Identification and characterization of Huntington related pathology: An in vivo DKI imaging study Ines Blockx a, ⁎, Marleen Verhoye a , Johan Van Audekerke a , Irene Bergwerf e , Jack X. Kane d , Rafael Delgado y Palacios a , Jelle Veraart b , Ben Jeurissen b , Kerstin Raber c , Stephan von Hörsten c , Peter Ponsaerts e , Jan Sijbers b , Trygve B. Leergaard d , Annemie Van der Linden a a Bio-Imaging Lab, University of Antwerp, Antwerp, Belgium b Vision Lab, University of Antwerp, Antwerp, Belgium c Experimental Therapy, Friedrich-Alexander University, Erlangen, Germany d Centre for Molecular Biology and Neuroscience, Institute of Basic Medical Sciences, University of Oslo, Norway e Laboratorium Experimentele Hematologie, University of Antwerp, Antwerp, Belgium abstract article info Article history: Accepted 15 June 2012 Available online 25 June 2012 Keywords: Neuroimaging Diffusional kurtosis imaging Diffusion tensor imaging Glia Transgenic rat model Huntington disease An important focus of Huntington Disease (HD) research is the identification of symptom-independent biomarkers of HD neuropathology. There is an urgent need for reproducible, sensitive and specific outcome measures, which can be used to track disease onset as well as progression. Neuroimaging studies, in particular diffusion-based MRI methods, are powerful probes for characterizing the effects of disease and aging on tissue microstructure. We report novel diffusional kurtosis imaging (DKI) findings in aged transgenic HD rats. We demonstrate altered diffusion metrics in the (pre)frontal cerebral cortex, external capsule and striatum. Presence of increased diffusion complexity and restriction in the striatum is confirmed by an increased fiber dispersion in this region. Immunostaining of the same specimens reveals decreased number of microglia in the (pre)frontal cortex, and increased numbers of oligodendrocytes in the striatum. We conclude that DKI allows sensitive and specific characterization of altered tissue integrity in this HD rat model, indicating a promising potential for diagnostic imaging of gray and white matter pathology. © 2012 Elsevier Inc. All rights reserved. Introduction Huntington disease (HD) is a neurodegenerative disorder, caused by a CAG trinucleotide repeat expansion in the HD gene. Although consider- able progress has been made, no cure exists, and the pathological mech- anism by which HD leads to neuronal degeneration remains largely unknown. Due to a lack of early biomarkers, the current standard method for the detection of early onset in HD, is based on clinical evaluation in presymptomatic patients (Bohanna et al., 2008; Zuccato et al., 2010). Given the complex phenotypic heterogeneity of HD, another research challenge is to find highly sensitive screening methods (Esmaeilzadeh et al., 2011). Magnetic Resonance Imaging (MRI) has recently contributed to an improved understanding of striatal atrophy and cortical dysfunction (Paulsen et al., 2004; Rosas et al., 2004; Wolf et al., 2007, 2009). Moreover, diffusion-based MRI techniques are the only non-invasive imaging techniques that can be applied to study the pathways and connections of not only the human brain, but also of the rodent brain (Douaud et al., 2009; Mascalchi et al., 2004; Reading et al., 2005; Rosas et al., 2006; Seppi et al., 2006; Van Camp et al., 2012). Diffusional kurtosis imaging (DKI) is a very promising diffusion imaging technique (Jensen et al., 2005; Lu et al., 2006), which is expanded towards quanti- fication of non-Gaussian water diffusion. Recent studies have demon- strated that DK measures offer an improved sensitivity in detecting developmental and pathological changes in neuronal tissues, compared to conventional DTI (Cheung et al., 2009; Hui et al., 2008). In addition, di- rectional kurtosis analyses have been formulated to reveal directionally specific information, such as the water diffusional kurtoses along the direction parallel or perpendicular to the principle water diffusion direction (Blockx et al., 2011a; Delgado Y Palacios et al., 2011; Hui et al., 2008; Wu and Cheung, 2010). Because kurtosis is a measure of the deviation of the diffusion displacement profile from a Gaussian distribution, DKI analyses quantify the degree of diffusion restriction or tissue complexity. Transgenic models reflecting elements of human pathology allow the examination of the onset and further progression of neurodegeneration, neuronal dysfunction, and the development and validation of new potential therapies, using translational tools and complementary techniques. The first transgenic rat model of HD (tgHD) was generated by von Hörsten and colleagues in 2003 (von Horsten et al., 2003). These rats display symptoms similar to the late-onset form of HD and develop NeuroImage 63 (2012) 653–662 ⁎ Corresponding author at: University of Antwerp, Bio-Imaging lab, Universiteitsplein 1, 2610 Wilrijk, Belgium. E-mail address: Ines.Blockx@ua.ac.be (I. Blockx). 1053-8119/$ – see front matter © 2012 Elsevier Inc. All rights reserved. doi:10.1016/j.neuroimage.2012.06.032 Contents lists available at SciVerse ScienceDirect NeuroImage journal homepage: www.elsevier.com/locate/ynimg