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

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.

Cerebrospinal fluid brevican and neurocan fragment patterns in human traumatic brain injury.

BACKGROUND: Altered levels of two extracellular matrix (ECM) proteoglycans, brevican and neurocan, have been found in brain injury models; however, their proteolytic processing in traumatic brain injury (TBI) remains unexplored. A disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS) is a possible contributor to ECM remodelling following TBI. The aims of this study were to evaluate proteolytic brevican/neurocan patterns and ADAMTS-like activity in cerebrospinal fluid (CSF) in the context of TBI. MATERIALS AND METHODS: Forty-two acute TBI patients and 37 idiopathic normal pressure hydrocephalus (iNPH) patients were included in the analysis of tryptic brevican and neurocan peptides in CSF using parallel reaction monitoring mass spectrometry. Twenty-nine TBI and 36 iNPH patients were analysed for ADAMTS-like activity in CSF using a quenched fluorescent substrate. RESULTS: The majority of CSF concentrations of brevican peptides significantly decreased in TBI patients compared with the iNPH group (p ≤ 0.002), while ADAMTS-like activity increased (p < 0.0001). Two C-terminal brevican peptides strongly correlated with unfavourable outcome of TBI patients (rho = 0.85-0.93, p ≤ 0.001). CONCLUSIONS: The decreased CSF concentrations of brevican peptides in TBI are associated with their increased degradation by ADAMTS enzymes. Furthermore, the N- and C-terminal parts of brevican are differentially regulated following TBI and may serve as outcome markers.

Cerebrospinal Fluid Concentrations of Extracellular Matrix Proteins in Alzheimer's Disease.

BACKGROUND: Brevican, neurocan, tenascin-C, and tenascin-R are extracellular matrix (ECM) proteins that are mainly expressed in the brain. They play important roles in proliferation and migration of neurons and other cell types in the brain. These ECM proteins may also be involved in various pathologies, including reactive gliosis. OBJECTIVE: The aim of the study was to investigate if ECM protein concentrations in cerebrospinal fluid (CSF) are linked to the neurodegenerative process in Alzheimer's disease (AD). METHODS: Lumbar CSF samples from a non-AD control group (n = 50) and a clinically diagnosed AD group (n = 42), matched for age and gender, were analyzed using commercially available ELISAs detecting ECM proteins. Mann-Whitney U test was used to examine group differences, while Spearman's rho test was used for correlations. RESULTS: Brevican, neurocan, tenascin-R, and tenascin-C concentrations in AD patients did not differ compared to healthy controls or when the groups were dichotomized based on the Aß42/40 cut-off. CSF tenascin-C and tenascin-R concentrations were significantly higher in women than in men in the AD group (p = 0.02). CONCLUSION: ECM proteins do not reflect AD-pathology in CSF. CSF tenascin-C and tenascin-R upregulation in women possibly reveal sexual dimorphism in the central nervous system immunity during AD.