EVALUATION OF: Nicholson AM, Finch NA, Thomas CS et al. Progranulin protein levels are differently regulated in plasma and CSF. Neurology 82(21), 1871–1878 (2014). Nicholson et al. report the first population-based comparative study of progranulin (GRN) levels in plasma and cerebrospinal fluid (CSF) in a large human cohort. Age, sex and rs5848 were found to be important modifiers of GRN levels in both plasma and CSF. The correlation between plasma and CSF levels was rather weak. Moreover, a differential regulation of GRN levels in plasma and CSF was noted. Although blood GRN measurements can be used to predict GRN mutation status, this study provides compelling evidence not to rely exclusively on plasma GRN measurements to assess the efficacy of future CNS-targeted GRN-modulating therapies. Further studies should assess the correlation between CSF and brain GRN levels in a longitudinal fashion and try to correlate CSF GRN levels with clinical parameters.