Levels of high-energy phosphates are reduced bilaterally in the putamen and midbrain of patients with Parkinson disease (PD), Hattingen and colleagues at Goethe University, Germany have discovered. Low levels of high-energy phosphates are associated with mitochondrial dysfunction and are evident early in the course of the disorder, indicating that dysfunctional energy metabolism might be a central element of the pathological process underlying the development of PD.

PD is clinically characterized by the development of movement and postural disturbances, which are thought to result from the selective degeneration of dopaminergic neurons in the substantial nigra. In vitro and animal studies indicate that these dopaminergic neurons might be particularly vulnerable to variations in energy metabolism; however, our understanding of cerebral mitochondrial dysfunction in patients with PD is limited owing to the challenging nature of measuring such dysfunction in patients.

Using phosphorus and proton magnetic spectroscopy to measure cerebral high-energy phosphates such as phosphocreatine and ATP, the researchers investigated the functional integrity of cerebral mitochondria in 26 patients with PD and 19 age-matched controls. The investigators observed that levels of ATP were markedly reduced in both the putamen and midbrain of patients in the early and advanced stages of the disease when compared with controls. Similarly, levels of the high-energy phosphate phosphocreatine were substantially reduced bilaterally in the putamen of patients with PD compared with healthy individuals. By contrast, levels of low-energy phosphates and ADP, which do not seem to be associated with mitochondrial dysfunction, were not appreciably different between patients with PD and controls. These results support the findings from earlier studies that demonstrated positive associations between decreased levels of high-energy phosphates and PD. The present study is also in agreement with the results of earlier studies that found that familial PD is linked to mutations in genes involved in mitochondrial function.

By providing a comprehensive account of absolute ATP and phosphocreatine concentrations in patients with PD, the authors are the first to establish that mitochondrial dysfunction exists in the midbrain and putamen of these patients in both early and late stages of the disease. Importantly, by identifying dysfunctional energy metabolism early in the disease process, the authors provide evidence that therapies designed to alleviate mitochondrial dysfunction might be able to slow the functional decline that until now has been an unavoidable consequence of PD progression.