Lockhart A

References (3)

Title : A 24-week study to evaluate the effect of rilapladib on cognition and cerebrospinal fluid biomarkers of Alzheimer's disease - Maher-Edwards_2015_Alzheimer.Dement.(New York)_1_131
Author(s) : Maher-Edwards G , De'Ath J , Barnett C , Lavrov A , Lockhart A
Ref : Alzheimer's & Dementia: Translational Research & Clinical Interventions , 1 :131 , 2015
Abstract : Background The lipoprotein-associated phospholipase A2 inhibitor (Lp-PLA2), rilapladib (SB659032), is being evaluated as a potential treatment to slow the progression of Alzheimer's disease (AD). Methods One hundred twenty-four subjects with possible mild AD and with neuroimaging evidence of cerebrovascular disease were randomized to placebo or 250-mg rilapladib once daily, for 24 weeks, in addition to stable background acetylcholinesterase inhibitor and/or memantine. The study assessed the safety and tolerability of rilapladib and its effects on cognition, mechanistic, and disease-related biomarkers. Although the overall intent behind the study was to take a broad exploratory view of the data, two primary end points of interest (cerebrospinal fluid [CSF] amyloid beta peptide 1-42 [Abeta1-42] and CogState executive function/working memory [EF/WM] composite score at week 24) were prespecified in the analysis plan for inferential statistical analysis. Results Rilapladib was well tolerated with no significant safety concerns. A significant difference from placebo was observed for rilapladib on change from baseline in EF/WM (effect size, 0.45; P = .026). There was no significant difference between groups on the change from baseline in CSF Abeta1-42 (P = .133). Preliminary evidence of effects was detected on other mechanistic (albumin quotient) and disease-related biomarkers (tau/P-tau and neurofilament light chain). Conclusion These data provide initial evidence supporting Lp-PLA2 inhibition as a novel treatment for dementia.
ESTHER : Maher-Edwards_2015_Alzheimer.Dement.(New York)_1_131
PubMedSearch : Maher-Edwards_2015_Alzheimer.Dement.(New York)_1_131
PubMedID:

Title : A 24-week study to evaluate the effect of rilapladib on cognition and cerebrospinal fluid biomarkers of Alzheimer's disease - Maher-Edwards_2015_Alzheimers.Dement.(N.Y)_1_131
Author(s) : Maher-Edwards G , De'Ath J , Barnett C , Lavrov A , Lockhart A
Ref : Alzheimers Dement (N Y) , 1 :131 , 2015
Abstract : BACKGROUND: The lipoprotein-associated phospholipase A(2) inhibitor (Lp-PLA(2)), rilapladib (SB659032), is being evaluated as a potential treatment to slow the progression of Alzheimer's disease (AD). METHODS: One hundred twenty-four subjects with possible mild AD and with neuroimaging evidence of cerebrovascular disease were randomized to placebo or 250-mg rilapladib once daily, for 24 weeks, in addition to stable background acetylcholinesterase inhibitor and/or memantine. The study assessed the safety and tolerability of rilapladib and its effects on cognition, mechanistic, and disease-related biomarkers. Although the overall intent behind the study was to take a broad exploratory view of the data, two primary end points of interest (cerebrospinal fluid [CSF] amyloid beta peptide 1-42 [Abeta(1-42)] and CogState executive function/working memory [EF/WM] composite score at week 24) were prespecified in the analysis plan for inferential statistical analysis. RESULTS: Rilapladib was well tolerated with no significant safety concerns. A significant difference from placebo was observed for rilapladib on change from baseline in EF/WM (effect size, 0.45; P = .026). There was no significant difference between groups on the change from baseline in CSF Abeta(1-42) (P = .133). Preliminary evidence of effects was detected on other mechanistic (albumin quotient) and disease-related biomarkers (tau/P-tau and neurofilament light chain). CONCLUSION: These data provide initial evidence supporting Lp-PLA(2) inhibition as a novel treatment for dementia. CLINICAL TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT01428453.
ESTHER : Maher-Edwards_2015_Alzheimers.Dement.(N.Y)_1_131
PubMedSearch : Maher-Edwards_2015_Alzheimers.Dement.(N.Y)_1_131
PubMedID: 29854933

Title : Plasma lipoprotein-associated phospholipase A2 activity in Alzheimer's disease, amnestic mild cognitive impairment, and cognitively healthy elderly subjects: a cross-sectional study - Davidson_2012_Alzheimers.Res.Ther_4_51
Author(s) : Davidson JE , Lockhart A , Amos L , Stirnadel-Farrant HA , Mooser V , Sollberger M , Regeniter A , Monsch AU , Irizarry MC
Ref : Alzheimers Res Ther , 4 :51 , 2012
Abstract : INTRODUCTION: Lipoprotein-associated phospholipase A2 (Lp-PLA2) is a circulating enzyme with pro-inflammatory and oxidative activities associated with cardiovascular disease and ischemic stroke. While high plasma Lp-PLA2 activity was reported as a risk factor for dementia in the Rotterdam study, no association between Lp-PLA2 mass and dementia or Alzheimer's disease (AD) was detected in the Framingham study. The objectives of the current study were to explore the relationship of plasma Lp-PLA2 activity with cognitive diagnoses (AD, amnestic mild cognitive impairment (aMCI), and cognitively healthy subjects), cardiovascular markers, cerebrospinal fluid (CSF) markers of AD, and apolipoprotein E (APOE) genotype.
METHODS: Subjects with mild AD (n = 78) and aMCI (n = 59) were recruited from the Memory Clinic, University Hospital, Basel, Switzerland; cognitively healthy subjects (n = 66) were recruited from the community. Subjects underwent standardised medical, neurological, neuropsychological, imaging, genetic, blood and CSF evaluation. Differences in Lp-PLA2 activity between the cognitive diagnosis groups were tested with ANOVA and in multiple linear regression models with adjustment for covariates. Associations between Lp-PLA2 and markers of cardiovascular disease and AD were explored with Spearman's correlation coefficients.
RESULTS: There was no significant difference in plasma Lp-PLA2 activity between AD (197.1 (standard deviation, SD 38.4) nmol/min/ml) and controls (195.4 (SD 41.9)). Gender, statin use and low-density lipoprotein cholesterol (LDL) were independently associated with Lp-PLA2 activity in multiple regression models. Lp-PLA2 activity was correlated with LDL and inversely correlated with high-density lipoprotein (HDL). AD subjects with APOE-epsilon4 had higher Lp-PLA2 activity (207.9 (SD 41.2)) than AD subjects lacking APOE-epsilon4 (181.6 (SD 26.0), P = 0.003) although this was attenuated by adjustment for LDL (P = 0.09). No strong correlations were detected for Lp-PLA2 activity and CSF markers of AD. CONCLUSION: Plasma Lp-PLA2 was not associated with a diagnosis of AD or aMCI in this cross-sectional study. The main clinical correlates of Lp-PLA2 activity in AD, aMCI and cognitively healthy subjects were variables associated with lipid metabolism.
ESTHER : Davidson_2012_Alzheimers.Res.Ther_4_51
PubMedSearch : Davidson_2012_Alzheimers.Res.Ther_4_51
PubMedID: 23217243