{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,25]],"date-time":"2026-08-25T22:50:27Z","timestamp":1787698227972,"version":"build-2784847793"},"reference-count":85,"publisher":"Oxford University Press (OUP)","issue":"12","license":[{"start":{"date-parts":[[2023,7,14]],"date-time":"2023-07-14T00:00:00Z","timestamp":1689292800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100010269","name":"Wellcome Trust","doi-asserted-by":"publisher","award":["108890\/Z\/15\/Z"],"award-info":[{"award-number":["108890\/Z\/15\/Z"]}],"id":[{"id":"10.13039\/100010269","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Pathological Society and Jean Shanks Foundation","award":["CLSG 202002"],"award-info":[{"award-number":["CLSG 202002"]}]},{"DOI":"10.13039\/100000002","name":"NIH","doi-asserted-by":"publisher","award":["5-R01-NS127186-02"],"award-info":[{"award-number":["5-R01-NS127186-02"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Motor Neuron Disease","award":["2021\/MNDS\/RP\/8440GREG"],"award-info":[{"award-number":["2021\/MNDS\/RP\/8440GREG"]}]},{"name":"Sir Henry Dale Fellowship"},{"DOI":"10.13039\/501100000288","name":"Royal Society","doi-asserted-by":"publisher","award":["215454\/Z\/19\/Z"],"award-info":[{"award-number":["215454\/Z\/19\/Z"]}],"id":[{"id":"10.13039\/501100000288","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2023,12,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by progressive loss of upper and lower motor neurons. ALS is on a pathogenetic disease spectrum with frontotemporal dementia, referred to as ALS-frontotemporal spectrum disorder (ALS-FTSD). For mutations associated with ALS-FTSD, such as the C9orf72 hexanucleotide repeat expansion, the molecular factors associated with heterogeneity along this spectrum require further characterization.<\/jats:p>\n               <jats:p>Here, using a targeted NanoString molecular barcoding approach, we interrogate neuroinflammatory dysregulation and heterogeneity at the level of gene expression in post-mortem motor cortex tissue from a cohort of clinically heterogeneous C9-ALS-FTSD cases.<\/jats:p>\n               <jats:p>We identified 20 dysregulated genes in C9-ALS-FTSD, with enrichment of microglial and inflammatory response gene sets. Two genes with significant correlations to available clinical metrics were selected for validation: FKBP5, a correlate of cognitive function, and brain-derived neurotrophic factor (BDNF), a correlate of disease duration. FKBP5 and its signalling partner, NF-\u03baB, appeared to have a cell type-specific staining distribution, with activated (i.e. nuclear) NF-\u03baB immunoreactivity in C9-ALS-FTSD. Expression of BDNF, a correlate of disease duration, was confirmed to be higher in individuals with long compared to short disease duration using BaseScope\u2122 in situ hybridization. Our analyses also revealed two distinct neuroinflammatory panel signatures (NPS), NPS1 and NPS2, delineated by the direction of expression of proinflammatory, axonal transport and synaptic signalling pathways. We compared NPS between C9-ALS-FTSD cases and those from sporadic ALS and SOD1-ALS cohorts and identified NPS1 and NPS2 across all cohorts. Moreover, a subset of NPS was also able to separate publicly available RNA sequencing data from independent C9-ALS and sporadic ALS cohorts into two inflammatory subgroups.<\/jats:p>\n               <jats:p>Importantly, NPS subgroups did not clearly segregate with available demographic, genetic, clinical or pathological features, highlighting the value of molecular stratification in clinical trials for inflammatory subgroup identification. Our findings thus underscore the importance of tailoring therapeutic approaches based on distinct molecular signatures that exist between and within ALS-FTSD cohorts.<\/jats:p>","DOI":"10.1093\/brain\/awad243","type":"journal-article","created":{"date-parts":[[2023,7,14]],"date-time":"2023-07-14T17:48:54Z","timestamp":1689356934000},"page":"5124-5138","source":"Crossref","is-referenced-by-count":19,"title":["Distinct neuroinflammatory signatures exist across genetic and sporadic amyotrophic lateral sclerosis cohorts"],"prefix":"10.1093","volume":"146","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0996-1110","authenticated-orcid":false,"given":"Olivia M","family":"Rifai","sequence":"first","affiliation":[{"name":"Translational Neuroscience PhD Programme, Centre for Clinical Brain Sciences, University of Edinburgh , Edinburgh, EH8 9XD , UK"},{"name":"Centre for Clinical Brain Sciences, University of Edinburgh , Edinburgh, EH16 4SB , UK"},{"name":"UK Dementia Research Institute, University of Edinburgh , Edinburgh , EH16 4SB , UK"},{"name":"Euan MacDonald Centre for Motor Neurone Disease Research, University of Edinburgh , Edinburgh , EH16 4SB , UK"},{"name":"Centre for Discovery Brain Sciences, University of Edinburgh , Edinburgh, EH8 9XD , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Judi","family":"O\u2019Shaughnessy","sequence":"additional","affiliation":[{"name":"Centre for Clinical Brain Sciences, University of Edinburgh , Edinburgh, EH16 4SB , UK"},{"name":"Euan MacDonald Centre for Motor Neurone Disease Research, University of Edinburgh , Edinburgh , EH16 4SB , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6269-6408","authenticated-orcid":false,"given":"Owen R","family":"Dando","sequence":"additional","affiliation":[{"name":"UK Dementia Research Institute, University of Edinburgh , Edinburgh , EH16 4SB , UK"},{"name":"Centre for Discovery Brain Sciences, University of Edinburgh , Edinburgh, EH8 9XD , UK"},{"name":"Simons Initiative for the Developing Brain, University of Edinburgh , Edinburgh, EH8 9XF , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alison F","family":"Munro","sequence":"additional","affiliation":[{"name":"Cancer Research UK Edinburgh Centre, Institute of Genetics and Cancer, The University of Edinburgh , Edinburgh, EH4 2XU , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0113-6551","authenticated-orcid":false,"given":"Michael D E","family":"Sewell","sequence":"additional","affiliation":[{"name":"Translational Neuroscience PhD Programme, Centre for Clinical Brain Sciences, University of Edinburgh , Edinburgh, EH8 9XD , UK"},{"name":"UK Dementia Research Institute, University of Edinburgh , Edinburgh , EH16 4SB , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sharon","family":"Abrahams","sequence":"additional","affiliation":[{"name":"Human Cognitive Neuroscience-Psychology, School of Philosophy, Psychology and Language Sciences, University of Edinburgh , Edinburgh, EH8 9AD , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fergal M","family":"Waldron","sequence":"additional","affiliation":[{"name":"Institute of Medical Sciences, University of Aberdeen , Aberdeen, AB25 2ZD , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher R","family":"Sibley","sequence":"additional","affiliation":[{"name":"Euan MacDonald Centre for Motor Neurone Disease Research, University of Edinburgh , Edinburgh , EH16 4SB , UK"},{"name":"Centre for Discovery Brain Sciences, University of Edinburgh , Edinburgh, EH8 9XD , UK"},{"name":"Simons Initiative for the Developing Brain, University of Edinburgh , Edinburgh, EH8 9XF , UK"},{"name":"Institute of Quantitative Biology, Biochemistry and Biotechnology, School of Biological Sciences, University of Edinburgh, The King\u2019s Buildings , Edinburgh, EH9 3FF , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jenna M","family":"Gregory","sequence":"additional","affiliation":[{"name":"Institute of Medical Sciences, University of Aberdeen , Aberdeen, AB25 2ZD , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2023,7,14]]},"reference":[{"key":"2023120106160023900_awad243-B1","doi-asserted-by":"crossref","first-page":"323","DOI":"10.1016\/S1474-4422(12)70043-1","article-title":"Frequency of the C9orf72 hexanucleotide repeat expansion in patients with amyotrophic lateral sclerosis and frontotemporal dementia: A cross-sectional study","volume":"11","author":"Majounie","year":"2012","journal-title":"Lancet Neurol"},{"key":"2023120106160023900_awad243-B2","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1038\/nature20413","article-title":"Decoding ALS: From genes to 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associated with hexanucleotide repeat expansion in C9ORF72","volume":"122","author":"Murray","year":"2011","journal-title":"Acta Neuropathol"},{"key":"2023120106160023900_awad243-B6","first-page":"1","article-title":"C9ORF72 hexanucleotide repeats in behavioral and motor neuron disease: Clinical heterogeneity and pathological diversity","volume":"3","author":"Yokoyama","year":"2014","journal-title":"Am J Neurodegener Dis"},{"key":"2023120106160023900_awad243-B7","doi-asserted-by":"crossref","first-page":"575","DOI":"10.1002\/mdc3.12677","article-title":"C9orf72 and its relevance in parkinsonism and movement disorders: A comprehensive review of the literature","volume":"5","author":"Bourinaris","year":"2018","journal-title":"Mov Disord Clin Pract."},{"key":"2023120106160023900_awad243-B8","doi-asserted-by":"crossref","first-page":"e1498","DOI":"10.1212\/WNL.0000000000006344","article-title":"Psychiatric disorders in C9orf72 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