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Associations of CSF PDGFRβ With Aging, Blood-Brain Barrier Damage, Neuroinflammation, and Alzheimer Disease Pathologic Changes

Cicognola, Claudia LU orcid ; Mattsson-Carlgren, Niklas LU orcid ; van Westen, Danielle LU orcid ; Zetterberg, Henrik LU ; Blennow, Kaj LU ; Palmqvist, Sebastian LU orcid ; Ahmadi, Khazar LU ; Strandberg, Olof LU ; Stomrud, Erik LU orcid and Janelidze, Shorena LU , et al. (2023) In Neurology 101(1). p.30-39
Abstract

BACKGROUND AND OBJECTIVES: Injured pericytes in the neurovascular unit release platelet-derived growth factor β (PDGFRβ) into the cerebrospinal fluid (CSF). However, it is not clear how pericyte injury contributes to Alzheimer's disease (AD)-related changes and blood brain barrier (BBB) damage. We aimed to test if CSF PDGFRβ was associated with different AD- and age-associated pathological changes leading to dementia.

METHODS: PDGFRβ was measured in the CSF of 771 cognitively unimpaired (CU, n=408), mild cognitive impairment (MCI, n=175) and dementia subjects (n=188) from the Swedish BioFINDER-2 cohort. We then checked association Aβ-PET and tau-PET SUVR,
APOE ε4 genotype and MRI measurements of cortical thickness, white... (More)

BACKGROUND AND OBJECTIVES: Injured pericytes in the neurovascular unit release platelet-derived growth factor β (PDGFRβ) into the cerebrospinal fluid (CSF). However, it is not clear how pericyte injury contributes to Alzheimer's disease (AD)-related changes and blood brain barrier (BBB) damage. We aimed to test if CSF PDGFRβ was associated with different AD- and age-associated pathological changes leading to dementia.

METHODS: PDGFRβ was measured in the CSF of 771 cognitively unimpaired (CU, n=408), mild cognitive impairment (MCI, n=175) and dementia subjects (n=188) from the Swedish BioFINDER-2 cohort. We then checked association Aβ-PET and tau-PET SUVR,
APOE ε4 genotype and MRI measurements of cortical thickness, white matter lesions (WML) and cerebral blood flow (CBF). We also analysed the role of CSF PDGFRβ in the relationship between aging, BBB dysfunction (measured by CSF/plasma albumin ratio, QAlb) and neuroinflammation (i.e., CSF levels of YKL-40 and glial fibrillary acidic protein [GFAP], preferentially expressed in reactive astrocytes).

RESULTS: The cohort had a mean age of 67 years (CU=62.8, MCI=69.9, dementia=70.4) and 50.1% were male (CU=46.6%, MCI=53.7%, dementia=54.3%). Higher CSF PDGFRβ concentrations were related to higher age (b=19.1, β=0.5, 95% CI=16-22.2, p<0.001), increased CSF neuroinflammatory markers of glial activation YKL-40 (b=3.4, β=0.5, 95% CI=2.8-3.9, p<0.001) and GFAP (b=27.4, β=0.4, 95% CI=20.9-33.9, p<0.001), and worse BBB integrity measured by QAlb (b=37.4, β=0.2, 95% CI=24.9-49.9, p<0.001). Age was also associated with worse BBB integrity, and this was partly mediated by PDGFRβ and neuroinflammatory markers (16-33% of total effect). However, PDGFRβ showed no associations with APOE ε4 genotype, PET imaging of Aβ and tau pathology or MRI measures of brain atrophy and white matter lesions (p>0.05).

