A whole brain longitudinal study in the YAC128 mouse model of Huntington's disease shows distinct trajectories of neurochemical, structural connectivity and volumetric changes

Abstract Huntington's disease (HD) is a neurodegenerative disorder causing cognitive and motor impairments, evolving to death within 15-20 years after symptom onset. We previously established a mouse model with the entire human HD gene containing 128 CAG repeats (YAC128) which accurately recapi...

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Published in:	Human molecular genetics Vol. 27; no. 12; pp. 2125 - 2137
Main Authors:	Petrella, Lorena I, Castelhano, João M, Ribeiro, Mario, Sereno, José V, Gonçalves, Sónia I, Laço, Mário N, Hayden, Michael R, Rego, A Cristina, Castelo-Branco, Miguel
Format:	Journal Article
Language:	English
Published:	England Oxford University Press 15-06-2018
Subjects:	Animals Brain - diagnostic imaging Brain - metabolism Brain - pathology Corpus Striatum - diagnostic imaging Corpus Striatum - metabolism Corpus Striatum - pathology Disease Models, Animal gamma-Aminobutyric Acid - genetics gamma-Aminobutyric Acid - metabolism Gene Expression Regulation - genetics Humans Huntingtin Protein - genetics Huntington Disease - diagnostic imaging Huntington Disease - genetics Huntington Disease - pathology Longitudinal Studies Mice Mice, Transgenic Neostriatum - diagnostic imaging Neostriatum - metabolism Neostriatum - pathology Neurons - metabolism Neurons - pathology Thalamus - diagnostic imaging Thalamus - metabolism Thalamus - pathology Trinucleotide Repeats - genetics
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Summary:	Abstract Huntington's disease (HD) is a neurodegenerative disorder causing cognitive and motor impairments, evolving to death within 15-20 years after symptom onset. We previously established a mouse model with the entire human HD gene containing 128 CAG repeats (YAC128) which accurately recapitulates the natural history of the human disease. Defined time points in this natural history enable the understanding of longitudinal trajectories from the neurochemical and structural points of view using non-invasive high-resolution multi-modal imaging. Accordingly, we designed a longitudinal structural imaging (MRI and DTI) and spectroscopy (1H-MRS) study in YAC128, at 3, 6, 9 and 12 months of age, at 9.4 T. Structural analysis (MRI/DTI), confirmed that the striatum is the earliest affected brain region, but other regions were also identified through connectivity analysis (pre-frontal cortex, hippocampus, globus pallidus and thalamus), suggesting a striking homology with the human disease. Importantly, we found for the first time, a negative correlation between striatal and hippocampal changes only in YAC128. In fact, the striatum showed accelerated volumetric decay in HD, as opposed to the hippocampus. Neurochemical analysis of the HD striatum suggested early neurometabolic alterations in neurotransmission and metabolism, with a significant increase in striatal GABA levels, and specifically anticorrelated levels of N-acetyl aspartate and taurine, suggesting that the later is homeostatically adjusted for neuroprotection, as neural loss, indicated by the former, is progressing. These results provide novel insights into the natural history of HD and prove a valuable role for longitudinal multi-modal panels of structural and metabolite/neurotransmission in the YAC128 model.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0964-6906 1460-2083
DOI:	10.1093/hmg/ddy119