Characterizing Neurodegenerative Disease Biomarkers in Cerebrospinal Fluid of Non-human Primates

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.