult in the early stages as there is overlap with the normal changes in intellect seen with aging. CNS disorders such as Alzheimer’s, Parkinson’s, Schizophrenia and others represent more than 15% of the global cost of disease, e.g. costs of $100 billion per annum make Alzheimer’s the third most expensive disease in the USA.
Treatment strategies (e.g. anticholinesterases) and preventative strategies (e.g. neuroprotective agents and vitamin E) have highlighted the problems of early diagnosis, however, present tools available to assist clinical diagnosis are often not helpful in early diagnosis. These are images of brain structure (e.g. CT or MRI scan) or of brain function (e.g. SPECT).
PharmaLinks, a collaborative initiative between the universities of Strathclyde and Glasgow, is also conducting research specifically into the cellular and molecular processes underlying major symptoms of neurodegenerative disorders, such as poor memory and cognitive dysfunction.
‘Project Shikanko’ has arisen out of the combined research experience and activities of Professor Trevor Stone, University of Glasgow Institute of Biomedical and Life Sciences, and Professor Alan Harvey from Strathclyde University Institute for Drug Research. A portfolio of products have been produced to treat the symptoms of Alzheimer’s, with the possibility of slowing down or stopping the progress of the disease itself.
Diagnostic Potentials, a spin-out company from the Department of Psychology, Glasgow University is developing a range of diagnostic and monitoring systems for Central Nervous System (CNS) disease states, the first being a system for the early diagnosis of Alzheimer’s Disease. The company is also working on tools for assessing Parkinson’s disease.
The assessment of Alzheimer’s Disease is done in two parts. Firstly, syndrome –specific tests tap into aspects of intellectual function that are vulnerable to specific CNS disorders. Secondly dense array EEG is used, consisting of a 128-channel sensor net which unlike more traditional forms of EEG does not involve abrasion of the skin or the use of sticky gels, which improves comfort and virtually eliminates the risk of infection This provides extremely detailed information on the brain’s electrical activity. The product has several advantages including immediate feedback and it being non-invasive. Early detection of Alzheimer’s Disease will allow patients to participate more fully in decisions about their own treatment and care as well as maximising the effectiveness of new drug therapies which may slow or even halt the disease.
In the UK, 1 in 500 people have Parkinson’s disease, (around 120, 000) and symptoms usually appear after the age of 50, however in some cases it can start below the age of 40 (Young-Onset Parkinson’s Disease). About 10,000 people are diagnosed each year and 1 in 20 of these will be aged under 40.
The cause is unknown but the substantia negra (a part of the brain controlling mo vement) loses many of its neurones. These use a chemical messenger known as dopamine to send messages to other parts of the brain and eventually to the spinal cord, but due to the shortage of the dopamine containing cells the symptoms of Parkinson’s appear- tremor, rigidity or stiffness of the muscles, and slow, uncoordinated movement.
PharmaLinks, a collaborative initiative between the universities of Strathclyde and Glasgow, is also conducting research specifically into the cellular and molecular processes underlying major symptoms of neurodegenerative disorders, such as poor memory and cognitive dysfunction. The University of Strathclyde’s expertise in pharmacy, pharmacology and the Strathclyde Institute for Drug Research (SIDR) are omplimented by the University of Glasgow’s strengths in the molecular and cellular biosciences and clinical medicine.
‘Project Shikanko’ has arisen out of the combined research experience and activities of Professor Trevor Stone, University of Glasgow Institute of Biomedical and Life Sciences, and Professor Alan Harvey from Strathclyde University Institute for drug Research. A portfolio of products have been produced to treat the symptoms of Alzheimer’s, with the possibility of slowing down or stopping the progress of the disease itself.
Dr. Pauline Banks at the University of Glasgow has investigated the key factors enabling people with the disease to remain in or re-enter employment. Dr. Debbie Tolson of Glasgow Caledonian University has looked at how women with Parkinson’s experience and cope with menstruation and associated gynaecological problems. Dr. Anja Lowit, of Strathclyde University, Glasgow, has researched the use of altered auditory feedback as a rate control tool for speakers with Parkinson’s. See "Seeking Solutions- Summaries of Medical and welfare Research funded by the Parkinsons Disease Society" pages 36,52 and 55.
