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Associations Between CSF Markers of Inflammation, White Matter Lesions, and Cognitive Decline in Individuals Without Dementia

Gertje, Eske Christiane LU ; Janelidze, Shorena LU ; van Westen, Danielle LU orcid ; Cullen, Nicholas LU ; Stomrud, Erik LU orcid ; Palmqvist, Sebastian LU orcid ; Hansson, Oskar LU orcid and Mattsson-Carlgren, Niklas LU orcid (2023) In Neurology 100(17). p.1812-1824
Abstract

Background and Objectives Small vessel disease (SVD) and neuroinflammation both occur in Alzheimer disease (AD) and other neurodegenerative diseases. It is unclear whether these processes are related or independent mechanisms in AD, especially in the early stages of disease. We therefore investigated the association between white matter lesions (WML; the most common manifestation of SVD) and CSF biomarkers of neuroinflammation and their effects on cognition in a population without dementia. Methods Individuals without dementia from the Swedish BioFINDER study were included. The CSF was analyzed for proinflammatory markers (interleukin [IL]-6 and IL-8), cytokines (IL-7, IL-15, and IL-16), chemokines (interferon γ-induced protein 10,... (More)

Background and Objectives Small vessel disease (SVD) and neuroinflammation both occur in Alzheimer disease (AD) and other neurodegenerative diseases. It is unclear whether these processes are related or independent mechanisms in AD, especially in the early stages of disease. We therefore investigated the association between white matter lesions (WML; the most common manifestation of SVD) and CSF biomarkers of neuroinflammation and their effects on cognition in a population without dementia. Methods Individuals without dementia from the Swedish BioFINDER study were included. The CSF was analyzed for proinflammatory markers (interleukin [IL]-6 and IL-8), cytokines (IL-7, IL-15, and IL-16), chemokines (interferon γ-induced protein 10, monocyte chemoattractant protein 1), markers of vascular injury (soluble intercellular adhesion molecule 1, soluble vascular adhesion molecule 1), and markers of angiogenesis (placental growth factor [PlGF], soluble fms-related tyrosine kinase 1 [sFlt-1], vascular endothelial growth factors [VEGF-A and VEFG-D]), and amyloid β (Aβ)42 Aβ40, and p-tau217. WML volumes were determined at baseline and longitudinally over 6 years. Cognition was measured at baseline and follow-up over 8 years. Linear regression models were used to test associations. Results A total of 495 cognitively unimpaired (CU) elderly individuals and 247 patients with mild cognitive impairment (MCI) were included. There was significant worsening in cognition over time, measured by Mini-Mental State Examination, Clinical Dementia Rating, and modified preclinical Alzheimer composite score in CU individuals and patients with MCI, with more rapid worsening in MCI for all cognitive tests. At baseline, higher levels of PlGF (β = 0.156, p < 0.001), lower levels of sFlt-1 (β = −0.086, p = 0.003), and higher levels of IL-8 (β = 0.07, p = 0.030) were associated with more WML in CU individuals. In those with MCI, higher levels of PlGF (β = 0.172, p = 0.001), IL-16 (β = 0.125, p = 0.001), IL-8 (β = 0.096, p = 0.013), IL-6 (β = 0.088, p = 0.023), VEGF-A (β = 0.068, p = 0.028), and VEGF-D (β = 0.082, p = 0.028) were associated with more WML. PlGF was the only biomarker that was associated with WML independent of Aβ status and cognitive impairment. Longitudinal analyses of cognition showed independent effects ofCSF inflammatory markers andWMLon longitudinal cognition, especially in peoplewithout cognitive impairment at baseline. Discussion Most neuroinflammatory CSF biomarkers were associated with WML in individuals without dementia. Our findings especially highlight a role for PlGF, which was associated with WML independent of Aβ status and cognitive impairment.

