Multi-compartment analysis of the complex gradient-echo signal quantifies myelin breakdown in premanifest Huntington's disease

Casella, Chiara; Kleban, Elena; Rosser, Anne Elizabeth; Coulthard, Elizabeth; Rickards, Hugh; Fasano, Fabrizio; Metzler‐Baddeley, Claudia; Jones, Derek K.

doi:10.1016/j.nicl.2021.102658

Cited by 9 publications

(8 citation statements)

References 104 publications

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“…As metabolic dysfunction and alterations in energetics play important mechanistic roles in HD (Beal, 2005 ; Browne, 2008 ), these changes may contribute to early microstructural impairment in this callosal portion. The suggestion for myelin impairment in this callosal segment is consistent with a previous study carried out by our group at 7 Tesla (Casella et al, 2021 ), which demonstrated significantly lower myelin water signal fraction in the posterior callosum of premanifest HD patients. Moreover, this suggestion is in accord with the demyelination hypothesis, which argues that early myelinated fibers are more susceptible to myelin disorder in the disease (Bartzokis et al, 2007 ).…”

Section: Discussionsupporting

confidence: 92%

“…Huntington disease (HD), a neurodegenerative disorder leading to devastating cognitive, psychiatric, and motor symptoms, cannot currently be cured, and a research priority is to increase understanding of its pathogenesis. Subtle and progressive white matter (WM) alterations have been observed early in HD progression (Casella et al, 2021 ; Gregory et al, 2019 ; McColgan et al, 2015 ; McColgan et al, 2017 ; McColgan et al, 2018 ; Paulsen et al, 2008 ; Scahill et al, 2020 ), but their etiology and role remain unclear. Therefore, the present study aimed to disentangle the contribution of changes in axon microstructure versus changes in magnetization transfer as a proxy measure of myelin and/or iron, to WM pathology in premanifest HD.…”

Section: Introductionmentioning

confidence: 99%

“…Both explanations fit within the demyelination hypothesis as they implicate an increasingly unsuccessful compensation for the disease‐related myelin loss. For a critical review of human and animal studies lending support to the demyelination hypothesis (see Casella et al, 2021 ).…”

Section: Introductionmentioning

confidence: 99%

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

Casella

Chamberland

Laguna

et al. 2022

Human Brain Mapping

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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.

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Section: Discussionsupporting

confidence: 92%

Section: Introductionmentioning

confidence: 99%

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

Casella

Chamberland

Laguna

et al. 2022

Human Brain Mapping

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“…The posterior section of the corpus callosum showed lower MWF values than controls. Significant correlations were found between MWF in the posterior corpus callosum and the individuals’ scores on executive function but the MWF was not related to proximity to disease onset [36 ▪▪ ].…”

Section: Huntington's Diseasementioning

confidence: 83%

Update on myelin imaging in neurological syndromes

Balaji¹,

Johnson²,

Dvorak

et al. 2022

Current Opinion in Neurology

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Purpose of reviewMyelin water imaging (MWI) is generally regarded as the most rigorous approach for noninvasive, in-vivo measurement of myelin content, which has been histopathologically validated. As such, it has been increasingly applied to neurological diseases with white matter involvement, especially those affecting myelin. This review provides an overview of the most recent research applying MWI in neurological syndromes.Recent findingsMyelin water imaging has been applied in neurological syndromes including multiple sclerosis, Alzheimer's disease, Huntington's disease, traumatic brain injury, Parkinson's disease, cerebral small vessel disease, leukodystrophies and HIV. These syndromes generally showed alterations observable with MWI, with decreased myelin content tending to correlate with lower cognitive scores and worse clinical presentation. MWI has also been correlated with genetic variation in the APOE and PLP1 genes, demonstrating genetic factors related to myelin health.SummaryMWI can detect and quantify changes not observable with conventional imaging, thereby providing insight into the pathophysiology and disease mechanisms of a diverse range of neurological syndromes.

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“…Recent investigations in HD have recognized alterations in the brain's white matter (WM) as relevant pathophysiological feature of HD [1][2][3][4][5][6][7][8][9][10][11][12] . Specifically, WM atrophy has been shown both in animal models and in human HD carriers by histopathological post-mortem studies [13][14][15][16][17] , and MRI studies 2,4,5,11,[17][18][19][20][21] . For example, structural neuroimaging studies of HD carriers have shown that WM atrophy can be found across several WM areas, including the corpus callosum (CC), the anterior commissure, internal and external capsules, and the cingulum.…”

Section: Introductionmentioning

confidence: 99%

Differences in white matter detected byex vivo9.4T MRI are associated with axonal changes in the R6/1 model of Huntington’s Disease

Casella,

Kelly,

Murillo Bartolome

et al. 2023

Preprint

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White matter (WM) volume loss has been reported in people with Huntington’s disease (HD), but the cellular basis of this deficit remains to be elucidated. To address this, we assessed ex vivo WM microstructure in the transgenic R6/1 mouse model of HD with magnetic resonance imaging (MRI) and studied the neurobiological basis of the MRI brain signals with histological and electron microscopy analyses in a separate cohort of age- and sex-matched mice. Differences in the macromolecular proton fraction (MPF) from quantitative magnetization transfer (qMT) as a proxy myelin measure, and the intra-axonal signal fraction (FR) from the composite hindered and restricted model of diffusion (CHARMED) as a proxy marker of axon density, were assessed alongside diffusion tensor imaging (DTI) parameters. A tractometry approach was employed to inspect region-specific differences across the corpus callosum (CC). Furthermore, voxel-based morphometry (VBM) and tract-based spatial statistics (TBSS) were used to explore brain-wise WM macro- and microstructure abnormalities. To gain insight into disease-associated impairments in attentional and visuospatial processing, a third cohort of age-matched mice was assessed with the 5-choice serial reaction time task (5-CSRTT). We report cognitive impairments in R6/1 mice and, by evaluating MRI and light and electron microscopy results, we show that this HD mouse model presents disruptions in axonal morphology (i.e. less complex, thinner axons) and organization (i.e. more densely packed axons). Furthermore, we show that, at least early in disease progression, R6/1 mice present a reduction in the expression or content of myelin-associated proteins without significant alterations in the structure of myelin sheaths. Finally, our findings indicate that neuroinflammation-driven glial and axonal swelling might also affect this mouse model early in disease progression. Crucially, we demonstrate the potential of FR, an in vivo estimate of axon density, as a novel MRI biomarker of HD-associated changes in WM microstructure.

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Multi-compartment analysis of the complex gradient-echo signal quantifies myelin breakdown in premanifest Huntington's disease

Cited by 9 publications

References 104 publications

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

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

Update on myelin imaging in neurological syndromes

Differences in white matter detected byex vivo9.4T MRI are associated with axonal changes in the R6/1 model of Huntington’s Disease

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