Two novel cerebrospinal fluid markers for vascular injury are associated with CSF markers of AD, neurodegeneration, and gliosis

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AbstractBackgroundVascular dysfunction often occurs concurrently with Alzheimer’s disease (AD). Breakdown of the blood–brain barrier (BBB) and vascular injury may be related to amyloid and tau pathology. In preliminary analyses, we examined the relationship between cerebrospinal fluid (CSF) biomarkers of AD, neurodegeneration, and glial activation, and two novel CSF markers of vascular dysfunction: soluble platelet‐derived growth factor receptor beta (sPDGFRβ) a marker of BBB integrity, and angiopoietin‐2 (Ang2), a marker of vascular injury.MethodCSF samples from participants enrolled in the Wisconsin Registry for Alzheimer’s Prevention (WRAP) or the Wisconsin Alzheimer’s Disease Research Center (WADRC) studies were assayed for markers of AD, neurodegeneration, and gliosis, using Roche NeuroToolKit® immunoassays (Roche Diagnostics International Ltd, Switzerland). A subset of serially sampled participants (N = 209, Nob s = 531) who spanned the AD clinical spectrum (cognitively unimpaired, MCI, dementia) underwent sPDGFRβ measurement (ELISA); a sample of N = 121 (Nobs = 276) was also assayed for Ang2 (ELISA) (Table 1). Pearson correlations were calculated for all CSF biomarkers. Linear mixed‐effects models with random intercepts, age‐at‐lumbar‐puncture as the measure of time, and CSF vascular biomarker as the outcome were used to test associations with tau positivity (>24.8 pg/mL), and cognitive status.ResultsPDGFRβ correlated with all CSF biomarkers (rs range .18 to .45, ps<.001, Figure 1A) except AB42/40. Ang2 correlated with all CSF biomarkers (rs range .21 to .45 ps <.001, Figure 1B) except AB42/40, and S100B. sPDGFRβ and Ang2 correlated most strongly with Aβ40 and biomarkers of synaptic function (neurogranin and α‐synuclein). Tau positivity was associated with sPDGFRβ in the whole sample (estimate = 64.5, p<.001) and excluding participants with MCI/dementia (estimate = 77.7, p<.001). Tau positivity was associated with Ang2 (estimate = 18.1, p = .007), however the association was not significant after excluding participants with MCI/dementia. There was no difference in sPDGFRβ across the AD clinical spectrum. Ang2 was higher among participants with MCI than cognitively unimpaired participants (estimate = 21.0, p = .037, Figure 2).ConclusionCSF markers of vascular injury were elevated in MCI and were moderately related to tau pathology and markers of neuronal injury and neuroinflammation, but not amyloid pathology, providing insight into the association of of vascular injury to AD related disease