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author
; ; ; ; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Neurology
volume
100
issue
17
pages
1812 - 1824
publisher
Lippincott Williams & Wilkins
external identifiers
  • pmid:36882326
  • scopus:85153804500
ISSN
0028-3878
DOI
10.1212/WNL.0000000000207113
language
English
LU publication?
yes
id
c329c505-317c-4d4f-b3d1-36bd30b0bae1
date added to LUP
2023-07-13 12:16:24
date last changed
2024-04-19 23:22:50
@article{c329c505-317c-4d4f-b3d1-36bd30b0bae1,
  abstract     = {{<p>Background and Objectives Small vessel disease (SVD) and neuroinflammation both occur in Alzheimer disease (AD) and other neurodegenerative diseases. It is unclear whether these processes are related or independent mechanisms in AD, especially in the early stages of disease. We therefore investigated the association between white matter lesions (WML; the most common manifestation of SVD) and CSF biomarkers of neuroinflammation and their effects on cognition in a population without dementia. Methods Individuals without dementia from the Swedish BioFINDER study were included. The CSF was analyzed for proinflammatory markers (interleukin [IL]-6 and IL-8), cytokines (IL-7, IL-15, and IL-16), chemokines (interferon γ-induced protein 10, monocyte chemoattractant protein 1), markers of vascular injury (soluble intercellular adhesion molecule 1, soluble vascular adhesion molecule 1), and markers of angiogenesis (placental growth factor [PlGF], soluble fms-related tyrosine kinase 1 [sFlt-1], vascular endothelial growth factors [VEGF-A and VEFG-D]), and amyloid β (Aβ)42 Aβ40, and p-tau217. WML volumes were determined at baseline and longitudinally over 6 years. Cognition was measured at baseline and follow-up over 8 years. Linear regression models were used to test associations. Results A total of 495 cognitively unimpaired (CU) elderly individuals and 247 patients with mild cognitive impairment (MCI) were included. There was significant worsening in cognition over time, measured by Mini-Mental State Examination, Clinical Dementia Rating, and modified preclinical Alzheimer composite score in CU individuals and patients with MCI, with more rapid worsening in MCI for all cognitive tests. At baseline, higher levels of PlGF (β = 0.156, p &lt; 0.001), lower levels of sFlt-1 (β = −0.086, p = 0.003), and higher levels of IL-8 (β = 0.07, p = 0.030) were associated with more WML in CU individuals. In those with MCI, higher levels of PlGF (β = 0.172, p = 0.001), IL-16 (β = 0.125, p = 0.001), IL-8 (β = 0.096, p = 0.013), IL-6 (β = 0.088, p = 0.023), VEGF-A (β = 0.068, p = 0.028), and VEGF-D (β = 0.082, p = 0.028) were associated with more WML. PlGF was the only biomarker that was associated with WML independent of Aβ status and cognitive impairment. Longitudinal analyses of cognition showed independent effects ofCSF inflammatory markers andWMLon longitudinal cognition, especially in peoplewithout cognitive impairment at baseline. Discussion Most neuroinflammatory CSF biomarkers were associated with WML in individuals without dementia. Our findings especially highlight a role for PlGF, which was associated with WML independent of Aβ status and cognitive impairment.</p>}},
  author       = {{Gertje, Eske Christiane and Janelidze, Shorena and van Westen, Danielle and Cullen, Nicholas and Stomrud, Erik and Palmqvist, Sebastian and Hansson, Oskar and Mattsson-Carlgren, Niklas}},
  issn         = {{0028-3878}},
  language     = {{eng}},
  number       = {{17}},
  pages        = {{1812--1824}},
  publisher    = {{Lippincott Williams & Wilkins}},
  series       = {{Neurology}},
  title        = {{Associations Between CSF Markers of Inflammation, White Matter Lesions, and Cognitive Decline in Individuals Without Dementia}},
  url          = {{http://dx.doi.org/10.1212/WNL.0000000000207113}},
  doi          = {{10.1212/WNL.0000000000207113}},
  volume       = {{100}},
  year         = {{2023}},
}