Altered diffusion tensor imaging measurements in aged transgenic Huntington disease rats

Antonsen, Bjørnar Torske; Jiang, Yi; Veraart, Jelle; Qu, Hong; Nguyen, Huu Phuc; Sijbers, Jan; Hörsten, Stephan von; Johnson, G. Allan; Leergaard, Trygve B.

doi:10.1007/s00429-012-0427-0

Cited by 19 publications

(14 citation statements)

References 80 publications

(159 reference statements)

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“…Compared with the already existing fragment tgHD rats BACHD rats show an earlier onset and a faster progression of motor deficits without the need to breed for homozygosity as heterozygous tgHD rats show only subtle deficits . Recently, a milder phenotype in tgHD rats as originally described has been reported (Casteels et al, 2011;Antonsen et al, 2012;Blockx et al, 2012). Also, while striatal atrophy was found in some groups of old tgHD rats (von Hörsten et al, 2003;, other studies revealed little or no evidence for atrophy (Winkler et al, 2006;Bode et al, 2008;Blockx et al, 2011).…”

Section: Discussionmentioning

confidence: 82%

A Novel BACHD Transgenic Rat Exhibits Characteristic Neuropathological Features of Huntington Disease

et al. 2012

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Huntington disease (HD) is an inherited progressive neurodegenerative disorder, characterized by motor, cognitive, and psychiatric deficits as well as neurodegeneration and brain atrophy beginning in the striatum and the cortex and extending to other subcortical brain regions. The genetic cause is an expansion of the CAG repeat stretch in the HTT gene encoding huntingtin protein (htt). Here, we generated an HD transgenic rat model using a human bacterial artificial chromosome (BAC), which contains the full-length HTT genomic sequence with 97 CAG/CAA repeats and all regulatory elements. BACHD transgenic rats display a robust, early onset and progressive HD-like phenotype including motor deficits and anxiety-related symptoms. In contrast to BAC and yeast artificial chromosome HD mouse models that express full-length mutant huntingtin, BACHD rats do not exhibit an increased body weight. Neuropathologically, the distribution of neuropil aggregates and nuclear accumulation of N-terminal mutant huntingtin in BACHD rats is similar to the observations in human HD brains. Aggregates occur more frequently in the cortex than in the striatum and neuropil aggregates appear earlier than mutant htt accumulation in the nucleus. Furthermore, we found an imbalance in the striatal striosome and matrix compartments in early stages of the disease. In addition, reduced dopamine receptor binding was detectable by in vivo imaging. Our data demonstrate that this transgenic BACHD rat line may be a valuable model for further understanding the disease mechanisms and for preclinical pharmacological studies.

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Section: Discussionmentioning

confidence: 82%

A Novel BACHD Transgenic Rat Exhibits Characteristic Neuropathological Features of Huntington Disease

et al. 2012

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“…Despite the structural changes in HD tissue, we have not seen a significant change in the diffusion anisotropy among matched axes between HD and WT mice. In contrast, other studies report an increased FA in the GP (Douaud et al, 2009;Antonsen et al, 2013). Douaud and colleagues (2009) proposed that increased FA in striatal gray matter structures is due to the loss of efferent fibers, which in turn leads to increased coherence.…”

Section: Discussionmentioning

confidence: 94%

Brain Diffusivity and Structural Changes in the R6/2 Mouse Model of Huntington Disease

Voříšek

Syka

Vargová

2016

J of Neuroscience Research

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Diffusion-weighted magnetic resonance (DW-MR) is an important diagnostic tool in Huntington disease (HD), a fatal hereditary neurodegenerative disorder. To clarify the nature of diffusivity changes in HD, we compared the apparent diffusion coefficient of water (ADC ) acquired by DW-MR with extracellular space volume fraction α and tortuosity λ, measured by the iontophoretic method in the R6/2 mouse model of HD and in wild-type controls (WT). In anisotropic globus pallidus (GP), diffusion measurements were performed in the mediolateral (x), rostrocaudal (y), and ventrodorsal (z) axes. In HD animals, we detected an increase in ADC in all axes and larger α than in WT mice. No significant difference between WT and HD mice was found in the values of tortuosity (λ , λ , λ ). Despite structural changes in GP, diffusion anisotropy was unaffected in HD mice. Immunohistochemical analysis revealed in HD mice weaker expression of extracellular matrix and a decrease in neuron numbers compared with WT mice. Glial fibrillary acidic protein staining detected astrogliosis-like changes in the morphology of astrocytic processes in HD GP. In the somatosensory cortex, no significant differences in the studied parameters were found. We conclude that in the R6/2 model of HD, a decrease in the number of neurons in the GP results in increased ADC and α values. Values of λ were not significantly changed as the increase of diffusion obstacles formed by reactive astrocytes was compensated for by the extracellular matrix reduction. © 2016 Wiley Periodicals, Inc.

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“…Investigations that go beyond simple structural measures, as used here, should be performed. Ideally, MR spectroscopy and diffusion MRI complement T 2 -weighted structural scans, as these can potentially provide more specific markers of tissue changes in the striatum and cortex [68, 69]. It is important to note though that even in transgenic animals these investigations are not trivial in terms of logistics and costs, but could provide robustly quantifiable and validated biomarkers to define the various stages of the condition.…”

Section: Discussionmentioning

confidence: 99%

Correlations of Behavioral Deficits with Brain Pathology Assessed through Longitudinal MRI and Histopathology in the HdhQ150/Q150 Mouse Model of Huntington’s Disease

et al. 2017

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A variety of mouse models have been developed that express mutant huntingtin (mHTT) leading to aggregates and inclusions that model the molecular pathology observed in Huntington’s disease. Here we show that although homozygous HdhQ150 knock-in mice developed motor impairments (rotarod, locomotor activity, grip strength) by 36 weeks of age, cognitive dysfunction (swimming T maze, fear conditioning, odor discrimination, social interaction) was not evident by 94 weeks. Concomitant to behavioral assessments, T2-weighted MRI volume measurements indicated a slower striatal growth with a significant difference between wild type (WT) and HdhQ150 mice being present even at 15 weeks. Indeed, MRI indicated significant volumetric changes prior to the emergence of the “clinical horizon” of motor impairments at 36 weeks of age. A striatal decrease of 27% was observed over 94 weeks with cortex (12%) and hippocampus (21%) also indicating significant atrophy. A hypothesis-free analysis using tensor-based morphometry highlighted further regions undergoing atrophy by contrasting brain growth and regional neurodegeneration. Histology revealed the widespread presence of mHTT aggregates and cellular inclusions. However, there was little evidence of correlations between these outcome measures, potentially indicating that other factors are important in the causal cascade linking the molecular pathology to the emergence of behavioral impairments. In conclusion, the HdhQ150 mouse model replicates many aspects of the human condition, including an extended pre-manifest period prior to the emergence of motor impairments.

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Altered diffusion tensor imaging measurements in aged transgenic Huntington disease rats

Cited by 19 publications

References 80 publications

A Novel BACHD Transgenic Rat Exhibits Characteristic Neuropathological Features of Huntington Disease

A Novel BACHD Transgenic Rat Exhibits Characteristic Neuropathological Features of Huntington Disease

Brain Diffusivity and Structural Changes in the R6/2 Mouse Model of Huntington Disease

Correlations of Behavioral Deficits with Brain Pathology Assessed through Longitudinal MRI and Histopathology in the HdhQ150/Q150 Mouse Model of Huntington’s Disease

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