Description
The anatomy of neurodegenerative disease can be understood
in terms of two key aspects: onset and progression. Mechanisms controlling
onset timing and location remain mysterious, and each disease features striking
heterogeneity in its onset sites. Regarding progression, network analyses have
revealed that each clinical syndrome reflects degeneration of a specific
large-scale network. Each vulnerable network, in turn, is anchored by a pivotal
“epicenter” whose functional-anatomical connections govern the vulnerability of
other regions, perhaps because prion-like corruptive templating begets trans-synaptic
disease protein spread. I will illustrate these principles with a focus on the
behavioral variant of frontotemporal dementia (bvFTD). BvFTD begins within the “salience network,” a
system anchored by the anterior cingulate and frontoinsular cortices and
specialized for social-emotional-autonomic processing. Patients with bvFTD lose
the capacity for adaptive, real-time behavioral guidance, possibly in part
because salience-driven viscero-autonomic cues and responses are late,
degraded, or improperly modulated.
Within the salience network hubs, Layer 5 von Economo neurons and fork
cells show a particular predilection for disease protein aggregation and cell
death, providing a cellular focus for bvFTD selective vulnerability research
and a potential window into the neural computations that contribute to
sophisticated human social-emotional functions.
Contributors
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William Seeley