Differences in metalloproteinases and their tissue inhibitors in the cerebrospinal fluid are associated with delirium

Mari Aksnes; Mari Haavig Schibstad; Farrukh Abbas Chaudhry; Bjørn Erik Neerland; Gideon Caplan; Ingvild Saltvedt; Rannveig S. Eldholm; Marius Myrstad; Trine Holt Edwin; Karin Persson; Ane-Victoria Idland; Christian Thomas Pollmann; Roy Bjørkholt Olsen; Torgeir Bruun Wyller; Henrik Zetterberg; Emma Cunningham; Leiv Otto Watne

doi:10.1038/s43856-024-00558-z

Differences in metalloproteinases and their tissue inhibitors in the cerebrospinal fluid are associated with delirium

Mari Aksnes^*, Mari Haavig Schibstad, Farrukh Abbas Chaudhry, Bjørn Erik Neerland, Gideon Caplan, Ingvild Saltvedt, Rannveig S. Eldholm, Marius Myrstad, Trine Holt Edwin, Karin Persson, Ane-Victoria Idland, Christian Thomas Pollmann, Roy Bjørkholt Olsen, Torgeir Bruun Wyller, Henrik Zetterberg, Emma Cunningham, Leiv Otto Watne

^*Corresponding author for this work

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Abstract

Background
The aetiology of delirium is not known, but pre-existing cognitive impairment is a predisposing factor. Here we explore the associations between delirium and cerebrospinal fluid (CSF) levels of matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs), proteins with important roles in both acute injury and chronic neurodegeneration.

Methods
Using a 13-plex Discovery Assay®, we quantified CSF levels of 9 MMPs and 4 TIMPs in 280 hip fracture patients (140 with delirium), 107 cognitively unimpaired individuals, and 111 patients with Alzheimer’s disease dementia. The two delirium-free control groups without acute trauma were included to unravel the effects of acute trauma (hip fracture), dementia, and delirium.

Results
Here we show that delirium is associated with higher levels of MMP-2, MMP-3, MMP-10, TIMP-1, and TIMP-2; a trend suggests lower levels of TIMP-4 are also associated with delirium. Most delirium patients had pre-existing dementia and low TIMP-4 is the only marker associated with delirium in adjusted analyses. MMP-2, MMP-12, and TIMP-1 levels are clearly higher in the hip fracture patients than in both control groups and several other MMP/TIMPs are impacted by acute trauma or dementia status.

Conclusions
Several CSF MMP/TIMPs are significantly associated with delirium in hip fracture patients, but alterations in most of these MMP/TIMPs could likely be explained by acute trauma and/or pre-fracture dementia. Low levels of TIMP-4 appear to be directly associated with delirium, and the role of this marker in delirium pathophysiology should be further explored.

Original language	English
Article number	124
Number of pages	10
Journal	Communications Medicine
Volume	4
Issue number	1
Early online date	27 Jun 2024
DOIs	https://doi.org/10.1038/s43856-024-00558-z
Publication status	Early online date - 27 Jun 2024

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Differences in metalloproteinases and their tissue inhibitors in the cerebrospinal fluid are associated with delirium
Copyright 2024 The Authors. This is an open access article published under a Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution and reproduction in any medium, provided the author and source are cited.
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Aksnes, M., Schibstad, M. H., Chaudhry, F. A., Neerland, B. E., Caplan, G., Saltvedt, I., Eldholm, R. S., Myrstad, M., Edwin, T. H., Persson, K., Idland, A.-V., Pollmann, C. T., Olsen, R. B., Wyller, T. B., Zetterberg, H., Cunningham, E., & Watne, L. O. (2024). Differences in metalloproteinases and their tissue inhibitors in the cerebrospinal fluid are associated with delirium. Communications Medicine, 4(1), Article 124. Advance online publication. https://doi.org/10.1038/s43856-024-00558-z

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title = "Differences in metalloproteinases and their tissue inhibitors in the cerebrospinal fluid are associated with delirium",

abstract = "BackgroundThe aetiology of delirium is not known, but pre-existing cognitive impairment is a predisposing factor. Here we explore the associations between delirium and cerebrospinal fluid (CSF) levels of matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs), proteins with important roles in both acute injury and chronic neurodegeneration.MethodsUsing a 13-plex Discovery Assay{\textregistered}, we quantified CSF levels of 9 MMPs and 4 TIMPs in 280 hip fracture patients (140 with delirium), 107 cognitively unimpaired individuals, and 111 patients with Alzheimer{\textquoteright}s disease dementia. The two delirium-free control groups without acute trauma were included to unravel the effects of acute trauma (hip fracture), dementia, and delirium.ResultsHere we show that delirium is associated with higher levels of MMP-2, MMP-3, MMP-10, TIMP-1, and TIMP-2; a trend suggests lower levels of TIMP-4 are also associated with delirium. Most delirium patients had pre-existing dementia and low TIMP-4 is the only marker associated with delirium in adjusted analyses. MMP-2, MMP-12, and TIMP-1 levels are clearly higher in the hip fracture patients than in both control groups and several other MMP/TIMPs are impacted by acute trauma or dementia status.ConclusionsSeveral CSF MMP/TIMPs are significantly associated with delirium in hip fracture patients, but alterations in most of these MMP/TIMPs could likely be explained by acute trauma and/or pre-fracture dementia. Low levels of TIMP-4 appear to be directly associated with delirium, and the role of this marker in delirium pathophysiology should be further explored.",

