Blood inflammation relates to neuroinflammation and survival in frontotemporal lobar degeneration

Maura Malpetti; Peter Swann; Kamen A Tsvetanov; Leonidas Chouliaras; Alexandra Strauss; Tanatswa Chikaura; Alexander G Murley; Nicholas J Ashton; Peter Barker; P Simon Jones; Tim D Fryer; Young T Hong; Thomas E Cope; George Savulich; Duncan Street; W Richard Bevan-Jones; Timothy Rittman; Kaj Blennow; Henrik Zetterberg; Franklin I Aigbirhio; John T O'Brien; James B Rowe

doi:10.1093/brain/awae269

Blood inflammation relates to neuroinflammation and survival in frontotemporal lobar degeneration

Brain. 2024 Aug 19:awae269. doi: 10.1093/brain/awae269. Online ahead of print.

Authors

Maura Malpetti¹, Peter Swann², Kamen A Tsvetanov^{1

3}, Leonidas Chouliaras², Alexandra Strauss¹, Tanatswa Chikaura¹, Alexander G Murley¹, Nicholas J Ashton^{4

5

6

7}, Peter Barker⁸, P Simon Jones¹, Tim D Fryer¹, Young T Hong¹, Thomas E Cope^{1

9}, George Savulich², Duncan Street¹, W Richard Bevan-Jones², Timothy Rittman¹, Kaj Blennow^{4

10}, Henrik Zetterberg^{4

10

11

12

13

14}, Franklin I Aigbirhio¹, John T O'Brien², James B Rowe^{1

9}

Affiliations

¹ University of Cambridge Department of Clinical Neurosciences and Cambridge University Hospitals NHS Trust, Cambridge, CB2 0SZ, UK.
² Department of Psychiatry, University of Cambridge, Cambridge, CB2 0QQ, UK.
³ Department of Psychology, University of Cambridge, Cambridge, CB2 3EB, UK.
⁴ Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, Mölndal, S-431 80, Sweden.
⁵ Wallenberg Centre for Molecular Medicine, University of Gothenburg, Gothenburg, S-413 45, Sweden.
⁶ King's College London, Institute of Psychiatry, Psychology and Neuroscience, Maurice Wohl Institute Clinical Neuroscience Institute, London, SE5 9RT, UK.
⁷ NIHR Biomedical Research Centre for Mental Health and Biomedical Research Unit for Dementia at South London and Maudsley NHS Foundation, London, SE5 8AF, UK.
⁸ NIHR Cambridge Biomedical Research Centre, Core BiochemicalAssay Laboratory, Cambridge University Hospitals NHS Foundation Trust, Cambridge, CB2 0QQ, UK.
⁹ Medical Research Council Cognition and Brain Sciences Unit, Cambridge, UK.
¹⁰ Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, S-431 80, Sweden.
¹¹ Department of Neurodegenerative Disease, UCL Institute of Neurology, London, WC1N 6BG, UK.
¹² UK Dementia Research Institute at UCL, London, WC1N 6BG, UK.
¹³ Hong Kong Center for Neurodegenerative Diseases, Clear Water Bay, Hong Kong, China.
¹⁴ Wisconsin Alzheimer's Disease Research Center, University of Wisconsin School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, 53792, USA.

PMID: 39155063
DOI: 10.1093/brain/awae269

Abstract

Neuroinflammation is an important pathogenic mechanism in many neurodegenerative diseases, including those caused by frontotemporal lobar degeneration (FTLD). Postmortem and in vivo imaging studies have shown brain inflammation early in these conditions, proportionate to symptom severity and rate of progression. However, evidence for corresponding blood markers of inflammation and their relationship with central inflammation and clinical outcome are limited. There is a pressing need for such scalable, accessible and mechanistically relevant blood markers as 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 FTLD as compared to healthy controls, including their correlation with brain regional microglial activation and disease progression. Serum assays used the MesoScale Discovery V-Plex-Human Cytokine 36 plex panel plus five additional cytokine assays. A sub-group of patients underwent 11C-PK11195 TSPO PET imaging, as an index of microglial activation. A Principal Component Analysis (PCA) was used to reduce the dimensionality of cytokine data, excluding cytokines that were undetectable in >50% of participants. Frequentist and Bayesian analyses were performed on the principal components, to compare each patient cohort to controls, and test for associations with central inflammation, neurodegeneration-related plasma markers and survival. The first component identified by the PCA (explaining 21.5% variance) was strongly loaded by pro-inflammatory cytokines, including TNF-α, 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 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 TSPO 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. This data-driven approach identified a pro-inflammatory profile across the FTLD 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.

Keywords: PET; blood markers; frontotemporal lobar degeneration; inflammation; survival.