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

Mehta, Puja R; Lashley, Tammaryn; Fratta, Pietro; Bampton, Alexander; (2022) Markers of cognitive resilience and a framework for investigating clinical heterogeneity in ALS. Journal of Pathology , 257 (3) pp. 251-254. 10.1002/path.5897. Green open access

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Abstract

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.

Type: Article
Title: Markers of cognitive resilience and a framework for investigating clinical heterogeneity in ALS
Location: England
Open access status: An open access version is available from UCL Discovery
DOI: 10.1002/path.5897
Publisher version: https://doi.org/10.1002/path.5897
Language: English
Additional information: This version is the author accepted manuscript. For information on re-use, please refer to the publisher's terms and conditions.
Keywords: amyotrophic lateral sclerosis, motor neuron disease, cognition, inflammasome, NLRP3, SIRT2, IL-1, IL-6
UCL classification: UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Neurodegenerative Diseases
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Department of Neuromuscular Diseases
URI: https://discovery.ucl.ac.uk/id/eprint/10146817
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