In vivo evidence for cerebral depletion in high-energy phosphates in progressive supranuclear palsy

Indirect evidence from laboratory studies suggests that mitochondrial energy metabolism is impaired in progressive supranuclear palsy (PSP), but brain energy metabolism has not yet been studied directly in vivo in a comprehensive manner in patients. We have used combined phosphorus and proton magnetic resonance spectroscopy to measure adenosine-triphosphate (ATP), adenosine-diphosphate (ADP), phosphorylated creatine, unphosphorylated creatine, inorganic phosphate and lactate in the basal ganglia and the frontal and occipital lobes of clinically probable patients (N21; PSP stages II to III) and healthy controls (N9). In the basal ganglia, which are severely affected creatine in PSP patients, the concentrations of high-energy phosphates (ATPphosphorylated creatine) and inorganic phosphate, but not low-energy phosphates (ADPunphosphorylated creatine), were decreased. The decrease probably does not reflect neuronal death, as the neuronal marker N-acetylaspartate was not yet significantly reduced in the early-stage patients examined. The frontal lobe, also prone to neurodegeneration in PSP, showed similar alterations, whereas the occipital lobe, typically unaffected, showed less pronounced alterations. The levels of lactate, a product of anaerobic glycolysis, were elevated in 35% of the patients. The observed changes in the levels of cerebral energy metabolites in PSP are consistent with a functionally relevant impairment of oxidative phosphorylation.