Novel MRI Techniques for Brain Banking and Motor Neuron Disease Research
Lead Research Organisation:
University of Oxford
Department Name: Clinical Neurosciences
Abstract
Neurodegenerative diseases are brain disorders in which neurons (brain cells) die prematurely, with devastating consequences. Parkinson's, Alzheimer's and motor neuron disease (MND) each affect different aspects of brain function, none with effective treatments to reverse neurodegeneration. There is an urgent need to develop "biomarkers": measurements that can be made in living patients with neurodegenerative disease to guide clinical decisions and assess treatment outcomes in drug trials. In this project, we will investigate a technique to validate potential imaging biomarkers for neurodegeneration in MND.
Brain scanning technologies like Magnetic Resonance Imaging (MRI) are known to have enormous potential as biomarkers by revealing subtle brain changes in disease. However, despite this exquisite sensitivity, MRI currently lacks specificity. A given change measured with MRI could come from several plausible changes to brain tissue. For example, neurons could be shrinking, losing outer membranes, or become more chaotically packed in disease. The "gold standard" for studying neurodegeneration is to look at the neurons directly under a microscope, providing a more interpretable picture of what aspects of the neurons are affected in disease. However, extracting brain (or spinal) tissue for microscopic examination cannot be done during life without causing irreparable damage.
Our research will bring together these two complementary areas of research, MRI scanning and tissue microscopy, to maximise the strengths of each. Brain banks, collections of brains donated by individuals after death, are a critically important resource in neurodegeneration research. They provide a crucial link between microscopic measurements that can be made in donated brain tissue and the MRI measurements that can be taken in living patients. Our project will explore this link via two strands of research: the first developing the necessary techniques and the second demonstrating the potential of this approach in MND.
The first research strand will build on proof-of-principle methods we have developed for scanning donated brains before they are sectioned for microscopy. We will translate these methods to make them suitable for studies of disease in a practical setting. This will require merging recently pioneered acquisition techniques with cutting-edge hardware. Equally exciting is the opportunity to obtain much better quality images on donated brains by scanning for extended periods, enabling unprecedented anatomical detail that has value on its own. Finally, we will explore technologies that may allow doctors to study neurons more directly than is currently possible by measuring properties that previously have only been detected in tissue samples under a microscope.
These techniques will be used to scan a unique set of brains donated to research by MND patients, in comparison with those from individuals with no known pathology. These MRI data will then be compared to histological measures of tissue properties that are expected to underpin the MRI signal, including microscopic geometry and molecular content. We will investigate regions of the brain that are known to be affected by MND, including the motor system and areas involved in MND-related dementia. Some of these patients will have previously taken part in a MRI study during life, which will provide a vital link to the post mortem imaging we propose to develop in this project. In reverse, the insights gained will allow us to improve and inform future MRI studies in living patients. This has the potential to improve the diagnostic process, and develop more sensitive tools to assess candidate drug therapies.
This research aims to provide neuroscientists with a general approach for directly comparing post-mortem MRI with histopathological measures, with the ultimate goal of improving the interpretation of MRI scans in living patients.
Brain scanning technologies like Magnetic Resonance Imaging (MRI) are known to have enormous potential as biomarkers by revealing subtle brain changes in disease. However, despite this exquisite sensitivity, MRI currently lacks specificity. A given change measured with MRI could come from several plausible changes to brain tissue. For example, neurons could be shrinking, losing outer membranes, or become more chaotically packed in disease. The "gold standard" for studying neurodegeneration is to look at the neurons directly under a microscope, providing a more interpretable picture of what aspects of the neurons are affected in disease. However, extracting brain (or spinal) tissue for microscopic examination cannot be done during life without causing irreparable damage.
Our research will bring together these two complementary areas of research, MRI scanning and tissue microscopy, to maximise the strengths of each. Brain banks, collections of brains donated by individuals after death, are a critically important resource in neurodegeneration research. They provide a crucial link between microscopic measurements that can be made in donated brain tissue and the MRI measurements that can be taken in living patients. Our project will explore this link via two strands of research: the first developing the necessary techniques and the second demonstrating the potential of this approach in MND.
The first research strand will build on proof-of-principle methods we have developed for scanning donated brains before they are sectioned for microscopy. We will translate these methods to make them suitable for studies of disease in a practical setting. This will require merging recently pioneered acquisition techniques with cutting-edge hardware. Equally exciting is the opportunity to obtain much better quality images on donated brains by scanning for extended periods, enabling unprecedented anatomical detail that has value on its own. Finally, we will explore technologies that may allow doctors to study neurons more directly than is currently possible by measuring properties that previously have only been detected in tissue samples under a microscope.
