Reduced CSF IL-12/23 p40 concentration in patients with cognitive impairment.

<p>(A) Serum IL-12/23 p40 concentration, (B) CSF IL-12/23 p40 concentration, and (C) CSF/serum IL-12/23 p40 ratio in the study population of AD patients (n = 30), other dementias (n = 11), SMCI (n = 11), and healthy controls (n = 18). Values in the box plots are given as medians (horizontal lines), 25th-75th percentiles (boxes), and 10th-90th percentiles (whiskers). Differences between multiple groups were assessed using the Kruskal-Wallis test, followed by the Mann-Whitney U test for pair-wise comparisons. * p < 0.05, ** p < 0.01 vs. control group.</p

CSF IL-12/23 p40 correlates positively with the CSF AD biomarker phosphorylated tau protein (P-tau).

<p>(A) In the total study population (n = 70; r = 0.25, p < 0.05) as well as (B) in the AD group (n = 30; r = 0.46, p = 0.01), CSF IL-12/23 p40 concentration correlated positively with CSF P-tau concentration. Note the logarithmic scale on both the x-axis and the y-axis. Correlations were sought using the Spearman rank order correlation test.</p

Reduced CSF IL-12/23 p40 concentration in patients with cognitive impairment.

<p>(A) Serum IL-12/23 p40 concentration, (B) CSF IL-12/23 p40 concentration, and (C) CSF/serum IL-12/23 p40 ratio in the study population of AD patients (n = 30), other dementias (n = 11), SMCI (n = 11), and healthy controls (n = 18). Values in the box plots are given as medians (horizontal lines), 25th-75th percentiles (boxes), and 10th-90th percentiles (whiskers). Differences between multiple groups were assessed using the Kruskal-Wallis test, followed by the Mann-Whitney U test for pair-wise comparisons. * p < 0.05, ** p < 0.01 vs. control group.</p

Serum and CSF levels of cytokines and chemokines (pg/mL) in 52 patients with cognitive impairment and 18 healthy matched controls.

<p>Serum and CSF levels of cytokines and chemokines (pg/mL) in 52 patients with cognitive impairment and 18 healthy matched controls.</p

Anthropometric measures, MMSE score, and CSF AD biomarkers in 52 patients with cognitive impairment and 18 healthy matched controls.

<p>Anthropometric measures, MMSE score, and CSF AD biomarkers in 52 patients with cognitive impairment and 18 healthy matched controls.</p

CSF acetylcholinesterase (AChE) activity correlates positively with the CSF level of the AD biomarker phosphorylated tau protein (P-tau).

<p>A) In the total study population (n = 69; r = 0.41, <i>P</i> < 0.001) as well as in B) AD patients (n = 28; r = 0.50, <i>P</i> = 0.009), CSF AChE activity correlated positively with CSF P-tau level. Correlations were sought using the Spearman rank order correlation test.</p

Reduced CSF acetylcholinesterase (AChE) activity both in patients with AD and other dementias compared to healthy controls.

<p>A) CSF AChE activity, B) CSF butyrylcholinesterase (BuChE) activity, and C) CSF AChE/BuChE ratio in the study population of patients with AD (n = 28), other dementias (n = 12), SMCI (n = 12), and healthy controls (n = 17). Values in the box plots are given as medians (horizontal lines), 25th-75th percentiles (boxes), and ranges (whiskers). Between-group differences were assessed using the Kruskal-Wallis test for multiple variables, followed by the Mann-Whitney U test for pair-wise comparisons. <b><i>^*</i></b><i> P</i> < 0.05 <b>^**</b><i>P</i> < 0.01 .</p

Data_Sheet_1_Predicting AT(N) pathologies in Alzheimer’s disease from blood-based proteomic data using neural networks.pdf

Background and objectiveBlood-based biomarkers represent a promising approach to help identify early Alzheimer’s disease (AD). Previous research has applied traditional machine learning (ML) to analyze plasma omics data and search for potential biomarkers, but the most modern ML methods based on deep learning has however been scarcely explored. In the current study, we aim to harness the power of state-of-the-art deep learning neural networks (NNs) to identify plasma proteins that predict amyloid, tau, and neurodegeneration (AT[N]) pathologies in AD.MethodsWe measured 3,635 proteins using SOMAscan in 881 participants from the European Medical Information Framework for AD Multimodal Biomarker Discovery study (EMIF-AD MBD). Participants underwent measurements of brain amyloid β (Aβ) burden, phosphorylated tau (p-tau) burden, and total tau (t-tau) burden to determine their AT(N) statuses. We ranked proteins by their association with Aβ, p-tau, t-tau, and AT(N), and fed the top 100 proteins along with age and apolipoprotein E (APOE) status into NN classifiers as input features to predict these four outcomes relevant to AD. We compared NN performance of using proteins, age, and APOE genotype with performance of using age and APOE status alone to identify protein panels that optimally improved the prediction over these main risk factors. Proteins that improved the prediction for each outcome were aggregated and nominated for pathway enrichment and protein–protein interaction enrichment analysis.ResultsAge and APOE alone predicted Aβ, p-tau, t-tau, and AT(N) burden with area under the curve (AUC) scores of 0.748, 0.662, 0.710, and 0.795. The addition of proteins significantly improved AUCs to 0.782, 0.674, 0.734, and 0.831, respectively. The identified proteins were enriched in five clusters of AD-associated pathways including human immunodeficiency virus 1 infection, p53 signaling pathway, and phosphoinositide-3-kinase–protein kinase B/Akt signaling pathway.ConclusionCombined with age and APOE genotype, the proteins identified have the potential to serve as blood-based biomarkers for AD and await validation in future studies. While the NNs did not achieve better scores than the support vector machine model used in our previous study, their performances were likely limited by small sample size.</p

GSK933776 plasma pharmacodynamics.

<p>A) Geometric mean plasma Aβ concentration–time plots over the three dosing intervals (semi-log plot). Plasma levels of total Aβ42 and Aβ increased whereas plasma levels of free Aβ decreased in dose-dependent manner. Peak:trough ratios for Aβ decreased with increasing dose of GSK933776. B) Week 12 ratio to baseline for CSF Aβ (Aβ1–42 and AβX–42) concentrations. Presented as individual values and mean (95%CI). There were no significant changes from baseline for Aβ1–42 or AβX–42.</p

GSK933776 plasma pharmacokinetics.

<p>Time-course of plasma concentrations of GSK933776 by dose: medians (lines) and individual data (dots). LLQ is 100 ng/mL for the 0.1 mg/kg dose and 5 μg/mL for the 1, 3, and 6 mg/kg doses. SD = single dose; RD = repeat dose. Maximum plasma concentrations increased with dose.</p