Develop sensitive behavioural and neuroimaging markers in detecting cognitive ageing

Lead Research Organisation: University of Edinburgh
Department Name: Centre for Clinical Brain Sciences

Abstract

Abstracts are not currently available in GtR for all funded research. This is normally because the abstract was not required at the time of proposal submission, but may be because it included sensitive information such as personal details.

Publications

10 25 50
 
Description Work 1 Behaivour and Cognition: Through visit and discussion with the research partners in National Taiwan University, our research on cognitive ageing and memory processes was refined and published in Neuropharmacology and Neurobiology of Ageing and presented in various conferences (see engagement activities).
Work 2: Rident fMRI: Through collaboration with radiologists in CCBS, University of Edinburgh, and the partner researchers in Chang-Gung University, we develop a pipeline to ameliorate noise in awake rodent brain imaging. It involves adapting two of the major imaging analysis platforms (FSL and SPM) that are mainly designed for human research and requires developing original steps to register and align rodent brains for further analysis. The results were presented at Medical Image Understanding and Analysis (see engagement activities).
Work 3: Rodent MicroPET: Through visiting imaging facilities and experience exchange with radiologists in National Taiwan University, we have started pilot studies for MicroPET imaging in University of Edinburgh. The data collection still continues and will be used in future project or funding application.
Work 4: Human fMRI: There has been intensive discussion with partner researchers in Chang-Gung University and proactive publication in abstracts and presentation in conferences (see engagement activities). Broader collaborative work stemming from this award has been published in NeuroImage: Clinical, Frontiers in NeuroInformatics, and Frontiers in Ageing Neuroscience.
This award also allows training of the next-generation scientists. PhD student, Ms Pei, from National Taiwan University received funding from this award for training in University of Edinburgh on brain region segmentation and image analysis. MSc student, Mr Chhetri, from University of Edinburgh received funding from this award for training in Chang-Gung University on MRI image analysis. Four additional PhD students or postdocs also participated in the bilateral visits and scientific discussion.
Exploitation Route The majority of the outcomes have been published. Relevant URLs are provided in 'Publications. Enhanced learning techniques in segmenting brain images and softwares for white matter image analysis have been made available for use by others (see URLs in software and technical products).
Sectors Digital/Communication/Information Technologies (including Software),Pharmaceuticals and Medical Biotechnology

 
Description Alzheimer's Research UK Masonic PhD Scholarship
Amount £107,581 (GBP)
Organisation Alzheimer's Research UK 
Sector Charity/Non Profit
Country United Kingdom
Start 09/2019 
End 08/2022
 
Description Senior research fellowship
Amount £420,000 (GBP)
Organisation Alzheimer's Research UK 
Sector Charity/Non Profit
Country United Kingdom
Start 07/2019 
End 06/2023
 
Description Small Grant
Amount £2,000 (GBP)
Organisation Alzheimer's Research UK 
Sector Charity/Non Profit
Country United Kingdom
Start 03/2017 
End 03/2018
 
Description Determine the contribution of sleep in memory consolidation 
Organisation University of Tsukuba
Department International Institute for Integrative Sleep Medicine
Country Japan 
Sector Academic/University 
PI Contribution I have helped with the experimental design and data analysis and interpretation.
Collaborator Contribution The collaborator's group perform experiments deciphering the contribution of sleep on the subsequent memory consolidation and recall.
Impact This is an ongoing collaboration at the data collection stage. It involves electrophysiology and behavioural conditioning. It also allows training of postdocs and project students.
Start Year 2016
 
Description Develop methods of psycho-physiological interaction in rodent fMRI 
Organisation National Taiwan University
Department Department of Psychology
Country Taiwan, Province of China 
Sector Academic/University 
PI Contribution I designed and conducted awake rodent fMRI research and collected structural and functional brain images.
Collaborator Contribution Prof Chou's team provides methods and support for analysing psycho-physiological interaction.
Impact Neuroscience and Psychology
Start Year 2017
 