Almost 20 degenerative disorders including Myotonic Dystrophy and Huntington’s disease involve the expansion of CAG or CTG triplet repeats. Myotonic Dystrophy is often associated with Alzheimer’s Disease -like pathology, with patients developing amyloid plaques and neurofibrillary tangles in the brain. They also develop diabetes due to insulin resistance. The mutations are becoming more frequent and disease severity is increasing.
PharmaLinks is close to identifying key elements in the mechanism of triplet expansion and characterising them as possible novel drug targets for the treatment of Myotonic Dystrophy, and potentially, some forms of Alzheimer’s disease and diabetes.
One research group in PharmaLinks has identified several candidate genes responsible for the lack of myelination in multiple sclerosis, and which would provide potential targets for drug development.
Several candidate genes have been identified responsible for the lack of myelination in Multiple Sclerosis and which would provide potential targets for drug development.
After a severe head injury or rupture of a blood vessel in the brain fluid starts to build up. Being contained in the skull, the brain cannot swell hence pressure builds up and the brain gets tight. If the pressure gets too high the heart cannot pump enough blood into the brain, resulting in permanent damage.
Dr. Ian Piper and his group at the Institute of Neurological science, Southern General Hospital, Glasgow are exploring a new technique involving the measurement of blood pressure, pressure in the brain, and the velocity of blood vessel in the brain. The latter is done by measuring the Doppler shift in an ultrasonic beam. The new monitoring method will hopefully allow doctors to know when to allow nature to control brain pressure, whilst knowledge of the nature of the change could help to determine the cause of the pressure rise and the exact way to treat it.
The European Brain Injury Consortium is co-ordinated from the Southern General Hospital in Glasgow. This group promotes international, multi-centre, inter-disciplinary research aimed at improving the outcome of patients who have experienced a head injury or other kind of acute brain damage. Members include over 100 Neurosurgical Units from all over Europe.
Glasgow Coma and Outcome Scales are now internationally accepted as the standard methods of assessment of head-injured patients. Basic mechanistic knowledge of the biochemical cascades leading to brain damage provided the scientific basis for clinical trials of pharmacological agents in stroke and head-injured patients. The group is developing new methods to enhance the information gained from clinical studies and the outcomes of therapeutic trials.
The Brain Monitoring with Information Technology (Brain IT) group, based at the Southern General Hospital in Glasgow, is a trans-national collaborative group of clinicians, scientists and industry developing multi-centre, neuro-intensive care data collection an analysis methods.
A stroke occurs when the blood supply to part of the brain is cut off. Ischaemic stroke or Cerebral Infarct results from arteries becoming blocked, and Haemorrhagic stroke or Cerebral Haemorrhage from arteries bursting. The
part of the brain served by the blocked or bleeding artery artery is damaged and may even die, resulting in disability. 80% of all strokes are Ischaemic, and 15% are Haemorrhagic.
Mhairi Macrae, Professor of Neuroscience in the division of Clinical Neuroscience at Glasgow University is researching stroke and ischaemic injury of the brain, investigating mechanisms for inducing brain damage during ischaemia and reperfusion, and subsequent mechanisms for repair and recovery. Her research group evaluates new drugs to inhibit ischaemic brain damage and to promote and repair and recovery of cerebral tissue.
PharmaLinks has developed models of focal cerebral ischaemia for the study of ischaemic and reperfusion injury associated with experimental stroke. Current projects include:
· Investigation of the inflammatory component of stroke.
· Potential role of activated microglia in the injury process.
· Neuroprotective efficacy of a wide range of anti-oxidant drugs.
· Role of stroke sensitivity genes.
· Kynurenine pathway as a drug target for neuroprotective drugs.
