  The motor neuron disease amyotrophic lateral sclerosis (ALS) typically begins
with localized muscle weakness. Progressive, widespread paralysis often follows
over a few years. Does the disease begin with local changes in a small piece of
neural tissue and then spread? Or does neural decay happen independently across
diverse spatial locations? The distinction matters, because local initiation
may arise by local changes in a tissue microenvironment, by somatic mutation,
or by various epigenetic or regulatory fluctuations in a few cells. A local
trigger must be coupled with a mechanism for spread. By contrast, independent
decay across spatial locations cannot begin by a local change, but must depend
on some global predisposition or spatially distributed change that leads to
approximately synchronous decay. This article outlines the conceptual frame by
which one contrasts local triggers and spread versus parallel spatially
distributed decay. Various neurodegenerative diseases differ in their
mechanistic details, but all can usefully be understood as falling along a
continuum of interacting local and global processes. Cancer provides an example
of disease progression by local triggers and spatial spread, setting a
conceptual basis for clarifying puzzles in neurodegeneration. Heart disease
also has crucial interactions between global processes, such as circulating
lipid levels, and local processes in the development of atherosclerotic
plaques. The distinction between local and global processes helps to understand
these various age-related diseases.