Description Structural Neuroimaging Differentiates Vulnerability from Disease Manifestation in Colombian Families with Huntington's Disease 
Organisation Corporación Universitaria del Caribe
Country Colombia 
Sector Academic/University 
PI Contribution Analysed neuroimaging indicators of global atrophy, PVS burden and GM tissue volume in the basal ganglia and thalami, in relation to behavioural, motor and cognitive scores, in 15 HD patients and 14 first-degree relatives from the region of Magdalena, Colombia.
Collaborator Contribution Behavioural, motor and cognitive assessments
Impact Manuscript written and under revision in Brain and Behaviour ABSTRACT The volume of the striatal structures has been associated with disease progression in individuals with Huntington's disease (HD) from North America, Europe and Australia. However, it is not known whether the grey matter (GM) volume in the striatum is also sensitive in differentiating vulnerability from disease manifestation in HD families from a South-American region known to have high incidence of the disease. In addition, the association of enlarged brain perivascular spaces (PVS) with cognitive, behavioural and motor symptoms of HD is unknown. We have analysed neuroimaging indicators of global atrophy, PVS burden and GM tissue volume in the basal ganglia and thalami, in relation to behavioural, motor and cognitive scores, in 15 HD patients and 14 first-degree relatives from the region of Magdalena, Colombia. We found that poor fluid intelligence as per the Raven's Standard Progressive Matrices was associated with global brain atrophy (p=0.002) and PVS burden (p=<0.02) in HD patients, where the GM volume in all subcortical structures, with the exception of the right globus pallidus, was associated with motor or cognitive scores. Only the GM volume in the right putamen was associated with envy and MOCA scores (p=0.008 and 0.015 respectively) in first-degree relatives. In conclusion, striatal GM volume, global brain atrophy and PVS burden may serve as differential indicators of disease manifestation in HD. The Raven's Standard Progressive Matrices could be a cognitive test worth to consider in the differentiation of vulnerability vs. overt disease in HD. SIGNIFICANCE STATEMENT The volume of grey matter in the basal ganglia and thalami is a sensitive differential indicator of disease manifestation vs. vulnerability in HD families from a South-American region with high incidence of this disease. This is the first study that analysed and found that the burden of brain enlarged perivascular spaces is associated with less fluid intelligence in HD patients and not in their first-degree relatives; and that the Raven's Standard Progressive Matrices discriminated overt HD vs. vulnerability after accounting for age, biological sex and years of education; thus suggesting their usefulness in the study of HD.
Start Year 2017
 
Description Structural Neuroimaging Differentiates Vulnerability from Disease Manifestation in Colombian Families with Huntington's Disease 
Organisation Favaloro University
Country Argentina 
Sector Academic/University 
PI Contribution Analysed neuroimaging indicators of global atrophy, PVS burden and GM tissue volume in the basal ganglia and thalami, in relation to behavioural, motor and cognitive scores, in 15 HD patients and 14 first-degree relatives from the region of Magdalena, Colombia.
Collaborator Contribution Behavioural, motor and cognitive assessments
Impact Manuscript written and under revision in Brain and Behaviour ABSTRACT The volume of the striatal structures has been associated with disease progression in individuals with Huntington's disease (HD) from North America, Europe and Australia. However, it is not known whether the grey matter (GM) volume in the striatum is also sensitive in differentiating vulnerability from disease manifestation in HD families from a South-American region known to have high incidence of the disease. In addition, the association of enlarged brain perivascular spaces (PVS) with cognitive, behavioural and motor symptoms of HD is unknown. We have analysed neuroimaging indicators of global atrophy, PVS burden and GM tissue volume in the basal ganglia and thalami, in relation to behavioural, motor and cognitive scores, in 15 HD patients and 14 first-degree relatives from the region of Magdalena, Colombia. We found that poor fluid intelligence as per the Raven's Standard Progressive Matrices was associated with global brain atrophy (p=0.002) and PVS burden (p=<0.02) in HD patients, where the GM volume in all subcortical structures, with the exception of the right globus pallidus, was associated with motor or cognitive scores. Only the GM volume in the right putamen was associated with envy and MOCA scores (p=0.008 and 0.015 respectively) in first-degree relatives. In conclusion, striatal GM volume, global brain atrophy and PVS burden may serve as differential indicators of disease manifestation in HD. The Raven's Standard Progressive Matrices could be a cognitive test worth to consider in the differentiation of vulnerability vs. overt disease in HD. SIGNIFICANCE STATEMENT The volume of grey matter in the basal ganglia and thalami is a sensitive differential indicator of disease manifestation vs. vulnerability in HD families from a South-American region with high incidence of this disease. This is the first study that analysed and found that the burden of brain enlarged perivascular spaces is associated with less fluid intelligence in HD patients and not in their first-degree relatives; and that the Raven's Standard Progressive Matrices discriminated overt HD vs. vulnerability after accounting for age, biological sex and years of education; thus suggesting their usefulness in the study of HD.
Start Year 2017
 
Description Structural Neuroimaging Differentiates Vulnerability from Disease Manifestation in Colombian Families with Huntington's Disease 
Organisation University of Strathclyde
Department School of Psychological Sciences and Health
Country United Kingdom 
Sector Academic/University 
PI Contribution Analysed neuroimaging indicators of global atrophy, PVS burden and GM tissue volume in the basal ganglia and thalami, in relation to behavioural, motor and cognitive scores, in 15 HD patients and 14 first-degree relatives from the region of Magdalena, Colombia.
Collaborator Contribution Behavioural, motor and cognitive assessments
Impact Manuscript written and under revision in Brain and Behaviour ABSTRACT The volume of the striatal structures has been associated with disease progression in individuals with Huntington's disease (HD) from North America, Europe and Australia. However, it is not known whether the grey matter (GM) volume in the striatum is also sensitive in differentiating vulnerability from disease manifestation in HD families from a South-American region known to have high incidence of the disease. In addition, the association of enlarged brain perivascular spaces (PVS) with cognitive, behavioural and motor symptoms of HD is unknown. We have analysed neuroimaging indicators of global atrophy, PVS burden and GM tissue volume in the basal ganglia and thalami, in relation to behavioural, motor and cognitive scores, in 15 HD patients and 14 first-degree relatives from the region of Magdalena, Colombia. We found that poor fluid intelligence as per the Raven's Standard Progressive Matrices was associated with global brain atrophy (p=0.002) and PVS burden (p=<0.02) in HD patients, where the GM volume in all subcortical structures, with the exception of the right globus pallidus, was associated with motor or cognitive scores. Only the GM volume in the right putamen was associated with envy and MOCA scores (p=0.008 and 0.015 respectively) in first-degree relatives. In conclusion, striatal GM volume, global brain atrophy and PVS burden may serve as differential indicators of disease manifestation in HD. The Raven's Standard Progressive Matrices could be a cognitive test worth to consider in the differentiation of vulnerability vs. overt disease in HD. SIGNIFICANCE STATEMENT The volume of grey matter in the basal ganglia and thalami is a sensitive differential indicator of disease manifestation vs. vulnerability in HD families from a South-American region with high incidence of this disease. This is the first study that analysed and found that the burden of brain enlarged perivascular spaces is associated with less fluid intelligence in HD patients and not in their first-degree relatives; and that the Raven's Standard Progressive Matrices discriminated overt HD vs. vulnerability after accounting for age, biological sex and years of education; thus suggesting their usefulness in the study of HD.
Start Year 2017
 
