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 (HD) 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 HD and 15 age-matched normal controls by direct measurements of the molar ratio of cerebral oxygen metabolism to cerebral glucose metabolism (CMRO(2)/CMRglc) with positron emission tomography. There was a significant increase in striatal CMRO(2)/CMRglc in HD rather than the decrease characteristic of defects in mitochondrial oxidative metabolism (6.0 +/- 1.6 vs. 5.1 +/- 0.9, P = 0.04). CMRO(2) was not different from controls (126 +/- 37 vs. 134 +/- 31 micromol 100 g(-1) min(-1), P = 0.49), whereas CMRglc was decreased (21.6 +/- 6.1 vs. 26.4 +/- 4.6 micromol 100 g(-1) min(-1), P = 0.01). Striatal volume was decreased as well (13.9 +/- 3.5 vs. 17.6 +/- 2.0 ml, P = 0.001). Increased striatal CMRO(2)/CMRglc with unchanged CMRO(2) is inconsistent with a defect in mitochondrial oxidative phosphorylation due to reduced activity of the mitochondrial ETS. Because HD 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 HD. 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 HD.
Powers
William J
WJ
Department of Neurology, Program in Physical Therapy, and Mallinckrodt Institute of Radiology, Washington University School of Medicine, Campus Box 8225, 4525 Scott Avenue, St. Louis, MO 63110, USA. wjp@npg.wustl.edu
Videen
Tom O
TO
Markham
Joanne
J
McGee-Minnich
Lori
L
Antenor-Dorsey
Joann V
JV
Hershey
Tamara
T
Perlmutter
Joel S
JS
D000328:Adult; D016022:Case-Control Studies; D006019:Glycolysis; D006801:Humans; D006816:Huntington Disease / Q000378:metabolism* / Q000473:pathology*; D008928:Mitochondria / Q000378:metabolism; D017072:Neostriatum / Q000378:metabolism* / Q000473:pathology*; D010085:Oxidative Phosphorylation; D013997:Time Factors