08. Neurosciences - Recent Highlights

(1) Locating the Wolfson Brain Imaging Centre (providing functional MR, spectroscopy and PET imaging) adjacent to the Neurosciences Critical Care Unit supports many different studies of acute brain injury including randomised control trials. The radiopharmaceuticals laboratory is accredited with MHRA-GMP licences and generates the widest range of PET radiotracers available in the UK. Software developed for physiological brain monitoring is used by around 40 centres worldwide.

A novel approach has been introduced based on transcranial Doppler interrogation of compartmental compliances within the brain for non-invasive prediction of intracranial hypertension, cerebral vasospasm and carotid artery stenosis. Near Infrared Spectroscopy has been introduced for the continuous monitoring of cerebral autoregulation and hence individual optimisation of arterial blood pressure and brain protection during cardiopulmonary bypass and in pediatric neuro-intensive care. Novel studies of drug penetration, 13C labelled investigations of glucose, lactate and pyruvate utilisation and cytokines following brain injury have been carried out in association with PET and MR spectroscopy. These technologies show that multimodal, computer-supported, brain monitoring in acute brain injury can be used to optimize cerebral perfusion pressure for the individual patient, a concept which has already been taken up in the International Guidelines for the management of severe traumatic brain injury.

(2) The assessment of cerebrospinal fluid dynamics in patients suffering from hydrocephalus and idiopathic intracranial hypertension has improved the management of complex disorders. The 3-D topography of changes in white matter around the ventricles before and after shunting is being explored using diffusion-weighted MR techniques and correlated with cognitive function.

(3) Collaboration with the MRC Cognition and Brain Sciences Unit pioneered the study of awareness in coma using functional MR; to date, 5 of 54 patients have demonstrated responses that could not be detected on clinical assessment. This work has led to the refinement of Management Guidelines; and brain computer interfaces are being developed.

(4) Several phase III trials are in progress: chronic subdural haematoma randomised study of drains versus no drain; RESCUEicp decompressive craniectomy trial (www.RESCUEicp.com) involving 267 patients from 43 centres in 17 countries, the largest surgical trial for the management of head injury to date; STASH ' a multicentre placebo controlled trial of acute statin therapy following aneurysmal subarachnoid haemorrhage based on extensive phase I/II studies (midway through recruitment); and the SILVER trial of uncoated versus silver coated external ventricular drains in the prevention of infection has been completed and shows a significant benefit.

Work in this area has investigated disease mechanisms, the natural history and strategies for repair. Adult neurogenesis in the subventricular zone is regulated by dopamine through an epidermal growth factor regulated pathway and similar processes may also be important in the dentate gyrus of the hippocampus, the other site of constitutive neurogenesis in the mature central nervous system.

Adult hippocampal neurogenesis has been shown to have a specific role in memory involving pattern separation. This can now be studied clinically and modelled experimentally. The cognitive deficits in Parkinson's disease result either from frontostriatal damage to dopaminergic networks or posterior cortical involvement dependent upon Lewy body pathology; the former is determined by polymorphisms in genes that impact on dopaminergic function (COMT) whereas the latter is influenced by genes involved in the pathogenesis of Lewy body disease (Tau). These predictors of dementia allow better screening of patients for therapeutic trials. These include novel cell based treatments (TRANSEURO) and optimised delivery of more conventional treatments such as cholinesterase inhibitors (MUSTARDD study). A method has been developed for protecting dysfunctional and dying neurons in Parkinson's disease using a specific non-coding RNA from cytomegalovirus. Work in Huntington's disease has defined the extent of sleep and metabolic abnormalities and this will inform the selection of patients for clinical trials. Biomarkers based on metabanomics have been developed that distinguish patients with Parkinson's disease from progressive supranuclear palsy in which the dementia is attributed to loss of frontal grey matter leading to impairments of social and emotional cognition. Based on mapping the neural landscape of Alzheimer's disease, a novel neuropsychological test has been designed to discriminate Alzheimer's from semantic dementia using the comparative distribution of lesions and activation patterns in navigation memory demonstrated by fMRI. Computational methods have been used to develop image analysis from historical datasets, enabling the discrimination of typical fronto-temporal dementia from variants with Alzheimer pathology. As with all other disease related research, close contact is maintained with patients and their carers providing a support group that also offers a forum in which to discuss issues such as whether the introduction of disease-modifying therapy that prolongs but does not cure the disease prolonging is welcome (it is not). Much of the work on neurodegenerative disease is supported by platform funding for the Brain Bank.