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Dynamic glucose enhanced (DGE) MRI at 3T detects alterations in glucose uptake and clearance in young and old Alzheimer’s mice1Department of Biomedical Engineering, City University of Hong Kong, Hong Kong, China, 2Department of Electrical and Electronic Engineering, The University of Hong Kong, Hong Kong, China, 3Department of Health Technology and Informatics, The Hong Kong Polytechnic University, Hong Kong, China, 4Russell H. Morgan Department of Radiology and Radiological Science, The Johns Hopkins University School of Medicine, Baltimore, MD, United States, 5F.M. Kirby Research Center for Functional Brain Imaging, Kennedy Krieger Research Institute, Baltimore, MD, United States
Synopsis
On-resonance variable delay multiple pulse (onVDMP) CEST MRI was applied to detect dynamic D-glucose enhanced signal in brain parenchyma and CSF of 6- and 16-month old APP/PS1 AD mice. A significantly slower D-glucose clearance from CSF was observed in young AD mice compared to age-matched wild type (WT) mice. Moreover, a reduced D-glucose uptake was observed both in parenchyma and CSF of old APP/PS1 mice. D-glucose kinetics detected by onVDMP can be used to assess the alterations in D-glucose uptake and clearance in AD and in the course of AD progression at 3T, a clinical relevant MRI field.
Introduction
Alzheimer’s disease (AD) is the most common form of dementia, which causes an increasing burden to aging societies (1-5). A change in cerebral glucose uptake is one of the hallmarks of AD (6,7). We and others have demonstrated that sugars can be detected by glucoCEST MRI (8-13). Alternative methods, such as chemical exchange sensitive spin-lock (CESL) (14-16) and T2 relaxation (17-19), can also detect glucose uptake in vivo. Dynamic glucose enhanced (DGE) MRI contains information regarding perfusion, tissue transport, and cellular metabolism (15,16,20-30). DGE studies are challenging at 3T, due to the scaling effects from magnetization transfer contrast (MTC) and water direct saturation (DS) and the fast exchange limit for OH protons. In this study, we applied an on-resonance variable delay multiple pulse (onVDMP) MRI (31-34) to dynamically detect D-glucose uptake and clearance in mouse brain parenchyma and CSF on a 3T animal scanner. By adjusting the length of the saturation period, onVDMP can simultaneously monitor kinetics for brain parenchyma and CSF. We studied kinetics in AD (amyloid precursor protein and presenilin-1, APP/PS1) (35) and wild type (WT) mouse brains for two age groups (6-month (6M) and 16-month (6M)). Studying the uptake and clearance of D-glucose in CSF could be a potential approach to examine the functioning of the glymphatic pathway, which has been reported to be affected in AD (36,37).Methods
Ten APP/PS1 mice (five 6M and five 16M, male, Jackson Laboratory, Maine) and ten age-matched WT mice were used in this study. MRI experiments were performed on a horizontal bore 3T Bruker BioSpec system (Bruker, Germany). The basic saturation module in the onVDMP sequence (Fig. 1A) is a train of high-power binomial pulses with zero binomial pulse interval and offset at the water frequency (31-34). A phase cycling scheme was introduced to improve the resistance to B0 and B1 inhomogeneities (38). By setting different saturation lengths (60ms for parenchyma and 900ms for CSF here), we can image the parenchyma and CSF alternatingly. Time resolution for each pair of images was 15s (7.5s for parenchyma and CSF respectively), resulting in a total scanning time of 1h7min30s (540 images, 270 for parenchyma and CSF respectively). A bolus of 0.15 mL filtered 50% D-glucose was injected into mice at 7min30s through tail vein (1min) using a MRI-compatible syringe pump. Hence the baseline is 7min30s and the post monitoring time is 1h (Fig. 1B). The DGE kinetic curves were constructed as:$$\triangle S(t) = \frac{S_{base}-S(t)}{S_{base}}$$The parenchymal DGE uptake was fitted by an exponential model:$$\triangle S_{par}^\prime(t)=S_{e}(40min)\cdot(1-e^{-\mu(t-t_{0})})$$where t0 indicates the time point of D-glucose enhancing, μ is the D-glucose uptake rate and Se is the DGE signal at equilibrium. The CSF DGE uptake was approximated by a sigmoid model (39,40):$$\triangle S_{CSF}^\prime(t) = \frac{S_{max}e^{-\mu_{out}(t-t_{0})}}{1+e^{-\mu_{in}(t-t_{0})}}$$where μin represents the D-glucose uptake rate, μout the washout rate, and Smax the maximum signal reached.Results and Discussion
At younger age (6M), APP/PS1 mice showed a trend towards slightly higher D-glucose uptake (Se) than WT mice (2.22±0.39% vs 1.71±0.60%, P=0.150) in the brain parenchyma (Figs. 2A,C,E,G). The difference became significant at the later stage of the DGE curves (60 minutes) (APP/PS1:2.15±0.32% vs WT:1.29±0.43%, P<0.05), which may be due to similar transport but decreased D-glucose consumption in APP/PS1 mice. By comparing the two age groups (16M:6M), the WT mice did not show clear age dependence on the D-glucose uptake (Fig. 2G), but the D-glucose uptake of APP/PS1 significantly reduced, showing much smaller values compared to WT at old age (0.85±0.10% vs 1.60±0.47%, P=0.009) (Fig. 2G). Similarly, the D-glucose uptake rate μ of WT mice did not show a clear age dependence (P=0.429), but increased significantly for APP/PS1 mice at the older age (P=0.004). D-glucose uptake in the CSF (Smax) for APP/PS1 mice was close to that of WT at 6M (P=0.581) as seen from the CSF DGE curves (Figs. 3E,F). Similar to the D-glucose uptake in brain parenchyma, the CSF D-glucose uptake Smax was not age dependent in WT mice. However, the Smax became much lower at 16M for APP/PS1 compared to the younger APP/PS1 and age matched WT mice (Fig. 3G). In both young and old groups, the D-glucose clearance (μout), which is an indirect measurement of the brain glymphatic pathway, was significantly slower in APP/PS1 compared to WT (6M:P=0.007, 16M:P=0.046). This echoes a recent study showing impaired glymphatic function in the early stage of APP/PS1 AD mice prior to plaque formation (41). In parenchyma, D-glucose uptake measured by DGE MRI provides information on D-glucose transporter functioning as well as metabolism. In CSF, transport function and clearance can be visualized. For parenchyma, our results suggest that dysfunction of D-glucose metabolism occurs already in young AD mice, while transport and metabolism are impaired in older AD mice, in line with literature (42). Uptake in and clearance from CSF are impaired for APP/PS1 mice in the later stage of the disease.Conclusion
The onVDMP DGE method has potential as a diagnostic tool for the assessment of alterations in D-glucose uptake and clearance in AD mice at 3T. Moreover, it could be a robust method to study D-glucose transporter functioning at both the blood brain and blood CSF barriers, as well as functioning of the glymphatic pathway.Acknowledgements
We are grateful to receive funding support from the RGC [9042620], City University of Hong Kong [9610362, 9680247, 7200516, 7004859] and National Institutes of Health [R01EB019934].References
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