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. 2022 Mar 25;14(1):e12296.
doi: 10.1002/dad2.12296. eCollection 2022.

Blood-brain barrier dysfunction and reduced cerebrospinal fluid levels of soluble amyloid precursor protein-β in patients with subcortical small-vessel disease

Petronella Kettunen  1 , Maria Bjerke  2   3 , Carl Eckerström  1   4 , Michael Jonsson  1 , Henrik Zetterberg  1   5   6   7   8 , Kaj Blennow  1   5 , Johan Svensson  9   10 , Anders Wallin  1
Affiliations

Blood-brain barrier dysfunction and reduced cerebrospinal fluid levels of soluble amyloid precursor protein-β in patients with subcortical small-vessel disease

Petronella Kettunen et al. Alzheimers Dement (Amst). .

Abstract

Introduction: Subcortical small-vessel disease (SSVD) is the most common vascular cognitive disorder. However, because no disease-specific cerebrospinal fluid (CSF) biomarkers are available for SSVD, our aim was to identify such markers.

Methods: We included 170 healthy controls and patients from the Gothenburg Mild Cognitive Impairment (MCI) study clinically diagnosed with SSVD dementia, Alzheimer's disease (AD), or mixed AD/SSVD. We quantified CSF levels of amyloid-β (Aβ)x-38, Aβx-40, Aβx-42, as well as soluble amyloid precursor protein (sAPP)-α and sAPP-β.

Results: sAPP-β was lower in SSVD patients than in AD patients and controls. Receiver-operating characteristic (ROC) analyses showed that sAPP-β moderately separated SSVD from AD and controls. Moreover, the CSF/serum albumin ratio was elevated exclusively in SSVD and could moderately separate SSVD from the other groups in ROC analyses.

Discussion: SSVD has a biomarker profile that differs from that of AD and controls, and to some extent also from mixed AD/SSVD, suggesting that signs of blood-brain barrier (BBB) dysfunction and sAPP-β could be additional tools to diagnose SSVD.

Highlights: Patients with subcortical small-vessel disease (SSVD) exhibited reduced levels of sAPP-β and disturbances of the blood-brain barrier (BBB).This biochemical pattern is different from that of Alzheimer's disease (AD) and to some degree from that of mixed AD/SSVD.Our findings are speaking in favor of the concept that SSVD is a distinct vascular cognitive disorder (VCD) form.

Keywords: Alzheimer's disease; amyloid beta; blood‐brain barrier; cerebrospinal fluid; subcortical small‐vessel disease.

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Conflict of interest statement

Petronella Kettunen, Maria Bjerke, Carl Eckerström, and Johan Svensson: no conflicts of interest. Michael Jonsson: Consulting fees for assignment as paid advisory board member for Biogen 2020‐2021. Henrik Zetterberg has served at scientific advisory boards and/or as a consultant for Abbvie, Alector, Eisai, Denali, Roche, Wave, Samumed, Siemens Healthineers, Pinteon Therapeutics, Nervgen, AZTherapies, CogRx, and Red Abbey Labs; has given lectures in symposia sponsored by Cellectricon, Fujirebio, Alzecure, and Biogen; and is a co‐founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program (outside submitted work). Kaj Blennow has served as a consultant, on advisory boards, or on data‐monitoring committees for Abcam, Axon, Biogen, JOMDD/Shimadzu. Julius Clinical, Lilly, MagQu, Novartis, Prothena, Roche Diagnostics, and Siemens Healthineers; and is a co‐founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program, all unrelated to the work presented in this article. Anders Wallin: Lecture fees from Lundbeck.

Figures

FIGURE 1
FIGURE 1
Cerebrospinal fluid (CSF) levels of Aβx‐38, Aβx‐40, Aβx‐42, sAPP‐α, and sAPP‐β, as well as Aβx‐42/x‐38, Aβx‐42/x‐40, and CSF/serum albumin ratios in patients and controls. Values are given as means (SD). Different letters above each group correspond to significant differences of P < .05. For details regarding significance values, see Table 2. SSVD, subcortical small vessel disease; AD, Alzheimer's disease; Aβ, amyloidbeta; sAPP, soluble amyloid precursor protein.
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