Simian varicella virus infection and reactivation in rhesus macaques trigger cytokine and Aß40/42 alterations in serum and cerebrospinal fluid.

Simian varicella virus (SVV) produces peripheral inflammatory responses during varicella (primary infection) and zoster (reactivation) in rhesus macaques (RM). However, it is unclear if peripheral measures are accurate proxies for central nervous system (CNS) responses. Thus, we analyzed cytokine and Aß42/Aß40 changes in paired serum and cerebrospinal fluid (CSF) during the course of infection. During varicella and zoster, every RM had variable changes in serum and CSF cytokine and Aß42/Aß40 levels compared to pre-inoculation levels. Overall, peripheral infection appears to affect CNS cytokine and Aß42/Aß40 levels independent of serum responses, suggesting that peripheral disease may contribute to CNS disease.

Neurodegenerative disease biomarkers Aß1-40, Aß1-42, tau, and p-tau181 in the vervet monkey cerebrospinal fluid: Relation to normal aging, genetic influences, and cerebral amyloid angiopathy.

Background: The Caribbean vervet monkey (Chlorocebus aethiops sabaeus) is a potentially valuable animal model of neurodegenerative disease. However, the trajectory of aging in vervets and its relationship to human disease is incompletely understood. Methods: To characterize biomarkers associated with neurodegeneration, we measured cerebrospinal fluid (CSF) concentrations of Aß1-40, Aß1-42, total tau, and p-tau181 in 329 members of a multigenerational pedigree. Linkage and genome-wide association were used to elucidate a genetic contribution to these traits. Results: Aß1-40 concentrations were significantly correlated with age, brain total surface area, and gray matter thickness. Levels of p-tau181 were associated with cerebral volume and brain total surface area. Among the measured analytes, only CSF Aß1-40 was heritable. No significant linkage (LOD > 3.3) was found, though suggestive linkage was highlighted on chromosomes 4 and 12. Genome-wide association identified a suggestive locus near the chromosome 4 linkage peak. Conclusions: Overall, these results support the vervet as a non-human primate model of amyloid-related neurodegeneration, such as Alzheimer's disease and cerebral amyloid angiopathy, and highlight Aß1-40 and p-tau181 as potentially valuable biomarkers of these processes.

Japanese macaque encephalomyelitis: a spontaneous multiple sclerosis-like disease in a nonhuman primate.

OBJECTIVE: To describe Japanese macaque encephalomyelitis (JME), a spontaneous inflammatory demyelinating disease occurring in the Oregon National Primate Research Center's (ONPRC) colony of Japanese macaques (JMs, Macaca fuscata). METHODS: JMs with neurologic impairment were removed from the colony, evaluated, and treated with supportive care. Animals were humanely euthanized and their central nervous systems (CNSs) were examined. RESULTS: ONPRC's JM colony was established in 1965 and no cases of JME occurred until 1986. Since 1986, 57 JMs spontaneously developed a disease characterized clinically by paresis of 1 or more limbs, ataxia, or ocular motor paresis. Most animals were humanely euthanized during their initial episode. Three recovered, later relapsed, and were then euthanized. There was no gender predilection and the median age for disease was 4 years. Magnetic resonance imaging of 8 cases of JME revealed multiple gadolinium-enhancing T(1) -weighted hyperintensities in the white matter of the cerebral hemispheres, brainstem, cerebellum, and cervical spinal cord. The CNS of monkeys with JME contained multifocal plaque-like demyelinated lesions of varying ages, including acute and chronic, active demyelinating lesions with macrophages and lymphocytic periventricular infiltrates, and chronic, inactive demyelinated lesions. A previously undescribed gamma-herpesvirus was cultured from acute JME white matter lesions. Cases of JME continue to affect 1% to 3% of the ONPRC colony per year. INTERPRETATION: JME is a unique spontaneous disease in a nonhuman primate that has similarities with multiple sclerosis (MS) and is associated with a novel simian herpesvirus. Elucidating the pathogenesis of JME may shed new light on MS and other human demyelinating diseases.

Effect of tryptophan treatment on self-biting and central nervous system serotonin metabolism in rhesus monkeys (Macaca mulatta).

UNLABELLED: Two studies were conducted to examine the effects of oral L-tryptophan (TRP) supplementation as a treatment for self-injurious behavior (SIB) and to investigate behavior and central serotonin turnover of male rhesus monkeys. In Study One, TRP was administered to seven individually housed rhesus monkeys with a recent history of spontaneous SIB. While the monkeys were on TRP treatment (100 mg/kg twice a day), cisternal cerebrospinal fluid (CSF) concentrations of 5-hydroxyindoleacetic acid increased markedly (p = .0013) above baseline (baseline mean = 207.6 pmol/ml +/- 39; TRP mean = 320.3 pmol/ml +/- 83.4), and the duration of self-biting behavior decreased below baseline (p = .03). In Study Two, 14 individually housed rhesus monkeys without a history of SIB were placed on three different doses of TRP in random order (50, 100, and 200 mg/kg twice a day). TRP had no effect on any behavioral or biochemical variables in the normal monkeys. CONCLUSIONS: Supplemental tryptophan in well-tolerated doses reduced self-biting and increases serotonin turnover rate in male monkeys with a recent history of SIB. The same doses of TRP do not affect behavior or serotonin metabolism in male monkeys without a history of SIB.

Naturally occurring melioidosis in a colonized rhesus monkey (Macaca mulatta).

An aged wild-caught male rhesus monkey (Macaca mulatta), maintained in a research facility for 10 years, developed bilateral pelvic limb paralysis without other signs of disease. Unresponsive to therapy, the monkey was killed and necropsied. Chronic inflammation with osteolysis of thoracic vertebrae 10-13 was observed. Pseudomonas pseudomallei was cultured and identified from cerebrospinal fluid obtained at the site of the thoracic lesion. This Gram-negative bacterium can cause infection in animals and man and may remain latent for years before the appearance of clinical signs.