author = "Mari Aksnes and Schibstad, {Mari Haavig} and Chaudhry, {Farrukh Abbas} and Neerland, {Bj{\o}rn Erik} and Gideon Caplan and Ingvild Saltvedt and Eldholm, {Rannveig S.} and Marius Myrstad and Edwin, {Trine Holt} and Karin Persson and Ane-Victoria Idland and Pollmann, {Christian Thomas} and Olsen, {Roy Bj{\o}rkholt} and Wyller, {Torgeir Bruun} and Henrik Zetterberg and Emma Cunningham and Watne, {Leiv Otto}",

year = "2024",

month = jun,

day = "27",

doi = "10.1038/s43856-024-00558-z",

language = "English",

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issn = "2730-664X",

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Aksnes, M, Schibstad, MH, Chaudhry, FA, Neerland, BE, Caplan, G, Saltvedt, I, Eldholm, RS, Myrstad, M, Edwin, TH, Persson, K, Idland, A-V, Pollmann, CT, Olsen, RB, Wyller, TB, Zetterberg, H, Cunningham, E & Watne, LO 2024, 'Differences in metalloproteinases and their tissue inhibitors in the cerebrospinal fluid are associated with delirium', Communications Medicine, vol. 4, no. 1, 124. https://doi.org/10.1038/s43856-024-00558-z

TY - JOUR

T1 - Differences in metalloproteinases and their tissue inhibitors in the cerebrospinal fluid are associated with delirium

AU - Aksnes, Mari

AU - Schibstad, Mari Haavig

AU - Chaudhry, Farrukh Abbas

AU - Neerland, Bjørn Erik

AU - Caplan, Gideon

AU - Saltvedt, Ingvild

AU - Eldholm, Rannveig S.

AU - Myrstad, Marius

AU - Edwin, Trine Holt

AU - Persson, Karin

AU - Idland, Ane-Victoria

AU - Pollmann, Christian Thomas

AU - Olsen, Roy Bjørkholt

AU - Wyller, Torgeir Bruun

AU - Zetterberg, Henrik

AU - Cunningham, Emma

AU - Watne, Leiv Otto

PY - 2024/6/27

Y1 - 2024/6/27

N2 - BackgroundThe aetiology of delirium is not known, but pre-existing cognitive impairment is a predisposing factor. Here we explore the associations between delirium and cerebrospinal fluid (CSF) levels of matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs), proteins with important roles in both acute injury and chronic neurodegeneration.MethodsUsing a 13-plex Discovery Assay®, we quantified CSF levels of 9 MMPs and 4 TIMPs in 280 hip fracture patients (140 with delirium), 107 cognitively unimpaired individuals, and 111 patients with Alzheimer’s disease dementia. The two delirium-free control groups without acute trauma were included to unravel the effects of acute trauma (hip fracture), dementia, and delirium.ResultsHere we show that delirium is associated with higher levels of MMP-2, MMP-3, MMP-10, TIMP-1, and TIMP-2; a trend suggests lower levels of TIMP-4 are also associated with delirium. Most delirium patients had pre-existing dementia and low TIMP-4 is the only marker associated with delirium in adjusted analyses. MMP-2, MMP-12, and TIMP-1 levels are clearly higher in the hip fracture patients than in both control groups and several other MMP/TIMPs are impacted by acute trauma or dementia status.ConclusionsSeveral CSF MMP/TIMPs are significantly associated with delirium in hip fracture patients, but alterations in most of these MMP/TIMPs could likely be explained by acute trauma and/or pre-fracture dementia. Low levels of TIMP-4 appear to be directly associated with delirium, and the role of this marker in delirium pathophysiology should be further explored.

AB - BackgroundThe aetiology of delirium is not known, but pre-existing cognitive impairment is a predisposing factor. Here we explore the associations between delirium and cerebrospinal fluid (CSF) levels of matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs), proteins with important roles in both acute injury and chronic neurodegeneration.MethodsUsing a 13-plex Discovery Assay®, we quantified CSF levels of 9 MMPs and 4 TIMPs in 280 hip fracture patients (140 with delirium), 107 cognitively unimpaired individuals, and 111 patients with Alzheimer’s disease dementia. The two delirium-free control groups without acute trauma were included to unravel the effects of acute trauma (hip fracture), dementia, and delirium.ResultsHere we show that delirium is associated with higher levels of MMP-2, MMP-3, MMP-10, TIMP-1, and TIMP-2; a trend suggests lower levels of TIMP-4 are also associated with delirium. Most delirium patients had pre-existing dementia and low TIMP-4 is the only marker associated with delirium in adjusted analyses. MMP-2, MMP-12, and TIMP-1 levels are clearly higher in the hip fracture patients than in both control groups and several other MMP/TIMPs are impacted by acute trauma or dementia status.ConclusionsSeveral CSF MMP/TIMPs are significantly associated with delirium in hip fracture patients, but alterations in most of these MMP/TIMPs could likely be explained by acute trauma and/or pre-fracture dementia. Low levels of TIMP-4 appear to be directly associated with delirium, and the role of this marker in delirium pathophysiology should be further explored.

U2 - 10.1038/s43856-024-00558-z

DO - 10.1038/s43856-024-00558-z

M3 - Article

C2 - 38937571

SN - 2730-664X

VL - 4

JO - Communications Medicine

JF - Communications Medicine

IS - 1

M1 - 124

ER -

Differences in metalloproteinases and their tissue inhibitors in the cerebrospinal fluid are associated with delirium

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