Assessing blood-brain barrier dysfunction and its association with Alzheimer's pathology, cognitive impairment and neuroinflammation.

Abstract

Background: Blood-brain barrier (BBB) alterations may contribute to AD pathology through various mechanisms, including impaired amyloid-β (Aβ) clearance and neuroinflammation. Soluble platelet-derived growth factor receptor beta (sPDGFRβ) has emerged as a potential biomarker for BBB integrity. Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) offers a direct assessment of BBB permeability. However, the relationship between BBB dysfunction, cognitive impairment, and AD pathology remains unclear, with inconsistent findings in the literature.

Methods: We conducted a cross-sectional study using data from the DELCODE and DESCRIBE cohorts to investigate BBB dysfunction in participants with normal cognition (NC), mild cognitive impairment (MCI), and AD dementia. BBB function was assessed using DCE-MRI and sPDGFRβ levels in cerebrospinal fluid and AD biomarkers Aβ and tau were measured. In a subset of patients, the CSF/plasma-ratio of albumin (QAlb) as a standard marker of BBB integrity and markers of neuroinflammation were analyzed.

Results: 91 participants (NC: 44, MCI: 21, AD: 26) were included in the analysis. The average age was 74.4 years, 42% were female. Increased hippocampal BBB disruption was observed in the AD-group (K^trans: 0.55 × 10^- 3 min^- 1 ± 0.74 × 10^- 3 min^- 1) but not the MCI-group (K^trans: 0.177 × 10^- 3 min^- 1 ± 0.22 × 10^- 3 min^- 1), compared to the NC group (K^trans: 0.19 × 10^- 3 min^- 1 ± 0.37 × 10^- 3 min^- 1, p < .01). sPDGFRβ was not significantly different between the cognitive groups. However, sPDGFRβ levels were significantly associated with age (r = .33, p < .01), independent of vascular risk factors. Further, sPDGFRβ showed significant positive associations with soluble Aβ levels (Aβ40: r = .57, p < .01; Aβ42: r = .39, p < .01) and YKL-40 (r = .53, p < .01), a marker of neuroinflammation. sPDGFRβ/DCE-MRI was not associated with overall AD biomarker positivity or APOE-status.

Conclusion: In dementia, but not MCI, hippocampal BBB disruption was observed. sPDGFRβ increased with age and was associated with neuroinflammation independent of cognitive impairment. The association between Aβ and sPDGFRβ may indicate a bidirectional relationship reflecting pericytes' clearance of soluble Aβ and/or vasculotoxic properties of Aβ.