Do astrocytes exist in discrete A1/A2 subtypes or along a continuous activation spectrum in human neurodegeneration?

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Description

The skeptic challenged the fundamental A1/A2 binary model underlying multiple hypotheses, but this wasn’t resolved. The answer critically determines whether subtype-switching therapies are even conceptually valid for human disease.

Source: Debate session sess_astrocyte-subtypes (Analysis: astrocyte-subtypes)

Resolution criteria

Gap closes when: (1) Single-nucleus RNA-seq of astrocytes from human postmortem AD, PD, and ALS tissue (>= 15 donors per disease, >= 500 astrocytes per donor) is analyzed by both graph-based clustering and trajectory/pseudotime methods; and (2) the analysis formally tests the discrete model (gap statistics, silhouette coefficient) vs. continuous model (diffusion pseudotime entropy) with a pre-registered analytical plan; and (3) the dominant model is validated by orthogonal protein-level readout (spatial transcriptomics or multiplex IHC). Deliverable: pre-registered analysis, public snRNA-seq dataset, and model comparison statistics.

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