Blood-Cerebrospinal Fluid Barrier Gradients in Mild Cognitive Impairment and Alzheimer's Disease: Relationship to Inflammatory Cytokines and Chemokines

Abstract

Background: The pathophysiology underlying altered blood-cerebrospinal fluid barrier (BCSFB) function in Alzheimer's disease (AD) is unknown but may relate to endothelial cell activation and cytokine mediated inflammation.Methods: Cerebrospinal fluid (CSF) and peripheral blood were concurrently collected from cognitively healthy controls (N = 21) and patients with mild cognitive impairment (MCI) (N = 8) or AD (N = 11). The paired serum and CSF samples were assayed for a panel of cytokines, chemokines, and related trophic factors using multiplex ELISAs. Dominance analysis models were conducted to determine the relative importance of the inflammatory factors in relationship to BCSFB permeability, as measured by CSF/serum ratios for urea, creatinine, and albumin.Results: BCSFB disruption to urea, a small molecule distributed by passive diffusion, had a full model coefficient of determination (r2) = 0.35, and large standardized dominance weights (>0.1) for monocyte chemoattractant protein-1, interleukin (IL)-15, IL-1rα, and IL-2 in serum. BCSFB disruption to creatinine, a larger molecule governed by active transport, had a full model r2 = 0.78, and large standardized dominance weights for monocyte inhibitor protein-1b in CSF and tumor necrosis factor-α in serum. BCSFB disruption to albumin, a much larger molecule, had a full model r2 = 0.62, and large standardized dominance weights for IL-17a, interferon-gamma, IL-2, and VEGF in CSF, as well IL-4 in serum.Conclusions: Inflammatory proteins have been widely documented in the AD brain. The results of the current study suggest that changes in BCSFB function resulting in altered permeability and transport are related to expression of specific inflammatory proteins, and that the shifting distribution of these proteins from serum to CSF in AD and MCI is correlated with more severe perturbations in BCSFB function.

Peripheral inflammatory biomarkers in Alzheimer's disease and mild cognitive impairment: a systematic review and meta‐analysis

“…The results corresponded to a recent meta‐analysis which showed that several inflammatory markers (CRP, IL‐6, α1‐antichymotrypsin, lipoprotein‐associated phospholipase A2 and fibrinogen) are associated with an increased risk of all‐cause dementia; however, these markers were not specific for AD . Another study showed significantly elevated IL‐15, IL‐1α, and IL‐2 in combined MCI/AD serum samples . In a study, 18 predictive plasma signalling proteins (cytokines and chemokines) can be used to separate AD patients and HC with an accuracy of 90% .…”

“…13 Another study showed significantly elevated IL-15, IL-1α, and IL-2 in combined MCI/AD serum samples. 24 In a study, 18 predictive plasma signalling proteins (cytokines and chemokines) can be used to separate AD patients and HC with an accuracy of 90%. 25 In addition, previous studies indicated that peripheral CRP, 26 IL-1β, 9,17 IL-6, 27 IL-12, 28 IL-18, 28,29 IL-8 30 concentrations were negatively associated with MMSE scores in AD patients.…”

Inflammatory markers in Alzheimer’s disease and mild cognitive impairment: a meta-analysis and systematic review of 170 studies

“…With no changes in plasma during this time, it is suggested that CSF inflammatory responses to lumbar catheter placement vary between the AD and the control groups 20. Analysing the correlation of these marker levels with the CSF to serum albumin ratio, which is regarded as an index assessing the blood–cerebrospinal fluid barrier (BCSFB) integrity, peripheral plus central inflammatory processes were supported to play a critical role in the early changes of BCSFB function 21. This indicated a disruption of the blood–brain barrier (BBB), resulting in alterations of its permeability and transport capacity 21.…”

“…Analysing the correlation of these marker levels with the CSF to serum albumin ratio, which is regarded as an index assessing the blood–cerebrospinal fluid barrier (BCSFB) integrity, peripheral plus central inflammatory processes were supported to play a critical role in the early changes of BCSFB function 21. This indicated a disruption of the blood–brain barrier (BBB), resulting in alterations of its permeability and transport capacity 21. Based on these, it is reasoned to speculate that the variances of specific inflammatory marker levels in body fluid may be related to that shifting distribution between the periphery and CSF.…”

Cellular Senescence in Neurodegenerative Diseases

“…AD patients and mouse models of AD, present increased oxidative stress and mitochondrial dysfunction, similar to that observed in senescence. These events are present in the early stages of AD and precede the major pathologic hallmarks, such as senile plaques and NFTs (Yates et al, 2015;Ott et al, 2018).…”