Spinal cord hypermetabolism extends to skeletal muscle in amyotrophic lateral sclerosis: a computational approach to [18F]-fluorodeoxyglucose PET/CT images.

PURPOSE: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease leading to neuromuscular palsy and death. We propose a computational approach to [18F]-fluorodeoxyglucose (FDG) PET/CT images to analyze the structure and metabolic pattern of skeletal muscle in ALS and its relationship with disease aggressiveness. MATERIALS AND METHODS: A computational 3D method was used to extract whole psoas muscle's volumes and average attenuation coefficient (AAC) from CT images obtained by FDG PET/CT performed in 62 ALS patients and healthy controls. Psoas average standardized uptake value (normalized on the liver, N-SUV) and its distribution heterogeneity (defined as N-SUV variation coefficient, VC-SUV) were also extracted. Spinal cord and brain motor cortex FDG uptake were also estimated. RESULTS: As previously described, FDG uptake was significantly higher in the spinal cord and lower in the brain motor cortex, in ALS compared to controls. While psoas AAC was similar in patients and controls, in ALS a significant reduction in psoas volume (3.6 ± 1.02 vs 4.12 ± 1.33 mL/kg; p < 0.01) and increase in psoas N-SUV (0.45 ± 0.19 vs 0.29 ± 0.09; p < 0.001) were observed. Higher heterogeneity of psoas FDG uptake was also documented in ALS (VC-SUV 8 ± 4%, vs 5 ± 2%, respectively, p < 0.001) and significantly predicted overall survival at Kaplan-Meier analysis. VC-SUV prognostic power was confirmed by univariate analysis, while the multivariate Cox regression model identified the spinal cord metabolic activation as the only independent prognostic biomarker. CONCLUSION: The present data suggest the existence of a common mechanism contributing to disease progression through the metabolic impairment of both second motor neuron and its effector.

Effect of starvation on brain glucose metabolism and 18F-2-fluoro-2-deoxyglucose uptake: an experimental in-vivo and ex-vivo study.

BACKGROUND: The close connection between neuronal activity and glucose consumption accounts for the clinical value of 18F-fluoro-2-deoxyglucose (FDG) imaging in neurodegenerative disorders. Nevertheless, brain metabolic response to starvation (STS) might hamper the diagnostic accuracy of FDG PET/CT when the cognitive impairment results in a severe food deprivation. METHODS: Thirty six-week-old BALB/c female mice were divided into two groups: "control" group (n = 15) were kept under standard conditions and exposed to fasting for 6 h before the study; the remaining "STS" mice were submitted to 48 h STS (absence of food and free access to water) before imaging. In each group, nine mice were submitted to dynamic micro-PET imaging to estimate brain and skeletal muscle glucose consumption (C- and SM-MRGlu*) by Patlak approach, while six mice were sacrificed for ex vivo determination of the lumped constant, defined as the ratio between CMRGlu* and glucose consumption measured by glucose removal from the incubation medium (n = 3) or biochemical analyses (n = 3), respectively. RESULTS: CMRGlu* was lower in starved than in control mice (46.1 ± 23.3 vs 119.5 ± 40.2 nmol × min-1 × g-1, respectively, p < 0.001). Ex vivo evaluation documented a remarkable stability of lumped constant as documented by the stability of GLUT expression, G6Pase activity, and kinetic features of hexokinase-catalyzed phosphorylation. However, brain SUV in STS mice was even (though not significantly) higher with respect to control mice. Conversely, a marked decrease in both SM-MRGlu* and SM-SUV was documented in STS mice with respect to controls. CONCLUSIONS: STS markedly decreases brain glucose consumption without altering measured FDG SUV in mouse experimental models. This apparent paradox does not reflect any change in lumped constant. Rather, it might be explained by the metabolic response of the whole body: the decrease in FDG sequestration by the skeletal muscle is as profound as to prolong tracer persistence in the bloodstream and thus its availability for brain uptake.

Fasting induces anti-Warburg effect that increases respiration but reduces ATP-synthesis to promote apoptosis in colon cancer models.

Tumor chemoresistance is associated with high aerobic glycolysis rates and reduced oxidative phosphorylation, a phenomenon called "Warburg effect" whose reversal could impair the ability of a wide range of cancer cells to survive in the presence or absence of chemotherapy. In previous studies, Short-term-starvation (STS) was shown to protect normal cells and organs but to sensitize different cancer cell types to chemotherapy but the mechanisms responsible for these effects are poorly understood. We tested the cytotoxicity of Oxaliplatin (OXP) combined with a 48hour STS on the progression of CT26 colorectal tumors. STS potentiated the effects of OXP on the suppression of colon carcinoma growth and glucose uptake in both in vitro and in vivo models. In CT26 cells, STS down-regulated aerobic glycolysis, and glutaminolysis, while increasing oxidative phosphorylation. The STS-dependent increase in both Complex I and Complex II-dependent O(2) consumption was associated with increased oxidative stress and reduced ATP synthesis. Chemotherapy caused additional toxicity, which was associated with increased succinate/Complex II-dependent O(2) consumption, elevated oxidative stress and apoptosis .These findings indicate that the glucose and amino acid deficiency conditions imposed by STS promote an anti-Warburg effect characterized by increased oxygen consumption but failure to generate ATP, resulting in oxidative damage and apoptosis.