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Post-mortem and in vivo imaging studies have shown brain inflammation early in these conditions, proportional to symptom severity and rate of progression. However, evidence for corresponding blood markers of inflammation and their relationships to central inflammation and clinical outcome are limited. There is a pressing need for such scalable, accessible and mechanistically relevant blood markers because these will reduce the time, risk and costs of experimental medicine trials. We therefore assessed inflammatory patterns of serum cytokines from 214 patients with clinical syndromes associated with frontotemporal lobar degeneration in comparison to healthy controls, including their correlation with brain regional microglial activation and disease progression.<\/jats:p>\n                  <jats:p>Serum assays used the MesoScale Discovery V-Plex-Human Cytokine 36 plex panel plus five additional cytokine assays. A subgroup of patients underwent 11C-PK11195 mitochondrial translocator protein PET imaging, as an index of microglial activation. A principal component analysis was used to reduce the dimensionality of cytokine data, excluding cytokines that were undetectable in &amp;gt;50% of participants. Frequentist and Bayesian analyses were performed on the principal components to compare each patient cohort with controls and test for associations with central inflammation, neurodegeneration-related plasma markers and survival.<\/jats:p>\n                  <jats:p>The first component identified by the principal component analysis (explaining 21.5% variance) was strongly loaded by pro-inflammatory cytokines, including TNF-\u03b1, TNF-R1, M-CSF, IL-17A, IL-12, IP-10 and IL-6. Individual scores of the component showed significant differences between each patient cohort and controls. The degree to which a patient expressed this peripheral inflammatory profile at baseline was correlated negatively with survival (higher inflammation, shorter survival), even when correcting for baseline clinical severity. Higher pro-inflammatory profile scores were associated with higher microglial activation in frontal and brainstem regions, as quantified with 11C-PK11195 mitochondrial translocator protein PET. A permutation-based canonical correlation analysis confirmed the association between the same cytokine-derived pattern and central inflammation across brain regions in a fully data-based manner.<\/jats:p>\n                  <jats:p>This data-driven approach identified a pro-inflammatory profile across the frontotemporal lobar degeneration clinical spectrum, which is associated with central neuroinflammation and worse clinical outcome. Blood-based markers of inflammation could increase the scalability and access to neuroinflammatory assessment of people with dementia, to facilitate clinical trials and experimental medicine studies.<\/jats:p>","DOI":"10.1093\/brain\/awae269","type":"journal-article","created":{"date-parts":[[2024,8,14]],"date-time":"2024-08-14T17:57:27Z","timestamp":1723658247000},"page":"493-505","source":"Crossref","is-referenced-by-count":47,"title":["Blood inflammation relates to neuroinflammation and survival in frontotemporal lobar degeneration"],"prefix":"10.1093","volume":"148","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8923-9656","authenticated-orcid":false,"given":"Maura","family":"Malpetti","sequence":"first","affiliation":[{"name":"Department of Clinical Neurosciences and Cambridge University Hospitals NHS Trust, University of Cambridge , Cambridge CB2 0SZ ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Swann","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, University of Cambridge , Cambridge CB2 0QQ ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kamen A","family":"Tsvetanov","sequence":"additional","affiliation":[{"name":"Department of Clinical Neurosciences and Cambridge University Hospitals NHS Trust, University of Cambridge , Cambridge CB2 0SZ ,","place":["UK"]},{"name":"Department of Psychology, University of Cambridge , Cambridge CB2 3EB ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3052-3879","authenticated-orcid":false,"given":"Leonidas","family":"Chouliaras","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, University of Cambridge , Cambridge CB2 0QQ ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexandra","family":"Strauss","sequence":"additional","affiliation":[{"name":"Department of Clinical Neurosciences and Cambridge University Hospitals NHS Trust, University of Cambridge , Cambridge CB2 0SZ ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tanatswa","family":"Chikaura","sequence":"additional","affiliation":[{"name":"Department of Clinical Neurosciences and Cambridge University Hospitals NHS Trust, University of Cambridge , Cambridge CB2 0SZ ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0813-0670","authenticated-orcid":false,"given":"Alexander G","family":"Murley","sequence":"additional","affiliation":[{"name":"Department of Clinical Neurosciences and