ABSTRACT
Monkeys are becoming important translational models of neurodegenerative disease. To facilitate model development, we measured cerebrospinal fluid (CSF) concentrations of key biomarkers in healthy male and female cynomolgus and rhesus macaques. Amyloid beta (Aß40, Aß42), tau (total tau [t-tau], phosphorylated tau [pThr181]), and neurofilament light (NfL) concentrations were measured in CSF of 82 laboratory-housed, experimentally naïve cynomolgus (n = 33) and rhesus (n = 49) macaques. Aß40 and Aß42 were significantly higher in rhesus, and female rhesus were higher than males. NfL and t-tau were higher in males, and NfL was higher in rhesus macaques. p-tau was not affected by species or sex. We also examined whether sample location (lumbar or cisterna puncture) affected concentrations. Sample acquisition site only affected NfL, which was higher in CSF from lumbar puncture compared to cisterna magna puncture. Establishing normative biomarker values for laboratory-housed macaque monkeys provides an important resource by which to compare to monkey models of neurodegenerative diseases.
ABSTRACT
INTRODUCTION: Neurofilament light (NFL) in cerebrospinal fluid (CSF) is elevated in neurodegenerative disease patients, and may track disease progression and treatment. Macaque monkeys are emerging as important translational models of neurodegeneration, and NFL may be a useful biomarker. METHODS: To determine the influence of a previous lumbar puncture (LP) on NFL, we collected CSF at multiple time points in macaque monkeys via LP or cisterna magna puncture. NFL, amyloid beta (Aß40, Aß42), and tau (tTau, pTau) in CSF were measured by standard enzyme-linked immunosorbent assay and multiplex. RESULTS: NFL was significantly elevated at 14 to 23 days after an LP (median increase: 162%). Aß and tau biomarkers remained stable. NFL peaked and decayed over 1 to 2 months after LP. NFL was not elevated after cisterna magna puncture. DISCUSSION: Results suggest damage of the cauda equina during LP may increase NFL. Caution should be taken in interpreting NFL concentration in studies in which repeat LPs are performed.
ABSTRACT
BACKGROUND: The Cambridge neuropsychological test automated battery (CANTAB) is a set of computerized visuospatial tests used to probe cognition in humans. The non-human primate (NHP) version of the battery is a valuable translational research tool to quantify cognitive changes in NHP models of disease by allowing direct comparison with performance data from human patient populations. One limitation is the long training times required for NHPs to reach appropriate levels of task performance, which is prohibitive for high throughput experimental designs. NEW METHOD: We report a new training regimen to teach NHPs a subset of CANTAB cognitive tasks using a method of successive approximations (shaping), where rewarded behaviors progressively approximate the goal behavior, and sequential task learning is used to build upon previously learned rules. Using this refined method, we taught 9 adult rhesus macaques to perform three tasks: the self-ordered spatial search (SOSS), delayed match-to-sample (DMTS), and paired associative learning (PAL) tasks. RESULTS AND COMPARISON WITH EXISTING METHODS: NHPs learned all three cognitive tasks in approximately 130 training sessions, roughly 200 sessions faster than previously published training times. NHPs were able to perform each task to a stable level of performance (>80 % correct) enabling their use in future cognitive experiments. CONCLUSIONS: Our approach of behavioral shaping reduced the time to train NHPs to performance criteria on SOSS, DMTS, and PAL tasks. This allows efficient use of the NHP-adapted CANTAB to compare cognitive changes in NHP models of neurological disease with those observed in human patient populations.
Subject(s)
Cognition , Learning , Animals , Humans , Macaca mulatta , Motivation , Neuropsychological TestsABSTRACT
Neurophysiologic studies of NHP commonly involve their transfer from a housing enclosure to a laboratory by using a mobile chair. This transfer should be performed in a manner that is safe and minimizes stress for both animal and handler. The risk of harm associated with attempting to transfer these animals is increased when they are mature and naïve. We have modified previous chair designs and transfer methodologies to reduce this risk by maintaining a constant barrier between NHP and handler while providing control to the handler to facilitate chairing. Chair modifications were built inhouse, and a commercial, hydraulic lift table was used to dock the primate chair to home cages of different heights. The docking chair method was used with 8 adult, male rhesus macaques. A graduate student transferred the animals without complications. These modifications did not compromise existing features of the chair, they did not require training time in addition to that for the standard chairing method in our facility, and they improved safety. These refinements to a commonly used chair and transfer methodology support rapid habituation, safe transfer and reduced stress for both animal and handler. The refinements we describe mitigate the potential risk of harm during NHP transfers and thus advance animal welfare.
