Early detection of Alzheimer's disease using creatine chemical exchange saturation transfer magnetic resonance imaging

Abstract

Detecting Alzheimer’s disease (AD) at an early stage brings a lot of benefits including disease management and actions to slow the progression of the disease. Here, we demonstrate that reduced creatine chemical exchange saturation transfer (CrCEST) contrast has the potential to serve as a new biomarker for early detection of AD. The results on wild type (WT) mice and two age-matched AD models, namely tauopathy (Tau) and A β amyloidosis (APP), indicated that CrCEST contrasts of the cortex and corpus callosum in the APP and Tau mice were significantly reduced compared to WT counterpart at an early stage (6-7 months) ( p < 0.011). Two main causes of the reduced CrCEST contrast, i.e. cerebral pH and creatine concentration, were investigated. From phantom and hypercapnia experiments, CrCEST showed excellent sensitivity to pH variations. From MRS results, the creatine concentration in WT and AD mouse brain was equivalent, which suggests that the reduced CrCEST contrast was dominated by cerebral pH change involved in the progression of AD. Immunohistochemical analysis revealed that the abnormal cerebral pH in AD mice may relate to neuroinflammation, a known factor that can cause pH reduction.

Magnetic Resonance Imaging in Animal Models of Alzheimer’s Disease Amyloidosis

“…Igarashi et al demonstrated a reduced level of glutamate measured by using glutamate CEST, as an indicator of synaptic dysfunction, in the parietal cortex but not in the hippocampus of 5 × FAD mice compared to wild-type mice [ 129 ]. Using creatine CEST MRI, Chen et al demonstrated a reduced level of creatine in the cortex and corpus callosum of APP/PS1 mice compared to wild-type mice at 6 months-of-age [ 145 ]. Chen et al showed a reduced saturation transfer difference for the composite protein amide proton in APP/PS1 mice compared to the age-matched wild-type mice [ 144 ].…”

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

“…However, it may serve as a tool for investigating cerebral pH changes in AD. Chen et al have investigated CrCEST in mouse models of AD: Aβ-related (APP/PS1 mice) and tau-related (Tau4RΔK mice) [ 146 ]. As a simple asymmetry analysis can confound results due to signals present on the opposite side of the spectrum, the authors use a different approach to analysis by converting their acquired z-spectrum into an R-spectrum: rotating-frame relaxation spectrum [ 147 ] to obtain the rotating frame relaxation rate (R Cr ).…”

“…The authors conclude that the R Cr change in both AD models is due to a decrease in pH. Chen et al further demonstrate that a reduction in mouse brain pH caused by hypercapnia results in a decrease in both CrCEST and APT, and use phantom studies to determine that both the CrCEST signal intensity and exchange rate, R Cr at 2 ppm are linearly dependent on pH over a physiological range [ 146 ]. The region of R Cr decrease observed in the APP/PS1 model corresponds to the areas where reactive forms of both astrocytes and microglia are present as confirmed by GFAP and IBA1 (Ionized calcium-Binding Adapter molecule 1) immunostaining.…”

Magnetic Resonance Imaging in Animal Models of Alzheimer’s Disease Amyloidosis

“…Igarashi et al demonstrated a reduced level of glutamate as an indicator of synaptic dysfunction measured by using glutamate CEST in the parietal cortex, but not in the hippocampus of 5×FAD mice [135]. Chen et al demonstrated that creatine CEST detection of creatine level were reduced in the cortex and corpus callosum of APP/PS1 mice compared to wild-type mice at 6 months-of-age [136]. Chen et al showed that reduced saturation transfer difference for the composite protein amide proton in APP/PS1 mice at compared to the age-matched wild-type mice [137].…”

“…The authors declare no completing interest relevant to the submitted manuscript. T2*w GE, T2w SE APP/PS1, APPV717I mice [32,49,225,226] CESL APP/PS1 mice [36] T1w, CE-MR APP/PS1, PDAPP mice [227] 3D GE T2*w APP/PS1, PS1 mice [228] MTC APP/PS1 mice T2*, Gd-DTPA-K6Aβ1-30 APP/PS1, APPswe mice [46] T1w, Cyanine-Gd(III) complex 5×FAD mice CEST APP23 mice [133] APP/PS1 mice [136,137].…”