Cambridge University Hospitals NHS Trust, University of Cambridge , Cambridge CB2 0SZ ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicholas J","family":"Ashton","sequence":"additional","affiliation":[{"name":"Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg , M\u00f6lndal S-431 80 ,","place":["Sweden"]},{"name":"Wallenberg Centre for Molecular Medicine, University of Gothenburg , Gothenburg S-413 45 ,","place":["Sweden"]},{"name":"King\u2019s College London, Institute of Psychiatry, Psychology and Neuroscience, Maurice Wohl Institute Clinical Neuroscience Institute , London SE5 9RT ,","place":["UK"]},{"name":"NIHR Biomedical Research Centre for Mental Health and Biomedical Research Unit for Dementia at South London and Maudsley NHS Foundation , London SE5 8AF ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Barker","sequence":"additional","affiliation":[{"name":"NIHR Cambridge Biomedical Research Centre, Core Biochemical Assay Laboratory, Cambridge University Hospitals NHS Foundation Trust , Cambridge CB2 0QQ ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter Simon","family":"Jones","sequence":"additional","affiliation":[{"name":"Department of Clinical Neurosciences and Cambridge University Hospitals NHS Trust, University of Cambridge , Cambridge CB2 0SZ ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tim D","family":"Fryer","sequence":"additional","affiliation":[{"name":"Department of Clinical Neurosciences and Cambridge University Hospitals NHS Trust, University of Cambridge , Cambridge CB2 0SZ ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Young T","family":"Hong","sequence":"additional","affiliation":[{"name":"Department of Clinical Neurosciences and Cambridge University Hospitals NHS Trust, University of Cambridge , Cambridge CB2 0SZ ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas E","family":"Cope","sequence":"additional","affiliation":[{"name":"Department of Clinical Neurosciences and Cambridge University Hospitals NHS Trust, University of Cambridge , Cambridge CB2 0SZ ,","place":["UK"]},{"name":"Medical Research Council Cognition and Brain Sciences Unit , University of Cambridge, Cambridge CB2 7EF ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6513-5454","authenticated-orcid":false,"given":"George","family":"Savulich","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, University of Cambridge , Cambridge CB2 0QQ ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2168-2242","authenticated-orcid":false,"given":"Duncan","family":"Street","sequence":"additional","affiliation":[{"name":"Department of Clinical Neurosciences and Cambridge University Hospitals NHS Trust, University of Cambridge , Cambridge CB2 0SZ ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William Richard","family":"Bevan-Jones","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, University of Cambridge , Cambridge CB2 0QQ ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1063-6937","authenticated-orcid":false,"given":"Timothy","family":"Rittman","sequence":"additional","affiliation":[{"name":"Department of Clinical Neurosciences and Cambridge University Hospitals NHS Trust, University of Cambridge , Cambridge CB2 0SZ ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kaj","family":"Blennow","sequence":"additional","affiliation":[{"name":"Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg , M\u00f6lndal S-431 80 ,","place":["Sweden"]},{"name":"Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital , M\u00f6lndal S-431 80 ,","place":["Sweden"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3930-4354","authenticated-orcid":false,"given":"Henrik","family":"Zetterberg","sequence":"additional","affiliation":[{"name":"Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg , M\u00f6lndal S-431 80 ,","place":["Sweden"]},{"name":"Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital , M\u00f6lndal S-431 80 ,","place":["Sweden"]},{"name":"Department of Neurodegenerative Disease, UCL Institute of Neurology , London WC1N 6BG ,","place":["UK"]},{"name":"UK Dementia Research Institute at UCL , London WC1N 6BG ,","place":["UK"]},{"name":"Hong Kong Center for Neurodegenerative Diseases , Clear Water Bay, Hong Kong ,","place":["China"]},{"name":"Wisconsin Alzheimer\u2019s Disease Research Center, University of Wisconsin School of Medicine and Public Health, University of Wisconsin-Madison , Madison, WI 53792 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Franklin I","family":"Aigbirhio","sequence":"additional","affiliation":[{"name":"Department of Clinical Neurosciences and Cambridge University Hospitals NHS Trust, University of Cambridge , Cambridge CB2 0SZ ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0837-5080","authenticated-orcid":false,"given":"John T","family":"O\u2019Brien","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, University of Cambridge , Cambridge CB2 0QQ ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7216-8679","authenticated-orcid":false,"given":"James 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