Focality, stochasticity and neuroanatomic propagation in ALS pathogenesis

Amyotrophic lateral sclerosis (ALS) phenotypes such as limb ALS, bulbar ALS, primary lateral sclerosis and primary muscular atrophy are highly heterogeneous and exist on a continuum. These are largely determined by the neuroanatomy of the underlying pathological changes, which can be clinically imputed. Deconstructing these early in disease, before temporal-spatial summation induces complexity, shows that ALS begins focally at a seemingly random location and progresses contiguously. This suggests that focality and anatomic propagation of pathology are significant parts of pathogenesis disease propagates over space as well as progresses over time. Focality and neuroanatomic propagation can explain how dominant genetic traits manifest with heterogeneous phenotypes, since the anatomic site of outbreak is a prime determinant of phenotype. Focality and neuroanatomic propagation can also explain why frontotemporal dementia (FTD), a neurodegeneration closely related to ALS, has heterogeneous phenotypes, since here too the anatomic site of the outbreak is a prime determinant of phenotype. There are two distinct types of neuroanatomic propagation: contiguous propagation, which occurs side-to-side regionally through the extracellular matrix independent of synaptic connection; and network propagation, which occurs end-to-end dependent on synaptic connections and axonal transmission in connected neuronal networks. The molecular basis of neuroanatomic propagation is unknown, although prion-like misfolding and templating of pathogenic proteins is a compelling unifying hypothesis. (C) 2014 Elsevier Inc. All rights reserved.