Investigations On The Activated-state Metabolism In Rhesus Monkey Brain:A[¹⁸F]BCPP-EF-PET Study

Glucose is the main energy source of the brain.Under resting state,catabolism of glucose in the brain is dominated by oxidative phosphorylation,and only about 10%of glucose is broken down through aerobic glycolysis.Induced by physiological stimulation,the cerebral blood flow and metabolism alter in activated region.Most activation positron emission tomography(PET)studies found out that aerobic glycolysis was strengthened in the early phase of brain activation.However,there was no agreement on whether oxidative phosphorylation was strengthened.In addition,it remained unclear whether there existed a pathway switch from aerobic glycolysis to oxidative phosphorylation during continued brain activation.Mitochondrial complex I(MC-I)plays a catalyzing role in oxidative phosphorylation.[18F]BCPP-EF,a novel PET probe for MC-I activity,has been applied in imaging changes in MC-I activity related to several neurodegenerative diseases.To investigate the glucose metabolism under brain activation and the capability of[18F]BCPP-EF to detect MC-I activity,the current work conducted[18F]BCPP-EF-PET imaging of activated rhesus monkey brain,as well as measured the regional cerebral blood flow(rCBF)and the regional cerebral metabolic rate of glucose(rCMRglc).This work consisted of three studies.Study 1 aimed to investigate changes in MC-I activity in the early phase of brain activation compared to resting state,as well as evaluate the capability of[18F]BCPP-EF to detect such changes.[15O]H2O,[18F]FDG and[18F]BCPP-EF scans were conducted under resting state and vibrotactile stimulation.It turned out that:1)Under activated state,rCBF(measured by[150]H2O)response was significant while rCMRglc(measured by[18F]FDG)response did not reach a significant level;2)Under activated state,[18F]BCPP-EF response was significant,which was mainly contributed by the initial rCBF response,causing overestimation of MC-I activity.These results indicated that due to the influence of rCBF response,[18F]BCPP-EF scan started simultaneously with stimulation cannot detect MC-I activity in the early phase of brain activation.Study 2 aimed to investigate changes in MC-I activity during continued brain activation compared to the early phase of brain activation,as well as evaluate the influence of rCBF response on[18F]BCPP-EF response.[15O]H2O and[18F]BCPP-EF scans were conducted under resting state,at the beginning of vibrotactile stimulation,after 15-min stimulation and after 30-min stimulation.It turned out that:1)During continued brain activation,rCBF response significantly decreased;2)During continued brain activation,early[18F]BCPP-EF response also significantly decreased or showed decreasing tendency,while late[18F]BCPP-EF response remained unchanged.These results indicated that[18F]BCPP-EF response in later phase of scans started after 15-min and 30-min stimulation was not influenced by the decrease in initial rCBF response,thus was capable to detect increase in MC-I activity during continued brain activation.Study 3 aimed to investigate whether there existed a metabolic pathway switch during continued brain activation,as well as evaluate the capability of combined[18F]BCPP-EF-PET imaging and[18F]FDG-PET imaging to detect such pathway switch.[18F]FDG and[18F]BCPP-EF scans were conducted under resting state,at the beginning of vibrotactile stimulation and after 30-min stimulation.It turned out that:1)During continued brain activation,rCMRglc response remained unchanged;2)During continued brain activation,MC-I activity showed increasing tendency.These results indicated that the pathway switch was not detected by current experimental design and scan protocol,which needed further investigations.This work was the first activation PET study on the activity of enzyme related to oxidative phosphorylation,as well as the first application of[18F]BCPP-EF in activation PET imaging.It preliminarily revealed the changes in MC-I activity during continued brain activation,which brought us brand new perspective to understand the metabolism under brain activation.