Association of glial and neuronal degeneration markers with Alzheimer’s disease cerebrospinal fluid profile and cognitive functions

• Published in: Alzheimer's research & therapy Vol. 12; no. 1; pp. 1 - 92
• Main Authors: Teitsdottir, Unnur D, Jonsdottir, Maria K, Lund, Sigrun H, Darreh-Shori, Taher, Snaedal, Jon, Petersen, Petur H
• Format: Journal Article
• Language: English
• Published: London BioMed Central Ltd 04-08-2020; BioMed Central; BMC
• Subjects: Advertising executives; Alzheimer's disease; Binding proteins; Biomarkers; Brain research; Calmodulin; Cerebrospinal fluid; Chitinase; Cognitive ability; Dementia; Development and progression; Enzymes; Glial fibrillary acidic protein; Laboratories; Medicin och hälsovetenskap; Memory; Neurodegeneration; Neurofilament light; Neurons; Pathology; Physiological aspects; Protein binding; Proteins; S100 calcium-binding protein B; YKL-40; Germany
• ISSN: 1758-9193; 1758-9193
• DOI: 10.1186/s13195-020-00657-8

Background Neuroinflammation has gained increasing attention as a potential contributing factor in the onset and progression of Alzheimer's disease (AD). The objective of this study was to examine the association of selected cerebrospinal fluid (CSF) inflammatory and neuronal degeneration markers with signature CSF AD profile and cognitive functions among subjects at the symptomatic pre- and early dementia stages. Methods In this cross-sectional study, 52 subjects were selected from an Icelandic memory clinic cohort. Subjects were classified as having AD (n = 28, age = 70, 39% female, Mini-Mental State Examination [MMSE] = 27) or non-AD (n = 24, age = 67, 33% female, MMSE = 28) profile based on the ratio between CSF total-tau (T-tau) and amyloid-[beta].sub.1-42 (A[beta].sub.42) values (cut-off point chosen as 0.52). Novel CSF biomarkers included neurofilament light (NFL), YKL-40, S100 calcium-binding protein B (S100B) and glial fibrillary acidic protein (GFAP), measured with enzyme-linked immunosorbent assays (ELISAs). Subjects underwent neuropsychological assessment for evaluation of different cognitive domains, including verbal episodic memory, non-verbal episodic memory, language, processing speed, and executive functions. Results Accuracy coefficient for distinguishing between the two CSF profiles was calculated for each CSF marker and test. Novel CSF markers performed poorly (area under curve [AUC] coefficients ranging from 0.61 to 0.64) compared to tests reflecting verbal episodic memory, which all performed fair (AUC > 70). LASSO regression with a stability approach was applied for the selection of CSF markers and demographic variables predicting performance on each cognitive domain, both among all subjects and only those with a CSF AD profile. Relationships between CSF markers and cognitive domains, where the CSF marker reached stability selection criteria of > 75%, were visualized with scatter plots. Before calculations of corresponding Pearson's correlations coefficients, composite scores for cognitive domains were adjusted for age and education. GFAP correlated with executive functions (r = - 0.37, p = 0.01) overall, while GFAP correlated with processing speed (r = - 0.68, p < 0.001) and NFL with verbal episodic memory (r = - 0.43, p = 0.02) among subjects with a CSF AD profile. Conclusions The novel CSF markers NFL and GFAP show potential as markers for cognitive decline among individuals with core AD pathology at the symptomatic pre- and early stages of dementia. Keywords: Alzheimer's disease, Cerebrospinal fluid, Neurofilament light, YKL-40, S100 calcium-binding protein B, Glial fibrillary acidic protein, AD biomarker profile, Cognitive domains