Subcortical elevation of metabolism in Parkinson's disease - A critical reappraisal in the context of global mean normalization

In a recent issue of NeuroImage, we presented evidence that biased global mean (GM) normalization of brain PET data can generate the appearance of subcortical foci with relative hypermetabolism in patients with Parkinson's disease (PD), and other degenerative disorders. In a commentary to our article, Ma and colleagues presented a study seeking to establish that a pattern of widespread hypermetabolism, known as the Parkinson's disease related pattern (PDRP) is a genuine metabolic feature of PD. In the present paper, we respond to the arguments presented by Ma et al., and we provide a critical reappraisal of the evidence for the existence of the PDRP. To this end, we present new analyses of PET data sets, which demonstrate that very similar patterns of relative subcortical increases are seen in PD, Alzheimer's disease, hepatic encephalopathy, healthy aging, and simulation data. Furthermore, longitudinal studies of PD previously reported relative hypermetabolism in very small anatomical structures such as the subthalamic nucleus. We now demonstrate how focal hypermetabolism attributed to small nuclei can similarly arise as a consequence of GM normalization. Finally, we give a comprehensive summary of the entire deoxyglucose autoradiography literature on acquired parkinsonism in experimental animals. Based on this evidence, we conclude that (1) there is no quantitative evidence for widespread subcortical hypermetabolism in PD, (2) very similar patterns of subcortical hyperactivity are evident in various other brain disorders whenever GM normalization is utilized, and (3) the PDRP is not evident in animal models of PD. In the absence of quantitative evidence for the PDRP, our alternative interpretation of normalization bias seems the more parsimonious explanation for the reports of relative hypermetabolism in PD.