Eleni Demetriou1, Mohamed Tachrount2, Karin Shmueli3, Mark Farrow4, and Xavier Golay1
1Brain Repair and Rehabilitation, Institute of Neurology, London, United Kingdom, 2Brain repair and rehabilitation, Institute of Neurology, London, United Kingdom, 3Medical Physics and Biomedical Engineering, University College of London, London, United Kingdom, 4MRC prion unit, University College of London, London, United Kingdom
Synopsis
The neurochemical profile of prion disease in mice at
different disease stages was evaluated using high-quality MR spectra obtained
in thalamus. Seven metabolites were measured in vivo and longitudinally
providing substantial metabolic information.
Metabolic changes were obtained throughout the disease course, however
only glutamate and myo-inositol were significantly different at all stages of
the disease. We conclude that MR spectroscopy provides additional information over
previous histological studies [1].Introduction
Prion diseases are fatal neurodegenerative disorders that
have prolonged asymptomatic incubation periods. The mechanism by which prions
cause brain damage remains unclear and therefore characterization of early pathology would be of
benefit for the diagnosis and treatment of this chronic neurodegenerative
disorder. In-vivo proton spectroscopy allows quantitative measures of
metabolite concentrations. Moreover, there are few MRS studies in murine models
of prion disease and the data were acquired with relatively long-TE
spectroscopic sequences [2,3]. To gain a better insight into metabolic
alterations associated with prion disease in mice we performed MRS at short TE
in the thalamus of prion-infected mice at different stages of prion disease.
Methods
Two groups of 7-week-old FVB mice were intracerebrally
inoculated with 30μl of
1% brain homogenate from Rocky Mountain Laboratory prion-infected mice (n=19)
or brain homogenate from uninfected mice as controls (n=11). The prion-infected
group was separated into three groups of mice scanned at different stages of
prion disease: 80 days post injection (dpi) – asymptomatic-stage (n=6), 130 dpi
– early-stage (n=6), and 160 dpi – late-stage (n=7). Control mice were
separated into two groups: 80 dpi (n=5) and 160 dpi (n=6). All mice were
anaesthetized (1.5-1.8% isoflurane in 1.5% oxygen with balance in air) and
scanned on a 9.4 T Agilent system using a 33-mm-diameter transmit/receive coil
(Rapid Biomedical). Anatomical scans were acquired in an axial slice (thickness
= 2mm) using a fast spin-echo sequence (data matrix: 256x128, TR=3000ms,
TE=20ms, FOV=20x20mm). In vivo proton spectra were acquired using a PRESS
sequence (TR = 5000msec, TE = 7.5msec and TE = 144 mec, 128 averages, total
acquisition time=10 min) with a voxel centered on the thalamus (1.7 x 4.3 x 1.8
mmᶾ). After first and second order shimming, the typical linewidth of the water
resonance was 20-23Hz.
Data analysis: Metabolite concentrations were estimated
using TARQUIN [4]. Experimental data were modelled as a linear combination of
modified simulated basis signals. The Cramer-Rao lower bounds were used as a
reliability measure of the metabolite concentration estimates. All metabolite concentrations
are presented as mean ± standard deviation. Statistical analysis was performed
using a two-tailed test. Significant changes in metabolite concentrations are
indicated by p<0.05.
Results
The metabolite concentrations were evaluated for age
dependence between the two control groups scanned at 80 dpi and 160 dpi. The
only change with age was an increase in N-acetylaspartate (NAA ) (p=0.009) and creatine
(Cr) (p=0.005 ). Therefore, the control groups were merged into one group when
compared with prion-infected mice for all the metabolites except NAA and Cr.
Significant changes were detected in glutamate (Glu) and myo-inositol (Ins) at all
stages of prion disease (80 dpi, 130 dpi, 160 dpi) when compared with the
control group. However, there was no significant change in Choline (Cho). NAA,
Cr, Lactate and Lipids were only found to be significantly different at 130 dpi
and 160 dpi compared with the control group. Moreover, Taurine (Tau) was only significantly
increased at 80 dpi without any significant change at 130 dpi and 160 dpi (fig
1). Figure 2 shows representative MRS spectra in thalamus from a control and a prion-infected
mouse at 160 dpi.
Discussion and Conclusion
In this study, we evaluated the neurochemical profile of
prion-infected mice at different stages of prion disease. There are very few In-vivo
MRS studies in mice infected with scrapie/prions and these have reported
changes including a decrease in the ratio of NAA to both Cho and Cr and an increase
of Ins in prion-infected mice [2,3]. Our experiments showed additional results
compared with previous studies in prion-infected mice including a significant
increase in lactate and lipids at 130 dpi and 160 dpi. Increased Ins most
likely reflects neuronal loss and microglial activation as shown in previous
histological studies [1], while a reduction in Glu might be secondary to
reduced brain function. We conclude that high-quality/short-TE MR spectroscopy
provides additional information about characteristic changes occurring in
thalamus of prion-infected mice in line with previous histological studies [1].
Acknowledgements
No acknowledgement found.References
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