%0 Journal Article %J J Alzheimers Dis %D 2020 %T Dickkopf-1 Overexpression in vitro Nominates Candidate Blood Biomarkers Relating to Alzheimer's Disease Pathology. %A Shi, Liu %A Winchester, Laura M %A Liu, Benjamine Y %A Killick, Richard %A Ribe, Elena M %A Westwood, Sarah %A Baird, Alison L %A Buckley, Noel J %A Hong, Shengjun %A Dobricic, Valerija %A Kilpert, Fabian %A Franke, Andre %A Kiddle, Steven %A Sattlecker, Martina %A Dobson, Richard %A Cuadrado, Antonio %A Hye, Abdul %A Ashton, Nicholas J %A Morgan, Angharad R %A Bos, Isabelle %A Vos, Stephanie J B %A Ten Kate, Mara %A Scheltens, Philip %A Vandenberghe, Rik %A Gabel, Silvy %A Meersmans, Karen %A Engelborghs, Sebastiaan %A De Roeck, Ellen E %A Sleegers, Kristel %A Frisoni, Giovanni B %A Blin, Olivier %A Richardson, Jill C %A Bordet, Régis %A Molinuevo, José L %A Rami, Lorena %A Wallin, Anders %A Kettunen, Petronella %A Tsolaki, Magda %A Verhey, Frans %A Lleo, Alberto %A Alcolea, Daniel %A Popp, Julius %A Peyratout, Gwendoline %A Martínez-Lage, Pablo %A Tainta, Mikel %A Johannsen, Peter %A Teunissen, Charlotte E %A Freund-Levi, Yvonne %A Frölich, Lutz %A Legido-Quigley, Cristina %A Barkhof, Frederik %A Blennow, Kaj %A Rasmussen, Katrine Laura %A Nordestgaard, Børge Grønne %A Frikke-Schmidt, Ruth %A Nielsen, Sune Fallgaard %A Soininen, Hilkka %A Vellas, Bruno %A Kloszewska, Iwona %A Mecocci, Patrizia %A Zetterberg, Henrik %A Morgan, B Paul %A Streffer, Johannes %A Visser, Pieter Jelle %A Bertram, Lars %A Nevado-Holgado, Alejo J %A Lovestone, Simon %X

BACKGROUND: Previous studies suggest that Dickkopf-1 (DKK1), an inhibitor of Wnt signaling, plays a role in amyloid-induced toxicity and hence Alzheimer's disease (AD). However, the effect of DKK1 expression on protein expression, and whether such proteins are altered in disease, is unknown.

OBJECTIVE: We aim to test whether DKK1 induced protein signature obtained in vitro were associated with markers of AD pathology as used in the amyloid/tau/neurodegeneration (ATN) framework as well as with clinical outcomes.

METHODS: We first overexpressed DKK1 in HEK293A cells and quantified 1,128 proteins in cell lysates using aptamer capture arrays (SomaScan) to obtain a protein signature induced by DKK1. We then used the same assay to measure the DKK1-signature proteins in human plasma in two large cohorts, EMIF (n = 785) and ANM (n = 677).

RESULTS: We identified a 100-protein signature induced by DKK1 in vitro. Subsets of proteins, along with age and apolipoprotein E ɛ4 genotype distinguished amyloid pathology (A + T-N-, A+T+N-, A+T-N+, and A+T+N+) from no AD pathology (A-T-N-) with an area under the curve of 0.72, 0.81, 0.88, and 0.85, respectively. Furthermore, we found that some signature proteins (e.g., Complement C3 and albumin) were associated with cognitive score and AD diagnosis in both cohorts.

CONCLUSIONS: Our results add further evidence for a role of DKK regulation of Wnt signaling in AD and suggest that DKK1 induced signature proteins obtained in vitro could reflect theATNframework as well as predict disease severity and progression in vivo.

%B J Alzheimers Dis %V 77 %P 1353-1368 %8 2020 Sep 29 %G eng %N 3 %R 10.3233/JAD-200208 %0 Journal Article %J J Alzheimers Dis %D 2020 %T Exploration of Plasma Lipids in Mild Cognitive Impairment due to Alzheimer's Disease. %A Bergland, Anne Katrine %A Proitsi, Petroula %A Kirsebom, Bjørn-Eivind %A Soennesyn, Hogne %A Hye, Abdul %A Larsen, Alf Inge %A Xu, Jin %A Legido-Quigley, Cristina %A Rajendran, Lawrence %A Fladby, Tormod %A Aarsland, Dag %X

BACKGROUND: Lipids have important structural roles in cell membranes and changes to these membrane lipids may influence β- and γ-secretase activities and thus contribute to Alzheimer's disease (AD) pathology.

OBJECTIVE: To explore baseline plasma lipid profiling in participants with mild cognitive impairment (MCI) with and without AD pathology.

METHODS: We analyzed 261 plasma lipid profiles using reversed phase chromatography mass spectrometry in cerebrospinal fluid amyloid positive (Aβ+) or negative (Aβ-) participants with MCI as compared to controls. Additionally, we analyzed the potential associations of plasma lipid profiles with performance on neuropsychological tests at baseline and after two years.

RESULTS: Sphingomyelin (SM) concentrations, particularly, SM(d43:2), were lower in MCI Aβ+ individuals compared to controls. Further, SM(d43:2) was also nominally reduced in MCI Aβ+ individuals compared to MCI Aβ-. No plasma lipids were associated with performance on neuropsychological tests at baseline or between the two time points after correction for multiple testing.

