Dissection of blood-brain barrier dysfunction through CSF PDGFRβ and amyloid, tau, neuroinflammation, and synaptic CSF biomarkers in neurodegenerative disorders.

BACKGROUND: Blood-brain barrier (BBB) dysfunction is an early event in neurodegenerative disorders. Pericytes are key cells for BBB maintenance. Upon pericyte injury, the platelet-derived growth factor receptor-β (PDGFRβ) is released in the cerebrospinal fluid (CSF). The relation of CSF PDGFRβ with markers of amyloid pathology, neuroinflammation, and axonal and synaptic damage across dementia remains unclear. METHODS: Retrospectively, we quantified CSF PDGFRβ and CSF core Alzheimer's disease (AD), astrocytic (GFAP), microglial (sTREM 2, YKL-40), axonal (NfL), and synaptic (GAP-43, neurogranin) biomarkers in 210 patients from the Cognitive Neurology Centre, Paris, France, including n = 23 neurological controls (NC), n = 84 patients with mild cognitive impairment (MCI) [AD, n = 41; non-AD, n = 43], and n = 103 patients with dementia (AD, n = 73; non-AD, n = 30). FINDINGS: Comparing clinical stages, CSF PDGFRβ levels were increased at the MCI stage (Cohen's d = 0.55 [CI(95%) 0.066, 1.0], P = 0.025) compared with NC. Non-AD MCI displayed higher levels than controls (Cohen's d = 0.74 [CI(95%) 0.22, 1.3], P = 0.042). No association was observed with CSF Aβ42/Aβ40 ratio but with p-tau 181 (β = 0.102 [CI(95%) 0.027, 0.176], P = 0.0080) and t-tau levels (β = 0.133 [0.054, 0.213], P = 0.0010). CSF PDGFRβ levels were positively associated with CSF neuroinflammation and synaptic markers levels. Higher CSF PDGFRβ levels were associated with lower MMSE scores at MCI (β = -1.23 [CI(95%) -2.33, -0.260], P = 0.015) and dementia stages (β = -2.24 [CI(95%) -3.62, -0.85], P = 0.0020). CSF neuroinflammation biomarkers mediated the association of CSF PDGFRβ with neurodegeneration and synaptic integrity markers. INTERPRETATION: CSF PDGFRβ, a candidate biomarker of BBB dysfunction, is increased in the early stages of neurodegenerative disorders, in association with neuroinflammation and axonal and synaptic damage. FUNDING: Association des Anciens Internes des Hôpitaux de Paris, Edmond de Rothschild Program, Fondation Vaincre Alzheimer, Demensförbundet, Gamla Tjänarinnor, Anna-Lisa och Bror Björnssons Stiftelse.