Description Structural Neuroimaging Differentiates Vulnerability from Disease Manifestation in Colombian Families with Huntington's Disease 
Organisation University of the Andes
Country Colombia 
Sector Academic/University 
PI Contribution Analysed neuroimaging indicators of global atrophy, PVS burden and GM tissue volume in the basal ganglia and thalami, in relation to behavioural, motor and cognitive scores, in 15 HD patients and 14 first-degree relatives from the region of Magdalena, Colombia.
Collaborator Contribution Behavioural, motor and cognitive assessments
Impact Manuscript written and under revision in Brain and Behaviour ABSTRACT The volume of the striatal structures has been associated with disease progression in individuals with Huntington's disease (HD) from North America, Europe and Australia. However, it is not known whether the grey matter (GM) volume in the striatum is also sensitive in differentiating vulnerability from disease manifestation in HD families from a South-American region known to have high incidence of the disease. In addition, the association of enlarged brain perivascular spaces (PVS) with cognitive, behavioural and motor symptoms of HD is unknown. We have analysed neuroimaging indicators of global atrophy, PVS burden and GM tissue volume in the basal ganglia and thalami, in relation to behavioural, motor and cognitive scores, in 15 HD patients and 14 first-degree relatives from the region of Magdalena, Colombia. We found that poor fluid intelligence as per the Raven's Standard Progressive Matrices was associated with global brain atrophy (p=0.002) and PVS burden (p=<0.02) in HD patients, where the GM volume in all subcortical structures, with the exception of the right globus pallidus, was associated with motor or cognitive scores. Only the GM volume in the right putamen was associated with envy and MOCA scores (p=0.008 and 0.015 respectively) in first-degree relatives. In conclusion, striatal GM volume, global brain atrophy and PVS burden may serve as differential indicators of disease manifestation in HD. The Raven's Standard Progressive Matrices could be a cognitive test worth to consider in the differentiation of vulnerability vs. overt disease in HD. SIGNIFICANCE STATEMENT The volume of grey matter in the basal ganglia and thalami is a sensitive differential indicator of disease manifestation vs. vulnerability in HD families from a South-American region with high incidence of this disease. This is the first study that analysed and found that the burden of brain enlarged perivascular spaces is associated with less fluid intelligence in HD patients and not in their first-degree relatives; and that the Raven's Standard Progressive Matrices discriminated overt HD vs. vulnerability after accounting for age, biological sex and years of education; thus suggesting their usefulness in the study of HD.
Start Year 2017
 
Description The Striatum, the Hippocampus, and Short-Term Memory Binding: Volumetric Analysis of the Subcortical Grey Matter's Role in Mild Cognitive Impairment 
Organisation University of Strathclyde
Department School of Psychological Sciences and Health
Country United Kingdom 
Sector Academic/University 
PI Contribution Hippocampal and corpus striatum volumes were fully automatically quantified in brain magnetic resonance images from 30 cognitively healthy people and 30 patients with Mild Cognitive Impairment (MCI) at high risk of AD progression, who undertook a battery of cognitive tests and the short-term memory binding test. Associations were assessed using linear regression models and group differences were assessed using the Mann-Whitney U test.
Collaborator Contribution Short-Term Memory Binding and neuropsychological assessments
Impact Manuscript under consideration in NeuroImage Clinical: ABSTRACT Background: Deficits in short-term memory binding are a distinguishing feature of preclinical stages leading to Alzheimer's disease (AD). However, the neurological correlates of conjunctive binding are largely unexplored. Here we examine the possible association between the grey matter volumes within the hippocampal and other limbic structures with cognitive tests related to this cognitive function. Materials and methods: Hippocampal and corpus striatum volumes were fully automatically quantified in brain magnetic resonance images from 30 cognitively healthy people and 30 patients with Mild Cognitive Impairment (MCI) at high risk of AD progression, who undertook a battery of cognitive tests and the short-term memory binding test. Associations were assessed using linear regression models and group differences were assessed using the Mann-Whitney U test. Results: Grey matter volumes in the hippocampus and parahippocampal gyrus differed between MCI and control groups. However, regression analysis found that only variations in grey matter volume of the globus pallidus were associated with binding deficits that characterised MCI patients, although with borderline significance. Conclusions: Loss of hippocampal volume plays no role in the processing of short-term memory binding. Structures within the basal ganglia, namely the globus pallidus, could be part of the extrahippocampal network supporting binding.
Start Year 2017
 
