Non-linear relationships of cerebrospinal fluid biomarker levels with cognitive function: an observational study

INTRODUCTION: Levels of cerebrospinal fluid (CSF) β-amyloid (Aβ) and Tau proteins change in Alzheimer's disease (AD). We tested if the relationships of these biomarkers with cognitive impairment are linear or non-linear. METHODS: We assessed cognitive function and assayed CSF Aβ and Tau biomarkers in 95 non-demented volunteers and 97 AD patients. We then tested non-linearities in their inter-relations. RESULTS: CSF biomarkers related to cognitive function in the non-demented range of cognition, but these relations were weak or absent in the patient range; Aβ1-40's relationship was biphasic. CONCLUSIONS: Major biomarker changes precede clinical AD and index cognitive impairment in AD poorly, if at all

The effects of laropiprant, a selective prostaglandin D₂ receptor 1 antagonist, on the antiplatelet activity of clopidogrel or aspirin.

Laropiprant (LRPT) is being developed in combination with Merck\u27s extended-release niacin (ERN) formulation for the treatment of dyslipidemia. LRPT, an antagonist of the prostaglandin PGD₂ receptor DP1, reduces flushing symptoms associated with ERN. LRPT also has affinity for the thromboxane A₂ receptor TP (approximately 190-fold less potent at TP compared with DP1). Aspirin and clopidogrel are two frequently used anti-clotting agents with different mechanisms of action. Since LRPT may potentially be co-administered with either one of these agents, these studies were conducted to assess the effects of steady-state LRPT on the antiplatelet activity of steady-state clopidogrel or aspirin. Bleeding time at 24 h post-dose (trough) was pre-specified as the primary pharmacodynamic endpoint in both studies. Two separate, double-blind, randomized, placebo-controlled, crossover studies evaluated the effects of multiple-dose LRPT on the pharmacodynamics of multiple-dose clopidogrel or aspirin. Healthy subjects were randomized to once-daily oral doses of LRPT 40 mg or placebo to LRTP co-administered with clopidogrel 75 mg or aspirin 81 mg for 7 days with at least a 21-day washout between treatments. In both studies, bleeding time and platelet aggregation were assessed 4 and 24 hours post-dose on Day 7. Comparability was declared if the 90% confidence interval for the estimated geometric mean ratio ([LRPT+clopidogrel]/clopidogrel alone or [LRPT+aspirin]/aspirin alone) for bleeding time at 24 hours post-dose on Day 7 was contained within (0.66, 1.50). Concomitant daily administration of LRPT 40 mg with clopidogrel 75 mg or aspirin 81 mg resulted in an approximate 4-5% increase in bleeding time at 24 hours after the last dose vs. bleeding time after treatment with clopidogrel or aspirin alone, demonstrating that the treatments had comparable effects on bleeding time. Percent inhibition of platelet aggregation was not significantly different between LRPT co-administered with clopidogrel or aspirin vs. clopidogrel or aspirin alone at 24 hours post-dose at steady state. At 4 hours after the last dose, co-administration of LRPT 40 mg resulted in 3% and 41% increase in bleeding time vs. bleeding time after treatment with aspirin or clopidogrel alone, respectively. Co-administration of LPRT with clopidogrel or aspirin was generally well tolerated in healthy subjects. Co-administration of multiple doses of LRPT 40 mg and clopidogrel 75 mg or aspirin 81 mg had no clinically important effects on bleeding time or platelet aggregation

High Resolution Discovery Proteomics Reveals Candidate Disease Progression Markers of Alzheimer’s Disease in Human Cerebrospinal Fluid

