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

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

Attentional deficits in Alzheimer’s: investigating the role of acetylcholine with computational modelling

Attention is a very important cognitive process that is employed for many actions in our everydaylife (e.g. watching television, reading a paper, washing our face, eatingand so on). It is therefore essential to investigate further the underlying mechanisms inneuro-degenerativeconditions, like Alzheimer’s disease, in which ourattentional abilities are reduced(Festa, Heindel, & Ott, 2010; Foster, Behrmann, & Stuss, 1999; Hao et al., 2005; Porter, Tales, et al., 2010; Redel et al., 2012; A. Tales et al., 2002a; Vallejo et al., 2016).Alzheimer’s disease is a condition that can take severalyears if not decades from the time it starts to the time the full symptoms are shown (Tijms & Visser, 2018).In those years of disease progression,there are a number of pathological processes that are taking place, however one of the starting point of the pathologyis believed to be the aggregation of βamyloids into plaques(Gordon et al., 2018; Tijms & Visser, 2018). Irrespective ofthe amount of research that has taken place,manyquestionsremain on how the disease unfolds and how to identify individual’s position in the disease’s trajectory(Gordon et al., 2018; Ryman et al., 2014)

Current concepts in Alzheimer's disease: a multidisciplinary review

This comprehensive, pedagogically-oriented review is aimed at a heterogeneous audience representative of the allied disciplines involved in research and patient care. After a foreword on epidemiology, genetics, and risk factors, the amyloid cascade model is introduced and the main neuropathological hallmarks are discussed. The progression of memory, language, visual processing, executive, attentional, and praxis deficits, and of behavioral symptoms is presented. After a summary on neuropsychological assessment, emerging biomarkers from cerebrospinal fluid assays, magnetic resonance imaging, nuclear medicine, and electrophysiology are discussed. Existing treatments are briefly reviewed, followed by an introduction to emerging disease-modifying therapies such as secretase modulators, inhibitors of Abeta aggregation, immunotherapy, inhibitors of tau protein phosphorylation, and delivery of nerve growth factor