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

Abstract

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.

Current Techniques for Investigating the Brain Extracellular Space

“…In the latter study, the authors presented parallel RTI data from the same animals that corroborated the increase in cortical ECS volume compared with controls. MRI has further been used to show an increase in α of the globus pallidus in experimental Huntington's disease, consistent with observed cell death in this nucleus (Vorisek et al, 2017; Figure 3). The cell death and increased ECS volume were interestingly not associated with changes in FIGURE 3 | In vivo mouse brain MRI images depicted as the apparent diffusion coefficient of water (ADC W ), as per the calibration bar.…”

“…It is apparent that water diffusion in the ventricles is much higher than in denser parenchyma, as expected. From Vorisek et al (2017), with permission.…”

An Optimization of AAV-82Q-Delivered Rat Model of Huntington’s Disease

“…Several transgenic mouse models have been introduced to overcome this drawback of neurotoxic lesion models 31,33,34) . These models express genomic DNA or cDNAs encoding mutant HTT under the control of endogenous promoters and display many of the typical pathological features of early HD 9,16,24,28,30,35,36) .…”

“…A proper animal model for HD is essential to determine the exact mechanism of HD and to develop new therapeutic modalities, such as cell therapy. Thus, some investigators have developed animal models, including a drug-induced rat model using quinolinic acid and knock-in and transgenic mouse models [ 8 , 27 , 31 , 33 , 34 ]. In addition, in vivo genetic rat models induced by lentiviral-mediated expression of mutant HTT in the striatum have been introduced [ 6 , 20 , 26 ].…”

Aging lowers PEX5 levels in cortical neurons in male and female mouse brains

“…After all, HD is an age-related disease, and in normal brain aging, changes to the cortex also occur (Gray, Shirasaki et al 2008, Nana, Kim et al 2014, Vorisek, Syka et al 2017. While some studies indicated a link between peroxisomes and Alzheimer's disease, it was also unclear if PEX5 levels were affected at all in the normal, aging brain (Kou, Kovacs et al 2011, Dorninger, Forss-Petter et al 2017, Islinger, Voelkl et al 2018.…”