In vivo assessment of neuronal dysfunction in rats transgenic for Huntington's disease using small animal FDG-PET and MRI – a 16 months follow-up study

Background: Huntington's Disease (HD) is a dominant neurodegenerative disorder. Human FDG-PET and MRI imaging show functional changes and signs of atrophy in the striatum, even in pre-manifest HD. Transgenic animal models of HD provide invaluable insights into disease mechanisms and may facilitate evaluation of new therapeutic targets. Several established rodent models, e.g., the R6/2 and YAC-128 mice, carry CAG-repeat expansions far longer than usually observed in humans. In contrast, the tgHD rat carries 51 CAG repeats, which is within ranges observed in human genotypes. It was previously reported that small animal FDG-PET is able to detect hypometabolism in the whole brain of tgHD rats at 18–24 months of age. However, this initial imaging study was limited by its cross-sectional nature, the resolution of the small animal PET employed and the lack of a regional striatal analysis. Due to the delayed development of phenotype in tgHD rats compared to, e.g., the R6/2 mouse, in-vivo imaging may facilitate phenotype assessment in therapeutic studies.

Objective: To study striatal glucose uptake in individual tgHD rats over time with high spatial resolution using PET (FWHM: 0.7mm) and MRI in a larger cohort.

Methods: 20 tgHD and 20 wt rats were included in this study. Repeated small animal FDG-PET (50 MBq, 15min acquisition 1h p.i., quadHIDAC, Oxford, UK) and MRI were performed at 4, 8, 12, and 16 months of age. ROIs encompassing striatum and cerebellum were placed manually on the MRI and transferred to the co-registered PET data set (MPI-Tool, ATV, Germany). Mean FDG-PET activity in the striatum was calculated and normalized to mean cerebellar uptake.

Results: Although striatal FDG uptake showed changes in the rats over time there was no difference in glucose uptake between similar age and sex matched tgHD and wt rats at any time point.

Conclusions: In this study employing high resolution small animal PET, we did not reproduce the typical clinical finding of reduced striatal glucose uptake in the tgHD rat animal model in an individual follow-up of 16 months. We conclude that FDG-PET on ROIs is not sensitive for in-vivo assessment of functional changes in brains of tgHD rats. Future studies should investigate sensitivity of other tracers to assess the phenotype in-vivo.

RR was supported by grant #RE-120524 from the Innovative Medical Research Fund (IMF) of the Faculty of Medicine of the University of Münster. OR and SvH were supported by a grant from CHDI.