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. 2023 Apr;13(4):e2940.
doi: 10.1002/brb3.2940. Epub 2023 Mar 14.

Progressive alterations in white matter microstructure across the timecourse of Huntington's disease

Carlos Estevez-Fraga  1 , Michael S Elmalem  1 , Marina Papoutsi  1 , Alexandra Durr  2 , Elin M Rees  3 , Nicola Z Hobbs  1 , Raymund A C Roos  4 , Bernhard Landwehrmeyer  5 , Blair R Leavitt  6 , Douglas R Langbehn  7 , Rachael I Scahill  1 , Geraint Rees  8 , Sarah J Tabrizi  1 , Sarah Gregory  1
Affiliations

Progressive alterations in white matter microstructure across the timecourse of Huntington's disease

Carlos Estevez-Fraga et al. Brain Behav. 2023 Apr.

Abstract

Background: Whole-brain longitudinal diffusion studies are crucial to examine changes in structural connectivity in neurodegeneration. Here, we investigated the longitudinal alterations in white matter (WM) microstructure across the timecourse of Huntington's disease (HD).

Methods: We examined changes in WM microstructure from premanifest to early manifest disease, using data from two cohorts with different disease burden. The TrackOn-HD study included 67 controls, 67 premanifest, and 10 early manifest HD (baseline and 24-month data); the PADDINGTON study included 33 controls and 49 early manifest HD (baseline and 15-month data). Longitudinal changes in fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity, and radial diffusivity from baseline to last study visit were investigated for each cohort using tract-based spatial statistics. An optimized pipeline was employed to generate participant-specific templates to which diffusion tensor imaging maps were registered and change maps were calculated. We examined longitudinal differences between HD expansion-carriers and controls, and correlations with clinical scores, including the composite UHDRS (cUHDRS).

Results: HD expansion-carriers from TrackOn-HD, with lower disease burden, showed a significant longitudinal decline in FA in the left superior longitudinal fasciculus and an increase in MD across subcortical WM tracts compared to controls, while in manifest HD participants from PADDINGTON, there were significant widespread longitudinal increases in diffusivity compared to controls. Baseline scores in clinical scales including the cUHDRS predicted WM microstructural change in HD expansion-carriers.

Conclusion: The present study showed significant longitudinal changes in WM microstructure across the HD timecourse. Changes were evident in larger WM areas and across more metrics as the disease advanced, suggesting a progressive alteration of WM microstructure with disease evolution.

Keywords: Huntington's disease; diffusion tensor imaging; longitudinal; presymptomatic; symptomatic.

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Conflict of interest statement

During the previous 12 months, Carlos Estevez‐Fraga, Sarah Gregory, Rachael I. Scahill, Geraint Rees, and Sarah J. Tabrizi report support from a Wellcome Trust Collaborative Award (200181/Z/15/Z).

Sarah J. Tabrizi receives research grant funding from the CHDI Foundation, Vertex Pharmaceuticals, the UK Medical Research Council, the Wellcome Trust (200181/Z/15/Z), and the UK Dementia Research Institute that receives its funding from DRI Ltd., funded by the UK MRC, Alzheimer's Society, and Alzheimer's Research UK. She has undertaken consultancy services for Alnylam Pharmaceuticals Inc., Atalanta Pharmaceuticals (SAB), F. Hoffmann‐La Roche Ltd./Genentech, Guidepoint, Horama, Locanobio, LoQus23 Therapeutics Ltd. (SAB), Novartis Pharma, PTC Therapeutics, Sanofi, Spark Therapeutics, Takeda Pharmaceuticals Ltd., Triplet Therapeutics (SAB), University College Irvine, Vertex Pharmaceuticals Incorporated, and Wave Life Sciences. All honoraria for these consultancies were paid through the offices of UCL Consultants Ltd., a wholly owned subsidiary of University College London. Sarah J. Tabrizi has a patent Application number 2105484.6 on the FAN1‐MLH1 interaction and structural analogs licensed to Adrestia Therapeutics.

