Campaign run · Parkinson's disease

parkinson-asyn-propagation-r1

PDTested, stopped before reviewAttempt 1 of 2 at this topic

Does a Susceptible-Infected-Removed (SIR) compartmental model of α-synuclein spread between brain regions, parameterised by Fullard 2024 multi-region snRNA-seq cell-type fractions and SNCA expression, plus Allen Human Brain Connectivity Atlas projection edges, reproduce the canonical Braak staging order (DMNX → SNpc → cingulate → M1 → V1) at qualitatively correct relative timing?

212

Supported 2
Not supported 1
Inconclusive 2

This run in the hypothesis explorer

Status

How far it got: Tested, stopped before review
Tested at least one hypothesis, then stopped before the multi-agent review stage.
Hypotheses: 5 nominated; 5 evaluated.
Recorded status: Halted. The run recorded a final status of halted: it was closed without being marked done. A halted run can still have tested hypotheses and written a final report.
Census class: Success. Census class is a label from an earlier, process-level census of the campaign. It does not map one-to-one onto the stages above. How the classes compare.

Research question

The sentence under the run id is quoted from this brief.

Full research brief given to the run

Braak staging (Braak 2003 Neurobiol Aging) is the most-cited spatial-temporal claim in PD neuropathology, but its mechanistic explanation — that α-syn spreads cell-to-cell along a connectome gradient, modulated by selective vulnerability — has been tested in mouse atlases (Henderson 2019, Zheng 2019) but not at human cell-type granularity. Fullard 2024 provides the missing per-region cell-fraction and SNCA-expression priors.

Hypotheses (pre-registered):

H1 (primary — Braak rank-order recovery): An SIR + connectivity model with SNCA-expression-weighted per-region susceptibility recovers the rank-order of predicted regional peak-prevalence times consistent with Braak rank, with Spearman ρ ≥ 0.7 across the 5 modelled regions (DMNX, SNpc, cingulate, M1, V1). Bootstrap 95% CI of ρ excludes 0.

H2 (secondary — SNCA-weighting necessity): Ablating the SNCA-expression weighting (uniform susceptibility across regions) degrades rank-order recovery by ≥ 0.3 in Spearman ρ. (Test that cell-specific susceptibility is necessary, not sufficient.)

H3 (secondary — cingulate cell-type prediction): The model predicts which cingulate cell types reach infection threshold first; we pre-register "excitatory layer-5/6 neurons" as the top prediction. The top-3 model-predicted cell types overlap ≥ 2 with the top-3 Lewy-burdened cell types reported by Goralski 2024 LAMDA (Zenodo 10.5281/zenodo.10729767).

H4 (secondary — vagal-route ablation): Removing the DMNX → SN projection edge (parameter ablation) shifts predicted peak-time rank-order by > 1 rank position. A falsifiable mechanistic claim about the vagal spread route.

H5 (secondary — connectome-only vs. cell-autonomous): Compare three models — (A) connectome-only SIR, no cell-type weighting; (B) cell-type-weighted SIR (this proposal's primary); (C) cell-autonomous-only (each region's I trajectory independent of others). Report which best fits Braak rank-order. A finding that (A) or (C) wins is an informative inversion of the spread-only hypothesis.

Null payoff. If no SIR variant recovers Braak rank-order, the connectome-only hypothesis is incomplete and pure cell-autonomous selective vulnerability (independent of spread) dominates. Informative as a head-to-head test of two competing field-level hypotheses.

The research question comes from the topic's current research brief. All attempts at a topic share it; earlier attempts may have started from an earlier wording.

Hypotheses and verdicts

Each hypothesis was written with its decision rule before any analysis (or, for on-the-fly hypotheses, recorded during execution). AI adjudication agents applied that rule to the run's latest outputs and quoted the evidence verbatim. Where the data did not meet the rule, the verdict follows the data, even if the run's own label or report claimed support.

Each hypothesis as pre-registered (a condensed statement with its decision rule), the adjudicated verdict, the verbatim evidence and the adjudicator's note.
ID	Hypothesis and decision rule	Verdict
H1Pre-registered	SNCA-weighted SIR (model B) recovers Braak rank order of t_peak across 5 regions (Spearman rho>=0.70, bootstrap CI lower bound >0).	SupportedIn the explorer
Evidence (verbatim from the run outputs) Pre-registered threshold: ρ ≥ 0.70 with CI excluding 0. Both criteria met. H1 is supported. Adjudication note rho=1.000, degenerate CI [1,1], perm p=0.0083. Caveat: literature-fallback (murine) connectivity, connectome-only model A also rho=1.0 (ceiling). Superseded sibling run parkinson-asyn-propagation-r2 with Allen connectivity found H1 NOT SUPPORTED. This run never reached write/review.
H2Pre-registered	Removing SNCA weighting (model A) degrades rho by >=0.30 vs model B (paired bootstrap CI excl. 0).	Not supportedIn the explorer
Evidence (verbatim from the run outputs) Δρ(B − A) = 0.000 (95% CI [0.000, 0.000]; p_directional = 0.998) Adjudication note Both models at ceiling.
H3Pre-registered	Within PFC, model predicts excitatory neurons reach infection threshold first; model top-3 overlaps >=2 with LAMDA pSyn-enriched top-3.	InconclusiveIn the explorer
Evidence (verbatim from the run outputs) Vocabulary mismatch (pSyn+ TrueID format not matching profile index barcodes) forced use of all 48,702 profile rows, biasing LAMDA top-3 toward abundant cell types Adjudication note OmiCairn: NOT SUPPORTED (overlap 0, EN ranked 3rd). But LAMDA side is an all-spots proxy, and model PFC top-3 contains DMNX_Neu/GPI_Neu (annotation artefact, judged uninterpretable in sibling run parkinson-asyn-propagation-r2). Strict reading: NOT_SUPPORTED.
H4Pre-registered	Ablating DMNX->GPi edge shifts predicted rank of at least one region by >1 position.	SupportedIn the explorer
Evidence (verbatim from the run outputs) Maximum rank shift = 3 > pre-registered threshold of > 1. Adjudication note Deterministic model result under literature-fallback connectivity; reversed (0 shift) in sibling run parkinson-asyn-propagation-r2 with Allen connectivity.
H5Pre-registered	Model-family comparison: rank connectome-only (A), SNCA-weighted (B, primary), cell-autonomous (C) by Braak rho.	InconclusiveIn the explorer
Evidence (verbatim from the run outputs) Models A and B tie at ρ = 1.000; Model C achieves ρ = 0.400. Adjudication note Descriptive; A=B at ceiling, B-C Delta 0.601 CI [0, 2] p=0.336.