Description Validate automatic cell counting of fluorescent images 
Organisation University of Lethbridge
Country Canada 
Sector Academic/University 
PI Contribution We are collaborating with the Lethbridge Brain Dynamics lab to optimise automatic counting of foci fluorescent signals and validate the computer codes with our data. We aim to provide objective cell counting of brain cells that will bypass the shortcomings in subjective counting by experimenters. We provide the brain images.
Collaborator Contribution Our collaborator provides the computer codes that are compatible with NIH-funded open-access software.
Impact Neuroscience. Computer Science.
Start Year 2017
 
Title Dilated Saliency U-Net for White Matter Hyperintensities Segmentation using Irregularity Age Map 
Description White matter hyperintensities (WMH) appear as regions of abnormally high signal intensity on T2-weighted magnetic resonance image (MRI) sequences. In particular, WMH have been noteworthy in age-related neuroscience for being a crucial biomarker for Alzheimer's disease and brain aging processes. However, the automatic WMH segmentation is challenging because of the variable intensity range, size and shape. U-Net tackled this problem through the dense prediction and showed competitive performances on not only WMH segmentation/detection but also on varied image segmentation tasks, but it still accompanies a high complexity of the network architecture. This software contains the Saliency U-Net architecture and irregularity age map(IAM). Saliency U-Net is trained using both T2-FLAIR MRI sequence and IAM. Since IAM guides where irregularities, in which WMH is possibly included, exist on the MRI slice, Saliency U-Net performs better than the original U-Net trained only using T2-FLAIR. The better performance was achieved with fewer parameters and shorter training time. Moreover, the application of dilated convolution enhanced Saliency U-Net to recognise the shape of large WMH more accurately by learning multi-context on MRI slices. 
Type Of Technology Software 
Year Produced 2018 
Open Source License? Yes  
Impact Since IAM guides where irregularities, in which WMH is possibly included, exist on the MRI slice, Saliency U-Net performs better than the original U-Net trained only using T2-FLAIR. The better performance was achieved with fewer parameters and shorter training time. Moreover, the application of dilated convolution enhanced Saliency U-Net to recognise the shape of large WMH more accurately by learning multi-context on MRI slices. This network named Dilated Saliency U-Net improved Dice coefficient score to 0.5588 which is the best score among our experimental models, and recorded a relatively good sensitivity of 0.4747 with the shortest train time and the least number of parameters. In conclusion, based on the experimental results, incorporating IAM through Dilated Saliency U-Net resulted an appropriate approach for WMH segmentation. 
URL https://www.biorxiv.org/content/10.1101/550517v1
 
Title Enhanced Learning Techniques for Segmenting Ischaemic Stroke Lesions in Brain Magnetic Resonance Perfusion Images using a Convolutional Neural Network Scheme 
Description We use a freely available CNN framework, developed for MR imaging lesion segmentation, as core algorithm to evaluate the impact of enhanced machine learning techniques, namely data augmentation, transfer learning and post-processing, in the segmentation of stroke lesions using the ISLES 2017 dataset, which contains expert annotated diffusion-weighted perfusion and diffusion brain MRI of 43 stroke patients. 
Type Of Technology New/Improved Technique/Technology 
Year Produced 2019 
Impact Of all the techniques evaluated, data augmentation with binary closing achieved the best results, improving the mean Dice score in 17% over the baseline model. Consistent with previous works, better performance was obtained in the presence of large lesions. 
URL https://github.com/CarlosUziel/ischleseg
 
Description Phenotyping facility for novel drug discovery programs 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Prof Holmes and Dr Tavares (UoE) had discussion with scientists at Academia Sinica, Taiwan to observe the Penotyping service for their drug discovery programme and discuss the role of imaging in this pipeline.
Year(s) Of Engagement Activity 2018
 
Description Collaborative discussion on Focussed ultrasound disruption of Blood-Brain-Barrier 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Focussed ultrasound disruption of the Blood-Brain Barrier is a new technique being trialled in patients for allowing better penetration of medications into the brain. Profs Holmes and Moran from UoE met with Prof Lao-Li Liu, an expert in this newly emerging technlogy, to collaborate on a project for preclinical studies on drug deveopment for CNS disorders using this technique.
Year(s) Of Engagement Activity 2018
 
Description Invite a speaker, Prof Jun-Jie Wang, at the Edinburgh imaging seminar 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Postgraduate students
Results and Impact We invited Prof JJ Wang, Chang-Gung University, Taiwan to give a talk titled 'Diffusion MRI on neurodegenerative diseases' at the Edinburgh Imaging Seminar Series through the BBSRC international partnering award. It sparked discussion and collaboration with local radiologists and imaging analysts.
Year(s) Of Engagement Activity 2018
 
