Chronic ischemic stroke model in cynomolgus monkeys: Behavioral, neuroimaging and anatomical study

Previous nonhuman primate stroke models have employed temporary occlusion of arteries, had limited behavioral testing and imaging, and focused on the short-term outcome. Our goals were 1. to develop a stable model of chronic stroke in the nonhuman primate, 2. to study in vivo the long-term biochemical changes in the area adjacent to the infarct, using proton magnetic resonance spectroscopy ( 1 H MRS), and 3. evaluate these changes in relation to the histopathological effects of stroke. Four adult cynomologous monkeys had an occlusion of the M1 segment of the right MCA. Behavioral tests included a clinical rating scale, motor planning task, fine motor task, and activity monitoring. Eight months afterwards, MRI and 1 H MRS were performed. Following the imaging studies the monkeys were perfused transcardially, their brains extracted and processed. Nissl staining and immunohistochemistry for neuronal markers (NeuN) were performed and used to measure the lesion volume and neuronal optical density (OD). All animals developed a left hemiparesis and were unable to perform a fine motor task with the left hand. There was a significant (31%) decline in the motor planning ability with the nonparetic extremity. Monkeys displayed a stooped posture, episodes of rotation to the side of the lesion, partial left hemianopsia, and transient changes in activity. The clinical signs improved over the first 6-8 weeks but the deficits remained stable for the remaining six months of follow up. MRI demonstrated a subcortical and cortical infarction in the right MCA distribution. 1 H MRS data detected a significant decrease in the N-acetyl-aspartate (NAA)/creatine (Cr) ratio in the area adjacent to the infarction (VOI-St) compared to a mirror area in the contralateral hemisphere (VOI-Co). Histopathological measurements revealed a significant decline in neuronal crosssectional area and neuronal optical density in the region of the VOI-St. We established a stable and reproducible model of chronic stroke in the MCA distribution, in the macaque monkey. Our data indicate that NAA detected by 1 H MRS can be used to measure neuronal loss in vivo and help target this area for intervention. Our model may be particularly suitable for studies testing the effects of therapeutic strategies involving neural or stem cell transplantation, trophic factors or gene therapy

Subthalamic Glutamic Acid Decarboxylase Gene Therapy: Changes in Motor Function and Cortical Metabolism

Parkinson\u27s disease (PD) is associated with increased excitatory activity within the subthalamic nucleus (STN). We sought to inhibit STN output in hemiparkinsonian macaques by transfection with adeno-associated virus (AAV) containing the gene for glutamic acid decarboxylase (GAD). In total, 13 macaques were rendered hemiparkinsonian by right intracarotid 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine injection. Seven animals were injected with AAV-GAD into the right STN, and six received an AAV gene for green fluorescent protein (GFP). Videotaped motor ratings were performed in a masked fashion on a weekly basis over a 55-week period. At 56 weeks, the animals were scanned with 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET). Histological examination was performed at the end of the study. No adverse events were observed after STN gene therapy. We found that the clinical rating scores for the two treatment groups had different patterns of change over time (group time interaction, PP