Short-term dichloroacetate treatment improves indices of cerebral metabolism in patients with mitochondrial disorders.
We performed a short-term, double-blind, placebo-controlled, crossover trial of sodium dichloroacetate (DCA) therapy in 11 patients affected by various primary mitochondrial disorders. Independent measures of oxidative metabolism (venous blood metabolites, exercise testing, phosphorus magnetic resonance [MR] spectroscopy of muscle, and proton MR spectroscopy of brain) were used in order to monitor metabolic responses to the drug. One week of DCA treatment produced significant decreases (p < 0.05) in blood lactate, pyruvate, and alanine at rest and after bicycle exercise. Proton MR spectra collected from a supraventricular volume of interest in brain of seven of 11 patients also showed significant changes. Brain lactate/creatine ratio decreased by 42% during DCA treatment (p < 0.05). Brain choline/creatine ratio (which is low in patients with myelinopathies) increased by 18% (p < 0.01) after therapy. N-Acetylaspartate/creatine ratio (an index of neuronal damage or loss) increased by 8% after treatment (p < 0.05). Proton MR spectra collected in two of 11 patients from a volume of interest including the basal ganglia showed similar results (decrease of 36.6% in lactate/creatine; increases of 16% in choline/creatine and 4.5% in N-acetylaspartate/creatine). Phosphorus MR spectroscopy of muscle and self-assessed clinical disability were unchanged. Our study indicates that short-term DCA treatment not only lowers blood lactate but also improves indices of both brain oxidative metabolism and neuronal and glial density or function.
De Stefano
N
N
Department of Neurology and Neurosurgery, Montreal Neurological Institute and Hospital, PQ, Canada.
Matthews
P M
PM
Ford
B
B
Genge
A
A
Karpati
G
G
Arnold
D L
DL
D000111:Acetylcysteine / Q000378:metabolism; D000244:Adenosine Diphosphate / Q000378:metabolism; D000293:Adolescent; D000328:Adult; D000368:Aged; D000409:Alanine / Q000097:blood; D001921:Brain / Q000378:metabolism*; D002648:Child; D003401:Creatine / Q000378:metabolism; D018592:Cross-Over Studies; D003999:Dichloroacetic Acid / Q000627:therapeutic use*; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D007773:Lactates / Q000097:blood; D019344:Lactic Acid; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D008875:Middle Aged; D017240:Mitochondrial Myopathies / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism*; D010919:Placebos; D011768:Pyruvate Dehydrogenase Complex / Q000378:metabolism
D007773:Lactates; D010919:Placebos; D011768:Pyruvate Dehydrogenase Complex; D019344:Lactic Acid; D000244:Adenosine Diphosphate; D003999:Dichloroacetic Acid; D003401:Creatine; D000409:Alanine; D000111:Acetylcysteine