Description Moderating public talks on Mental Health 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Undergraduate students
Results and Impact About 150-200 audience attended 2 TED-style talks and sparked questions and debate at the panel discussion
Year(s) Of Engagement Activity 2019
URL https://www.facebook.com/events/461385578058365/
 
Description Moderating public talks on Neurodegenerative disorders 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Undergraduate students
Results and Impact About 150-200 audience attended 2 TED-style talks and sparked questions and debate at the panel discussion
Year(s) Of Engagement Activity 2019
URL https://www.facebook.com/events/3032613256813822/
 
Description Morphometry of White and Grey Matter Changes in Huntington's Disease 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Undergraduate students
Results and Impact This is the presentation of the project entitled MORPHOMETRY OF WHITE AND GREY MATTER CHANGES IN HUNTINGTON'S DISEASE by OH SHER LI at the Department of Biological Sciences National University of Singapore under the scheme Undergraduate Research Opportunities in Science supervised by Professor Jiun-Jie Wang, Dr Chih-Chien Tsai, Sung-Han Lin, Shi-Ming Wang and Xiang-An Zhao of the Department of Medical Imaging and Radiological Sciences at Chang Gung University, Taiwan, using the computational tools and in collaboration with myself (Maria Valdes Hernandez).
The abstract reads:
Morphometry of White and Grey Matter Changes in Huntington's Disease
Sher Li Oha, Muhammad Faris Hazwan Bin Ramlia, Chih-Chien Tsaib, Sung-Han Linb, Shi-Ming Wangb, Xiang-An Zhaob, Maria Valdés Hernándezc, d, e, and Jiun-Jie Wangb

a Faculty of Science, National University of Singapore, Singapore
b Medical Imaging and Radiological Sciences, Chang Gung University, Taoyuan, Taiwan
c Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, Scotland, UK
d Department of Neuroimaging Sciences, Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, Scotland, UK
e UK Dementia Research Institute at The University of Edinburgh, Edinburgh, UK

Objective
Huntington's Disease (HD) is a genetic disease that results in progressive neurodegeneration1. We aim to identify subcortical regions that undergo diffusivity and volume changes in HD, and to investigate white matter atrophy between these regions.

Methods
This cross-sectional study compares HD, pre-symptomatic HD (pre-HD) patients, and healthy subjects using subcortical segmentation with FMRIB Software Library3-7 and fixel-based analysis with MRtrix38,9.

Images were acquired from 3T MR scanner (Trio, Magnetom, Siemens, Erlangen Germany), including T1-weighted magnetisation-prepared rapid acquisition gradient echo (T1-MPRAGE) and diffusion weighted imaging (DWI). Fixation pads were used to reduce bulk head motion. Total acquisition time was 20 min 10 s.

T1-weighted imaging parameters were: TR / TE = 1700 ms / 2.63 ms, number of slices = 160, voxel size = 1 ? 1 ? 1 mm3, inversion time = 900 ms, flip angle = 9º, matrix size = 224 ? 256, field of view (FOV) = 224 ? 256 mm2, slice thickness = 1 mm. Diffusion weighted images were acquired by spin-echo echo planar imaging (EPI) sequence with parameters: TR / TE = 5200 ms / 92 ms, voxel size = 2 ? 2 ? 3 mm3, matrix size = 128 ? 128, number of slices = 13, slice thickness = 3 mm, b-value = 0 and 1000 s/mm2. Diffusion weighted gradients were applied along 12 non-collinear directions.

Results
12 HD patients (aged 50 ? 9.53 years), 5 pre-HD patients (aged 36 ? 3.19 years), and 16 healthy subjects (aged 45 ? 10.45 years) were included (Table 1).

Table 1: Demographic comparisons between age-matched Huntington's Disease patients and control subjects

No. Age Gender CAG No.a UDHRSb MMSEc
Motor Independence Functional Total
1 36 F 49 76 50 5 131 21
2 60/58 M 43 52 60 4 116 17
3 52 F 42 52 50 1 103 22
4 35 M 46 47 50 3 100 25
5 46/45 F 45 39 70 7 116 28
6 46/47 F 43 58 50 1 109 22
7 54/50 M 50 50 3 103 25 42
8 58 M/F 44 9 100 12 121 26
9 66/68 F/M 42 39 70 6 115 19
10 53 M/F 43 13 100 13 126 30
11 54 M 43 17 100 11 128 26
12 41 M/F 48 22 80 8 110 22

Each row represents one age-matched pair between a patient with Huntington's Disease, and a control subject. Differences in age and gender are displayed as the patient's age followed by the age of the control subject, in their respective columns.
a The CAG score refers to the number of cytosine-adenine-guanine repeats present in the HTT gene for each Huntington's Disease patient.
bThe Unified Huntington's Disease Rating Scale and cMini-Mental State Examination scores of the Huntington's Disease patients are shown.

Subcortical segmentation shows significantly increased (p < 0.005) axial, radial and mean diffusivity (AD, RD, MD) and significantly reduced globus pallidi and putamina volumes (p < 0.005) in HD compared to controls. Fixel-based analysis shows significantly lower (p < 0.05) fibre density and cross-section in the corpus callosum and internal capsule (Fig. 1).

