Compensation in the course of Huntington's disease — More than just a hypothesis?

The discrepancy between progressive structural decline of the brain aspects (e.g. sensitivity of rs-fMRI to motion generated artifacts, choice e.g. generalized or focal atrophy including neuronal loss and the observation of persistent stable performance in clinical tasks has led to the hypothesis of functional compensation. Although characterization and detailed understanding of the underlying mechanisms are of fundamental interest and may eventually lead to novel symptomatic therapeutic strategies in neurodegenerative diseases, only a few systematic studies have addressed this topic so far (Scheller et al., 2014). This probably originates from the fact that brain reserve capacity or compensation mechanisms are difficult to measure. These take place on a functional level for example by activation of neuronal networks or as transient task-dependent phenomena based on both individual as well as disease specific structural prerequisites. Klöppel and colleagues have addressed this fascinating topic and present a new approach to visualize and characterize compensation in preclinical HD gene carriers (preHD) (Klöppel et al., 2015). For this purpose preHD subjects serve as ideal candidates since they have been shown to remain asymptomatic for years even when using sophisticated cognitive tests or motor tasks. Volumetric brain imaging indicates progressive neurodegeneration in these patients. The exact time point of preHD converting into the clinical stage of the disease however is poorly characterized and currently discussed (Bilgan et al., 2009; Tabrizi et al., 2013). Based on the assumption that compensation requires an enhanced neuronal activation (Cabeza and Dennis, 2013; Quiroz et al., 2010) accompanied by an increased metabolism and blood flow, Klöppel and colleagues used resting state (rs-fMRI) and task related functional MRI (fMRI) to investigate a comparatively large group of preHD gene carriers. To depict brain activity suspicious for compensation, they have searched for positive correlations between brain areas showing a high disease load as defined by volumetric measures and significant increase in brain activity while detailed motor and cognitive tasks had to be performed. Functional connectivity of certain brain areas in neuronal networks was investigated under resting state conditions. Since no alternative method to reliably investigate compensation in respect to area specific disease load has been established up to now, the presented results will need further validation. In addition methodical