These techniques will be used to scan a unique set of brains donated to research by MND patients, in comparison with those from individuals with no known pathology. These MRI data will then be compared to histological measures of tissue properties that are expected to underpin the MRI signal, including microscopic geometry and molecular content. We will investigate regions of the brain that are known to be affected by MND, including the motor system and areas involved in MND-related dementia. Some of these patients will have previously taken part in a MRI study during life, which will provide a vital link to the post mortem imaging we propose to develop in this project. In reverse, the insights gained will allow us to improve and inform future MRI studies in living patients. This has the potential to improve the diagnostic process, and develop more sensitive tools to assess candidate drug therapies.
This research aims to provide neuroscientists with a general approach for directly comparing post-mortem MRI with histopathological measures, with the ultimate goal of improving the interpretation of MRI scans in living patients.
Technical Summary
Magnetic resonance imaging (MRI) has enormous potential as a biomarker in neurodegenerative disease, in particular techniques that are sensitive to microstructure show great promise for phenotyping and monitoring disease progression. However, these measures currently lack specificity. We propose to combine post-mortem MRI with histopathology in the same tissue to aid in the interpretation of in-vivo MRI measures. We will focus on motor neuron disease (MND), an area of expertise in Oxford for which MRI has considerable potential as a biomarker.
MRI can provide various types of "contrast" (analogous to different tissue stains) with complementary information about anatomy and tissue composition. We will acquire images with a broad range of contrasts, with particular focus on diffusion MRI, a powerful method that presents particular challenges in post-mortem tissue. We will build on our recent advances in MRI software and cutting-edge hardware to improve signal strength by a factor of 5-6 and enable unprecedented spatial detail. We will also explore recent MRI techniques that aim to provide more biologically-meaningful information.
We will conduct a proof-of-concept study in MND, which provides an ideal testbed for these methods as a relatively "clean" pathology in which pre- and post-mortem MRI scans are available. A range of MRI scans will be acquired in MND and control brains, the latter being a crucial resource for future expansion into other diseases and conditions. We will demonstrate the potential of MRI-to-histology comparisons in neurodegenerative disease. Specifically, we will investigate whether histological staining supports the use of MRI as an early marker of MND and the related condition frontotemporal dementia. Finally, we will develop a basic prototype database for on-line data exploration and distribution, linked in to the Oxford Brain Bank and freely accessible to the neuroscience community.
MRI can provide various types of "contrast" (analogous to different tissue stains) with complementary information about anatomy and tissue composition. We will acquire images with a broad range of contrasts, with particular focus on diffusion MRI, a powerful method that presents particular challenges in post-mortem tissue. We will build on our recent advances in MRI software and cutting-edge hardware to improve signal strength by a factor of 5-6 and enable unprecedented spatial detail. We will also explore recent MRI techniques that aim to provide more biologically-meaningful information.
We will conduct a proof-of-concept study in MND, which provides an ideal testbed for these methods as a relatively "clean" pathology in which pre- and post-mortem MRI scans are available. A range of MRI scans will be acquired in MND and control brains, the latter being a crucial resource for future expansion into other diseases and conditions. We will demonstrate the potential of MRI-to-histology comparisons in neurodegenerative disease. Specifically, we will investigate whether histological staining supports the use of MRI as an early marker of MND and the related condition frontotemporal dementia. Finally, we will develop a basic prototype database for on-line data exploration and distribution, linked in to the Oxford Brain Bank and freely accessible to the neuroscience community.
Planned Impact
Our proposal is expected to have impact in a range of spheres outside of academia. Although we aim to focus on motor neuron disease, the techniques considered in this grant are applicable to a broad range of disorders and organ systems, resulting in broader impact within healthcare and across society. The ultimate aims of this research direction have significant potential impact on health and well-being, economy, and knowledge, albeit beyond the duration of this project.
The MRI methods that we propose to validate through comparison with histopathology have enormous potential as a tool for early detection of neurodegeneration and other neurological disorders. Further, they have the potential to more effectively target and assess future therapeutics. The development of more sensitive markers would reduce costs of early-stage drug trials, enabling faster 'no-go' decisions, earlier exclusion of ineffective compounds and thus allowing more compounds to be explored than is currently cost effective. The ability to directly link MRI measures with human post-mortem tissue may also reduce dependence on animal models, which is an ethical consideration of importance to society.
Neurodegenerative disorders already have an enormous physical, emotional and socioeconomic burden, which is set to increase with the ageing population. Economic impact via improved diagnosis and treatment of disease can lead to tremendous financial savings in the healthcare sector. There is also economic impact associated with the techniques themselves within the global market in healthcare. For example, the world-wide market for MRI scanners was $4.4 billion in 2010, with just three vendors dominating the market (GE, Siemens and Philips). We have a history of working with these vendors to patent technical advances (Dr Miller holds 3 patents funded by GE and Siemens). Similarly, drug trials run by pharmaceutical companies cost millions of pounds, and several UK companies (e.g., Ixico) have been founded to analyze data (including images) for these studies.