DISCUSSION: In summary, pericyte damage, reflected by CSF PDGFRβ, may be involved in age-related BBB disruption together with neuroinflammation, but is not related to Alzheimer-related pathological changes.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Neurology
volume
101
issue
1
pages
30 - 39
publisher
Lippincott Williams & Wilkins
external identifiers
  • pmid:37137722
  • scopus:85164211087
ISSN
1526-632X
DOI
10.1212/WNL.0000000000207358
language
English
LU publication?
yes
additional info
s
id
74272169-7f86-4a9a-93e2-8770ce4bbd7a
date added to LUP
2023-05-07 13:54:20
date last changed
2024-04-19 22:36:39
@article{74272169-7f86-4a9a-93e2-8770ce4bbd7a,
  abstract     = {{<p>BACKGROUND AND OBJECTIVES: Injured pericytes in the neurovascular unit release platelet-derived growth factor β (PDGFRβ) into the cerebrospinal fluid (CSF). However, it is not clear how pericyte injury contributes to Alzheimer's disease (AD)-related changes and blood brain barrier (BBB) damage. We aimed to test if CSF PDGFRβ was associated with different AD- and age-associated pathological changes leading to dementia.</p><p>METHODS: PDGFRβ was measured in the CSF of 771 cognitively unimpaired (CU, n=408), mild cognitive impairment (MCI, n=175) and dementia subjects (n=188) from the Swedish BioFINDER-2 cohort. We then checked association Aβ-PET and tau-PET SUVR,<br>
 APOE ε4 genotype and MRI measurements of cortical thickness, white matter lesions (WML) and cerebral blood flow (CBF). We also analysed the role of CSF PDGFRβ in the relationship between aging, BBB dysfunction (measured by CSF/plasma albumin ratio, QAlb) and neuroinflammation (i.e., CSF levels of YKL-40 and glial fibrillary acidic protein [GFAP], preferentially expressed in reactive astrocytes).<br>
 </p><p>RESULTS: The cohort had a mean age of 67 years (CU=62.8, MCI=69.9, dementia=70.4) and 50.1% were male (CU=46.6%, MCI=53.7%, dementia=54.3%). Higher CSF PDGFRβ concentrations were related to higher age (b=19.1, β=0.5, 95% CI=16-22.2, p&lt;0.001), increased CSF neuroinflammatory markers of glial activation YKL-40 (b=3.4, β=0.5, 95% CI=2.8-3.9, p&lt;0.001) and GFAP (b=27.4, β=0.4, 95% CI=20.9-33.9, p&lt;0.001), and worse BBB integrity measured by QAlb (b=37.4, β=0.2, 95% CI=24.9-49.9, p&lt;0.001). Age was also associated with worse BBB integrity, and this was partly mediated by PDGFRβ and neuroinflammatory markers (16-33% of total effect). However, PDGFRβ showed no associations with APOE ε4 genotype, PET imaging of Aβ and tau pathology or MRI measures of brain atrophy and white matter lesions (p&gt;0.05).</p><p>DISCUSSION: In summary, pericyte damage, reflected by CSF PDGFRβ, may be involved in age-related BBB disruption together with neuroinflammation, but is not related to Alzheimer-related pathological changes.</p>}},
  author       = {{Cicognola, Claudia and Mattsson-Carlgren, Niklas and van Westen, Danielle and Zetterberg, Henrik and Blennow, Kaj and Palmqvist, Sebastian and Ahmadi, Khazar and Strandberg, Olof and Stomrud, Erik and Janelidze, Shorena and Hansson, Oskar}},
  issn         = {{1526-632X}},
  language     = {{eng}},
  month        = {{05}},
  number       = {{1}},
  pages        = {{30--39}},
  publisher    = {{Lippincott Williams & Wilkins}},
  series       = {{Neurology}},
  title        = {{Associations of CSF PDGFRβ With Aging, Blood-Brain Barrier Damage, Neuroinflammation, and Alzheimer Disease Pathologic Changes}},
  url          = {{http://dx.doi.org/10.1212/WNL.0000000000207358}},
  doi          = {{10.1212/WNL.0000000000207358}},
  volume       = {{101}},
  year         = {{2023}},
}