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Low plasma neurofilament light levels associated with raised cortical microglial activation suggest inflammation acts to protect prodromal Alzheimer’s disease

BACKGROUND: Plasma and cerebrospinal fluid levels of neurofilament light (NfL), a marker of axonal degeneration, have previously been reported to be raised in patients with clinically diagnosed Alzheimer’s disease (AD). Activated microglia, an intrinsic inflammatory response to brain lesions, are al...

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Autores principales: Parbo, Peter, Madsen, Lasse Stensvig, Ismail, Rola, Zetterberg, Henrik, Blennow, Kaj, Eskildsen, Simon F., Vorup-Jensen, Thomas, Brooks, David J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6941285/
https://www.ncbi.nlm.nih.gov/pubmed/31898549
http://dx.doi.org/10.1186/s13195-019-0574-0
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author Parbo, Peter
Madsen, Lasse Stensvig
Ismail, Rola
Zetterberg, Henrik
Blennow, Kaj
Eskildsen, Simon F.
Vorup-Jensen, Thomas
Brooks, David J.
author_facet Parbo, Peter
Madsen, Lasse Stensvig
Ismail, Rola
Zetterberg, Henrik
Blennow, Kaj
Eskildsen, Simon F.
Vorup-Jensen, Thomas
Brooks, David J.
author_sort Parbo, Peter
collection PubMed
description BACKGROUND: Plasma and cerebrospinal fluid levels of neurofilament light (NfL), a marker of axonal degeneration, have previously been reported to be raised in patients with clinically diagnosed Alzheimer’s disease (AD). Activated microglia, an intrinsic inflammatory response to brain lesions, are also known to be present in a majority of Alzheimer or mild cognitive impaired (MCI) subjects with raised β-amyloid load on their positron emission tomography (PET) imaging. It is now considered that the earliest phase of inflammation may be protective to the brain, removing amyloid plaques and remodelling synapses. Our aim was to determine whether the cortical inflammation/microglial activation load, measured with the translocator protein marker (11)C-PK11195 PET, was correlated with plasma NfL levels in prodromal and early Alzheimer subjects. METHODS: Twenty-seven MCI or early AD cases with raised cortical β-amyloid load had (11)C-(R)-PK11195 PET, structural and diffusion magnetic resonance imaging, and levels of their plasma NfL measured. Correlation analyses were performed using surface-based cortical statistics. RESULTS: Statistical maps localised areas in MCI cases where levels of brain inflammation correlated inversely with plasma NfL levels. These areas were localised in the frontal, parietal, precuneus, occipital, and sensorimotor cortices. Brain inflammation correlated negatively with mean diffusivity (MD) of water with regions overlapping. CONCLUSION: We conclude that an inverse correlation between levels of inflammation in cortical areas and plasma NfL levels indicates that microglial activation may initially be protective to axons in AD. This is supported by the finding of an inverse association between cortical water diffusivity and microglial activation in the same regions. Our findings suggest a rationale for stimulating microglial activity in early and prodromal Alzheimer cases—possibly using immunotherapy. Plasma NfL levels could be used as a measure of the protective efficacy of immune stimulation and for monitoring efficacy of putative neuroprotective agents. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s13195-019-0574-0) contains supplementary material, which is available to authorized users.
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spelling pubmed-69412852020-01-06 Low plasma neurofilament light levels associated with raised cortical microglial activation suggest inflammation acts to protect prodromal Alzheimer’s disease Parbo, Peter Madsen, Lasse Stensvig Ismail, Rola Zetterberg, Henrik Blennow, Kaj Eskildsen, Simon F. Vorup-Jensen, Thomas Brooks, David J. Alzheimers Res Ther Research BACKGROUND: Plasma and cerebrospinal fluid levels of neurofilament light (NfL), a marker of axonal degeneration, have previously been reported to be raised in patients with clinically diagnosed Alzheimer’s disease (AD). Activated microglia, an intrinsic inflammatory response to brain lesions, are also known to be present in a majority of Alzheimer or mild cognitive impaired (MCI) subjects with raised β-amyloid load on their positron emission tomography (PET) imaging. It is now considered that the earliest phase of inflammation may be protective to the brain, removing amyloid plaques and remodelling synapses. Our aim was to determine whether the cortical inflammation/microglial activation load, measured with the translocator protein marker (11)C-PK11195 PET, was correlated with plasma NfL levels in prodromal and early Alzheimer subjects. METHODS: Twenty-seven MCI or early AD cases with raised cortical β-amyloid load had (11)C-(R)-PK11195 PET, structural and diffusion magnetic resonance imaging, and levels of their plasma NfL measured. Correlation analyses were performed using surface-based cortical statistics. RESULTS: Statistical maps localised areas in MCI cases where levels of brain inflammation correlated inversely with plasma NfL levels. These areas were localised in the frontal, parietal, precuneus, occipital, and sensorimotor cortices. Brain inflammation correlated negatively with mean diffusivity (MD) of water with regions overlapping. CONCLUSION: We conclude that an inverse correlation between levels of inflammation in cortical areas and plasma NfL levels indicates that microglial activation may initially be protective to axons in AD. This is supported by the finding of an inverse association between cortical water diffusivity and microglial activation in the same regions. Our findings suggest a rationale for stimulating microglial activity in early and prodromal Alzheimer cases—possibly using immunotherapy. Plasma NfL levels could be used as a measure of the protective efficacy of immune stimulation and for monitoring efficacy of putative neuroprotective agents. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s13195-019-0574-0) contains supplementary material, which is available to authorized users. BioMed Central 2020-01-02 /pmc/articles/PMC6941285/ /pubmed/31898549 http://dx.doi.org/10.1186/s13195-019-0574-0 Text en © The Author(s). 2020 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Research
Parbo, Peter
Madsen, Lasse Stensvig
Ismail, Rola
Zetterberg, Henrik
Blennow, Kaj
Eskildsen, Simon F.
Vorup-Jensen, Thomas
Brooks, David J.
Low plasma neurofilament light levels associated with raised cortical microglial activation suggest inflammation acts to protect prodromal Alzheimer’s disease
title Low plasma neurofilament light levels associated with raised cortical microglial activation suggest inflammation acts to protect prodromal Alzheimer’s disease
title_full Low plasma neurofilament light levels associated with raised cortical microglial activation suggest inflammation acts to protect prodromal Alzheimer’s disease
title_fullStr Low plasma neurofilament light levels associated with raised cortical microglial activation suggest inflammation acts to protect prodromal Alzheimer’s disease
title_full_unstemmed Low plasma neurofilament light levels associated with raised cortical microglial activation suggest inflammation acts to protect prodromal Alzheimer’s disease
title_short Low plasma neurofilament light levels associated with raised cortical microglial activation suggest inflammation acts to protect prodromal Alzheimer’s disease
title_sort low plasma neurofilament light levels associated with raised cortical microglial activation suggest inflammation acts to protect prodromal alzheimer’s disease
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6941285/
https://www.ncbi.nlm.nih.gov/pubmed/31898549
http://dx.doi.org/10.1186/s13195-019-0574-0
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