Mutation-related magnetization-transfer, not axon density, drives white matter differences in premanifest Huntington's disease: Evidence from in vivo ultra-strong gradient MRI

Casella, Chiara, Chamberland, Maxime ORCID: https://orcid.org/0000-0001-7064-0984, Luque Laguna, Pedro, Parker, Greg D., Rosser, Anne E. ORCID: https://orcid.org/0000-0002-4716-4753, Coulthard, Elizabeth, Rickards, Hugh, Berry, Samuel C., Jones, Derek K. ORCID: https://orcid.org/0000-0003-4409-8049 and Metzler-Baddeley, Claudia ORCID: https://orcid.org/0000-0002-8646-1144 2022. Mutation-related magnetization-transfer, not axon density, drives white matter differences in premanifest Huntington's disease: Evidence from in vivo ultra-strong gradient MRI. Human Brain Mapping 43 (11) , pp. 3439-3460. 10.1002/hbm.25859

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Abstract

White matter (WM) alterations have been observed in Huntington disease (HD) but their role in the disease-pathophysiology remains unknown. We assessed WM changes in premanifest HD by exploiting ultra-strong-gradient magnetic resonance imaging (MRI). This allowed to separately quantify magnetization transfer ratio (MTR) and hindered and restricted diffusion-weighted signal fractions, and assess how they drove WM microstructure differences between patients and controls. We used tractometry to investigate region-specific alterations across callosal segments with well-characterized early- and late-myelinating axon populations, while brain-wise differences were explored with tract-based cluster analysis (TBCA). Behavioral measures were included to explore disease-associated brain-function relationships. We detected lower MTR in patients' callosal rostrum (tractometry: p = .03; TBCA: p = .03), but higher MTR in their splenium (tractometry: p = .02). Importantly, patients' mutation-size and MTR were positively correlated (all p-values < .01), indicating that MTR alterations may directly result from the mutation. Further, MTR was higher in younger, but lower in older patients relative to controls (p = .003), suggesting that MTR increases are detrimental later in the disease. Finally, patients showed higher restricted diffusion signal fraction (FR) from the composite hindered and restricted model of diffusion (CHARMED) in the cortico-spinal tract (p = .03), which correlated positively with MTR in the posterior callosum (p = .033), potentially reflecting compensatory mechanisms. In summary, this first comprehensive, ultra-strong gradient MRI study in HD provides novel evidence of mutation-driven MTR alterations at the premanifest disease stage which may reflect neurodevelopmental changes in iron, myelin, or a combination of these.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Biosciences Cardiff University Brain Research Imaging Centre (CUBRIC) Psychology
Publisher:	Wiley Open Access
ISSN:	1097-0193
Date of First Compliant Deposit:	6 April 2022
Date of Acceptance:	27 March 2022
Last Modified:	06 Jan 2024 03:37
URI:	https://orca.cardiff.ac.uk/id/eprint/148913

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