Amnesia and the medial temporal lobes: an investigation in autoimmune limbic encephalitis
Lead Research Organisation:
University of Oxford
Department Name: Clinical Neurosciences
Abstract
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.
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.
Technical Summary
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.
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.
Planned Impact
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.
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.
Organisations
- University of Oxford (Lead Research Organisation)
- UNIVERSITY OF OXFORD (Collaboration)
- Macquarie University (Collaboration)
- University College London (Collaboration)
- Australian Research Council (Collaboration)
- Cardiff University (Collaboration)
- UNIVERSITY OF STRATHCLYDE (Collaboration)
- Imperial College London (Fellow)
People |
ORCID iD |
Christopher Butler (Principal Investigator / Fellow) |
Publications
Finger E
(2023)
Neurodevelopmental effects of genetic frontotemporal dementia in young adult mutation carriers.
in Brain : a journal of neurology
Dewar M
(2015)
Impaired picture recognition in transient epileptic amnesia.
in Epilepsy & behavior : E&B
De Rojas I
(2021)
Genomic Characterization of Host Factors Related to SARS-CoV-2 Infection in People with Dementia and Control Populations: The GR@ACE/DEGESCO Study.
in Journal of personalized medicine
Crutch S
(2017)
Consensus classification of posterior cortical atrophy
in Alzheimer's & Dementia
Convery RS
(2020)
Abnormal pain perception is associated with thalamo-cortico-striatal atrophy in C9orf72 expansion carriers in the GENFI cohort.
in Journal of neurology, neurosurgery, and psychiatry
Butler CR
(2014)
Persistent anterograde amnesia following limbic encephalitis associated with antibodies to the voltage-gated potassium channel complex.
in Journal of neurology, neurosurgery, and psychiatry
Butler CR
(2022)
Transcranial ultrasound stimulation to human middle temporal complex improves visual motion detection and modulates electrophysiological responses.
in Brain stimulation
Butler C
(2016)
The Behavioral Neurology of Dementia
Butler C
(2016)
Neuropsychiatry Case Studies
Butler C
(2014)
Encyclopedia of the Neurological Sciences
Description | ARUK Network Centre Grant |
Amount | £4,000 (GBP) |
Organisation | Alzheimer's Research UK |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 01/2014 |
End | 12/2014 |
Description | ARUK Network Centre grant |
Amount | £4,000 (GBP) |
Organisation | Alzheimer's Research UK |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 03/2017 |
End | 03/2018 |
Description | Alzheimer's Research UK Network Support Grant |
Amount | £30,000 (GBP) |
Organisation | Alzheimer's Research UK |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 03/2017 |
End | 04/2018 |
Description | Cerebrovascular disease and dementia |
Amount | £136,000 (GBP) |
Organisation | Oxford University Hospitals NHS Foundation Trust |
Department | NIHR Oxford Biomedical Research Centre |
Sector | Academic/University |
Country | United Kingdom |
Start | 03/2013 |
End | 03/2017 |
Description | IMPACT: Innovations using mHealth for People with Dementia and Co-morbidities |
Amount | £3,868,869 (GBP) |
Funding ID | NIHR150287 |
Organisation | Imperial College London |
Sector | Academic/University |
Country | United Kingdom |
Start | 11/2022 |
End | 10/2026 |
Description | John Fell Fund |
Amount | £71,526 (GBP) |
Organisation | University of Oxford |
Department | John Fell Fund |
Sector | Academic/University |
Country | United Kingdom |
Start | 07/2017 |
End | 12/2018 |
Description | MRC project grant |
Amount | £2,613,582 (GBP) |
Funding ID | MR/M023664/1 |
Organisation | Medical Research Council (MRC) |
Sector | Public |
Country | United Kingdom |
Start | 04/2015 |
End | 04/2020 |
Description | Non-invasive Deep Brain Stimulation for Alzheimer's Disease |
Amount | $1,546,367 (USD) |
Funding ID | PTCG-20-704320 |
Organisation | Alzheimer's Association |
Sector | Charity/Non Profit |
Country | United States |
Start | 03/2021 |
End | 03/2023 |
Description | Pathological emotionalism in temporal lobe epilepsy |
Amount | £30,000 (GBP) |
Organisation | Imperial College London |
Sector | Academic/University |
Country | United Kingdom |
Start | 08/2019 |
End | 08/2022 |
Description | RSE Arts and Humanities Research Network Aware |
Amount | £19,904 (GBP) |
Organisation | Royal Society of Edinburgh (RSE) |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 03/2017 |
End | 03/2019 |
Description | Research Workshops in the Arts and Humanities |
Amount | £9,659 (GBP) |
Organisation | Royal Society of Edinburgh (RSE) |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 01/2016 |
End | 12/2016 |
Description | ARC: Epileptic Amnesia project |
Organisation | Australian Research Council |
Country | Australia |
Sector | Public |
PI Contribution | Study concept and design initiated by us. Participants recruitment and data analysis by Australian partners and us. |
Collaborator Contribution | Participant recruitment and study design. |
Impact | I have been invited to become an Associate Investigator of the ARC CCD and was invited to give a plenary lecture at an ARC conference in Sydney. An abstract of our data has been submitted for an international meeting later in 2016. |
Start Year | 2014 |
Description | Epileptic amnesia collaboration |
Organisation | Macquarie University |
Country | Australia |
Sector | Academic/University |
PI Contribution | Research concept, planning of data collection, data analysis |
Collaborator Contribution | Data collection and analyses |
