The CNS-specific proteoglycan, brevican, and its ADAMTS4-cleaved fragment show differential serological levels in Alzheimer’s disease, other types of dementia and non-demented controls: A cross-sectional study

• Published in: PloS one 2020-06, Vol.15 (6), p.e0234632-e0234632
• Main Authors: Jonesco, Ditte S, Karsdal, Morten A, Henriksen, Kim
• Format: Article
• Language: English
• Subjects: Alzheimer's disease; Assaying; Bioassay; Biological markers; Biology and Life Sciences; Biomarkers; Blood; Brain research; Cerebrospinal fluid; Chondroitin sulfate; Cross-sectional studies; Dementia; Dementia disorders; Diagnosis; Diagnostic systems; Dilution; Disease; Epitopes; Fragments; Genetic aspects; Health aspects; Identification and classification; Innovations; Medicine and Health Sciences; Memory; Monoclonal antibodies; Neurodegeneration; Neurodegenerative diseases; Pathology; Proteins; Proteoglycans; Research and Analysis Methods; Serology; Serum levels; Target recognition; Traumatic brain injury
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0234632

Evidence indicate that the brain-specific protein, brevican, is proteolytically cleaved during neurodegeneration, hence positioning fragments of brevican as potential blood biomarkers of neurodegenerative diseases, such as dementia. We aimed to develop two assays capable of detecting the brevican N-terminal (N-Brev) and the ADAMTS4-generated fragment (Brev-A), cleaved at Ser.sup.401, in serum and to perform a preliminary assessment of their diagnostic potential in dementias. Monoclonal antibodies against N-Brev and Brev-A were used to develop two ELISAs detecting each epitope. A comparison of brevican fragments in serum from individuals with AD (n = 28), other dementia (OD) (n = 41), and non-dementia-related memory complaints (NDCs) (n = 48) was conducted. Anti-N-Brev and anti-Brev-A antibodies selectively recognized their targets and dilution and spike recoveries were within limits of ±20%. Intra- and inter-assay CVs were below limits of 10% and 15%, respectively. For the N-Brev biomarker, serum from patients with OD showed significantly lower levels than those with AD (p = 0.05) and NDCs (p < 0.01). The opposite pattern was evident for Brev-A: serum levels in patients with OD were significantly higher than for AD (p = 0.04) and NDCs (p = 0.01). For both N-Brev and Brev-A, levels did not differ between AD and NDCs. The ratio of N-Brev/Brev-A resulted in increased significant differences between OD and AD (p < 0.01) and between OD and NDCs (p < 0.0001). The ratio discriminated between NDCs and OD (AUC: 0.75, 95% CI: 0.65-0.85, p < 0.0001) and between OD and AD (AUC: 0.72, 95% CI: 0.59-0.85, p < 0.01). In conclusion, we developed the first assays detecting the N-terminal of brevican as well as an ADAMTS4-cleaved fragment of brevican in blood. Differential levels of N-Brev and Brev-A between AD and OD allow for these biomarkers to possibly distinguish between different forms of dementias.