Solanezumab at a dose of 400 mg administered every 4 weeks in patients with mild Alzheimer's disease did not significantly affect cognitive decline. (Funded by Eli Lilly; EXPEDITION3 ClinicalTrials.gov number, NCT01900665 .).

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Increased damage to proteins by glycation, oxidation and nitration has been implicated in neuronal cell death leading to Alzheimer's disease (AD). Protein glycation, oxidation and nitration adducts are consequently formed. Quantitative screening of these adducts in CSF may provide a biochemical indicator for the diagnosis of AD. To assess this, we measured 11 glycation adducts, three oxidation adducts and a nitration adduct, determining both protein adduct residues and free adducts, in CSF samples of age-matched normal healthy subjects (n ¼ 18) and subjects with Alzheimer's disease (n ¼ 32). In CSF protein, the concentrations of 3-nitrotyrosine, N e -carboxymethyl-lysine, 3-deoxyglucosone-derived hydroimidazolone and N-formylkynurenine residues were increased in subjects with Alzheimer's disease. In CSF ultrafiltrate, the concentrations of 3-nitrotyrosine, methylglyoxal-derived hydroimidazolone and glyoxal-derived hydroimidazolone free adducts were also increased. The Mini-Mental State Examination (MMSE) score correlated negatively with 3-nitrotyrosine residue concentration (p < 0.05), and the negative correlation with fructosyl-lysine residues just failed to reach significance (p ¼ 0.052). Multiple linear regression gave a regression model of the MMSE score on 3-nitrotyrosine, fructosyl-lysine and N e -carboxyethyl-lysine residues with p-values of 0.021, 0.031 and 0.052, respectively. These findings indicate that protein glycation, oxidation and nitration adduct residues and free adducts were increased in the CSF of subjects with Alzheimer's disease. A combination of nitration and glycation adduct estimates of CSF may provide an indicator for the diagnosis of Alzheimer's disease. Keywords: Alzheimer's disease, cerebrospinal fluid, glycation, methylglyoxal, nitrotyrosine, oxidative stress. Alzheimer's disease (AD) is characterized by the formation of extracellular protein deposits consisting predominantly of amyloid peptide and intracellular protein deposits of the microtubule-associated protein tau. These are found in the neocortex, entorhinal cortex, and hippocampus. Advanced glycation endproduct (AGE) residues accumulate in the deposited proteins. This contributes to their insolubility and protease resistance. Neuronal damage in AD is also associated with increased protein oxidation and nitration. These Abbreviations used: AGEs, advanced glycation endproducts; AD, Alzheimer's disease; CEL, N e -carboxyethyl-lysine; CML, N e -carboxymethyl-lysine; 3DG-H, N d -(5-hydro-5-(2,3,4-trihydroxybutyl)-4-imidazolon-2-yl)ornithine and related structural isomers; DOLD, 3-deoxyglucosone-derived lysine dimer; FL, fructosyl-lysine; G-H1, N d -(5-hydro-4-imidazolon-2-yl)ornithine; GOLD, glyoxal-derived lysine dimer; LC-MS/MS, liquid chromatography with triple quadrupole mass spectrometric detection; LOD, limit of detection; MG-H1, N d -(5-hydro-5-methyl-4-imidazolon-2-yl)-ornithine; MetSO, methionine sulfoxide; MMSE, Mini-Mental State Examination; MOLD, methylglyoxal-derived lysine dimer; MRM, multiple reaction monit...

Telomere dysfunction limits the proliferative capacity of human cells by activation of DNA damage responses, inducing senescence or apoptosis. In humans, telomere shortening occurs in the vast majority of tissues during aging, and telomere shortening is accelerated in chronic diseases that increase the rate of cell turnover. Yet, the functional role of telomere dysfunction and DNA damage in human aging and diseases remains under debate. Here, we identified marker proteins (i.e., CRAMP, stathmin, EF-1α, and chitinase) that are secreted from telomere-dysfunctional bone-marrow cells of late generation telomerase knockout mice (G4mTerc −/− ). The expression levels of these proteins increase in blood and in various tissues of aging G4mTerc −/− mice but not in aging mice with long telomere reserves. Orthologs of these proteins are up-regulated in late-passage presenescent human fibroblasts and in early passage human cells in response to γ-irradiation. The study shows that the expression level of these marker proteins increases in the blood plasma of aging humans and shows a further increase in geriatric patients with aging-associated diseases. Moreover, there was a significant increase in the expression of the biomarkers in the blood plasma of patients with chronic diseases that are associated with increased rates of cell turnover and telomere shortening, such as cirrhosis and myelodysplastic syndromes (MDS). Analysis of blinded test samples validated the effectiveness of the biomarkers to discriminate between young and old, and between disease groups (MDS, cirrhosis) and healthy controls. These results support the concept that telomere dysfunction and DNA damage are interconnected pathways that are activated during human aging and disease.