Characterizing Neurodegenerative Disease Biomarkers in Cerebrospinal Fluid of Non-human Primates
Loading...
Authors
Robertson, Emma
Date
Type
thesis
Language
eng
Keyword
Cerebrospinal Fluid , Non-human Primate , Rhesus macaque , Cynomolgus macaque , Amyloid-beta , Tau , Neurofilament Light , Alzheimer's disease , biomarkers
Alternative Title
Abstract
Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by several pathological changes including amyloid plaques, neurofibrillary tangles, synaptic loss, and neuroinflammation. There are currently no disease modifying therapeutics that have translated from preclinical animal models to human clinical trials. One solution to bridge this translational gap is to use non-human primate (NHP) models, which are phylogenetically similar to humans. However, a key issue with developing new preclinical models is the need to validate their disease progression and therapeutic outcomes.
Using similar methods to diagnosing human neurodegenerative disease patients, current NHP models of neurodegeneration have used identification of biomarkers in cerebrospinal fluid (CSF) and blood (e.g., amyloid-beta (Aβ), tau proteins, neurofilament light (NFL)). Despite these emerging NHP models, little is known about the properties of CSF neurodegenerative disease biomarkers in healthy, experimentally naïve NHPs, or what factors might influence their concentrations. Thus, it is difficult to interpret pathological CSF changes in animal models if baseline measures have not yet been adequately established.
Here, we collected lumbar CSF from a colony of healthy, experimentally naïve male and female cynomolgus and rhesus macaques (n=82). In a subset of these animals (n=16), cisterna CSF was also obtained. We analyzed Aβ40, Aβ42, tTau, pTau and NFL to assess if there were species, sex, age, and location effects. Aβ40 and Aβ42 were significantly higher in rhesus macaques, and female rhesus were higher than male rhesus. NFL and tTau were higher in males, and NFL was higher in rhesus macaques. pTau was not affected by species or sex. Sample acquisition site only affected NFL, which was higher in CSF from lumbar puncture compared with cisterna magna puncture. These values can be used as a reference guide for researchers developing NHP models of neurological diseases. Additionally, we analyzed the effect of performing repeated lumbar punctures on these biomarkers. Performing lumbar punctures in NHPs elevated NFL for up to 100 days but not other neurodegeneration biomarkers. Should these results translate to human clinical work, this has important implications for researchers when designing CSF sampling time points so that disease progression and treatment outcomes are not confounded.
Description
Citation
Publisher
License
Queen's University's Thesis/Dissertation Non-Exclusive License for Deposit to QSpace and Library and Archives Canada
ProQuest PhD and Master's Theses International Dissemination Agreement
Intellectual Property Guidelines at Queen's University
Copying and Preserving Your Thesis
This publication is made available by the authority of the copyright owner solely for the purpose of private study and research and may not be copied or reproduced except as permitted by the copyright laws without written authority from the copyright owner.
ProQuest PhD and Master's Theses International Dissemination Agreement
Intellectual Property Guidelines at Queen's University
Copying and Preserving Your Thesis
This publication is made available by the authority of the copyright owner solely for the purpose of private study and research and may not be copied or reproduced except as permitted by the copyright laws without written authority from the copyright owner.