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. 2014 Dec;76(6):837-44.
doi: 10.1002/ana.24270. Epub 2014 Oct 24.

Amyloid-β efflux from the central nervous system into the plasma

Kaleigh Filisa Roberts  1 , Donald L Elbert, Tom P Kasten, Bruce W Patterson, Wendy C Sigurdson, Rose E Connors, Vitaliy Ovod, Ling Y Munsell, Kwasi G Mawuenyega, Michelle M Miller-Thomas, Christopher J Moran, Dewitte T Cross 3rd, Colin P Derdeyn, Randall J Bateman
Affiliations

Amyloid-β efflux from the central nervous system into the plasma

Kaleigh Filisa Roberts et al. Ann Neurol. 2014 Dec.

Abstract

Objective: The aim of this study was to measure the flux of amyloid-β (Aβ) across the human cerebral capillary bed to determine whether transport into the blood is a significant mechanism of clearance for Aβ produced in the central nervous system (CNS).

Methods: Time-matched blood samples were simultaneously collected from a cerebral vein (including the sigmoid sinus, inferior petrosal sinus, and the internal jugular vein), femoral vein, and radial artery of patients undergoing inferior petrosal sinus sampling. For each plasma sample, Aβ concentration was assessed by 3 assays, and the venous to arterial Aβ concentration ratios were determined.

Results: Aβ concentration was increased by ∼7.5% in venous blood leaving the CNS capillary bed compared to arterial blood, indicating efflux from the CNS into the peripheral blood (p < 0.0001). There was no difference in peripheral venous Aβ concentration compared to arterial blood concentration.

Interpretation: Our results are consistent with clearance of CNS-derived Aβ into the venous blood supply with no increase from a peripheral capillary bed. Modeling these results suggests that direct transport of Aβ across the blood-brain barrier accounts for ∼25% of Aβ clearance, and reabsorption of cerebrospinal fluid Aβ accounts for ∼25% of the total CNS Aβ clearance in humans. Ann Neurol 2014;76:837-844.

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Conflict of interest statement

Conflict of interest: Ms. Roberts, Dr. Elbert, Dr. Patterson, Ms. Sigurdson, Ms. Connors, Mr. Ovod, Ms. Munsell, Dr. Mawuenyega, Dr. Miller-Thomas, Dr. Moran, and Dr. Cross declare no conflicts of interest.

Figures

Figure 1
Figure 1
A diagram of the central venous system including sampling sites for central Aβ measurements. CNS Aβ is removed by a variety of mechanisms including direct transport across the BBB into the venous blood, transport to the CSF with subsequent reabsorption into the venous blood, and degradation by phagocytes and enzymes. IPS= Inferior Petrosal Sinus, SS= Sigmoid Sinus, IJ= Internal Jugular
Figure 2
Figure 2
Ratios of venous to arterial plasma Aβ concentrations by 3 assays: IP/MS, ELISA, and xMAP. Central indicates veins draining the brain capillary bed and includes measurements from the internal jugular vein (IJ), sigmoid sinus (SS), left inferior petrosal sinus (IPSL), and right inferior petrosal sinus (IPSR). Peripheral represents measurements from the peripheral femoral vein (PV). *p < 0.01, ns = not significant. Error bars denote 95% confidence intervals.
Figure 3
Figure 3
Combined assay results. Central includes measurements from the internal jugular (IJ), sigmoid sinus (SS), left inferior petrosal sinus (IPSL), and right inferior petrosal sinus (IPSR). Peripheral represents measurements from the femoral vein (PV). Error bars denote 95% confidence intervals.
See this image and copyright information in PMC

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