Further impact to society will occur from our more general understanding of how the brain works, and in knowledge for broader use of imaging technologies. As discussed above, we will provide the neuroscience community with a unique resource of high-resolution brain scans for research. Further, the developed methods and experimental approaches will enable us to study how the brain develops after birth, how learning sculpts the brain's network at a microscopic level, even in adulthood, and how certain interventions such as transcranial direct current stimulation may improve our ability to learn. Our research will thus contribute broadly to our understanding of the brain, helping to answer fundamental scientific questions: how does the brain work, and how can we facilitate healthy function?
The MRI methods that we propose to validate through comparison with histopathology have enormous potential as a tool for early detection of neurodegeneration and other neurological disorders. Further, they have the potential to more effectively target and assess future therapeutics. The development of more sensitive markers would reduce costs of early-stage drug trials, enabling faster 'no-go' decisions, earlier exclusion of ineffective compounds and thus allowing more compounds to be explored than is currently cost effective. The ability to directly link MRI measures with human post-mortem tissue may also reduce dependence on animal models, which is an ethical consideration of importance to society.
Neurodegenerative disorders already have an enormous physical, emotional and socioeconomic burden, which is set to increase with the ageing population. Economic impact via improved diagnosis and treatment of disease can lead to tremendous financial savings in the healthcare sector. There is also economic impact associated with the techniques themselves within the global market in healthcare. For example, the world-wide market for MRI scanners was $4.4 billion in 2010, with just three vendors dominating the market (GE, Siemens and Philips). We have a history of working with these vendors to patent technical advances (Dr Miller holds 3 patents funded by GE and Siemens). Similarly, drug trials run by pharmaceutical companies cost millions of pounds, and several UK companies (e.g., Ixico) have been founded to analyze data (including images) for these studies.
Further impact to society will occur from our more general understanding of how the brain works, and in knowledge for broader use of imaging technologies. As discussed above, we will provide the neuroscience community with a unique resource of high-resolution brain scans for research. Further, the developed methods and experimental approaches will enable us to study how the brain develops after birth, how learning sculpts the brain's network at a microscopic level, even in adulthood, and how certain interventions such as transcranial direct current stimulation may improve our ability to learn. Our research will thus contribute broadly to our understanding of the brain, helping to answer fundamental scientific questions: how does the brain work, and how can we facilitate healthy function?
Organisations
Publications
Mollink J
(2019)
White matter changes in the perforant path area in patients with amyotrophic lateral sclerosis.
in Neuropathology and applied neurobiology
Tendler BC
(2020)
Use of multi-flip angle measurements to account for transmit inhomogeneity and non-Gaussian diffusion in DW-SSFP.
in NeuroImage
Mollink J
(2019)
The spatial correspondence and genetic influence of interhemispheric connectivity with white matter microstructure.
in Nature neuroscience
Xu T
(2018)
The effect of realistic geometries on the susceptibility-weighted MR signal in white matter.
in Magnetic resonance in medicine
Tendler BC
(2022)
The Digital Brain Bank, an open access platform for post-mortem imaging datasets.
in eLife
McKavanagh R
(2019)
Relating diffusion tensor imaging measurements to microstructural quantities in the cerebral cortex in multiple sclerosis.
in Human brain mapping
Kor D
(2023)
Quantitative methods for MRI-microscopy comparisons
Straathof M
(2015)
POST MORTEM MRI TO DECIPHER CORPUS CALLOSUM INVOLVEMENT IN ALS
Cardenas AM
(2017)
Pathology of callosal damage in ALS: An ex-vivo, 7 T diffusion tensor MRI study.
in NeuroImage. Clinical
Pallebage-Gamarallage M
(2015)
MRI-histology Correlates Of Cortical And White Matter Changes In Post-mortem MND/FTD Brain
Tendler BC
(2020)
Modeling an equivalent b-value in diffusion-weighted steady-state free precession.
in Magnetic resonance in medicine
Roumazeilles L
(2020)
Longitudinal connections and the organization of the temporal cortex in macaques, great apes, and humans.
in PLoS biology
Howard A
(2019)
Joint modelling of diffusion MRI and microscopy
Howard A
(2019)
Joint modelling of diffusion MRI and microscopy
in NeuroImage
Tang-Wright K
(2022)
Intra-Areal Visual Topography in Primate Brains Mapped with Probabilistic Tractography of Diffusion-Weighted Imaging.
in Cerebral cortex (New York, N.Y. : 1991)
Foxley S
(2014)
Improving diffusion-weighted imaging of post-mortem human brains: SSFP at 7 T.
in NeuroImage
Foxley ES
(2014)
Improved Tractography of Post Mortem Human Brain at 7T Using DWSSFP
in Proc International Society for Magnetic Resonance in Medicine
Alfaro-Almagro F
(2018)
Image processing and Quality Control for the first 10,000 brain imaging datasets from UK Biobank.
