Amnesia and the medial temporal lobes: an investigation in autoimmune limbic encephalitis

The overall aim of this project is to understand how damage to a region of the brain called the medial temporal lobe causes memory impairment.

Memory impairment is common in neurological diseases. It can be devastating to peoples' lives, leaving them unable to work and dependent on carers for many daily activities. It has been known for a long time that one particular part of the brain - the medial temporal lobe - is critical for memory. Damage to this region occurs in conditions such as Alzheimer's disease, epilepsy and encephalitis (inflammation of the brain) and may lead to severe memory loss. In order to diagnose and treat these conditions better, we need to understand how the medial temporal lobe is involved in memory.

This research project focusses on a neurological condition called limbic encephalitis, in which the medial temporal lobe becomes inflamed. Almost ten years ago, scientists in Oxford identified a common cause of limbic encephalitis - antibodies to the 'voltage-gated potassium channel complex' (or VGKC). This disease, known as VGKC-LE, typically occurs in middle age and is increasingly recognised as a cause of memory impairment and seizures in later life. Treatments are available but many patients have severe ongoing memory difficulties that disrupt their lives. The research will discover what are the causes of memory loss in patients with VGKC-LE and what can be done to prevent them. This will help doctors to recognise the condition earlier and prescribe the best medications. It will also teach us much more about the precise role of the medial temporal lobe in memory.

What we learn from this project will be directly relevant to other common conditions such as dementia and epilepsy. It will increase our understanding of why damage to the medial temporal lobes causes memory problems and enable us to detect these problems sooner - a vital step towards finding effective treatments.

The research will be carried out by Dr Christopher Butler, a neurologist at the University of Oxford and Oxford University Hospitals NHS Trust. Dr Butler has a specialist interest in memory disorders and runs a multidisciplinary memory clinic where many patients with VGKC-LE are seen. The project will involve one of the world's leading centres for brain scanning - the Oxford Centre for Functional Magnetic Resonance Imaging of the Brain (FMRIB). There is a large group of patients with VGKC-LE in the Oxford region. We will use detailed tests of memory and state-of-the-art brain scanning to discover the causes of memory impairment in VGKC-LE and improve the treatment of this often devastating disease. A special test of memory, developed as part of the project, will be used to try and improve the early detection of Alzheimer's disease.

Aim: To determine how different regions within the medial temporal lobe (MTL) contribute to human memory and its impairment in neurological disease

Objectives:
1. Characterise the cognitive and neuroanatomical profile of autoimmune limbic encephalitis
2. Test competing theoretical models of MTL function in a large cohort of amnesic patients
3. Develop a neurobiologically-motivated test of MTL function for clinical use in memory disorders

Methodology:
I will investigate the effects of MTL damage in a unique, Oxford-based cohort of patients with limbic encephalitis associated with antibodies to the voltage-gated potassium channel complex (VGKC-LE). Patients and matched controls will undergo detailed neuropsychological testing and MR imaging (at 3T and 7T). I will determine how clinical variables, e.g. antibody type/titre and treatment type/duration, affect lesion extent and cognitive outcome. I will test an influential new account of MTL function (the 'Binding of Items and Contexts' model) against more established, 'unitary' accounts in a subset of VGKC-LE patients with focal, bilateral MTL damage. Six experiments will explore whether regions of the MTL contribute differentially to both short- and long-term memory for items, contexts and their binding. I will apply this work to develop a neurobiologically motivated, clinical test of MTL function that will be validated in a longitudinal study of patients with mild cognitive impairment.

Scientific and medical opportunities:
The results of this study are likely to lead to improvements in the treatment and monitoring of VGKC-LE. The characterised cohort will be an invaluable resource for addressing many other questions about MTL function. A better understanding of the neural basis of memory will facilitate early diagnosis of patients with disorders such as Alzheimer's disease, appropriate patient inclusion into clinical trials and thus more efficient development of targeted therapeutic interventions.

Memory impairment is a disabling consequence of many neurological diseases including dementia, stroke, epilepsy, head injury and encephalitis, and can have a detrimental impact on independent living, financial wellbeing and social/emotional relationships. The proposed work has a wide range of potential impacts, some of which will be realised during the lifetime of the study, e.g. improved assessment and treatment of patients with VGKC-LE, and others of which, e.g. the development of novel therapeutics based on the findings of the study, would only be measurable after some years.

Patients with memory disorders, carers and families, the broader care community, research supporters/donors:
Patients with VGKC-LE and other memory disorders, together with their carers, will benefit from the important insights into memory dysfunction that will arise from this project. New memory tests that are sensitive and specific to medial temporal lobe damage, and which are to be developed in the lifetime of this fellowship, will improve diagnosis and assessment of memory dysfunction with potential consequences upon quality of life. Greater awareness of the role of neuropsychological profiling and imaging in translational research, communicated through patient support groups such as the Encephalitis Society, will encourage patient participation in clinical studies.

Wider public community:
Memory and its decline in aging and disease is a topic of great interest to many people. In the long-term, greater understanding of human memory function and dysfunction could benefit the broader community, for example by influencing educational strategies and techniques for 'cognitive enhancement'.

UK NHS, funding bodies:
Within the lifespan of this fellowship, the results obtained are likely to influence clinical practice, particularly in the assessment, management and follow-up of patients with VGKC-LE and other memory disorders. Improved assessment of patients with memory impairment, e.g. early Alzheimer's disease, will facilitate recruitment into clinical trials. The detailed characterisation of a large cohort of amnesic patients to be carried out in this project will provide numerous opportunities for future research into the neurobiology of human memory.

UK and International Biotech/Pharmaceutical industry:
Limited impact on the commercial sector is expected within the duration of the fellowship. However, greater understanding of the relationships between brain damage and memory loss in humans may result in the commercial development of memory tests with a much sounder neurobiological basis than those currently in use. The knowledge gained through the project may also translate into improved animal models and then back to the clinic for drug trials in memory disorders. The proposed work therefore has the potential to provide tools (e.g. cognitive and imaging biomarkers) to stimulate efficient drug discovery in this challenging area.

Economic and societal:
In the long-term, improving memory function in neurological patients can greatly reduce the economic burden of brain disease by minimising lost productivity and the costs of care.