Selective defect of in vivo glycolysis in early Huntington's disease striatum

Activity of complexes II, III, and IV of the mitochondrial electron transport system (ETS) is reduced in postmortem Huntington's disease (HID) striatum, suggesting that reduced cerebral oxidative phosphorylation may be important in the pathogenesis of neuronal death. We investigated mitochondrial oxidative metabolism in vivo in the striatum of 20 participants with early, genetically proven HID and 15 age-matched normal controls by direct measurements of the molar ratio of cerebral oxygen metabolism to cerebral glucose metabolism (CMRO2/CMRgIc) with positron emission tomography. There was a significant increase in striatal CMRO2/CMRgIc in HID rather than the decrease characteristic of defects in mitochondrial oxidative metabolism (6.0 +/- 1.6 vs. 5.1 +/- 0.9, P = 0.04). CMRO2 was not different from controls (126 +/- 37 vs. 134 +/- 31 mu mol 100 g(-1) min(-1), P = 0.49), whereas CMRglc was decreased (21.6 +/- 6.1 vs. 26.4 +/- 4.6 mu mol 100 g(-1) min(-1), P = 0.01). Striatal volume was decreased as well (113.9 +/- 3.5 vs. 17.6 +/- 2.0 ml, P = 0.001). Increased striatal CMRO2/CMRglc with unchanged CMRO2 is inconsistent with a defect in mitochondrial oxidative phosphorylation due to reduced activity of the mitochondrial ETS. Because HID pathology was already manifest by striatal atrophy, deficient energy production due to a reduced activity of the mitochondrial ETS is not important in the mechanism of neuronal death in early HID. Because glycolytic metabolism is predominantly astrocytic, the selective reduction in striatal CMRglc raises the possibility that astrocyte dysfunction may be involved in the pathogenesis of HID.