When ICNs are obtained using hierarchical graph clustering of functional correlation networks, they are mathematically congruent with eigenmodes of network

Laplacian (Kondor and Lafferty, 2002). This congruence may explain why dementias appear to fall into distinct ICNs—a strictly mechanical consequence of diffusive network dynamics. Even with possibly random starting configurations, network dynamics are sufficient to produce regional specificity; however, this does not imply that the conventional focal origin or selective vulnerability hypotheses are incorrect. It could be that the starting configuration is dictated by selective vulnerability due to various stressors (Saxena and Caroni, 2011, Palop et al., 2006, Braak et al., 2000 and Seeley et al., 2009), but the subsequent patterns are determined by MS-275 macroscopic network dynamics. Our model merely accommodates a conception of these diseases

that is fully consistent with known findings but does not require focal origin or selective vulnerability. Our model is based on current evidence of prion-like protein misfolding, which propagates within neurons as well as transsynaptically, where retrograde axonal transport deficits cut off the growth-factor supply to projection find more neurons, begetting axonal degeneration, synapse loss, and postsynaptic dendrite retraction. There is mounting neuropathological evidence that numerous disease proteins, including tau, alpha-synuclein, beta-amyloid, and TDP-43, have the capacity to misfold and march through neural circuits via transsynaptic spread ( Palop and Mucke, 2010 and Frost et al., 2009b). If a common concentration-dependent diffusive prion-like process can reproduce subsequent atrophy patterns, this raises a somewhat unorthodox

possibility that diverse degenerative etiologies have common macroscopic consequences. Indeed, our model does not differentiate between individual proteopathic carriers, bunching them together into a generalized old “disease factor.” This is justified on two grounds. First, there is a considerable diversity of published opinion on the etiology of neurodegeneration (Saxena and Caroni, 2011) and the effect of individual misfolding proteins (Whitwell et al., 2009, Palop and Mucke, 2010 and Frost et al., 2009b). Second, and more important, the specific biochemical properties of the prion-like agent may be inconsequential for the macroscopic and chronic manifestation of disease, as evidenced from recent joint histopathological/morphometric studies. The idea that proteopathic carriers with varied etiology can have a shared progression mechanism via “permissible templating” was first raised by Hardy (2005). The spatial distribution of beta amyloid pathology in AD is poorly correlated with whole brain atrophy patterns ( Rabinovici et al., 2010), while tau is well-correlated.