Up to 50% of amyotrophic lateral sclerosis patients present with cognitive deficits in addition to motor dysfunction, but the molecular mechanisms underlying diverse clinical and pathological presentations remain poorly understood. There is therefore an unmet need to identify molecular drivers of cognitive dysfunction to enable better therapeutic targeting and prognostication. To address this, we employed a non-biased approach to identify molecular targets using a deeply-phenotyped, clinically stratified cohort of cognitively affected and unaffected brain regions from three brain regions of thirteen amyotrophic lateral sclerosis patients with the same cognitive screening test performed during life. Using Nanostring molecular barcoding as a sensitive mRNA sequencing technique on post-mortem tissue, we profiled a data driven panel of 770 genes using the Neuropathology panel, followed by region and cell-type specific validation using BaseScope in situ hybridisation and immunohistochemistry. We identified 50 significantly dysregulated genes that are distinct between cognitively affected and unaffected brain regions. Using BaseScope in situ hybridisation we also demonstrate that macromolecular complex regulation, notably NLRP3-inflammasome modulation, is a potential, therapeutically-targetable, pathological correlate of cognitive resilience in ALS.

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