Permanent or Transient Chronic Ischemic Stroke in the Non-Human Primate: Behavioral, Neuroimaging, Histological, and Immunohistochemical Investigations

Abstract

Using multimodal magnetic resonance imaging (MRI), behavioral, and immunohistochemical analyses, we examined pathological changes at the acute, sub-acute, and chronic stages, induced by permanent or temporary ischemia in the common marmoset. Animals underwent either permanent (pMCAO) or 3-h transient (tMCAO) occlusion of the middle cerebral artery (MCAO) by the intraluminal thread approach. MRI scans were performed at 1 h, 8, and 45 days after MCAO. Sensorimotor deficits were assessed weekly up to 45 days after MCAO. Immunohistological studies were performed to examine neuronal loss, astrogliosis, and neurogenesis. Remote lesions were analyzed using retrograde neuronal tracers. At day 8 (D8), the lesion defined on diffusion tensor imaging (DTI)-MRI and T2-MRI was significantly larger in pMCAO as compared with that in the tMCAO group. At D45, the former still displayed abnormal signals in T2-MRI. Post-mortem analyses revealed widespread neuronal loss and associated astrogliosis to a greater extent in the pMCAO group. Neurogenesis was increased in both groups in the vicinity of the lesion. Disconnections between the caudate and the temporal cortex, and between the parietal cortex and the thalamus, were observed. Sensorimotor impairments were more severe and long-lasting in pMCAO relative to tMCAO. The profile of brain damage and functional deficits seen in the marmoset suggests that this model could be suitable to test therapies against stroke.

Diffusion Tensor MRI Reveals Chronic Alterations in White Matter Despite the Absence of a Visible Ischemic Lesion on Conventional MRI

“…10,12 At the chronic stage of ischemia (ie, Day 45) despite a slight hypointensity possibly consecutive to astrogliosis, ADC val- ues completely normalized. This contrasts to the data reported in other ischemia models in marmosets, 1,8 macaques, 9 and rats 11 in which the ADC values increased due to the formation of a cystic cavity.…”

“…The details of the procedure to induce ischemia were described previously. 8 Briefly, in isoflurane-anesthetized marmosets, a nylon thread was inserted into the external carotid artery and gently advanced up to the origin of the middle cerebral artery (MCA). The filament was removed 3 hours later to allow reperfusion.…”

“…The following behavioral tests were performed as previously described 8 : neurological score, tactile stimulation, hill and valley staircases, and adhesive removal. The animals were trained on behavioral tasks for the week preceding MCA occlusion, then evaluated on all tasks daily for 1 week, and thereafter at 5-week intervals.…”

“…We have taken advantage of the recent development of a focal stroke model in the nonhuman primate 8 and examined, first, the temporospatial evolution of diffusion abnormalities (ADC and FA) in acute, subacute, and chronic stages of ischemia; and second, the WM alterations at the chronic stage. These parameters were correlated to functional deficits evaluated through the use of a battery of behavioral tests.…”

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

“…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…”