Fig. 1: Significant loss of fibre density and cross-section in Huntington's Disease compared to healthy subjects. Fibre density (FD), fibre cross-section (FC), and a combined measure of fibre density and cross-section (FDC) are shown on a population white matter fibre orientation distribution template, in axial, coronal, and sagittal planes. Coloured lines represent significant fixels (p < 0.05) and are coloured by fibre direction.

Conclusion
There is increased diffusivity in subcortical regions in HD, with loss of white matter fibre density and cross-section.

Keywords
Huntington's Disease; magnetic resonance imaging; DWI; basal ganglia; fixel-based analysis; segmentation

References
1. Nance, M. A. Genetics of Huntington disease. Handbook of Clinical Neurology 144, (Elsevier B.V., 2017).
2. Huntington Study Group. Unified Huntington's disease rating scale: Reliability and consistency. Mov. Disord. 11, 136-142 (1996).
3. Patenaude, B., Smith, S. M., Kennedy, D. N. & Jenkinson, M. A Bayesian model of shape and appearance for subcortical brain segmentation. Neuroimage 56, 907-922 (2011).
4. Jenkinson, M., Bannister, P., Brady, M. & Smith, S. Improved Optimization for the Robust and Accurate Linear Registration and Motion Correction of Brain Images. Neuroimage 17, 825-841 (2002).
5. Andersson, J. L. R., Jenkinson, M. & Smith, S. Non-linear registration, aka spatial normalisation. (2007). doi:10.1016/j.neuroimage.2008.10.055
6. Smith, S. M. & Brady, J. M. SUSAN-A New Approach to Low Level Image Processing. Int. J. Comput. Vis. 23, 45-78 (1997).
7. Smith, S. M. Fast robust automated brain extraction. Hum. Brain Mapp. 17, 143-155 (2002).
8. Tournier, J. D., Calamante, F. & Connelly, A. Determination of the appropriate b value and number of gradient directions for high-angular-resolution diffusion-weighted imaging. NMR Biomed. 26, 1775-1786 (2013).
9. Raffelt, D. A. et al. Investigating white matter fibre density and morphology using fixel-based analysis. Neuroimage 144, 58-73 (2017).
Year(s) Of Engagement Activity 2018
 
Description Novel radiotracers for imaging the CNS with PET 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact The presentation at the National Taiwan University has led to discussions on collaboration opportunities between the University of Edinburgh radiotracer discovery group and the National Taiwan University PET facility. We are currently looking into funding opportunities to lift off a joint project focused on developing new PET radiotracers for imaging neuroinflammation.
Year(s) Of Engagement Activity 2018
 
Description Poster presentation in Medical Image Understanding and Analysis 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Postgraduate students
Results and Impact We presented a poster of our brain imaging studies in an international conference on Medical Image Understanding and Analysis (https://miua2017.wordpress.com/). It was selected and also invited to be presented orally as well (https://miua2017.files.wordpress.com/2017/05/miua_lighting_talks-thurs.pdf). About 150 researchers, clinicians, postgrad students and undergrad students attended this conference.
Year(s) Of Engagement Activity 2015,2017
URL https://miua2017.wordpress.com/
 
Description Poster presentation in Molecular Cellular Cognitive Society in Singapore 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Postgraduate students
Results and Impact The poster presentation attracted around 30-50 people and sparked discussion on the multi-faceted impact of ageing in learning and memory. The discussion contributed toward and enriched our recently accepted manuscript in Neurobiology of Aging and led to submission of a proposed symposium in an international conference in 2019.
Year(s) Of Engagement Activity 2017
URL http://medicine.nus.edu.sg/phys/MCCS/
 
Description Presentation at 9th Federation of Asian and Oceanian Physiological Societies Congress (FAOPS2019) 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact An invited talk to ca. 100 audience (including professional researchers, PG and UG students) that spark questions and discussions
Year(s) Of Engagement Activity 2019
URL https://www.nips.ac.jp/faops2019/FAOPS_circular.pdf
 
Description Presentation at the Edinburgh Neuroscience Day 2019 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Postgraduate students
Results and Impact An invited talk to ca. 300 audience (including professional researchers, PG and UG students) that spark questions and discussions
Year(s) Of Engagement Activity 2019
URL https://www.edinburghneuroscience.ed.ac.uk/neuroscience-day-2019-programme
 
Description Presentation at the Mediterranean Neuroscience Society 2019 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact An invited talk at a symposium on Alzheimer's research, ca. 100 audience (including professional researchers, PG and UG students) that spark questions and discussions
Year(s) Of Engagement Activity 2019
URL https://mnsocietylive.files.wordpress.com/2019/05/programma-finale.pdf
 
Description Presentation at the Ministry of Science and Technology (Taiwan) symposium in Edinburgh 2019 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact Sharing our BBSRC UK-Taiwan collaboration experience with Taiwanese researchers and policy makers in Scotland
Year(s) Of Engagement Activity 2019
 
