Abstract
Higher dietary intakes of saturated fatty acid increase the risk of developing Alzheimer’s disease and dementia, and even in people without diabetes higher glucose levels may be a risk factor for dementia. The mechanisms causing neuronal dysfunction and dementia by consuming high-fat diet degrading the integrity of the blood-brain barrier (BBB) has been suggested but are not yet fully understood, and metabolic state of the brain by this type of insult is still veiled. The objective of this study was to investigate the effect of high-fat diet on the brain metabolism by a multimodal imaging method using the hyperpolarizedcarbon 13 (13C)-pyruvate magnetic resonance (MR) spectroscopy and dynamic contrast-enhanced MR imaging in conjunction with the biochemical assay and the behavior test in a mouse model fed high-fat diet (HFD). In mice were fed 60% HFD for 6 months, hyperpolarized [1-13C] pyruvate MR spectroscopy showed decreased perfusion (p < 0.01) and increased conversion from pyruvate to lactate (p < 0.001) in the brain. The hippocampus and striatum showed the highest conversion ratio. The functional integrity of the blood-brain barrier tested by dynamic contrast-enhanced MR imaging showed no difference to the control. Lactate was increased in the cortex (p < 0.01) and striatum (p < 0.05), while PDH activity was decreased in the cortex (p < 0.01) and striatum (p < 0.001) and the phosphorylated PDH was increased in the striatum (p < 0.05). Mice fed HFD showed less efficiency in learning memory compared with control (p < 0.05). To determine whether hyperpolarized 13C-pyruvate magnetic resonance (MR) spectroscopy could detect a much earier event in the brain. Mice fed HFD for 3 months did not show a detectable cognitive decline in water maze based learning memory. Hyperpolarized [1-13C] pyruvate MR spectroscopy showed increased lactate conversion (P < .001), but no difference in cerebral perfusion. These results suggest that the increased hyperpolarized [1-13C] lactate signal in the brain of HFD-fed mice represent that altered metabolic alteration toward to glycolysis and hypoperfusion by the long-term metabolic stress by HFD further promote to glycolysis. The hyperpolarized [1-13C] pyruvate MR spectroscopy can be used to monitor the brain metabolism and will provide information helpful to understand the disease process.
Highlights
The metabolic disorder has been suggested as a risk factor to induce cognitive decline and dementia
No difference was observed in the glucose tolerance test, insulin tolerance test, and serum insulin level (n = 10 for both groups; p < 0.001; Fig. 1b-f )
We have investigated the metabolic influence of the hyperglycemic state in the brain of 24 weeks after high-fat diet (HFD) fed mice using by the hyperpolarized 13C magnetic resonance (MR) spectroscopy
Summary
The metabolic disorder has been suggested as a risk factor to induce cognitive decline and dementia. Higher dietary intakes of saturated fatty acid increase the risk of developing Alzheimer’s disease and dementia [1, 2]. Patients with diabetes have two-fold risk to develop Alzheimer’s disease and shorten the conversion time from preclinical to mild cognitive impairment [3, 4]. People with hyperglycemia without diabetes showed a positive correlation with the cognitive decline and dementia [5, 6]. The impairment of insulin homeostasis in diabetes has been suggested to accelerate susceptibility to Alzheimer’s disease [9] by activating glycogen synthesis kinase-3, a kinase for tau protein, promote neurofibrillary tangle and beta-amyloid production [10, 11]. The metabolic state of the brain affected by this type of insult is still veiled and imaging method to quantitatively present the metabolic information in the brain at the earlier process related to cognitive decline and dementia is needed
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