Premium
P4‐477: COMBINED GENOME‐WIDE NETWORK ANALYSIS REVEALS PERTURBATIONS TO IMMUNE SYSTEM, SYNAPTIC AND HIPPO SIGNALING IN ASSOCIATION WITH COGNITIVE DECLINE IN LATE‐ONSET ALZHEIMER'S DISEASE
Author(s) -
Malamon John Stephen,
Kriete Andres
Publication year - 2019
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2019.08.023
Subject(s) - biology , neuroinflammation , trem2 , immune system , disease , microglia , gene regulatory network , genome wide association study , cognitive decline , transcriptome , gene , neuroscience , genetics , immunology , gene expression , genotype , medicine , dementia , single nucleotide polymorphism , inflammation , pathology
Background: Cerebrospinal fluid (CSF) biomarker concentrations are valuable in the diagnosis of Alzheimer’s Disease (AD). CSF b-amyloid 1-42 (Ab42), is a core biomarker of AD. While analytic variability has been reduced with the advent of automated assays, pre-analytical variability has limited clinical use. The main purpose of this study was to evaluate the effect of patient-specific pre-analytical variables (fasting, inadvertent blood contamination, CSF gradients) on Ab42 concentrations. Methods: Freshly-collected and frozen CSF samples obtained from the Johns Hopkins Center for CSF Disorders were subjected to patient specific protocols. Ab42 concentrations were measured using Lumipulse G1200 (Fujirebio Diagnostics Inc., Malvern, PA). Fresh and frozen CSF was analyzed post-centrifugation (2000 g, 10 minutes, 5 6 3 C) with fresh samples analyzed within two hours of collection. Patient fasting was evaluated (n1⁄410) with fasting maintained a minimum of six hours. Prior to breakfast, CSF was collected in two or three 1 ml aliquots and simultaneous blood and CSF glucose measurements were obtained. Post-meal, these procedures were repeated each hour for 3 hours. Patient CSF gradients (n1⁄46) were studied using 20 serial 1 mL CSF aliquots. Blood contamination was evaluated in fresh CSF samples (n1⁄47) spiked with varying levels of whole blood (0.1%, 0.5%, 1%, 2.5%, 5%, 10%). Frozen CSF samples (n1⁄43) were also spiked with varying levels of whole blood (0.25%, 0.5%, 2.5%, 5%) and measured. Results: CSF gradients did not significantly alter Ab42 concentrations. Percent difference ranged from 0% to 6% using pairwise analysis across gradient aliquots. Ab42 levels were stable when fresh CSF samples were spiked with up to 2.5% of fresh blood. However, 0.25% blood contamination in frozen CSF samples significantly decreased Ab42 concentrations. No significant change was observed in CSFAb42 levels in fasting patients with an average % difference and standard deviation of -163.8 at 1 hour, -164.3 at 2 hours and 164.4 at 3 hours post-breakfast. Conclusions: Real world CSF Ab42 measurement may be impacted by fasting, gradient effects, and inadvertent blood contamination. Our data suggests that these pre-analytical variables do not have significant effects on concentrations of AB42 if fresh samples are processed within 2 hours. P4-477 COMBINED GENOME-WIDE NETWORK ANALYSIS REVEALS PERTURBATIONS TO IMMUNE SYSTEM, SYNAPTIC AND HIPPO SIGNALING IN ASSOCIATION WITH COGNITIVE DECLINE IN LATE-ONSET ALZHEIMER’S DISEASE