Description Presentations From Edinburgh Imaging to National Taiwan University 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Imaging studies were presented by Dr Adriana Tavares and Prof Carmel Moran to the Neuroscience Dept National Taiwan University, hosted by Prof Wen-Sung Lai. Discussions on novel techniques of imaging for Ageing research and future collaborations took place.
Year(s) Of Engagement Activity 2018
 
Description Seminar in Neuroscience Summer Camp in National Taiwan University 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Undergraduate students
Results and Impact I gave a seminar talk in the Neuroscience summer training camp in National Taiwan University. Both senior researchers and students asked questions at the end of the seminar and reported learning new methods and findings in the field of memory research.
Year(s) Of Engagement Activity 2017
URL http://oiasystem.ntu.edu.tw/summer/course/index.detail/season/2/course_sn/111/intro/911
 
Description Seminar talks in Chang-Gung University and National Taiwan University (Prof Holmes, Dr Harris) 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Prof Megan Holmes and Dr Anjie Harris gave seminar talks in both Ghang-Gung University and National Taiwan University through the scheme of BBSRC international partnering award. The titles were: 'Living a Life of Stress: Consequences on affective and cognitive Behaviour' and 'The Effect of Stress on Brain Function in Rodent Models'.
Year(s) Of Engagement Activity 2018
URL http://www.psy.ntu.edu.tw/index.php/eng/events/1757-1070126e
 
Description Small group discussion on Imaging in Healthy Ageing populations. 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact A focussed meeting was held between UoE representatives (Prof Holmes and Dr Tavares) and with Vice President of R&D (Prof Ming Ling Kuo) and Director of the Healthy Ageing Research Centre (Prof Ching-Yi Wu) and Prof Jiun-Jie Wang, Cheng Gung University. We discussed brain imaging studies in healthy ageing cohorts and were shown around their Residential Care home for Healthy Ageing.
Year(s) Of Engagement Activity 2018
 
Description Structural Neuroimage Analysis for Clinical Research 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Postgraduate students
Results and Impact From 20-50 people attended the Symposium organised at the University of Edinburgh on 08/09/2017, including collaborators from the School of Informatics at the University of Edinburgh, Heriot-Watt University in Edinburgh and an academic from Colombia (Universidad Autonoma del Caribe) who were visiting Edinburgh.
To access the talk, please, see link below.
Year(s) Of Engagement Activity 2017
URL https://www.research.ed.ac.uk/portal/en/activities/uktaiwan-partnership-cognitive-mind-and-ageing-br...
 
Description Symposium on Cognition Ageing and Medical Imaging 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact A public Symposium in Cognition, Ageing and Medical Imaging was organised for researchers interested in UK-Taiwanese collaborative research. Speakers were Prof Holmes and Dr Adriana Tavares from Edinburgh University UK and Taiwanese speakers from National Taiwan University and Cheng Gung University, Taipei. The purpose of the Symposium was to highlight areas of research that were complementary between the researchers to induce formal collaborations and joint applications for grant funding. The symposium was well attended and there were several areas of potential collaboration highlighted which will be explored further.
Year(s) Of Engagement Activity 2018
 
Description Symposium on Cognition and Ageing Brain 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Schools
Results and Impact I organised the mini-symposium that showcased brain research in our groups in University of Edinburgh and partnering groups in Department of Psychology of National Taiwan University. It provided a platform for facilitating UK-Taiwan bilateral collaboration.
Year(s) Of Engagement Activity 2017
URL https://www.edinburghneuroscience.ed.ac.uk/events/mini-symposium-cognition-and-ageing-brain
 
Description WHITE AND GREY MATTER ANALYSIS OF DYSTONIA PATIENTS 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact Abstract presented at the Chinese Congress of Radiology 2018.

