Impact of mitochondrial disfunction on 99mTc-HMPAO uptake in depressed patients

Background: Few functional studies have assessed the retention of radiotracers in mitochondrial disorders. 99mTc-HMPAO fixation in brain is proportional to cerebral blood flow but is also related to the cellular content of reduced glutathione. This in turn might be affected by the intracellular concentration of free radicals caused by impaired oxidative metabolism. The aim of the present study was to investigate the correlation between mitochondial activity in muscle and 99mTc-HMPAO distribution in brain.Methods: Mitochondrial mass (CS, citrate-synthase), and respiratory chain enzymes (NCR, NADH-cytochrome-reductase; SCR, succinate-cytochrome-c-reductase and COX, cytochrome-c-oxidase) involved in ATP production, were assessed in isolated muscle mitochondria of 19 patients with chronic unipolar depression and in ten normal controls (CTR). 99mTc-HMPAO distribution was evaluated by SPECT in all patients and regional analysis was performed at cluster of voxels level by SPM. K-means clustering was performed to group patients according to the mean values of all four enzymes.Results: K-means clustered 12 patients in the group with higher enzymes values (H) and 7 in the one with lower enzymes values (L). Enzymes values in H were significantly higher than those in L but there was no difference as compared to CTR. SPM showed significantly higher tracer uptake in L as compared to H in associative parietal (Brodmann 39, 40), cingulate (Brodmann 32, 24), occipital (Brodmann 18, 19) and temporal (Brodmann 21, 22, 37) cortex, in precuneus (Brodmann 7) and the nc.caudatus. The opposite comparison highlighted a significant cluster in orbito-frontal (Brodmann 11) cortex.Conclusions: Mitochondrial mass and respiratory chain enzymes concentration in muscles had a significant impact on 99mTc-HMPAO uptake in a variety of brain regions. The patients with lower enzyme activity showed higher tracer uptake suggesting an inverse correlation between the intracellular concentration of mitochondrial enzymes and the levels of glutathione, known to be the main antioxidant in brain contributing to the scavenging of free radicals. These results support previous observations of an uneven distribution in brain of mitochondrial enzymes and the correlation of mitochondrial disorder with tracer uptake changes in brain. They also suggest a selective vulnerability to oxidative/metabolic impairment of various brain regions implicated in neurodegenerative and psychiatric disorders.