Douglas R. Langbehn receives academic research funding from CHDI, NINDs, the University College of London (UCL), and the Wellcome Trust via (UCL). He reports personal consulting fees and non‐financial support from Voyager Therapeutics, personal consulting fees from Novartis, personal consulting fees and non‐financial support from uniQure, personal consulting fees from Takeda, personal consulting fees from AskBio, and personal consulting fees from Spark Therapeutics, all outside the submitted work.

Bernhard Landwehrmeyer has provided consulting services, advisory board functions, clinical trial services, and/or lectures for Acadia Pharmaceuticals, Affiris, Allergan, Alnylam, Amarin, AOP Orphan Pharmaceuticals AG, Bayer Pharma AG, Boehringer‐Ingelheim, CHDI Foundation, Deutsche Huntington‐Hilfe, Desitin, Genentech, Genzyme, GlaxoSmithKline, F. Hoffmann‐La Roche, Ipsen, ISIS Pharma (IONIS), Lilly, Lundbeck, Medesis, Medivation, Medtronic, NeuraMetrix, Neurosearch Inc., Novartis, Pfizer, Prana Biotechnology, Prilenia, PTC Therapeutics, Raptor, Remix Therapeutics, Rhône‐Poulenc Rorer, Roche Pharma AG Deutschland, Sage Therapeutics, Sanofi‐Aventis, Sangamo/Shire, Siena Biotech, Takeda, Temmler Pharma GmbH, Teva, Triplet TX, Trophos, UniQure, and Wave Life Sciences. He has received research grant support from the CHDI Foundation, the Bundesministerium für Bildung und Forschung (BMBF), the Deutsche Forschungsgemeinschaft (DFG), the European Commission (EU‐FP7), EU Joint Programme—Neurodegenerative Disease Research (JNPD), and ERA‐Net for Research Programmes on Rare Diseases (E‐Rare). His study site has received compensation in the context of the observational REGISTRY‐Study of European Huntington's Disease Network (EHDN) and the global observational Enroll‐HD. In the context of clinical trials, his institution, the University Hospital of Ulm, has received compensation from Allergan, Ionis, F. Hoffmann‐La Roche, Pfizer, and Teva.

Alexandra Durr serves on scientific advisory boards for Triplet Therapeutics and receives laboratory funding from BIOGEN, all outside the submitted work.

Blair R. Leavitt is on the Scientific Advisory Board of sRNAlytics (GateHouse Bio) for which he received stock options, and reports scientific consultancy fees from Teva, Roche/Genentech, Takeda, Triplet, Ionis, Novartis, Spark, Scintetica, LifeEdit, Design, Remix Therapeutics, and PTC Therapeutics. Dr Leavitt's Laboratory has obtained previous and current research grants from CIHR, HSC, NMIN, CHDI, Teva, ProMIS and uniQure. He is a founding co‐Editor‐in‐Chief, Journal of Huntington's Disease, Former Co‐Chair of the Huntington Study Group, and is a Co‐Founder and CEO of Incisive Genetics Inc., in which he has stock and stock options. Incisive Genetics Inc. is an early‐stage pre‐clinical biotechnology company that was founded to develop in vivo lipid nanoparticle delivery of CRISPR/Cas9 genome editing. This is not a therapeutic approach that is currently in clinical testing for HD, nor is this approach in late pre‐clinical stages. The company has no products to endorse, does not have an IND for HD, nor are any commercial efforts currently underway. Sarah J. Tabrizi was the global principal investigator (PI) for TrackOn‐HD. Alexandra Durr, Blair R. Leavitt, Raymund A. C. Roos, and Bernhard Landwehrmeyer were site PIs for Paris, Vancouver, Leiden, and Ulm, respectively. No other relevant disclosures or conflicts of interest.

