Figure 3.

Temporal evolution of disease and phenotypic heterogeneity. This schematic illustrates the application of the molecular nexopathy concept to the problem of phenotypic heterogeneity in neurodegenerative disease, using the example of corticobasal degeneration. The inset cartoon (left) shows major functional networks in a stylised normal dominant cerebral hemisphere, colour coded as in Figure 2 (main text). The panels illustrate evolving network involvement shortly after onset of the neurodegenerative insult (t0) and at two arbitrary later time points (t1 and t2). The initial location of the insult (wavy arrow) determines the clinical presentation (behavioural variant frontotemporal dementia, bvFTD; progressive nonfluent aphasia, PNFA; or ‘classical’ corticobasal syndrome, CBS). The core corticobasal functional network (light blue in inset) is involved with disease evolution in each case; however, variable additional involvement of other contiguous functional networks (the salience network, speech production network or default mode network) modulates the phenotype. Each of these phenotypes arises from a common template of network involvement determined by the type of neural connection predominantly involved (here, represented as longer-range distributed intrahemispheric projections); the common nexopathy signature of corticobasal degeneration is revealed in the temporal profile of disease evolution.