A.K. performed volumetric analysis of AD/bvFTD/aged patients and extracted the healthy-brain structural

network. She also helped fine-tune the manuscript. M.W. provided guidance, clinical input, and interpretation, MRI data for volumetric analysis, and improvement of the manuscript. A.R. would like to thank Dr. Norman Relkin for valuable advice. “
“Neurodegenerative diseases have long been linked to neural networks by the clinical and anatomical progression observed in patients (Braak and Braak, 1991, Pearson et al., 1985, Saper et al., 1987 and Weintraub and Mesulam, 1996). Emerging network-sensitive neuroimaging techniques selleck chemicals have allowed researchers to demonstrate that the spatial patterning of each disease relates closely to a distinct functional intrinsic connectivity network (ICN), mapped in the healthy brain with task-free or “resting-state” fMRI (Buckner et al.,

2005 and Seeley et al., 2009). Collectively, these findings raise mechanistic questions about whether and how connectivity in health predicts regional neurodegeneration severity in disease. In Alzheimer’s disease, increasing evidence suggests that pathology may begin within key vulnerable “hubs,” defined as central nodes within the target network’s architecture (Buckner et al., 2009). Still, open questions remain with regard to why each disease adopts a network-related spatial pattern. At least four disease-general hypotheses Linsitinib purchase have been offered and can be summarized as (1) “nodal stress,” in which regions subject to heavy network traffic (i.e., “hubs”) undergo activity-related “wear and tear” that gives rise to or worsens disease (Buckner et al., 2009 and Saxena and Caroni, 2011); (2) “transneuronal spread,” in which some toxic agent propagates along network connections, perhaps through “prion-like” templated conformational

change (Baker et al., 1994, Frost and Diamond, 2010, Frost et al., 2009, Jucker and Walker, 2011, Lee et al., 2010, Prusiner, 1984, Ridley et al., 2006 and Walker et al., Non-specific serine/threonine protein kinase 2006); (3) “trophic failure,” in which network connectivity disruption undermines inter-nodal trophic factor support, accelerating disease within nodes lacking collateral trophic sources (Appel, 1981 and Salehi et al., 2006); and (4) “shared vulnerability,” in which networked regions feature a common gene or protein expression signature that confers disease-specific susceptibility evenly distributed throughout the network. Although these hypothesized network degeneration mechanisms need not be considered mutually exclusive, they make competing predictions with regard to how healthy network architecture should influence disease-associated regional vulnerability (Figure 1).