Professor Hugh Willison is an Honorary Consultant Neurologist with the South Glasgow University Hospitals NHS Trust and has a specialist interest in the diagnosis and management of patients with peripheral nerve disorders. In particular, he combines his clinical and research activity on autoimmune diseases including Guillain Barre syndrome and chronic inflammatory neuropathies. Dr Sue Barnett at the Beatson Institute is studying the potential of a specialised glial cell from the olfactory system, termed olfactory ensheathing cell (OEC), to be used for transplant-mediated-repair of CNS lesions, and manipulation of oligodendrocytes to facilitate remyelination.
The Yoshitomi Research Institute of Neuroscience in Glasgow (YRING) is collaboration between one of Japan’s leading pharmaceutical companies, MPC (Mitsubishi Pharma Corporation) and scientists in the PharmaLinks neuroscience group, and was established in 1997.
Research within the Institute is directed by Professor Judy Pratt of the University of Strathclyde, and Professor Brian Morris of the University of Glasgow. They are assisted by a multidisciplinary team of Professor T. Stone, Dr. C.M.R. Turner, Dr.P.Shelbourne (Glasgow University), Dr. R.Hunter (Gartnavel Royal Hospital), Dr. M. Livingston (Southern General Hospital), Professor G. Reynolds (University of Sheffield) and Dr. S. Hammond (Scottish Biomedical Foundation).
The Institute aims to:
1) Understand the pathophsiological processes in schizophrenia at the cellular and neurochemical level and how these processes are altered during anti-psychotic drug therapy
2) Identify novel targets for schizophrenia
3) Discover candidate lead compounds active at the novel therapeutic targets.
Hypofrontality (decreased metabolic activity in the prefrontal cortex) has been linked to the cognitive deficits of the disease. Using a chronic intermittent phencyclidine (PCP) treatment programme produces a hypofrontality and deficits in GABAergic neurone activity that mirror the deficits seen in schizophrenia. This should give valuable insight into the abnormal functioning that develops with the disease. YRING has developed an entirely new model of schizophrenia and identified a group of completely novel targets which are being exploited to develop a new generation of drugs to treat schizophrenia, a mental illness affecting 1% of the population.
l Health
The Sakler Institute of Psychological Research in Glasgow was officially opened by Dr. Mortimer Sakler and his family on Monday 20 September 2004.Dr. Sakler is a major philanthropist with a long association with Glasgow University. The Institute is a collaboration with Edinburgh University.
In Glasgow, a significant amount of the award will be used to upgrade existing neuroimaging equipment and in providing state -of –the-cognitive neuroscience and sleep research laboratory facilities. These will be used to develop and extend research into emotional disorders. They will also allow research into the biological mechanisms of treatment response of those suffering from conditions such as depression and insomnia. These disorders are the most common mental health disorders in the UK adult community.
Psychological Medicine at the University of Glasgow is researching cognitive behaviour therapy, particularly the application of cognitive therapy and theory to personality disorders and deliberate self harm.
Organon Research Scotland are looking at depression and psychosis, but have interests in sleep disorders and and anxiety.
Pain can be defined on the basis of its severity i.e. mild moderate or severe, and on its aetiology, e.g. rheumatoid arthritis, diabetic neuropathy, cancer, and surgical.
The Neuroscience Research group at the Department of Physiology and Pharmacology at Strathclyde University has shown that the native P2X receptors in sensory neurones of the dorsal root ganglia are of the P2X3 subtype. When ATP binds to these receptors it evokes large inward cationic currents which depolarise the neurones and initiate action potentials. Many cell types release ATP when stressed or damaged. The ATP can act at P2X3 receptors present on periphery sensory nerves in an excitatory manner, which would be interpreted by the brain as pain. Charles Kennedy’s group is looking at how the properties of P2X3 receptors present in sensory neurones are regulated in situations associated with tissue damage, using intracellular ion-imaging, confocal and multiphoton microscopy.
