Distinguishing Alzheimer's Disease Patients and Biochemical Phenotype Analysis Using a Novel Serum Profiling Platform: Potential Involvement of the VWF/ADAMTS13 Axis.

Jay S Hanas,Megan R Lerner,Christian A Vannarath,Stan A Lightfoot,Linda A Hershey,Scott G Blair,James R S Hocker,James R Couch,Rushie J Hanas

doi:10.3390/brainsci11050583

Abstract

It is important to develop minimally invasive biomarker platforms to help in the identification and monitoring of patients with Alzheimer’s disease (AD). Assisting in the understanding of biochemical mechanisms as well as identifying potential novel biomarkers and therapeutic targets would be an added benefit of such platforms. This study utilizes a simplified and novel serum profiling platform, using mass spectrometry (MS), to help distinguish AD patient groups (mild and moderate) and controls, as well as to aid in understanding of biochemical phenotypes and possible disease development. A comparison of discriminating sera mass peaks between AD patients and control individuals was performed using leave one [serum sample] out cross validation (LOOCV) combined with a novel peak classification valuation (PCV) procedure. LOOCV/PCV was able to distinguish significant sera mass peak differences between a group of mild AD patients and control individuals with a p value of 10−13. This value became non-significant (p = 0.09) when the same sera samples were randomly allocated between the two groups and reanalyzed by LOOCV/PCV. This is indicative of physiological group differences in the original true-pathology binary group comparison. Similarities and differences between AD patients and traumatic brain injury (TBI) patients were also discernable using this novel LOOCV/PCV platform. MS/MS peptide analysis was performed on serum mass peaks comparing mild AD patients with control individuals. Bioinformatics analysis suggested that cell pathways/biochemical phenotypes affected in AD include those involving neuronal cell death, vasculature, neurogenesis, and AD/dementia/amyloidosis. Inflammation, autoimmunity, autophagy, and blood–brain barrier pathways also appear to be relevant to AD. An impaired VWF/ADAMTS13 vasculature axis with connections to F8 (factor VIII) and LRP1 and NOTCH1 was indicated and is proposed to be important in AD development.

Highlights

Classified serum mass peaks” is plotted versus patient number, a distribution plot is obtained in which a clear demarcation is observed between mild Alzheimer’s disease (AD) patients versus control individuals
A which is determined from the group standard deviations (SD, see Methods), and is used to quantify false positives (FP) and false negatives (FN), none of which are present in this sample/patient discrimination; all AD samples are indicated to be true positives and all control samples are indicated to be true negatives
electrospray ionization (ESI)-mass spectrometry (MS) combined with the novel leave one [serum sample] out cross validation (LOOCV)/peak classification valuation (PCV) approach in this study identified serum mass peak areas changing significantly upon comparison of patients with mild or moderate AD and upon comparison to control individuals

Summary

Introduction

Alzheimer’s disease (AD) is the most common form of dementia, affecting nearly 10%. Of adults 65 and over [1]. The AD brain pathologies (e.g., neuron cell loss, neurofibrillary tangles) are present in the normal aging brain but are more advanced in AD and that severity is a characteristic of the disease [1]. AD can be defined biologically by the biomarkers associated with these brain pathologies [2]). Identification and monitoring of AD are important aspects of elderly memory care.

Objectives

Methods

Results

Discussion

Conclusion