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A12 Identification of the key role of white matter in the pathogenesis of huntington’s disease
  1. Jean-Baptiste Pérot1,
  2. Marina Celestine1,
  3. Marc Dhenain1,
  4. Sandrine Humbert2,
  5. Emmanuel Brouillet1,
  6. Julien Flament1
  1. 1Université Paris-Saclay, Commissariat à l’Energie Atomique et aux Energies Alternatives (CEA), Centre National de la Recherche Scientifique (CNRS), Molecular Imaging Research Center (MIRCen), Laboratoire des Maladies Neurodégénératives, Fontenay-aux-Roses, France
  2. 2Université Grenoble Alpes, INSERM, Grenoble Institut Neurosciences, Grenoble, France

Abstract

Purpose Pathogenesis of Huntington’s Disease (HD) is complex and progressive. Subtle changes seem to occur in the brain of gene carriers far from the onset of symptoms.1 There is a need of early, functional biomarkers, for pathogenesis understanding and treatment evaluation. White matter seems to be affected early and independently from striatal degeneration.2 Here we present a longitudinal MRI study on the CAG140 mouse model of HD for assessing white matter integrity over the life of this very progressive mouse model.

Methods We scanned a cohort of 11 heterozygous CAG140 mice and 11 WT littermates, with 5 timepoints between 2.5 and 18 months of age. Structural MRI, Diffusion Tensor Imaging (DTI), Chemical Exchange Saturation Transfer of glutamate (gluCEST) and Magnetization Transfer (MT) imaging were acquired at each timepoint.

Results Our results show early defects of diffusion properties in the anterior part of the corpus callosum (CC) at 5 months of age, preceding gluCEST defects in the same region (-10.8% at 8 months, -19% at 12 months). At 12 months, frontal (-7.3%) and piriform (-16.7%) cortices showed reduced gluCEST too, 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. Figure 1 summarizes these results as variation maps between CAG140 and WT mice.

Abstract A12 Figure 1

Summary of main results. a-c) Variation maps between CAG140 and WT mice of volume (a), gluCEST signal (b) and MT (c) in an anterior slice of the mouse brain. Variation was calculated for every region as (Signal(CAG140)-Signal(WT))/Signal(WT). Yellow stars represent significance (* p <0.05, ** p < 0.01, repeated measures ANOVA + Bonferonni). d) Diffusion Tensor Imaging results after Tract-Based Spatial Statistics (TBSS) pipeline. Green regions represent white matter skeleton used for TBSS. Red-yellow regions represent clusters of significantly reduced FA (Threshold-free cluster enhancement).

Discussion Axonal projection data from Allen Connectivity Atlas3 is shown in figure 2 compared with our results. It illustrates the existence of a vulnerable network composed of the striatum and motor cortex in the CAG140 mouse model. Alterations of the diffusion properties and glutamate concentration in the anterior CC seem to point out the importance of white matter, in particular of cortico-striatal tracts, in this vulnerability. Our results, in line with literature, show the key role of white matter alteration in the pathogenesis of HD and the pertinence of gluCEST and DTI as biomarkers in HD.

Abstract A12 Figure 2

Summary of main results overlaid with graph-theory representation of axonal projection atlas of the mouse brain. Grey arrows and dots represent axonal projections and regions respectively. Colored dots represent affected regions according to our results. Colored arrows represent axonal projections between affected regions and can be associated with white matter alterations. For clarity, only highest degree nodes and affected nodes are labeled. ACB: Nucleus Accumbens, Alv: Alveus, CLI: Central linear nuclei raphe, ENTl: Lateral entorhinal area, LHA: Lateral hypothalamic area, PIR: Piriform area, PP: Peripeduncular nucleus, RSPv: Ventral retrosplenial area, RSPagl: Lateral agranular retrosplenial area.

References

  1. Tabrizi SJ, et al. Biological and clinical manifestations of Huntington’s disease in the longitudinal TRACK-HD study: cross-sectional analysis of baseline data. Lancet Neurol 2009;8:791–801.

  2. Casella C, Lipp I, Rosser A, Jones DK, Metzler-Baddeley CA. Critical review of white matter changes in Huntington’s disease. Movement Disorders 2020;35:1302–1311.

  3. Oh SW, et al. A mesoscale connectome of the mouse brain. Nature 2014;508:207–214.

  • white matter
  • imaging
  • biomarkers
  • mouse model

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