Short‐term dichloroacetate treatment improves indices of cerebral metabolism in patients with mitochondrial disorders

Abstract

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.

Neuroimaging of mitochondrial disease

“…Only two studies have demonstrated reductions in the Choline/Creatine ratio in mitochondrial patients (Bianchi et al, 2003;De Stefano, 1995). The limited data may reflect that choline in the 1 H spectrum represents the sum of both membrane precursors and catabolytes; since these components may not change in opposite directions; the sum may provide a negligible index of change.…”

Proton MR spectroscopy in clinical routine

“…Pathologic accumulation (resonance at 1.3 ppm) of this end product of anaerobe glycolysis indicates that oxidative metabolism is unable to meet energy requirements. Neurological diseases accompanied by positive lactate findings in MRS are, e.g., hypoxia, ischemia, epilepsy, tumors, and mitochondrial diseases (1,7,8,14,20).…”

The Elusive Magic Pill: Finding Effective Therapies for Mitochondrial Disorders

“…Dichloroacetate has been studied in small numbers of patients with mitochondrial myopathies, chronic progressive external ophthalmoplegia, Kearne-Sayre syndrome, Leigh syndrome, mitochondrial encephalopathy lactic acidosis and stroke-like episodes (MELAS), congenital lactic acidosis, and 1 patient with a mtDNA depletion syndrome [16][17][18][19]. Most of the studies have included children and adults with multiple mitochondrial disorders, making results difficult to interpret.…”

“…Study designs have been double blind, placebocontrolled crossover trials with washout periods of various lengths between study arms [16][17][18][19]. Statistically significant decreases in blood lactate, pyruvate, and alanine at rest and after exercise and improvements on brain MRS, including a reduction of the brain lactate/creatine ratio, increase in brain choline/ creatine ratio, and statistically significant increase in the N-acetyl aspartate (NAA)/creatine ratio, have been reported in some, but not all, studies [16,17]. A single study including only adults with the common MELAS mutation 3243A>G mtDNA was discontinued owing to peripheral nerve toxicity.…”