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Despite the unifying pathological hallmark of TDP\u201043 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 <jats:italic>The Journal of Pathology<\/jats:italic>, Banerjee, Elliott <jats:italic>et al<\/jats:italic> use region\u2010specific 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\u2010inflammatory IL\u20106 in the cognitively affected group and anti\u2010inflammatory IL\u20101 in the cognitively unaffected group. They then utilised BaseScope\u2122 <jats:italic>in situ<\/jats:italic> hybridisation and immunohistochemistry to validate upregulation of <jats:italic>NLRP3<\/jats:italic>, an activator of the inflammasome, in the cognitively affected group, and upregulation of <jats:italic>SIRT2<\/jats:italic>, an inhibitor of <jats:italic>NLRP3<\/jats:italic>, in the cognitively unaffected group. In summary, Banerjee, Elliott <jats:italic>et al<\/jats:italic> demonstrate the usefulness of combining a well\u2010curated 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. \u00a9 2022 The Pathological Society of Great Britain and Ireland.<\/jats:p>","DOI":"10.1002\/path.5897","type":"journal-article","created":{"date-parts":[[2022,3,27]],"date-time":"2022-03-27T22:46:10Z","timestamp":1648421170000},"page":"251-254","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Markers of cognitive resilience and a framework for investigating clinical heterogeneity in <scp>ALS<\/scp><sup>\u2020<\/sup>"],"prefix":"10.1002","volume":"257","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0255-407X","authenticated-orcid":false,"given":"Puja 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