Magnetization Transfer Imaging in Premanifest and Manifest Huntington Disease: A 2-Year Follow-Up

Bogaard, Simon J.A. van den; Dumas, Eve M.; Hart, Ellen P.; Milles, Julien; Reilmann, Ralf; Stout, Julie C.; Craufurd, David; Gibbard, Clare R.; Tabrizi, Sarah J.; Buchem, Mark A. van; Roos, R.A.C.

doi:10.3174/ajnr.a3303

Cited by 19 publications

(11 citation statements)

References 31 publications

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“…Several studies have addressed MT imaging, yet focusing on the MTR. A reduction of the MTR peak height in gray and white matter in manifest HD compared to healthy controls ( 23 ) has been reported, but no differences between presymptomatic gene carriers and controls. These studies concluded that there is no role for MTR as a biomarker in presymptomatic HD ( 24 ).…”

Section: Discussionmentioning

confidence: 99%

Model-Based Magnetization Transfer Imaging Markers to Characterize Patients and Asymptomatic Gene Carriers in Huntington’s Disease

2017

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Background and purposeHuntington’s disease (HD) is a chronic progressive neurodegenerative disorder with a long presymptomatic period that opens a window for potential therapies aimed at neuroprotection. Neuroimaging offers the potential to monitor disease-related progression of the disease burden (DB) using model-based magnetization transfer imaging.Materials and methodsWe have conducted a cross-sectional study to stratify healthy age-matched controls, premanifest and symptomatic HD patients (n = 30) according to their macromolecular depositions in the caudate nucleus. We employed a binary spin-bath magnetization transfer (MT) method for a quantitative description of macromolecule deposits and interactions with their adjacent environment.ResultsA region-of-interest based fuzzy clustering analysis identified representative clusters for several stages of the disease course related to its progression: one cluster represented subjects with a high DB <268 that encompassed all symptomatic HD patients and one presymptomatic gene carrier. The next cluster represented the presymptomatic gene carriers with a very low DB >230 and healthy controls. Three further clusters represented transition zones between both DB levels (230–268) consisting of presymptomatic carriers with DB values increasing with decreasing distance from the cluster that indicated low DB and healthy age-matched controls.ConclusionThe proposed binary spin-bath MT method offers the potential to monitor DB and progression in HD. The method may augment qualitative MT techniques since it depicts tissue changes related to interactions between macromolecules and protons in disease specific brain regions that follow the neurodegenerative process.

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Section: Discussionmentioning

confidence: 99%

Model-Based Magnetization Transfer Imaging Markers to Characterize Patients and Asymptomatic Gene Carriers in Huntington’s Disease

2017

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“…Reduced MT contrast can be symptomatic of disruption of myelin sheath or axonal loss 36,75 . In HD, decreased MT contrast was found in grey matter and white matter of pre-symptomatic gene carriers and HD patients, with correlation between MT loss and disease severity 76,77 . In this study, we reported for the first time MT defects in a mouse model of HD, especially in the septum and in the striatum.…”

Section: Figure 8: a White Matter Tracts Isolated From The Whole Brain Tractography Of A Representative Dataset Using Locally-constrainedmentioning

confidence: 94%

Identification of the key role of white matter alteration in the pathogenesis of Huntington’s Disease

Pérot¹,

Célestine²,

Palombo

et al. 2021

Preprint

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Pathogenesis of the inherited neurodegenerative disorder Huntington s Disease (HD) is complex and progressive, with a long presymptomatic phase in which subtle changes occur in the brain of gene carriers up to 15 years before the onset of symptoms. Thus, there is a need of early, functional biomarker to better understand disease progression and to evaluate treatment efficacy far from onset. In particular, recent studies have shown that white matter may be affected early in HD. In this study, we scanned longitudinally Ki140CAG mice with structural MRI, Diffusion Tensor Imaging (DTI), Chemical Exchange Saturation Transfer of glutamate (gluCEST) and Magnetization Transfer (MT) imaging, in order to assess white matter integrity over the life of this very progressive mouse model. Our results show early defects of diffusion properties in the anterior part of the corpus callosum, preceding gluCEST defects in the same region (-10.8% at 8 months, -19% at 12 months) that spread to adjacent regions. At 12 months, frontal (-7.3%) and piriform (-16.7%) cortices showed reduced gluCEST, as well as the pallidum (-21.0%). MT imaging showed reduced signal in the septum (-21.7%) at 12 months. Cortical and striatal atrophy then appear at 18 months. Vulnerability of the striatum and motor cortex, combined with alterations of anterior corpus callosum, seems to point out the pivotal role of white matter, in the pathogenesis of HD and the pertinence of gluCEST and DTI as biomarkers in HD.

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“…In HD patients also, neuronal degeneration occurs first in the striatum [6], then in other areas of the brain [28,76,77]. It is notable that significant loss of basal ganglia volume [78][79][80][81][82][83] and neuron loss [84] have been reported in asymptomatic HD patients. The appearance of inclusions in HD patients also precedes the onset of symptoms and neurodegeneration [4,5,16,85].…”

Section: Neurodegeneration In R6/2 Micementioning

confidence: 99%

Early Neurodegeneration in R6/2 Mice Carrying the Huntington’s Disease Mutation with a Super-Expanded CAG Repeat, Despite Normal Lifespan

Kielar

Morton

2018

JHD

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The threshold of CAG repeat expansion in the HTT gene that causes HD is 36 CAG repeats, although 'superlong' expansions are found in individual neurons in postmortem brains. Previously, we showed that, compared to mice with <250 CAG repeats, onset of disease in R6/2 mice carrying superlong (>440) CAG repeat expansions was delayed, and disease progression was slower. Inclusion pathology also differed from 250 CAG repeat mice, being dominated by a novel kind of extranuclear neuronal inclusion (nENNI) that resembles a class of aggregate seen in patients with the adult onset form of HD. Here, we characterised neuropathology in R6/2 mice with >400 CAG repeats using light and electron microscopy. nENNIs were found with increased frequency and wider distribution with age. Some nENNIs appear to 'mature' as the disease develops, developing a multi-layered cored structure. Mice with superlong CAG repeats do not develop clinical signs until they are around 30-40 weeks of age, and they attain a normal life span (>2 years). Nevertheless, they show brain atrophy and unequivocal neuron loss from the striatum and cortex by 22 weeks of age, an age at which similar pathology is seen in 250 CAG repeat mice. Since this time-point is 'end stage' for a 250 CAG mouse, but very far (at least 18 months) from end stage for a > 440 CAG repeat mouse, our data confirm that the appearance of clinical signs, the formation of inclusions, and neurodegeneration are processes that progress independently. A better understanding of the relationship between CAG repeat length, neurodegenerative pathways, and clinical behavioural signs is essential, if we are to find strategies to delay or reverse the course of this disease.

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Magnetization Transfer Imaging in Premanifest and Manifest Huntington Disease: A 2-Year Follow-Up

Cited by 19 publications

References 31 publications

Model-Based Magnetization Transfer Imaging Markers to Characterize Patients and Asymptomatic Gene Carriers in Huntington’s Disease

Model-Based Magnetization Transfer Imaging Markers to Characterize Patients and Asymptomatic Gene Carriers in Huntington’s Disease

Identification of the key role of white matter alteration in the pathogenesis of Huntington’s Disease

Early Neurodegeneration in R6/2 Mice Carrying the Huntington’s Disease Mutation with a Super-Expanded CAG Repeat, Despite Normal Lifespan

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