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In the past, determination of absolute values of cerebral metabolic rate of glucose (CMRGlc) in clinical routine was rarely carried out due to the invasive nature of arterial sampling. With the advent of combined PET/MR imaging technology, CMRGlc values can be obtained non-invasively, thereby providing the opportunity to take advantage of fully quantitative data in clinical routine. However, CMRGlc values display high physiological variability, presumably due to fluctuations in the intrinsic activity of the brain at rest. To reduce CMRGlc variability associated with these fluctuations, the objective of this study was to determine whether functional connectivity measures derived from resting-state fMRI (rs-fMRI) could be used to correct for these fluctuations in intrinsic brain activity., Methods: We studied 10 healthy volunteers who underwent a test-retest dynamic [18F]FDG-PET study using a fully integrated PET/MR system (Siemens Biograph mMR). To validate the non-invasive derivation of an image-derived input function based on combined analysis of PET and MR data, arterial blood samples were obtained. Using the arterial input function (AIF), parametric images representing CMRGlc were determined using the Patlak graphical approach. Both directed functional connectivity (dFC) and undirected functional connectivity (uFC) were determined between nodes in six major networks (Default mode network, Salience, L/R Executive, Attention, and Sensory-motor network) using either a bivariate-correlation (R coefficient) or a Multi-Variate AutoRegressive (MVAR) model. In addition, the performance of a regional connectivity measure, the fractional amplitude of low frequency fluctuations (fALFF), was also investigated., Results: The average intrasubject variability for CMRGlc values between test and retest was determined as (14 ±8%) with an average inter-subject variability of 25% at test and 15% at retest. The average CMRGlc value (umol/100 g/min) across all networks was 39 ±10 at test and increased slightly to 43 ±6 at retest. The R, MVAR and fALFF coefficients showed relatively large test-retest variability in comparison to the inter-subjects variability, resulting in poor reliability (intraclass correlation in the range of 0.11-0.65). More importantly, no significant relationship was found between the R coefficients (for uFC), MVAR coefficients (for dFC) or fALFF and corresponding CMRGlc values for any of the six major networks., Discussion: Measurement of functional connectivity within established brain networks did not provide a means to decrease the inter- or intrasubject variability of CMRGlc values. As such, our results indicate that connectivity measured derived from rs-fMRI acquired contemporaneously with PET imaging are not suited for correction of CMRGlc variability associated with intrinsic fluctuations of resting-state brain activity. Thus, given the observed substantial inter- and intrasubject variability of CMRGlc values, the relevance of absolute quantification for clinical routine is presently uncertain., (Copyright © 2020 Shiyam Sundar, Baajour, Beyer, Lanzenberger, Traub-Weidinger, Rausch, Pataraia, Hahn, Rischka, Hienert, Klebermass and Muzik.)