<div><p>Disease modifying treatments for Alzheimer’s disease (AD) constitute a major goal in medicine. Current trends suggest that biomarkers reflective of AD neuropathology and modifiable by treatment would provide supportive evidence for disease modification. Nevertheless, a lack of quantitative tools to assess disease modifying treatment effects remains a major hurdle. Cerebrospinal fluid (CSF) biochemical markers such as total tau, p-tau and Ab42 are well established markers of AD; however, global quantitative biochemical changes in CSF in AD disease progression remain largely uncharacterized. Here we applied a high resolution open discovery platform, dMS, to profile a cross-sectional cohort of lumbar CSF from post-mortem diagnosed AD patients versus those from non-AD/non-demented (control) patients. Multiple markers were identified to be statistically significant in the cohort tested. We selected two markers SME-1 (p<0.0001) and SME-2 (p = 0.0004) for evaluation in a second independent longitudinal cohort of human CSF from post-mortem diagnosed AD patients and age-matched and case-matched control patients. In cohort-2, SME-1, identified as neuronal secretory protein VGF, and SME-2, identified as neuronal pentraxin receptor-1 (NPTXR), in AD were 21% (p = 0.039) and 17% (p = 0.026) lower, at baseline, respectively, than in controls. Linear mixed model analysis in the longitudinal cohort estimate a decrease in the levels of VGF and NPTXR at the rate of 10.9% and 6.9% per year in the AD patients, whereas both markers increased in controls. Because these markers are detected by mass spectrometry without the need for antibody reagents, targeted MS based assays provide a clear translation path for evaluating selected AD disease-progression markers with high analytical precision in the clinic.</p></div

Twenty-five candidate disease progression biomarkers from post-hoc mixed-effect analysis of entire Cohort-2 proteomics data set.

<p>Linear mixed-effect model analysis of log area under the curve (AUC) intensity values for features quantitated by dMS in CSF samples taken annually in longitudinal cohort, Cohort-2. Details described in Methods.</p

The demographic characteristics of the cross sectional study population, Cohort-1, at the time of CSF collection.

<p>CTL = control; AD = Alzheimer's disease; N, n = number of subjects/patients; SD = standard deviation; MMSE = Mini- mental state examination; ApoE = Apolipoprotein E</p><p>The demographic characteristics of the cross sectional study population, Cohort-1, at the time of CSF collection.</p

Linear mixed effect model analysis of SME1 and SME2 and tau, p-tau, and AB42 in the longitudinal cohort, Cohort-2.

<p><b>SME1:</b> dMS feature ID 751080736 at m/z = 639.63 Da; z = 3; Mo = 1915.85 Da; AA sequence = NSEPQDEGELFQGVDPR; unique to protein sequence IPI00289501.2 Neurosecretory protein VGF.</p><p><b>SME2</b> = dMS feature ID751082515 at m/z = 635.98 Da, z = 3, Mo = 1903.90 Da, AA sequence = VAELEHGSSAYSPPDAFK, unique to protein sequence IPI00334238.1 Neuronal pentraxin receptor 1 (NPTXR).</p><p>Serial CSF samples were taken annually. Log area under the curve (AUC) intensity values for SME1 and SME2 measured by dMS and ELISA measurements for tau, p-tau, and AB42 were analyzed in the mixed-effect model described in methods.</p

Receiver-operator curves (ROC) for cross-sectional study (Cohort-1).

<p>Comparison of the AD samples versus the control samples was used to estimate the sensitivity, while the comparisons between two groups comprised of randomly selected but equally balanced AD and control samples were used to estimate specificity.</p

Quantitation of SME1 and SME2 by dMS (Cohort-1) and 2-way plot.

<p>SME 1 (Peptide NSEPQDEGELFQGVDPR, from neurosecretory protein VGF precursor) and SME2 (peptide VAELEHGSSAYSPPDAFK, from neuronal pentraxin receptor-1) are significantly reduced in AD patients as compared to controls. Area under the curve (AUC) intensity measurements are shown on linear scale. Horizontal bar represents the mean value, vertical error bar represents SD. (A) SME1, P < 0.0001. (B) SME2, P < 0.0005. (C) Two way plot of SME1 and SME2. The symbols (●, +) represent AD and control, respectively.</p