PharmaLinks is investigating the role of neuropeptides in synovial inflammation, mechanisms affecting proprioceptive responses in inflammatory joint disease, and the role of kinin peptides and other inflammatory mediators in the production of pain.
Organon Research Scotland is developing drugs to provide analgesia for moderate to severe pain produced during and after surgical operations. Surgery produces tissue injury, causing specialised pain receptors in the skin and internal organs to become more sensitive, a process known as peripheral sensitisation. In addition, a process known as central sensitisation causes the spread of extreme sensitivity causing tenderness not just at the site of injury but also in the surrounding areas this extreme tenderness is brought about by changes in excitability of neurones in the spinal cord.
The Analgesia group at Organon is seeking novel painkillers which lack the troublesome side effects (most notably depression of respiratory function) associated with opioid agonist drugs such as morphine and fentanyl, which currently dominate the surgical analgesia market. Dr. Hugh Marston heads the neurobiology section at Organon Research Scotland, with responsilbility for in vivo work in the areas of CNS and analgesia research.
The Spinal Cord Research Group at the University of Glasgow is part of the Institute Of Biomedical and Life Sciences.The group takes a multidisciplinary approach to investigating neuronal processing mechanisms in the spinal cord, including morphology, immunocytochemistry, electron microscopy, confocal microscopy, and in vivo electrophysiology.
The group is interested in the complex synaptic circuitry of the dorsal horn. This area has an important role in pain transmission, since it is the site where nociceptive primary different axons which carry information on tissue damaging stimuli, form their first synapses. The information conveyed may be subjected to local modification, and it is then carried to the brain through various ascending pathways (including the spinal-thalamic tract) where it is interpreted as ‘painful’. Many of the nociceptive afferents release the peptide Substance P which acts on neurokinin receptors present on the surface of some neurones in the spinal cord.
Current research projects include:
Organisation of spinal interneurones with respect to their involvement in reflex control of motor and postural pathways. Regeneration of the spinal cord. (J.S. Riddell).
Pain processing mechanisms in the spinal cord with particular respect to the role of substance P and the organisation of cells which express the substance P receptor. Synaptic circuitry of the dorsal horn (A.J. Todd)
Control of afferent input to the spinal cord with particular respect to the organisation of presynaptic inhibitory interneurone and descending monoaminergenic systems.
Synaptic circuitry of the dorsal and ventral horn (D.J.Maxwell).
PharmaLinks has a large spinal cord research group which uses advanced staining, imaging and reconstruction techniques in conjunction with electrophysiological recordings of cell physiology to clarify neurotransmitter functions in defined spinal pathways, especially the identification of transmitters used by physiologically defined populations of spinal interneurones.
A number of researchers in the Division of Clinical Neuroscience at the University of Glasgow are working on neuroinflammation, in particular post-herpetic neuralgia, which often follows herpes zoster (shingles).
The Neurovascular Inflammation Group is a collaborative venture between the Departments of Biological Sciences, and Chemistry and Chemical Engineering (University of Paisley) and the Centre for Rheumatic Diseases (University of Glasgow Department of Medicine). The primary focus of theGroup is on neurovascular regulatory mechanisms, their disturbance during disease processes such as rheumatoid arthritis and the development and evaluation of anti-inflammatory drug therapies. Other clinical interests include vascular disturbances and their treatment. Research spans from fundamental to clinical levels and Group expertise includes physiology, cell biology, pharmacology, molecular biology, chemistry, bioengineering and immunology. The Group has a base of doctoral students (4 currently) and meets twice monthly; most members share offices/laboratories, and collaborate on a daily basis. Ongoing projects include investigations of neuropeptidergic, nitrergic and prostanoid systems during inflammation and development of polymer conjugates for drug administration.
