Microstructural changes observed with DKI in a transgenic Huntington rat model: Evidence for abnormal neurodevelopment

• Published in: NeuroImage (Orlando, Fla.) Vol. 59; no. 2; pp. 957 - 967
• Main Authors: Blockx, Ines, De Groof, Geert, Verhoye, Marleen, Van Audekerke, Johan, Raber, Kerstin, Poot, Dirk, Sijbers, Jan, Osmand, Alexander P., Von Hörsten, Stephan, Van der Linden, Annemie
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 16-01-2012; Elsevier Limited
• Subjects: Age; Aging; Aging - pathology; Animals; Biomarkers; Brain - growth & development; Brain - pathology; Diffusion Magnetic Resonance Imaging - methods; Disease Models, Animal; Evidence-Based Medicine; Humans; Huntington disease; Huntington Disease - pathology; Huntington Disease - physiopathology; In vivo diffusion kurtosis Imaging; Laboratory animals; Males; Neurodegeneration; Neurodevelopment; Neuroimaging; NMR; Nuclear magnetic resonance; Proteins; Rats; Rats, Transgenic; Reproducibility of Results; Rodents; Sensitivity and Specificity; Studies; Transgenic rat model; Neuroimaging; Neurodevelopment; Transgenic rat model; In vivo diffusion kurtosis Imaging; Huntington disease
• ISSN: 1053-8119; 1095-9572
• DOI: 10.1016/j.neuroimage.2011.08.062

Huntington Disease (HD) is a fatal neurodegenerative disorder, caused by a mutation in the Huntington gene. Although HD is most often diagnosed in mid-life, the key to its clinical expression may be found during brain maturation. In the present work, we performed in vivo diffusion kurtosis imaging (DKI) in order to study brain microstructure alterations in developing transgenic HD rat pups. Several developing brain regions, relevant for HD pathology (caudate putamen, cortex, corpus callosum, external capsule and anterior commissure anterior), were examined at postnatal days 15 (P15) and 30 (P30), and DKI results were validated with histology. At P15, we observed higher mean (MD) and radial (RD) diffusivity values in the cortex of transgenic HD rat pups. In addition, at the age of P30, lower axial kurtosis (AK) values in the caudate putamen of transgenic HD pups were found. At the level of the external capsule, higher MD values at P15 but lower MD and AD values at P30 were detected. The observed DKI results have been confirmed by myelin basic protein immunohistochemistry, which revealed a reduced fiber staining as well as less ordered fibers in transgenic HD rat pups. These results indicate that neuronal development in young transgenic HD rat pups occurs differently compared to controls and that the presence of mutant huntingtin has an influence on postnatal brain development. In this context, various diffusivity parameters estimated by the DKI model are a powerful tool to assess changes in tissue microstructure and detect developmental changes in young transgenic HD rat pups.
► In vivo diffusion kurtosis imaging study of Huntington rat pups. ► Identification of sensitive biomarkers associated with early disease status. ► Suggestive for an early developmental origin of the disease. ► Mutant huntingtin interferes with brain development.