White and grey matter analysis of dystonia patients
Muhammad Faris Hazwan Ramlia, Sher Li Ohb, Chih-Chien Tsaib, Sung-Han Linb, Shi-Ming Wangb, Xiang-An Zhaob, Maria Valdés Hernándezc,d,e, and Jiun-Jie Wangb
a Faculty of Science, National University of Singapore, Singapore,
b Medical Imaging and Radiological Sciences, Chang Gung University, Taoyuan, Taiwan,
c Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, Scotland, UK,
d Department of Neuroimaging Sciences, Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, Scotland, UK,
e UK Dementia Research Institute at The University of Edinburgh, Edinburgh, UK
Objectives
This study proposed to investigate the white matter tracts and subcortical structures in patients with dystonia. Fixel-based analysis is used to study fiber tracts and FIRST segmentation can detect any grey matter changes.
Methods
Multi-shell diffusion weighted images (DWI) and T1-weighted magnetization-prepared rapid acquisition gradient echo (T1-MPRAGE) were acquired from 32 dystonia patients (mean age 45.9 ± 11.7) and 36 healthy subjects (mean age 50.6 ± 9.0) using 3T scanner (Trio, Magnetom, Siemens, Erlangen Germany). White matter tracts analysed using fixel-based analysis1-9 and subcortical brain segmentation performed using FIRST-FSL10-14. T1-MPRAGE parameters: repetition time (TR)/Echo time (TE)= 2000 ms /2.63 ms, number of slices=160, voxel size 2x2x2 mm, inversion time= 900 ms, flip angle= 9°, matrix size=224×256, field of view= 448x512 mm2, and slice thickness= 1mm. DWI parameters: repetition time (TR) / echo time (TE) = 8500 ms / 96 ms, voxel size=2x2x2 mm, matrix size =128x128, number of slices =64, slice thickness =2 mm , and b-value = 0 and 1000 s/mm2. Diffusion weighted gradients applied along 64 non-collinear directions. The fixation pads used to reduce the bulk head motion. Total acquisition time: 42 min 38 sec.
Results
Diffusion abnormalities reported in fiber tracts of the sensorimotor cortex to the subcortical structures15. But, fixel-based analysis revealed no significant differences (p<0.05) in the fiber tracts in dystonia patients. There are structural and functional grey matter alterations in dystonia patients16-18. Figure 1 shows the DTI measures (p<0.005) and volume change (p<0.05) of subcortical structures in dystonia patients. The grey matter changes were insignificant in dystonia patients.
Conclusion
There are no significant changes in subcortical structures and white matter tracts in dystonia found in this study.
Keywords
Dystonia; diffusion magnetic resonance imaging; diffusion weighted images; segmentation; basal ganglia.
References
1. Raffelt, D. A. et al. Investigating white matter fibre density and morphology using fixel-based analysis. Neuroimage 144, 58-73 (2017).
2. Raffelt, D. et al. Symmetric diffeomorphic registration of fibre orientation distributions. Neuroimage 56, 1171-1180 (2011).
3. Raffelt, D. A. et al. Connectivity-based fixel enhancement: Whole-brain statistical analysis of diffusion MRI measures in the presence of crossing fibres. Neuroimage 117, 40-55 (2015).
4. Kellner, E., Dhital, B., Kiselev, V. G. & Reisert, M. Gibbs-ringing artifact removal
based on local subvoxel-shifts. Magn. Reson. Med. 76, 1574-1581 (2016).
5. Andersson, J. L. R. & Sotiropoulos, S. N. An integrated approach to correction for off-resonance effects and subject movement in diffusion MR imaging. Neuroimage 125, 1063-1078 (2016).
6. Andersson, J. L. R. & Sotiropoulos, S. N. Non-parametric representation and prediction of single- and multi-shell diffusion-weighted MRI data using Gaussian processes. Neuroimage 122, 166-176 (2015).
7. Tustison, N. J. et al. N4ITK: Improved N3 Bias Correction. IEEE Trans. Med. Imaging 29, 1310-1320 (2010).
8. Tournier, J.-D., Calamante, F., Gadian, D. G. & Connelly, A. Direct estimation of the fiber orientation density function from diffusion-weighted MRI data using spherical deconvolution. Neuroimage 23, 1176-1185 (2004).
9. Tournier, J.-D., Calamante, F. & Connelly, A. Robust determination of the fibre orientation distribution in diffusion MRI: Non-negativity constrained super-resolved spherical deconvolution. Neuroimage 35, 1459-1472 (2007).
10. Patenaude, B., Smith, S. M., Kennedy, D. N. & Jenkinson, M. A Bayesian model of shape and appearance for subcortical brain segmentation. Neuroimage 56, 907-922 (2011).
11. Jenkinson, M. & Smith, S. A global optimisation method for robust affine registration of brain images. Med. Image Anal. 5, 143-156 (2001).
12. Jenkinson, M., Bannister, P., Brady, M. & Smith, S. Improved Optimization for the Robust and Accurate Linear Registration and Motion Correction of Brain Images. Neuroimage 17, 825-841 (2002).
13. Smith, S. M. Fast robust automated brain extraction. Hum. Brain Mapp. 17, 143-155 (2002).
14. Smith, S. M. & Brady, J. M. SUSAN-A New Approach to Low Level Image Processing. Int. J. Comput. Vis. 23, 45-78 (1997).
15. Delmaire, C. et al. Diffusion Abnormalities in the Primary Sensorimotor Pathways in Writer's Cramp. Arch. Neurol. 66, 502-8 (2009).
16. Garraux, G. et al. Changes in brain anatomy in focal hand dystonia. Ann. Neurol. 55, 736-739 (2004).
17. Hallett, M. Dystonia: abnormal movements result from loss of inhibition. Adv. Neurol. 94, 1-9 (2004).
18. Delmaire, C. et al. Structural abnormalities in the cerebellum and sensorimotor circuit in writer's cramp. Neurology 69, 376-380 (2007).
Year(s) Of Engagement Activity 2018
URL http://www.medmeeting.org/Content/80118
 
Description Workshop for widening participation for senior school students 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Schools
Results and Impact We (with another BBSRC-funded new investigator) participated the university's widening participation programme and organised a Kickstart workshop for senior school students. We gave a lecture and provided work stations where students could observe or try some of the neuroscience experiments we do. They rated highly positive and reported: The amount of content just right 88%, interested in looking further in the subject after the workshop 65%, Good chance to do practical's in the lab and on computers.
Year(s) Of Engagement Activity 2017
URL https://www.ed.ac.uk/student-recruitment/widening-participation/projects/partnership-projects/kickst...