White matter microstructure alterations in Huntington’s disease: a cross-species study
Poster No:
232
Submission Type:
Abstract Submission
Authors:
Chiara Casella1,2,3, Maxime Chamberland1,4, Pedro Laguna1, Brendan Kelly5, Alvaro Murillo Bartolome5, Bella Mills-Smith5, Greg Parker1, Christopher Von Ruhland6, Syed Yasir5, Vincent Dion5, Anne Rosser5,7,8, Mariah Lelos5, Derek Jones1, Claudia Metzler-Baddeley1
Institutions:
1Cardiff University Brain Research Imaging Centre (CUBRIC), Cardiff University, Cardiff, United Kingdom, 2Centre for the Developing Brain, King's College London, London, United Kingdom, 3Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, United Kingdom, 4Eindhoven University of Technology, Eindhoven, Netherlands, 5School of Biosciences, Cardiff University, Cardiff, United Kingdom, 6Electron and Light Microscopy Facility, Cardiff University, Cardiff, United Kingdom, 7UK Dementia Research Institute, Cardiff, United Kingdom, 8B.R.A.I.N unit, Neurosciences and Mental Health Institute, Cardiff, United Kingdom
First Author:
Chiara Casella
Cardiff University Brain Research Imaging Centre (CUBRIC), Cardiff University|Centre for the Developing Brain, King's College London|Institute of Psychiatry, Psychology and Neuroscience, King’s College London
Cardiff, United Kingdom|London, United Kingdom|London, United Kingdom
Cardiff University Brain Research Imaging Centre (CUBRIC), Cardiff University|Centre for the Developing Brain, King's College London|Institute of Psychiatry, Psychology and Neuroscience, King’s College London
Cardiff, United Kingdom|London, United Kingdom|London, United Kingdom
Co-Author(s):
Maxime Chamberland
Cardiff University Brain Research Imaging Centre (CUBRIC), Cardiff University|Eindhoven University of Technology
Cardiff, United Kingdom|Eindhoven, Netherlands
Cardiff University Brain Research Imaging Centre (CUBRIC), Cardiff University|Eindhoven University of Technology
Cardiff, United Kingdom|Eindhoven, Netherlands
Pedro Laguna
Cardiff University Brain Research Imaging Centre (CUBRIC), Cardiff University
Cardiff, United Kingdom
Cardiff University Brain Research Imaging Centre (CUBRIC), Cardiff University
Cardiff, United Kingdom
Greg Parker
Cardiff University Brain Research Imaging Centre (CUBRIC), Cardiff University
Cardiff, United Kingdom
Cardiff University Brain Research Imaging Centre (CUBRIC), Cardiff University
Cardiff, United Kingdom
Christopher Von Ruhland
Electron and Light Microscopy Facility, Cardiff University
Cardiff, United Kingdom
Electron and Light Microscopy Facility, Cardiff University
Cardiff, United Kingdom
Anne Rosser
School of Biosciences, Cardiff University|UK Dementia Research Institute|B.R.A.I.N unit, Neurosciences and Mental Health Institute
Cardiff, United Kingdom|Cardiff, United Kingdom|Cardiff, United Kingdom
School of Biosciences, Cardiff University|UK Dementia Research Institute|B.R.A.I.N unit, Neurosciences and Mental Health Institute
Cardiff, United Kingdom|Cardiff, United Kingdom|Cardiff, United Kingdom
Derek Jones
Cardiff University Brain Research Imaging Centre (CUBRIC), Cardiff University
Cardiff, United Kingdom
Cardiff University Brain Research Imaging Centre (CUBRIC), Cardiff University
Cardiff, United Kingdom
Claudia Metzler-Baddeley
Cardiff University Brain Research Imaging Centre (CUBRIC), Cardiff University
Cardiff, United Kingdom
Cardiff University Brain Research Imaging Centre (CUBRIC), Cardiff University
Cardiff, United Kingdom
Introduction:
White matter (WM) changes have been observed in Huntington's Disease (HD) 1, but their etiology is unclear. Here, we present cross-species work aiming to better understand such changes.
Firstly, we assessed WM microstructure in HD patients with ultra-strong gradients 2. We combined diffusion tensor (DT)-MRI, with the magnetization transfer ratio (MTR) as proxy measure of myelin 3, and the restricted diffusion signal fraction (FR) from the Composite Hindered and Restricted Model of Diffusion (CHARMED) 4, as proxy measure of axon density 5. Then, we assessed WM microstructure in the R6/1 HD mouse model using ex vivo MRI. We complemented DT-MRI with FR from CHARMED, and the macromolecular proton fraction (MPF) as proxy measure of myelin 3. Finally, we used light microscopy (LM) and transmission electron microscopy (TEM) in age- and sex-matched cohorts of R6/1 mice to gain insight into the neurobiological basis of imaging results.
Firstly, we assessed WM microstructure in HD patients with ultra-strong gradients 2. We combined diffusion tensor (DT)-MRI, with the magnetization transfer ratio (MTR) as proxy measure of myelin 3, and the restricted diffusion signal fraction (FR) from the Composite Hindered and Restricted Model of Diffusion (CHARMED) 4, as proxy measure of axon density 5. Then, we assessed WM microstructure in the R6/1 HD mouse model using ex vivo MRI. We complemented DT-MRI with FR from CHARMED, and the macromolecular proton fraction (MPF) as proxy measure of myelin 3. Finally, we used light microscopy (LM) and transmission electron microscopy (TEM) in age- and sex-matched cohorts of R6/1 mice to gain insight into the neurobiological basis of imaging results.
