This disconnect may reflect the complexity of underlying AD pathology which, in contrast to all other diseases studied here, features two co-occurring major molecular pathologies (amyloid-beta and tau). In bvFTD,

the identified epicenters in the right frontoinsula and pregenual anterior cingulate cortex are known for their coactivation during salience processing (Seeley et al., 2007), and both regions harbor a unique class of large, bipolar projection neurons targeted in early-stage bvFTD (Kim et al., 2011 and Seeley et al., 2006). The anterior temporal epicenters identified within the SD pattern feature prominent connections CB-839 to upstream cortices that may converge on the epicenters to foster multimodal semantic integration this website (Patterson et al., 2007). In PNFA, our epicenter search identified the inferior frontal gyrus (Broca’s area), as well as striatal and thalamic sites with robust operculofrontal connections (Alexander et al., 1986). The CBS epicenters occupy the rolandic and perirolandic cortices involved in skeletomotor planning, control, and execution functions compromised early in the course of typical CBS regardless of the underlying pathology (Lee et al., 2011). How does disease spread throughout the network once one of

its key epicenters is compromised? The present data suggest that at least two major factors Idoxuridine influence spread within the target network. First, across all five diseases, network nodes subject to greater intranetwork total connectional flow were found to undergo

greater atrophy. This observation raises the possibility that activity-dependent mechanisms, such as oxidative stress, local extracellular milieu fluctuations, or glia-dependent phenomena, influence regional neurodegeneration severity. Furthermore, nodes with shorter connectional paths to an epicenter showed greater vulnerability, suggesting that transneuronal spread represents one of the key factors driving early target network degeneration. In this regard, epicenter infiltration by disease may provide privileged but graded access across the network that determines where the disease will arrive next. Although trophic factor insufficiency or a shared gene or protein expression profile may help to determine sites of initial vulnerability, the present findings are more difficult to reconcile with these models. Regions exquisitely vulnerable to one neurodegenerative disease are often spared in another. On the other hand, once disease has spread throughout its target network, the process often extends into “neighboring” networks, defined as those with stronger functional relationships to the primary target network (Seeley et al., 2008). We reasoned that these observations might be best explained within a connectivity-based framework.