Brevican and Neurocan Peptides as Potential Cerebrospinal Fluid Biomarkers for Differentiation Between Vascular Dementia and Alzheimer’s Disease

Article type: Research Article

Authors: Minta, Karolina^{a; *} | Brinkmalm, Gunnar^{a; b} | Portelius, Erik^{a; b} | Johansson, Per^{c; d} | Svensson, Johan^{d; e} | Kettunen, Petronella^a | Wallin, Anders^a | Zetterberg, Henrik^{a; b; f; g} | Blennow, Kaj^{a; b} | Andreasson, Ulf^{a; b}

Affiliations: [a] Department of Psychiatry and Neurochemistry,Institute of Neuroscience and Physiology, the Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden | [b] Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden | [c] Department of Clinical Sciences Helsingborg, Lund University, Sweden | [d] Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, the Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden | [e] Department of Endocrinology, Skaraborg Central Hospital, Skövde, Sweden | [f] Department of Neurodegenerative Disease, UCL Institute of Neurology, London, UK | [g] UK Dementia Research Institute at UCL, London, UK

Correspondence: [*] Correspondence to: Karolina Minta, Department of Psychiatry and Neurochemistry, Sahlgrenska University Hospital/Mölndal, S-431 80 Mölndal, Sweden. Tel.: +46 735660741; E-mail: karolina.minta@neuro.gu.se.

Abstract: Background:Brevican and neurocan are central nervous system-specific extracellular matrix proteoglycans. They are degraded by extracellular enzymes, such as metalloproteinases. However, their degradation profile is largely unexplored in cerebrospinal fluid (CSF). Objective:The study aim was to quantify proteolytic peptides derived from brevican and neurocan in human CSF of patients with Alzheimer’s disease (AD) and vascular dementia (VaD) compared with controls. Methods:The first cohort consisted of 75 individuals including 25 patients with AD, 7 with mild cognitive impairment (MCI) diagnosed with AD upon follow-up, 10 patients with VaD or MCI diagnosed with VaD upon follow-up, and 33 healthy controls and cognitively stable MCI patients. In the second cohort, 31 individuals were included (5 AD patients, 14 VaD patients and 12 healthy controls). Twenty proteolytic peptides derived from brevican (n = 9) and neurocan (n = 11) were quantified using high-resolution parallel reaction monitoring mass spectrometry. Results:In the first cohort, the majority of CSF concentrations of brevican and neurocan peptides were significantly decreased inVaDas compared withADpatients (AUC = 0.83.0.93, p≤0.05) and as compared with the control group (AUC = 0.79.0.87, p ≤ 0.05). In the second cohort, CSF concentrations of two brevican peptides (B87, B156) were significantly decreased in VaD compared with AD (AUC = 0.86.0.91, p ≤ 0.05) and to controls (AUC = 0.80.0.82, p ≤ 0.05), while other brevican and neurocan peptides showed a clear trend to be decreased in VaD compared with AD (AUC = 0.64.80, p > 0.05). No peptides differed between AD and controls. Conclusion:Brevican and neurocan peptides are potential diagnostic biomarkers for VaD, with ability to separate VaD from AD.

Keywords: Alzheimer’s disease, brevican, cerebrospinal fluid, extracellular matrix, neurocan, vascular dementia

DOI: 10.3233/JAD-201039

Journal: Journal of Alzheimer's Disease, vol. 79, no. 2, pp. 729-741, 2021