Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 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.

PubMed Disclaimer

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.
See this image and copyright information in PMC

References

    1. Wallin A, Román GC, Esiri M, et al. Update on vascular cognitive impairment associated with subcortical small‐vessel disease. J Alzheimer's Dis. 2018;62:1417‐1441. - PMC - PubMed
    1. Chui H. Dementia due to subcortical ischemic vascular disease. Clin Cornerstone. 2001;3:40‐51. - PubMed
    1. Wardlaw JM, Smith EE, Biessels GJ, et al. Neuroimaging standards for research into small vessel disease and its contribution to ageing and neurodegeneration. Lancet Neurol. 2013;12:822‐838. - PMC - PubMed
    1. Walsh J, Tozer DJ, Sari H, et al. Microglial activation and blood‐brain barrier permeability in cerebral small vessel disease. Brain. 2021;144:1361‐1371. - PMC - PubMed
    1. Wardlaw JM, Makin SJ, Valdés Hernández MC, et al. Blood‐brain barrier failure as a core mechanism in cerebral small vessel disease and dementia: evidence from a cohort study. Alzheimer's Dement. 2017;13:634.