Novel fluid biomarkers for mild cognitive impairment: A systematic review and meta-analysis

Mild cognitive impairment (MCI) is a well-established prodromal stage of dementia (e.g., Alzheimer's disease) that is often accompanied by early signs of neurodegeneration. To facilitate a better characterization of the underlying pathophysiology, we assessed the available literature to evaluate potential fluid biomarkers in MCI. Peer-reviewed articles that measured cerebrospinal fluid (CSF) and/or peripheral biomarkers of neuronal injury (total-tau [T-tau], neurofilament light chain [NfL], heart-type fatty acid binding protein [HFABP], neuronspecific enolase, ubiquitin C-terminal hydrolase L1) and/or astroglial pathology (glial fibrillary acidic protein [GFAP], S100 calcium-binding protein B) in MCI and healthy controls were assessed. Group differences were summarized by standardized mean differences (SMDs) and 95% confidence intervals calculated using a randomeffects model. Heterogeneity was quantified using I2. A total of 107 studies were included in the meta-analysis and 10 studies were qualitatively reviewed. In CSF, concentrations of NfL (SMD = 0.69 [0.56, 0.83]), GFAP (SMD = 0.41 [0.07, 0.75]), and HFABP (SMD = 0.57 [0.26, 0.89]) were elevated in MCI. In blood, increased concentrations of T-tau (SMD = 0.19 [0.09, 0.29]), NfL (SMD = 0.41 [0.32, 0.49]), and GFAP (SMD = 0.39 [0.23, 0.55]) were found in MCI. Heterogeneity that was identified in all comparisons was explored using metaregression and subgroup analysis. Elevated NfL and GFAP can be detected in both CSF and peripheral blood. Monitoring these biomarkers in clinical settings may provide important insight into underlying neurodegenerative processes in MCI.