Crusade Laboratories was founded in December 1999 as a joint venture company between a Dayspring Ventures Ltd., a venture capital group, Glasgow University, and Cancer Research Ventures expressly to expand and accelerate the basic and clinical research of Professor Moira Brown and her team at the University of Glasgow. Crusade is based at the Southern General hospital in Glasgow. The company uses HSV1716 - a modified virus- to selectively kill tumour cells. This has been used mainly on brain cancers but also on others. Roy Rampling, Professor of Neuro-Oncology at the Beatson Oncology Centre, Western Infirmary also works on viral therapies for brain tumours.
Mr Varnavas (Vakis) Papanastassiou, a neurosurgeon in the Division of Clinical medicine at the University of Glasgow specialises in image-guided surgery, especially with regards to brain tumour surgery and the management of cerebral arteriovenous malformations (AVMs).
Epilepsy is a common problem affecting 1 in 200 of the population. The West of Scotland Neuroimaging Research Group, part of Glasgow University’s Institute of Neurological Sciences, at the Southern general Hospital in Glasgow is using SPECT to investigate epilepsy.
Molecular mechanisms of nerve cell death - focus on Parkinson's Disease
The research of Professor Wayne Davies at IBLS, at the University of Glasgow concerns genetic and molecular analysis of how particular nerve cells die. This reaserch group is taking two approaches to shed further light on the molecular events that happen when these nerve cells are triggered to die. We are focusing particularly on a new candidate pathway that has been discovered by work of this laboratory and collaborators, Dr RG Sutcliffe and Professor A.P.Payne. This is the nerve cell death pathway initiated by mutation in the agu gene, which we have recently identified by positional cloning. The protein altered by this mutation is a protein kinase that is centrally involved in cell signalling pathways, and offers an exciting opportunity to learn more about how these nerve cells can be triggered to die.
Genetics of Huntington's disease
The research effort of Dr Peggy Shelbourne at IBLS, University of Glasgow is focused on Huntington's disease (HD), an inherited disorder associated with an extended (CAG)n repeat encoding a polyglutamine tract in a gene product of unknown function. HD is a dominantly inherited, neurodegenerative disorder that follows a progressive course, leading to death after an interval of about 15-20 years. Although the mutation responsible for the disease was identified in March 1993, the biochemical basis for neuronal death in HD remains unclear and there is still no effective treatment for this disorder.
Neuroscientists at PharmaLinks are at the forefront of research into neurodegenerative, psychiatric and autoimmune diseases as well as leading fundamental research on novel receptor proteins and ion channels which may represent new therapeutic targets.
Several disease models are unique to PharmaLinks including:
· The AS/AGU mutant rat model of locomotor disorder. A spontaneous recessive mutation gives rise to movement disorders such as a staggering gait, which are similar to Parkinson’s disease and respond to treatment with L-Dopa
· A transgenic mouse model of Huntington’s disease involving highly specific inserts which do not disrupt the adjacent genome, and have clear advantages over the alternative R6/1 model.
· Several models of cerebral ischaemia (MCA occlusion, endothelin injection, and non-invasive photo-coagulation)
· The AS/AGU mutant rat model of locomotor disorder. A spontaneous recessive mutation gives rise to movement disorders such as a staggering gait, which are similar to Parkinson’s disease and respond to treatment with L-Dopa
· A transgenic mouse model of Huntington’s disease involving highly specific inserts which do not disrupt the adjacent genome, and have clear advantages over the alternative R6/1 model.
· Several models of cerebral ischaemia (MCA occlusion, endothelin injection, and non-invasive photo-coagulation)
The Neuroscience Research Group at the Department of Physiology and Pharmacology, University of Strathclyde are active in a number of areas of behaviour pharmacology.
Dr Ross Brett’s investigates the role of cannabinoids in appetite and their relationship to environmental factors and reward. A second research theme is the identification of neural systems involved in the performance of cognitive tasks in rodents, using 2-deoxyglucose uptake autoradiography and immediate early gene expression.
Professor Judy Pratt’s research focuses on the characterisation of the effects of cannabinoids upon cognitive thought processes and drug reward and identification of the neural systems recruited, using brain imaging techniques (with Dr. Brett). A second research theme is the development and characterisation of a recreational model of cannabinoid abuse ( with Dr. Brett); and the neurobiology of benzodiazepine dependence.
