Reduced Cerebral Glucose Uptake in an Alzheimer’s Rat Model With Glucose-Weighted Chemical Exchange Saturation Transfer Imaging

Abstract

A correlation between the abnormal cerebral glucose metabolism and the progression of Alzheimer’s disease (AD) has been found in previous studies, suggesting that glucose alterations may be used to predict the histopathological diagnosis in AD. In this study, we investigated the dynamic changes of cerebral glucose uptake in vivo using MR glucose chemical exchange saturation transfer (glucoCEST) imaging in a rat model of AD with an intracerebroventricular (i.c.v) injection of amyloid Aβ-protein (25–35), confirmed by Morris water maze and Nissl staining. In total, 6 rats in the AD group and 6 rats in the control group that were given an injection of sterile normal saline were included. At 28 days after injection, all rats performed a 7.0 T MR exanimation, including glucoCEST, diffusion tensor imaging (DTI) and hippocampus magnetic resonance spectra (MRS), to detect the possible metabolic and structural changes in the rat brain. A significantly elevated brain glucoCEST signal in the brain of AD rats was observed, and a decreased brain glucose uptake was also explored during the progression of glucose infusion compared with those in rats of the control group. In addition, there is a significant positive correlation between glucoCEST enhancement (GCE) and myo-Inosito (Ins) in the AD group and the control group (P < 0.05). A significantly reduced number of neurons in the cortex and hippocampus in AD rats combined with the significantly longer escape and a decreased number of crossings were verified at 28 days after Aβ25–35 injection by Nissl staining and Morris water maze, respectively. Our results indicated that an abnormal brain glucose mechanism in AD rats could be detected by glucoCEST imaging, suggesting a new method to explore the occurrence and progress of diabetes-related AD or dementia.

Saturation Transfer MRI for Detection of Metabolic and Microstructural Impairments Underlying Neurodegeneration in Alzheimer’s Disease

“…This is because of the DGE curve shape, which after reaching maximum maintains a plateau for 60 min in AD, while in control animals the curve starts to decrease after 40 min ( Figure 5 E). A similar glucose utilization curve is observed in older AD animals with severe Aβ protein aggregation in brain ( Figure 5 F), and is also reported by others, independently of Aβ or tau pathology [ 130 , 179 , 180 ]. Such dynamics indicate that glucose is not fully metabolized and accumulates in the tissue in both early and advanced stages of the disease.…”

“…Studies of glucoCEST in patients with Alzheimer’s disease are still missing, however they have been conducted in animal models focused on either Aβ-related pathology (APP23, AD-Aβ25–35, and APP/PS1) or tauopathy (rTg4510 or Tau4RΔK) [ 130 , 178 , 179 , 180 , 181 ] ( Table 6 ).…”

“…The dynamic glucose-enhanced (DGE) MRI experimental setup consists of baseline brain imaging, and then injection of glucose contrast bolus, after which the glucose uptake is continuously recorded by glucoCEST imaging. Most studies use D-glucose either in intravenous injection of 50% w / w solution [ 180 , 181 ], or in intraperitoneal injection [ 130 , 179 ]. CEST-based imaging is performed continuously during contrast infusion and then imaging is continued for another 30–60 min to register glucose retention and clearance from the brain.…”

Disruption of Glucose Metabolism in Aged Octodon degus: A Sporadic Model of Alzheimer's Disease

“…Importantly, these changes in glucose metabolism, possibly caused by abnormal Glut levels and reduced glycolytic flux, have been shown to contribute to the pathogenesis of AD (Ding et al, 2013;Sonntag et al, 2017). Several in vivo studies using transgenic mouse models of AD, such as Tg2576 and APP/PS1, have also corroborated a disruption in glucose metabolism (Bigl et al, 2003;Nicholson et al, 2010;Tiwari and Patel, 2014;Waldron et al, 2015;Chen et al, 2021). In accordance with these transgenic models, O. degus showed similar glucose metabolism impairments, including a reduction in glucose uptake, together with a decrease in both glycolytic and PPP fluxes.…”

Disentangling Mitochondria in Alzheimer’s Disease

“…These observations have been reinforced by multiple other studies over time [ 93 , 94 , 95 , 96 ]. The reduction in glucose utilization in AD brains could be a consequence of reduced glycolysis, neuronal loss, as well as a reduced glucose uptake [ 6 , 97 ]. Concentrations of GLUT1 and GLUT3 are reduced in the brains of AD patients and correlate with diminished brain glucose uptake and subsequent cognitive decline [ 98 , 99 , 100 , 101 , 102 , 103 , 104 ].…”