CONCLUSION: Reduced plasma concentrations of SM were associated with AD.

%B J Alzheimers Dis %V 77 %P 1117-1127 %8 2020 Sep 29 %G eng %N 3 %R 10.3233/JAD-200441 %0 Journal Article %J J Alzheimers Dis %D 2020 %T Validation of Plasma Proteomic Biomarkers Relating to Brain Amyloid Burden in the EMIF-Alzheimer's Disease Multimodal Biomarker Discovery Cohort. %A Westwood, Sarah %A Baird, Alison L %A Anand, Sneha N %A Nevado-Holgado, Alejo J %A Kormilitzin, Andrey %A Shi, Liu %A Hye, Abdul %A Ashton, Nicholas J %A Morgan, Angharad R %A Bos, Isabelle %A Vos, Stephanie J B %A Baker, Susan %A Buckley, Noel J %A Ten Kate, Mara %A Scheltens, Philip %A Teunissen, Charlotte E %A Vandenberghe, Rik %A Gabel, Silvy %A Meersmans, Karen %A Engelborghs, Sebastiaan %A De Roeck, Ellen E %A Sleegers, Kristel %A Frisoni, Giovanni B %A Blin, Olivier %A Richardson, Jill C %A Bordet, Régis %A Molinuevo, José L %A Rami, Lorena %A Wallin, Anders %A Kettunen, Petronella %A Tsolaki, Magda %A Verhey, Frans %A Lleo, Alberto %A Sala, Isabel %A Popp, Julius %A Peyratout, Gwendoline %A Martínez-Lage, Pablo %A Tainta, Mikel %A Johannsen, Peter %A Freund-Levi, Yvonne %A Frölich, Lutz %A Dobricic, Valerija %A Legido-Quigley, Cristina %A Bertram, Lars %A Barkhof, Frederik %A Zetterberg, Henrik %A Morgan, B Paul %A Streffer, Johannes %A Visser, Pieter Jelle %A Lovestone, Simon %X

We have previously investigated, discovered, and replicated plasma protein biomarkers for use to triage potential trials participants for PET or cerebrospinal fluid measures of Alzheimer's disease (AD) pathology. This study sought to undertake validation of these candidate plasma biomarkers in a large, multi-center sample collection. Targeted plasma analyses of 34 proteins with prior evidence for prediction of in vivo pathology were conducted in up to 1,000 samples from cognitively healthy elderly individuals, people with mild cognitive impairment, and in patients with AD-type dementia, selected from the EMIF-AD catalogue. Proteins were measured using Luminex xMAP, ELISA, and Meso Scale Discovery assays. Seven proteins replicated in their ability to predict in vivo amyloid pathology. These proteins form a biomarker panel that, along with age, could significantly discriminate between individuals with high and low amyloid pathology with an area under the curve of 0.74. The performance of this biomarker panel remained consistent when tested in apolipoprotein E ɛ4 non-carrier individuals only. This blood-based panel is biologically relevant, measurable using practical immunocapture arrays, and could significantly reduce the cost incurred to clinical trials through screen failure.

%B J Alzheimers Dis %V 74 %P 213-225 %8 2020 %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/31985466?dopt=Abstract %R 10.3233/JAD-190434 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Association between Plasma Ceramides and Phosphatidylcholines and Hippocampal Brain Volume in Late Onset Alzheimer's Disease. %A Kim, Min %A Nevado-Holgado, Alejo %A Whiley, Luke %A Snowden, Stuart G %A Soininen, Hilkka %A Kloszewska, Iwona %A Mecocci, Patrizia %A Tsolaki, Magda %A Vellas, Bruno %A Thambisetty, Madhav %A Dobson, Richard J B %A Powell, John F %A Lupton, Michelle K %A Simmons, Andy %A Velayudhan, Latha %A Lovestone, Simon %A Proitsi, Petroula %A Legido-Quigley, Cristina %X

Lipids such as ceramides and phosphatidylcholines (PC) have been found altered in the plasma of Alzheimer's disease (AD) patients in a number of discovery studies. For this reason, the levels of 6 ceramides and 3 PCs, with different fatty acid length and saturation levels, were measured in the plasma from 412 participants (AD n = 205, Control n = 207) using mass spectrometry coupled with ultra-performance liquid chromatography. After this, associations with AD status, brain atrophy, and age-related effects were studied. In the plasma of AD participants, cross-sectional analysis revealed elevated levels of three ceramides (Cer16:0 p < 0.01, Cer18:0 p < 0.01, Cer24:1 p < 0.05). In addition, two PCs in AD plasma (PC36:5 p < 0.05, PC38:6 p < 0.05) were found to be depleted compared to the control group, with PC36:5 also associating with hippocampal atrophy (p < 0.01). Age-specific analysis further revealed that levels of Cer16:0, Cer18:0, and Cer20:0 were associated with hippocampal atrophy only in younger participants (age < 75, p < 0.05), while all 3 PCs did so in the older participants (age > 75, p < 0.05). PC36:5 was associated with AD status in the younger group (p < 0.01), while PC38:6 and 40:6 did so in the older group (p < 0.05). In this study, elevated ceramides and depleted PCs were found in the plasma from 205 AD volunteers. Our findings also suggest that dysregulation in PC and ceramide metabolism could be occurring in different stages of AD progression.

%B J Alzheimers Dis %V 60 %P 809-817 %8 2017 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/27911300?dopt=Abstract %R 10.3233/JAD-160645