The Dying Forward Hypothesis of ALS: Tracing Its History

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.