Methods:
Human Imaging: 25 premanifest patients and 25 age- and sex-matched healthy controls (HC) scanned in a 300mT/m 3T MRI scanner (MAGNETOM Skyra CONNECTOM) with multi-shell diffusion and magnetisation transfer. We computed FA, AD, RD, FR and MTR as described in 8. WM microstructure was assessed across the corpus callosum (CC). Automated CC segmentation was performed using TractSeg6 and multi-shell constrained spherical deconvolution (MSMT-CSD)7. 7 segments were delineated. Principal component analysis (PCA) was used to extract a 'magnetization transfer' and a 'axon density' component. Whole-brain microstructure was inspected with tract-based cluster analysis (TBCA)8.
Rodent Imaging: 8 R6/1 and 7 wildtype (WT) mice scanned at 9.4T (Bruker Biospin) at 16 weeks of age with multi-shell diffusion and quantitative magnetization transfer. FA, AD, RD, and FR maps were computed using the same approaches as the ones used for the human data. MPF maps were obtained as described in 9. Microstructure was assessed in the CC genu, body, and splenium. MSMT-CSD7 was performed and fibres were reconstructed interactively10. Tract-based spatial statistics (TBSS) were used to examine brain-wise WM microstructure.
Microscopy: LM was used to visualize neurofilament light (NF-L) and myelin basic protein (MBP) in the CC genu, body, and splenium (N=9 WT and N=9 R6/1 mice). Thickness and area fraction were quantified. For TEM, diameter and g-ratio of myelinated axons were assessed in 5 CC regions (N=3 WT and N=3 R6/1 mice).
Rodent Imaging: 8 R6/1 and 7 wildtype (WT) mice scanned at 9.4T (Bruker Biospin) at 16 weeks of age with multi-shell diffusion and quantitative magnetization transfer. FA, AD, RD, and FR maps were computed using the same approaches as the ones used for the human data. MPF maps were obtained as described in 9. Microstructure was assessed in the CC genu, body, and splenium. MSMT-CSD7 was performed and fibres were reconstructed interactively10. Tract-based spatial statistics (TBSS) were used to examine brain-wise WM microstructure.
Microscopy: LM was used to visualize neurofilament light (NF-L) and myelin basic protein (MBP) in the CC genu, body, and splenium (N=9 WT and N=9 R6/1 mice). Thickness and area fraction were quantified. For TEM, diameter and g-ratio of myelinated axons were assessed in 5 CC regions (N=3 WT and N=3 R6/1 mice).
Results:
We detected lower MTR in the isthmus of patients (tractometry: p=0.03; TBCA: p=0.03) and higher in the rostrum (tractometry: p=0.02). MTR and CAG size in patients were positively associated in all CC segments (all p<0.01). Patients had higher FR in the cortico-spinal tract (p=0.03).
FR increases (p=0.03) and MPF decreases (p=0.05) were detected in the CC of R6/1 mice. TBSS uncovered increases in FR and some decreases in MPF beyond the CC.
Increased NFL and decreased MBP staining were detected in R6/1 mice. R6/1 mice had a thinner CC body (p<0.05) and splenium (p<0.05). A reduced g-ratio was detected in R6/1 mice (p=0.05), reflecting a thinner axonal diameter (p<0.05) and greater frequency of thinner axons. No difference in myelin thickness was observed.
FR increases (p=0.03) and MPF decreases (p=0.05) were detected in the CC of R6/1 mice. TBSS uncovered increases in FR and some decreases in MPF beyond the CC.
Increased NFL and decreased MBP staining were detected in R6/1 mice. R6/1 mice had a thinner CC body (p<0.05) and splenium (p<0.05). A reduced g-ratio was detected in R6/1 mice (p=0.05), reflecting a thinner axonal diameter (p<0.05) and greater frequency of thinner axons. No difference in myelin thickness was observed.
Conclusions:
We detected increased FR in both HD patients and HD mice, likely reflecting disruptions in axonal morphology (i.e., less complex, thinner axons ) and organization (i.e., more densely packed axons). Our findings point to the potential of FR as cross-species MRI marker of axonal changes in HD. Our findings also suggest a link between myelin alterations and the disease mutation and show that early in disease progression WM changes are associated with a reduction in myelin proteins without alterations in myelin sheath structure.
Disorders of the Nervous System:
Neurodegenerative/ Late Life (eg. Parkinson’s, Alzheimer’s) 1
Genetics:
Neurogenetic Syndromes 2
Modeling and Analysis Methods:
Diffusion MRI Modeling and Analysis
Neuroanatomy, Physiology, Metabolism and Neurotransmission:
White Matter Anatomy, Fiber Pathways and Connectivity
Novel Imaging Acquisition Methods:
Multi-Modal Imaging
Keywords:
ANIMAL STUDIES
Degenerative Disease
Movement Disorder
MRI
Myelin
STRUCTURAL MRI
White Matter
WHITE MATTER IMAGING - DTI, HARDI, DSI, ETC
1|2Indicates the priority used for review
Provide references using author date format
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