Michael S Elmalem, Nicola Z. Hobbs, and Elin M. Rees declare no conflict of interest.

Figures

FIGURE 1
FIGURE 1
Summary of processing pipeline. Raw FA data from the two visits of all subjects in each study were registered using FSL FLIRT to create halfway images. These images were averaged to create a subject‐wise FA mid‐space template. TBSS automatically aligned all mid‐space images to standard space. The warped FA templates were used to create the mean FA map. This map was thresholded at FA >0.2 to create the midspace FA skeleton for all subjects. All halfway image skeletons from the two visits for all DTI metrics were projected to the standardized FA skeleton. Finally, the skeleton for visit 3 was subtracted from the skeleton for visit 1 and statistical analysis was performed on the subtraction images to compare between HD gene expansion carriers and controls. The same process was repeated to obtain a template only in HD expansion carriers from each study in order to run the correlations in the subtracted images (adapted and reproduced with permission from Engvig et al., 2012). DTI, Diffusion Tensor Imaging; FA, fractional anisotropy; HD, Huntington's disease; TBSS, tract‐based spatial statistics.
FIGURE 2
FIGURE 2
Longitudinal changes in FA and MD between HD expansion‐carriers and controls in the TrackOn‐HD cohort. Data shown are areas with significant decreases in FA or increases in MD in HD expansion‐carriers compared to healthy controls. Results are shown on the FA skeleton (green), overlaid on the MNI standard brain template. All analyses presented are adjusted by age, sex, and study site; thresholded at p < .05 (TFCE cluster‐corrected). The color bar (yellow: red, higher: lower) represents p‐values above the statistical threshold for significance. FA, fractional anisotropy; HD, Huntington's disease; MD, mean diffusivity; MNI, Montreal Neurological Institute; TBSS, tract‐based spatial statistics; TFCE, threshold‐free cluster enhancement.
FIGURE 3
FIGURE 3
Longitudinal changes in MD, AD, and RD between HD expansion carriers and controls in the PADDINGTON cohort. Data shown are areas with significant increases in MD, AD, and RD in HD expansion‐carriers compared to healthy controls. Results are shown on the FA skeleton (green), overlaid on the MNI standard brain template. All analyses presented are adjusted by age, sex, and study site; thresholded at p < .05 (TFCE cluster‐corrected). The color bar (yellow: red, higher: lower) represents p‐values above the statistical threshold for significance. AD, axial diffusivity; FA, fractional anisotropy; HD, Huntington's disease; MD, mean diffusivity; RD, radial diffusivity; TBSS, tract‐based spatial statistics; TFCE, threshold‐free cluster enhancement.
FIGURE 4
FIGURE 4
Associations between baseline UHDRS‐TMS and change in mean diffusivity (A and B) and between baseline composite UHDRS and change in mean diffusivity (C and D) in HD expansion‐carriers in the PADDINGTON cohort. (A) TBSS results showing areas with significant positive correlations between change in mean diffusivity and baseline scores in the UHDRS‐TMS. (B) Scatterplot, linear trend, and 95% confidence interval depicting the association between baseline scores in UHDRS‐TMS and change in mean diffusivity within the largest significant cluster from (A). (C) TBSS results showing areas with significant negative correlations between change in mean diffusivity and baseline scores in the composite UHDRS. (D) Scatterplot, linear trend, and 95% confidence interval depicting the association between baseline composite UHDRS and change in mean diffusivity within the largest significant cluster from (C). TBSS results are shown on the FA skeleton (green), overlaid on the MNI standard brain template. All analyses presented are adjusted by age, sex, and study site; thresholded at p < .05 (TFCE cluster‐corrected). The color bar (yellow: red, higher: lower) represents p‐values above the statistical threshold for significance. HD, Huntington's disease; TBSS, tract‐based spatial statistics; TFCE, threshold‐free cluster enhancement; UHDRS‐TMS, Unified Huntington's Disease Rating Scale—total motor score
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