in NeuroImage
Wu W
(2016)
High-resolution diffusion MRI at 7T using a three-dimensional multi-slab acquisition.
in NeuroImage
Elliott LT
(2018)
Genome-wide association studies of brain imaging phenotypes in UK Biobank.
in Nature
Roebroeck A
(2019)
Ex vivo diffusion MRI of the human brain: Technical challenges and recent advances.
in NMR in biomedicine
Mollink J
(2017)
Evaluating fibre orientation dispersion in white matter: Comparison of diffusion MRI, histology and polarized light imaging.
in NeuroImage
Pallebage-Gamarallage M
(2015)
DISTINCTIVE PATHOLOGICAL FEATURES OF THE CU/ZN SUPEROXIDE DISMUTASE 1 (SOD1) MUTATION D102N
Pallebage-Gamarallage M
(2018)
Dissecting the pathobiology of altered MRI signal in amyotrophic lateral sclerosis: A post mortem whole brain sampling strategy for the integration of ultra-high-field MRI and quantitative neuropathology.
in BMC neuroscience
Bryant KL
(2021)
Diffusion MRI data, sulcal anatomy, and tractography for eight species from the Primate Brain Bank.
in Brain structure & function
Foxley ES
(2014)
Correcting for B1 inhomogeneities in post- mortem DWSSFP human brain data at 7T using multiple flip angles
in Proc International Society for Magnetic Resonance in Medicine
Kleinnijenhuis M
(2018)
Choice of reference measurements affects quantification of long diffusion time behaviour using stimulated echoes.
in Magnetic resonance in medicine
Tendler BC
(2021)
A method to remove the influence of fixative concentration on postmortem T2 maps using a kinetic tensor model.
in Human brain mapping
Description | Wellcome Trust Senior Research Fellowship |
Amount | £1,793,980 (GBP) |
Organisation | Wellcome Trust |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 09/2016 |
End | 09/2021 |
Title | Acquisition tools for MRI of post-mortem brains |
Description | We developed acquisition tools using SSFP for scanning post-mortem brain tissue and developed a modification of existing FSL diffusion tools that are appropriate for use with SSFP. These tools have been distributed to 16 other labs worldwide through our industrial agreeement with Siemens. |
Type Of Technology | New/Improved Technique/Technology |
Year Produced | 2014 |
Impact | 20 labs worldwide have so far benefited from these tools for MRI data acquisition and we expect to reach many more researchers through our agreeement with Siemens. |
Title | Tensor Image Registration Library (TIRL) |
Description | Tensor Image Registration Library is a modular general-purpose image registration framework for Python with prebaked scripts for histology-to-MRI registration. |
Type Of Technology | New/Improved Technique/Technology |
Year Produced | 2021 |
Open Source License? | Yes |
Impact | TIRL is used extensively within our imaging Centre. As it was released last year, it has not yet been adopted elsewhere. |
URL | https://git.fmrib.ox.ac.uk/ihuszar/tirl |
Description | Article in Scientific American about Biobank |
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 | Article in Scientific American about the first results of the Biobank study, including an interview with me. |
Year(s) Of Engagement Activity | 2016 |
URL | https://www.scientificamerican.com/article/massive-u-k-brain-mapping-project-releases-first-results/ |
Description | Brain Awareness week panel |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Public/other audiences |
Results and Impact | A free Brain Awareness Week screening of a documentary about renowned academic and research scientist Dr Marian Diamond, organised by the Nuffield Department of Clinical Neurosciences. I participated in a panel discussion with other Oxford University neuroscientists following the film. |
Year(s) Of Engagement Activity | 2018 |
URL | https://www.bna.org.uk/meetings/baw2018/ |
Description | Curiosity Carnival |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Public/other audiences |
Results and Impact | The Curiosity Carnival on Friday 29 September was a chance to find out what research is really all about, meet researchers, ask questions and discover how research affects and changes all our lives. The night was a huge festival of curiosity - a city-wide programme of activities across the University of Oxford's museums, libraries, gardens and woods. There was a wide range of activities for all ages and interests - live experiments, games, stalls, busking, debates, music, dance and a pub-style quiz. Oxford's Curiosity Carnival 2017 joined hundreds of other European cities in celebrating European Researchers' Night. |
Year(s) Of Engagement Activity | 2018 |
URL | http://www.ox.ac.uk/curiosity-carnival/about |
Description | Interview on BBC Radio 4's 'All in the Mind' |
Form Of Engagement Activity | A press release, press conference or response to a media enquiry/interview |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Public/other audiences |
Results and Impact | Interview for the Radio 4 programme 'All in the Mind' |
Year(s) Of Engagement Activity | 2015 |
URL | http://www.bbc.co.uk/programmes/b06np621 |