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

Abstract

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 (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 1H 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. 1H MRS data detected a significant decrease in the N-acetyl-aspartate (NAA)/creatine (Cr) ratio in the area adjacent to the infarction (VOl-St) compared to a mirror area in the contralateral hemisphere (VOl-Co). Histopathological measurements revealed a significant decline in neuronal cross-sectional area and neuronal optical density in the region of the VOl-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 1H 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.

Impaired Arm Function and Finger Dexterity in a Nonhuman Primate Model of Stroke

“…Various NHP models of stroke have been reported using different surgical techniques in the marmosets: 15,31 African green monkey, 26 baboon, 17,32 macaques, 20,21,[33][34][35][36] and squirrel monkeys. 16 However, to date, there has been less emphasis on outcome measures and disabilities relevant to daily living activities, such as dexterous movements.…”

“…Nonhuman primate (NHP) models offer an assessment of complex physiological, immunologic, biochemical, and behavioral outcomes most similar to those of humans. [14][15][16][17][18][19][20][21][22][23][24] These outcome measures complement those from other animal models by improving our understanding…”

Regional metabolite T2 in the healthy rhesus macaque brain at 7T

“…Since the brain of nonhuman primates is biochemically, morphologically, and functionally similar to its human counterpart, rhesus macaques are increasingly used as advanced models for disease and treatment studies, e.g., in neuroAIDS (1), ischemic stroke (2), and Parkinson's and Huntington's diseases (3). Due to the need for repeated measurements, these studies favor nondestructive means: MRI for morphology and function, and proton MR spectroscopy ( 1 H-MRS) for assessment of neuronal cells, cell energetics, and membrane turnover, through the levels of their surrogate markers, N-acetylaspartate (NAA), creatine (Cr), and choline (Cho) (4,5).…”

Recent advances in the pharmacology of neurological gene therapy

“…Furthermore, viral vectors have now been used to develop animal models of neurological diseases. Progress over this time has not been limited to the topics discussed, but has also encompassed novel approaches to the treatment of obesity through the delivery of leptin receptors or pro-opiomelanocortin to the hypothalamus [40,41], the use of a variety of antiapoptotic growth factor approaches to the treatment of ischemia [5,[42][43][44][45][46][47][48][49][50][51], the delivery of neprilysin, an enzyme that degrades amyloid-β in the brain, in animal models of Alzheimer's disease [52], and the use of neuropeptides for the treatment of seizures [53] or glaucoma-induced neurodegeneration [54]. The field of neurological gene therapy has thus continued to grow and expand towards the implementation of clinical trials of gene therapy for brain diseases.…”