Abstract Body:

We used ¹³C MRI of parahydrogen-polarized [1-¹³C] pyruvate to investigate brain metabolic alteration in congenital Pde6b mutation and light-exposure model mice of retinal degeneration and found the different shifts in brain metabolic fluxes.

[Purpose] Recent epidemiologic studies reported that sensory loss including vision impairment is associated with incidence of dementia and cognitive impairment⁽¹⁾. In this study, we investigate the changes in brain metabolic fluxes of hyperpolarized [1-¹³C] pyruvate in two types of retinal degenerated model mice as a non-invasive imaging biomarker of possible early detection of the neurological disorders induced by vision impairment.

[Method] Pathology of retinal degeneration was confirmed by H&E staining of the FFPE section of eyes. C3H/HeYokSlc mouse, which has congenital Pde6b mutation known as a “retinal degeneration (rd)-1” mouse and widely used as a model of retinitis pigmentosa, was compared to healthy C57BL/6NCrSlc mouse as a control. Light-induced retinal damage model mouse was created by exposing female C57BL/6NCrSlc mouse to approximately 8000 Lux fluorescent light for 10 hours and investigated one week after the light exposure.

Hyperpolarized [1-¹³C] pyruvate solution (80-90mM) was prepared by ParaHydrogen-Induced Polarization Side Arm Hydrogeneration (PHIP-SAH) technique⁽²⁾ using a lab-made PHIP polarizer system⁽³⁾ and intravenously injected into the mouse (12 µL/g body weight). Two-dimensional chemical shift imaging (CSI) was conducted 25 seconds after start of injection at the head of mouse using a multinuclear 1.5T preclinical MRI system. Typical CSI parameters are as follows; FOV 32x32mm, matrix 16×16, TR 75ms, FA15°, spectral width 122 ppm for 128 spectral data points, centric k-space acquisition. Metabolic images of hyperpolarized [1-¹³C] pyruvate, lactate and bicarbonate were reconstructed by a code written in MATLAB and analyzed using ImageJ software.

T₂-weighted fast spin echo MRI images of the brain and ¹⁸F-FDG PET images obtained independently by SIEMENS PET/CT were fused by AMIDE software. Regions of interest (ROI) were drawn over the whole brain on the co-registered T2W MRI images, and then a standard uptake value [SUV=average tissue concentration of FDG (kBq/mL)/ total injected dose (kBq)/body weight (g)] were calculated for the ROI.

Nighttime motor activity of both rd-1 and light-exposed mice were measured and expressed as the total moving distance per hour.

[Result] The thickness of the outer nuclear layer of the retina, which contains the nuclei of the cone and rod photoreceptors, decreased in both retinal degenerated models compared to the control mouse, and confirmed the distinctive retinal structures of each degeneration models. The metabolic flux ratio of lactate/bicarbonate was increased in the brain of rd-1 mouse compared to that of control mouse, indicating that the metabolic pathway in the brain was shifted more toward the glycolysis. The mean SUV of the brain in light-exposed mouse was significantly smaller than control group (p<0.05), and the decreasing trend of brain SUV was observed in rd-1mouse, implying the decreased brain glucose consumption in the brain of mice with vision impairment. Moreover, nighttime motor activity of rd-1 mouse was decreased compared to control mouse (p<0.01), indicating the decline of cognitive function in rd-1 mouse. This study not only demonstrates that brain metabolic changes due to retinal degeneration can be non-invasively measured by hyperpolarized ¹³C pyruvate MRI with PHIP-SAH, but also that the metabolic alteration patterns in the brain maybe different depend on the cause and time course of retinal degeneration.

[Conclusion] Brain metabolic alteration caused by retinal degeneration can be non-invasively observed by hyperpolarized ¹³C pyruvate MRI using PHIP-SAH technique. This method is expected to lead to a better understanding of the association between vision impairment and neurological disorders such as dementia and cognitive impairment.

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