As co-Director of YRING, Professor Pratt is researching the identification and characterisation of schizophrenia related genes using gene array technologies, brain imaging techniques and behavioural phenotyping of genetically manipulated animals (with Professor Morris of YRING).
Neuroimaging
The West Of Scotland Neuroimaging Research Group is a multidisciplinary department within the Institute of Neurological sciences, Glasgow University, undertakes research into the anatomy and function of the human brain using SPECT, MRI, and fMRI
SPECT (Single Photon Emission Computed Tomography) is a nuclear medicine technique used to image brain function. A slightly radioactive tracer is injected into the body and taken up in the brain. Images are produced representing the way the brain has functioned in taking up and using the tracer.
The SPECT scanner at the Institute of Neurological Sciences is used for diagnosis and patient monitoring in both neurology and psychiatry, including neurological diseases (dementias), epilepsy, head trauma, neoplasms, and cerebrovascular diseases.
MRI (Magnetic Resonance Imaging) uses a strong magnet and radiofrequency waves to produce high quality images of neuroanatomy and disease processes. It is an application of NMR (Nuclear Magnetic Resonance). MRI is primarily used as a technique for producing anatomical images but can also give information on the physical - chemical state of tissues, flow diffusion and motion information.
MRS (Magnetic Resonance Spectroscopy) is a rapidly developing technique for measuring chemicals within the brain without removing tissue or blood samples. It is provided both as a clinical service and as a research tool at the Institute of Neurological Sciences. Recent clinical research has focussed on the metabolic derangements associated with acute and chronic head injury, brain tumours and their response to therapy, and Chronic Fatigue Syndrome.
FMRI (Functional Magnetic Resonance Imaging) is a new use of existing MRI technology. It is used to visualise brain function by visualising changes in chemical composition of brain areas or changes in the flow of fluids that occur over timespans of seconds to minutes. In the brain, blood oxygen level is related to neural activity, so fMRI can aid finding out what the brain is doing when subjects perform specific tasks, or are exposed to specific stimuli.
A 7T MRI/MRS facility at the Garscube Estate of Glasgow University serves as a national resource for Scotland. It has the advantage of being a non-invasive imaging technique with resolutions down to 40 microns and permitting serial studies to be performed on the living animal. The primary use of the facility will be in biomedical research applications involving the in vivo imaging of small animals but the high image resolutions and multiplicity of parameters measurable by the system also have applications in the plant, materials, and food sciences, as well as for the study of some industrial process dynamics.
Neuro imaging in Glasgow and Edinburgh is being aided by the new Sakler Institute of Psychological Research.
The major components of a functional genomics approach are:
· bioinformatics - the extraction of biological utility from genomic sequence, and the reconciliation of multiple datasets
· microarrays - the global assessment of how the expression of all genes in the genome varies under changing conditions
· proteomics - the study of the total protein complement expressed by a particular cell under particular conditions
· reverse genetics - deducing the function of novel genes by mutating them and studying the mutant phenotype.
In fact, the most exciting advances come from applying these powerful techniques to fundamental physiological questions. The twin problems are (i) the learning curve, and (ii) the capital cost of the technologies.
Glasgow's Sir Henry Wellcome Functional Genomics Facility (FGF) addresses both of these problems. As it was only recently set up, it has been possible to pick a superior balance of the most modern equipment and technologies for functional genomics. And beyond the service provision element, we see our purpose as educational: we wish to build a community of scientists who understand what is on offer, and are excited about what these opportunities can do for their research.
The University of Glasgow School of Neuroscience
PharmaLinks
Yoshitomi Research Institute Of Neuroscience In Glasgow (YRING)
The Strathclyde Institute for Drug Research
Neurovascular Inflammation Group
Institute of Neurological science
Neuroscience Research Group, University of Strathclyde
Organon Research Scotland
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