The Dying Forward Hypothesis of ALS: Tracing Its History

Andrew Eisen

doi:10.3390/brainsci11030300

Abstract

The site of origin of amyotrophic lateral sclerosis (ALS), although unsettled, is increasingly recognized as being cortico-fugal, which is a dying-forward process primarily starting in the corticomotoneuronal system. A variety of iterations of this concept date back to over 150 years. Recently, the hallmark TAR DNA-binding protein 43 (TDP-43) pathology, seen in >95% of patients with ALS, has been shown to be largely restricted to corticofugal projecting neurons (“dying forward”). Possibly, soluble but toxic cytoplasmic TDP-43 could enter the axoplasm of Betz cells, subsequently causing dysregulation of nuclear protein in the lower brainstem and spinal cord anterior horn cells. As the disease progresses, cortical involvement in ALS becomes widespread, including or starting with frontotemporal dementia, implying a broader view of ALS as a brain disease. The onset at the motor and premotor cortices should be considered a nidus at the edge of multiple cortical networks which eventually become disrupted, causing failure of a widespread cortical connectome.

Highlights

Neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS), are complex polygenic diseases, resulting in multisystem impairment of neocortical networks, primarily involving the neocortex
In addition is the association of frontotemporal dementia (FTD), causing language impairment, failing executive function, and deteriorating socialization [5,6]
The histological patterns of TAR DNA-binding protein 43 (TDP-43) pathology in the motor cortex are shared in ALS and FTD, whether they occur together or independently. Both Betz cells, other pyramidal corticofugal neurons in the motor neocortex and alpha-motoneurons of the lower brainstem and spinal cord become involved at the beginning of the pathological cascade underlying ALS

Summary

Introduction

Neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS), are complex polygenic diseases, resulting in multisystem impairment of neocortical networks, primarily involving the neocortex. The histological patterns of TDP-43 pathology in the motor cortex are shared in ALS and FTD, whether they occur together or independently Both Betz cells, other pyramidal corticofugal neurons in the motor neocortex and alpha-motoneurons of the lower brainstem and spinal cord become involved at the beginning of the pathological cascade underlying ALS. Both Betz cells, other pyramidal corticofugal neurons in the motor neocortex and alpha-motoneurons of the lower brainstem and spinal cord become involved at the beginning of the pathological. This brief review traces how ALS came to be accepted as a primary disease of the human brain and in particular, its motor and pre-motor cortices

Nineteenth Century

Twentieth Century

The Growth of Electrophysiological Support

Beyond the Motor System

Findings

Conclusions