Fluid Biomarkers of Neurodegeneration in Mild Cognitive Impairment: A Meta‐Analysis

Abstract

AbstractBackgroundMild cognitive impairment (MCI) is a well‐established prodromal stage of Alzheimer’s disease and is often accompanied by early signs of neurodegeneration (e.g., neuronal loss) that may influence subsequent prognosis. To facilitate a better characterization of the underlying neuropathology, a thorough investigation of proteins associated with neurodegenerative processes in MCI is needed. Thus, the present study systematically assessed the available literature to quantitatively evaluate cerebrospinal fluid (CSF) and peripheral blood concentrations of biomarkers related to neurodegeneration in individuals with MCI compared to healthy controls (HCs).MethodOriginal peer‐reviewed articles that assessed the following CSF and/or peripheral biomarkers: neurofilament light chain (NFL), total‐tau (T‐tau), glial fibrillary acidic protein (GFAP), heart‐type fatty acid binding protein (HFABP), neuron‐specific enolase (NSE), and S100 calcium‐binding protein B (S100B) in both MCI and HCs were included for meta‐analysis. Standardized mean differences (SMDs) and 95% confidence intervals were calculated using a random‐effects model. Heterogeneity was assessed using the I2 statistic.ResultA total of 109 study cohorts were included in the meta‐analysis. In CSF, concentrations of NFL (MCI n = 2771, HC n = 4263, SMD [95% CI] = 0.69 [0.56, 0.83], p < 0.001), GFAP (MCI n = 513, HC n = 1620, SMD [95% CI] = 0.41 [0.08, 0.74], p = 0.02), and HFABP (MCI n = 363, HC n = 245, SMD [95% CI] = 0.57 [0.23, 0.55], p < 0.001) were elevated in MCI. In peripheral blood, concentrations of NFL (MCI n = 6520, HC n = 9439, SMD [95% CI] = 0.41 [0.32, 0.49], p < 0.001), T‐tau (MCI n = 4463, HC n = 5921, SMD [95% CI] = 0.19 [0.09, 0.29], p < 0.001), and GFAP (MCI n = 1758, HC n = 3179, SMD [95% CI] = 0.39 [0.23, 0.55], p < 0.001) were increased in MCI. Significant heterogeneity was identified for all comparisons and was explored through meta regression and subgroup analysis.ConclusionThe present study identified several fluid biomarkers of neurodegeneration in MCI. Importantly, elevated biomarker levels can be detected in both CSF and less‐invasively through peripheral blood. Future studies should focus on assessing the clinical utility of monitoring these biomarkers as they may provide further insight into neuronal and astroglial pathology occurring in the early stages of cognitive decline.