ReviewBrain sciences2021
The Dying Forward Hypothesis of ALS: Tracing Its History.
Review in Brain sciences, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 37 papers.
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
37 citing papers in PubMed, 53 citations in OpenAlex.
- Lateral sclerosis in amyotrophic lateral sclerosis is an upper motor neuron distal axonopathy ("dying back"): a clinical-neuropathological study.Acta neuropathologica · 2026Article
- Pridopidine Mediated Sigma-1 Receptor Activation and Therapeutic Implications in Neurodegenerative Diseases.Neurology international · 2026Review
- Dynamic integration of skeletal muscle signals via extracellular vesicles in motor neuron diseases.Acta neuropathologica communications · 2026Review
- BDNF insufficiency exacerbates ALS progression.Cell reports. Medicine · 2026Article
- Impact of tongue exercise on hypoglossal axis survival, structure, and output in a rodent model of hypoglossal motor neuron degeneration.Journal of neurophysiology · 2026Article
- Artificial Intelligence for Natural Products Drug Discovery in Neurodegenerative Therapies: A Review.Biomolecules · 2026Review
- Amyotrophic lateral sclerosis represents corticomotoneuronal system failure.Muscle & nerve · 2025Review
- Resting-State EEG Oscillations in Amyotrophic Lateral Sclerosis (ALS): Toward Mechanistic Insights and Clinical Markers.Journal of clinical medicine · 2025Review
- Twitch force in human Amyotrophic Lateral Sclerosis.Frontiers in neurology · 2025Article
- Review
- New perspectives of the role of skeletal muscle derived extracellular vesicles in the pathogenesis of amyotrophic lateral sclerosis: the 'dying back' hypothesis.Journal of extracellular biology · 2024Review
- Structural basis for the rescue of hyperexcitable cells by the amyotrophic lateral sclerosis drug Riluzole.Nature communications · 2024Article
- Review
- Nanoplastics and Neurodegeneration in ALS.Brain sciences · 2024Review
- Review
- How do we get from hyperexcitability to excitotoxicity in amyotrophic lateral sclerosis?Brain : a journal of neurology · 2024Review
- VEGF expression disparities in brainstem motor neurons of the SOD1Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics · 2024Article
- Skeletal muscle as a molecular and cellular biomarker of disease progression in amyotrophic lateral sclerosis: a narrative review.Neural regeneration research · 2024Review
- Betz cells of the primary motor cortex.The Journal of comparative neurology · 2024Review
- Neuromuscular Junction-on-a-Chip for Amyotrophic Lateral Sclerosis Modeling.Methods in molecular biology (Clifton, N.J.) · 2024Article
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
1 author at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
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.
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What OpenQuestion holds
Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.