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 [CI95% 0.066, 1.0], P = 0.025) compared with NC. Non-AD MCI displayed higher levels than controls (Cohen's d = 0.74 [CI95% 0.22, 1.3], P = 0.042). No association was observed with CSF Aβ42/Aβ40 ratio but with p-tau 181 (β = 0.102 [CI95% 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 [CI95% -2.33, -0.260], P = 0.015) and dementia stages (β = -2.24 [CI95% -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.