Aims An obstacle to developing new treatment strategies for Alzheimer's disease (AD) has been the inadequate translation of findings in current AD transgenic rodent models to the prediction of clinical outcomes. By contrast, nonhuman primates (NHPs) share a close neurobiology with humans in virtually all aspects relevant to developing a translational AD model. The present investigation used African green monkeys (AGMs) to refine an inducible NHP model of AD based on the administration of amyloid-beta oligomers (A beta Os), a key upstream initiator of AD pathology. Methods A beta Os or vehicle were repeatedly delivered over 4 weeks to age-matched young adult AGMs by intracerebroventricular (ICV) or intrathecal (IT) injections. Induction of AD-like pathology was assessed in subregions of the medial temporal lobe (MTL) by quantitative immunohistochemistry (IHC) using the AT8 antibody to detect hyperphosphorylated tau. Hippocampal volume was measured by magnetic resonance imaging (MRI) scans prior to, and after, intrathecal injections. Results IT administration of A beta Os in young adult AGMs revealed an elevation of tau phosphorylation in the MTL cortical memory circuit compared with controls. The largest increases were detected in the entorhinal cortex that persisted for at least 12 weeks after dosing. MRI scans showed a reduction in hippocampal volume following A beta O injections. Conclusions Repeated IT delivery of A beta Os in young adult AGMs led to an accelerated AD-like neuropathology in MTL, similar to human AD, supporting the value of this translational model to de-risk the clinical trial of diagnostic and therapeutic strategies.

The use of the St. Kitts green monkey (Chlorocebus Sabaeus) in safety pharmacology is not as well documented as other primates, but is gaining popularity as the importance of a more genetically homogeneous primate species for use in biomedical research is being understood. In this test system we have characterized Stellar TSE telemetry devices for acquiring left ventricular pressure (LVP), systemic blood pressure (BP), epicardial electrocardiography (ECG) and core body temperature. In the current study 4 normotensive monkeys were implanted. The systemic pressure catheter was advanced from the internal iliac to the mid aorta. The transmitter body was anchored to the abdominal wall, and the bio-potential leads and LVP catheter were tunneled to the left thorax. LVP was acquired and the bio-potential leads placed for epicardial ECG. Systemic BP, LVP, HR and ECG parameters were determined. Fifteen seconds of data were collected every 30 min for a 48 hr period. The mean for each test parameter were calculated for each 48h acquisition session and subsequently averaged over the in-life duration of the study. The mean systemic systolic, diastolic and pulse pressures as well as heart rate (from LVP) have been stable and consistent with expectation. The mean LV systolic, LV diastolic, mean LVP, pulse pressure as well as the heart rate (from ECG) have been slightly higher in 3 of the 4 monkeys at later time points compared to baseline, possibly due to the use of a shorter catheter that may be squeezed by the ventricular wall, for which reason a longer catheter model has been designed for subsequent studies. To date (6 months), the data generated with the TSE system have been comparable to other telemetry devices and has further supported the green monkey as an acceptable and reliable primate alternative for safety pharmacology or combination cardiovascular/toxicology studies.

Introduction: Understanding the appropriate application of telemetry and other technologies for nonclinical investigation of functional safety issues in the context of ongoing toxicology evaluations is a current industry challenge. One major issue is related to the potential impact of surgical implantation of a telemetry device on contemporarily established measures of drug toxicity, and potential for confounding pathological issues related to the systemic and local response of the experimental animal to the presence of a foreign body. This study was designed to evaluate the potential local and systemic impact of different implanted telemetry devices with varying requisite degrees of surgical complexity on general toxicology study endpoints. Methods: Sixteen male beagle dogs 1) no surgical instrumentation [n=4], 2) Jacketed External Telemetry (JET) with femoral artery blood pressure implant (PA-C10 LA) [n=4], or 3) fully implantable (DSI-D70-CCTP) devices [n=8], were assigned to experimental groups and evaluated within the context of a standard repeat-dose toxicology design to determine the potential impact of these treatments on routine in-life and post-mortem toxicological endpoints. Results: Device implantation, regardless of the level of invasiveness/complexity was without effect on any in-life safety parameter, including clinical chemistry and hematology, assessed in the experimental design. Histopathological findings were limited to the expected, primarily minimal to mild localized effects characteristic of a foreign body reaction (fibrosis, inflammation) in the area immediately in contact with the body of the transmitter device and associated sites of ECG lead and pressure catheter interface with local tissues. Discussion: This study represents the first definitive evaluation of the influence of variably invasive telemetry device implantation on standardized, essential toxicology endpoints in the context of a simulated repeated dose experimental design. The data suggest that, when carefully evaluated, the local effects of implanted telemetry devices can be managed in the context of a standard Investigational New Drug (IND)-enabling toxicology study. This study provides support for the potential incorporation of unrestrained cardiovascular assessments via implanted or external telemetry into standard multi-dose toxicology studies. (C) 2013 Elsevier Inc. All rights reserved.