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Record W3133902446 · doi:10.3390/brainsci11030300

The Dying Forward Hypothesis of ALS: Tracing Its History

2021· review· en· W3133902446 on OpenAlexaff
Andrew Eisen

Bibliographic record

VenueBrain Sciences · 2021
Typereview
Languageen
FieldMedicine
TopicAmyotrophic Lateral Sclerosis Research
Canadian institutionsUniversity of British Columbia
Fundersnot available
KeywordsAmyotrophic lateral sclerosisNeuroscienceBrainstemFrontotemporal dementiaMotor neurone diseaseSpinal cordMotor cortexBiologyDementiaDiseasePsychologyMedicinePathology

Abstract

fetched live from OpenAlex

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.

Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.

How this classification was reachedexpand

Full frame machine prediction

Teacher imitation

Not calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.

metaresearch head score (Codex)0.002
metaresearch head score (Gemma)0.002
Version: metacan-v3-hybrid-931329e0061cValidation status: machine_predicted_unvalidated
Candidate categoriesnone
Consensus categoriesnone
DomainCandidate signal: none · Consensus signal: none
Study designCandidate signal: Theoretical or conceptual · Consensus signal: none
GenreCandidate signal: Review · Consensus signal: Review
Teacher disagreement score0.003
Threshold uncertainty score0.013

Distilled classifier scores by category (both heads)

CategoryCodexGemma
Metaresearch0.0020.002
Meta-epidemiology (narrow)0.0010.000
Meta-epidemiology (broad)0.0020.001
Bibliometrics0.0030.003
Science and technology studies0.0010.002
Scholarly communication0.0020.004
Open science0.0010.001
Research integrity0.0020.004
Insufficient payload (model declined to judge)0.0020.001

Machine scores (provisional)

The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.

Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.

Opus teacher head0.327
GPT teacher head0.423
Teacher spread0.096 · how far apart the two teachers sit on this one work
Validation statusscore_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from it

Classification

machine, unvalidated

Machine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.

The models applied no category: nothing in the taxonomy fit this work.
Study designTheoretical or conceptual
Domainnot available
GenreReview

How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".

Quick stats

Citations57
Published2021
Admission routes1
Has abstractyes

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