Impact | Multi-disciplinary: neurology and psychology |
Start Year | 2014 |
Description | Focused ultrasound for neuromodulation |
Organisation | University of Oxford |
Department | Department of Engineering Science |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Overall concept, design of behavioural experiments, fMRI study design and analysis, grant writing |
Collaborator Contribution | Overall concept, design of ultrasound experiments, modelling of ultrasound, grant writing |
Impact | Pilot grant application submitted and outcome awaited. |
Start Year | 2016 |
Description | Genetic Frontotemporal Dementia Initiative (GENFI) |
Organisation | University College London |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Over the next five years, we will recruit a cohort of people with or at risk from genetic forms of frontotemporal dementia. We will obtain longitudinal biomarker data (neuropsychological, serum, CSF, imaging) from participants. These data will be shared with the international GENFI consortium. |
Collaborator Contribution | The study partners will all contribute data to this longitudinal cohort study of genetic frontotemporal dementia. |
Impact | The contracts for this project have just been signed. The collaboration is multi-disciplinary and involves neurology, psychiatry, psychology, pathology and neuroimaging. |
Start Year | 2015 |
Description | Material specificity in long-term memory |
Organisation | Cardiff University |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Research concept development, data collection, data analysis |
Collaborator Contribution | Research concept development, data collection, data analysis |
Impact | Multidisciplinary: neurology and psychology |
Start Year | 2011 |
Description | Spatial memory and navigation |
Organisation | University College London |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Paradigm development, data collection |
Collaborator Contribution | Paradigm development, data analysis |
Impact | Multidisciplinary: cognitive neuroscience, neurology |
Start Year | 2014 |
Description | Thalamic amnesia |
Organisation | University of Oxford |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Project design, data collection, data analysis |
Collaborator Contribution | Project design, data collection, data analysis |
Impact | Multidisciplinary: neurology and psychology |
Start Year | 2014 |
Description | The neuroscience of narrative |
Organisation | University of Strathclyde |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | This collaboration has led to the co-ordination of a series of interdisciplinary workshops on the neuroscience of narrative in film and literature. I have contributed intellectually and administratively to the organisation of these workshops. |
Collaborator Contribution | The partners coordinated the original grant application, organised the workshops and contributed intellectually particularly from the Humanities perspective. |
Impact | First multidisciplinary workshop held in Glasgow in February 2016. Next to be held in Edinburgh in June 2016. A partnership with the Scottish Book Trust and the Glasgow Women's Library has been established. The collaboration is multidisciplinary: Neuroscience, English Literature, Film Studies, Psychology. |
Start Year | 2015 |
Description | ARUK Oxford Public Open Day |
Form Of Engagement Activity | Participation in an open day or visit at my research institution |
Part Of Official Scheme? | Yes |
Geographic Reach | Regional |
Primary Audience | Public/other audiences |
Results and Impact | Talk resulted in good discussion and recruitment of subjects to dementia research project Audience members were recruited to a variety of dementia research projects in Oxford |
Year(s) Of Engagement Activity | 2014,2015,2016 |
URL | http://www.dpag.ox.ac.uk/research/wade-martins-group/oxford-aruk-network-centre/oxford-public-day |
Description | British Science Festival (Swansea) |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Public/other audiences |
Results and Impact | Alzheimer's Research UK organised a session on dementia at the British Science Festival. I chaired the session and gave a talk entitled 'Dementia: from cells to society'. |
Year(s) Of Engagement Activity | 2016 |
Description | Practical Cognition Course |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Type Of Presentation | keynote/invited speaker |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | Talk was followed by extensive questions and discussion A very favourable report on the course was published in the journal ACNR. |
Year(s) Of Engagement Activity | 2008,2009,2010,2011,2012,2013,2014,2015,2016 |
URL | http://www.ndcn.ox.ac.uk/courses/practical-cognition-course |
Description | Radio broadcast on The Health Report, ABC, Australia |
Form Of Engagement Activity | A press release, press conference or response to a media enquiry/interview |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Public/other audiences |
Results and Impact | Radio broadcast on international radio show/podcast with >300,000 listeners |
Year(s) Of Engagement Activity | 2020 |
Description | The Science of Stories (Glasgow) |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Public/other audiences |
Results and Impact | The Scottish Book Trust's annual Book Week organised this event, which focussed on the differences between textual and film narratives. There were three speakers at the event: Will Self (writer and commentator), Elspeth Jajdelska (Lecturer in English, Strathclyde University) and me. I spoke about interactions between memory, imagination and narrative comprehension. |
Year(s) Of Engagement Activity | 2016 |