Markers of cognitive resilience and a framework for investigating clinical heterogeneity in ALS^†

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder. Despite the unifying pathological hallmark of TDP-43 proteinopathy, ALS is clinically a highly heterogeneous disease, and little is known about the underlying mechanisms driving this phenotypic diversity. In a recent issue of The Journal of Pathology, Banerjee, Elliott et al use region-specific transcriptomic profiling in postmortem brains from a deeply phenotyped clinical cohort of ALS patients to detect molecular signatures differentiating cognitively affected and unaffected patients. They identified differential expression of specific genes, including upregulation of pro-inflammatory IL-6 in the cognitively affected group and anti-inflammatory IL-1 in the cognitively unaffected group. They then utilised BaseScope™ in situ hybridisation and immunohistochemistry to validate upregulation of NLRP3, an activator of the inflammasome, in the cognitively affected group, and upregulation of SIRT2, an inhibitor of NLRP3, in the cognitively unaffected group. In summary, Banerjee, Elliott et al demonstrate the usefulness of combining a well-curated clinical cohort with transcriptomic analysis of pathological samples to identify a perturbed pathway (e.g., the inflammasome), offering opportunities for novel therapeutic targets in ALS. © 2022 The Pathological Society of Great Britain and Ireland.