Associations of CSF PDGFR & beta; With Aging, Blood-Brain Barrier Damage, Neuroinflammation, and Alzheimer Disease Pathologic Changes

Background and ObjectivesInjured pericytes in the neurovascular unit release platelet-derived growth factor & beta; (PDGFR & beta;) into the CSF. However, it is not clear how pericyte injury contributes to Alzheimer disease (AD)-related changes and blood-brain barrier (BBB) damage. We aimed to test whether CSF PDGFR & beta; was associated with different AD-associated and age-associated pathologic changes leading to dementia.MethodsPDGFR & beta; was measured in the CSF of 771 participants with cognitively unimpaired (CU, n = 408), mild cognitive impairment (MCI, n = 175), and dementia (n = 188) from the Swedish BioFINDER-2 cohort. We then checked association with & beta;-amyloid (A & beta;)-PET and tau-PET standardized uptake value ratio, APOE & epsilon;4 genotype and MRI measurements of cortical thickness, white matter lesions (WMLs), and cerebral blood flow. We also analyzed the role of CSF PDGFR & beta; 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).ResultsThe 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 PDGFR & beta; concentrations were related to higher age (b = 19.1, & beta; = 0.5, 95% CI 16-22.2, p < 0.001), increased CSF neuroinflammatory markers of glial activation YKL-40 (b = 3.4, & beta; = 0.5, 95% CI 2.8-3.9, p < 0.001), GFAP (b = 27.4, & beta; = 0.4, 95% CI 20.9-33.9, p < 0.001), and worse BBB integrity measured by QAlb (b = 37.4, & beta; = 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 PDGFR & beta; and neuroinflammatory markers (16%-33% of total effect). However, PDGFR & beta; showed no associations with APOE & epsilon;4 genotype, PET imaging of A & beta; and tau pathology, or MRI measures of brain atrophy and WMLs (p > 0.05).DiscussionIn summary, pericyte damage, reflected by CSF PDGFR & beta;, may be involved in age-related BBB disruption together with neuroinflammation, but is not related to Alzheimer-related pathologic changes.

Automated summary

CSF PDGFRβ is associated with age-related blood-brain barrier dysfunction and neuroinflammation, but not with Alzheimer-related pathologies.