A comprehensive assessment of resting state networks: bidirectional modification of functional integrity in cerebro-cerebellar networks in dementia

In resting state fMRI (rs-fMRI), only functional connectivity (FC) reductions in the default mode network (DMN) are normally reported as a biomarker for Alzheimer's disease (AD). In this investigation we have developed a comprehensive strategy to characterize the FC changes occurring in multiple networks and applied it in a pilot study of subjects with AD and Mild Cognitive Impairment (MCI), compared to healthy controls (HC). Resting state networks (RSNs) were studied in 14 AD (70 ± 6 years), 12 MCI (74 ± 6 years), and 16 HC (69 ± 5 years). RSN alterations were present in almost all the 15 recognized RSNs; overall, 474 voxels presented a reduced FC in MCI and 1244 in AD while 1627 voxels showed an increased FC in MCI and 1711 in AD. The RSNs were then ranked according to the magnitude and extension of FC changes (gFC), putting in evidence 6 RSNs with prominent changes: DMN, frontal cortical network (FCN), lateral visual network (LVN), basal ganglia network (BGN), cerebellar network (CBLN), and the anterior insula network (AIN). Nodes, or hubs, showing alterations common to more than one RSN were mostly localized within the prefrontal cortex and the mesial-temporal cortex. The cerebellum showed a unique behavior where voxels of decreased gFC were only found in AD while a significant gFC increase was only found in MCI. The gFC alterations showed strong correlations (p < 0.001) with psychological scores, in particular Mini-Mental State Examination (MMSE) and attention/memory tasks. In conclusion, this analysis revealed that the DMN was affected by remarkable FC increases, that FC alterations extended over several RSNs, that derangement of functional relationships between multiple areas occurred already in the early stages of dementia. These results warrant future work to verify whether these represent compensatory mechanisms that exploit a pre-existing neural reserve through plasticity, which evolve in a state of lack of connectivity between different networks with the worsening of the patholog