Multimodal spatial transcriptomics redefines cortical pathology in Huntington's disease.

Layer 5-6 near-projecting and L6b deep-layer excitatory neurons in Huntington’s disease cortex show >50% loss, linked to large somatic CAG expansions (>450 ± 55 CAGs).

• Why it matters: It remains unclear how somatic CAG repeat instability and huntingtin (HTT) inclusions relate to selective cell loss in the human brain.
• What they did: The study developed multimodal spatial transcriptomics with subcellular resolution to measure somatic CAG repeat lengths and eight pathology markers, imaging 428,173 cells in control and HD cortex.
• The result: Intranuclear inclusions peak at intermediate somatic repeat expansions (250–350 CAGs) and associate with broader transcriptional changes than somatic repeat expansion alone, enabling cross-cell-type mapping of repeat and protein pathology.