The Time of Maximum Post-Ischemic Hyperperfusion Indicates Infarct Growth Following Transient Experimental Ischemia

Abstract

After recanalization, cerebral blood flow (CBF) can increase above baseline in cerebral ischemia. However, the significance of post-ischemic hyperperfusion for tissue recovery remains unclear. To analyze the course of post-ischemic hyperperfusion and its impact on vascular function, we used magnetic resonance imaging (MRI) with pulsed arterial spin labeling (pASL) and measured CBF quantitatively during and after a 60 minute transient middle cerebral artery occlusion (MCAO) in adult rats. We added a 5% CO2 - challenge to analyze vasoreactivity in the same animals. Results from MRI were compared to histological correlates of angiogenesis. We found that CBF in the ischemic area recovered within one day and reached values significantly above contralateral thereafter. The extent of hyperperfusion changed over time, which was related to final infarct size: early (day 1) maximal hyperperfusion was associated with smaller lesions, whereas a later (day 4) maximum indicated large lesions. Furthermore, after initial vasoparalysis within the ischemic area, vasoreactivity on day 14 was above baseline in a fraction of animals, along with a higher density of blood vessels in the ischemic border zone. These data provide further evidence that late post-ischemic hyperperfusion is a sequel of ischemic damage in regions that are likely to undergo infarction. However, it is transient and its resolution coincides with re-gaining of vascular structure and function.

How temporal evolution of intracranial collaterals in acute stroke affects clinical outcomes

“…12 In animal studies, if this subacute response resulted in hyperperfusion at day 4, it was associated with a larger final infarct size as compared to animals with maximal hyperperfusion at day 1. 23 Our study shows that collateral recruitment on the day 2 scan per se is an independent predictor of higher mortality, but not functional outcomes. This is contrary to our 2 previous studies that analyzed leptomeningeal collaterals in isolation at the pre-tPA CTA and at the repeat CTA; both studies showed that good collaterals are associated with good outcomes.…”

3-Nitropropionic Acid-Induced Ischemia Tolerance in the Rat Brain is Mediated by Reduced Metabolic Activity and Cerebral Blood Flow

“…This pattern of less extensive postischemic hyperperfusion with an earlier peak after reperfusion is an indicator of less severe ischemic damage. 17 Indeed, infarct size as determined from T2-weighted MRI on D14 was dramatically smaller in preconditioned animals ( Figure 2D). Diffusion tensor imaging revealed that callosal and descending corticospinal fiber tracts were initially damaged, reflected by a hyperacute increase and subacute decrease in fractional anisotropy, but, in contrast to controls, regained structural integrity in the NPA group ( Figure 2E).…”

“…For details of the MRI sequences and analysis strategies please see also Wegener et al (2007 and. 17,19 Images from all animals at all time points were first co-registered and then averaged using codes written in Matlab (Mathworks, Natick, MA, USA) software. Vasoreactivity (VR) maps were generated by subtracting the CBF map acquired in air from the one acquired in 5% CO 2. Voxels with significantly reduced apparent diffusion coefficient values were automatically selected as all voxels with a value of omean þ 2 s.d.…”

“…20,21 The 18-point observational score for assessment of sensorimotor deficits after MCAO was also applied; results from this score for the control group have been previously published. 17,22 In this test, a maximum of three points is scored for each of the following observations: (1) spontaneous activity, (2) symmetry in limb movement, (3) forepaw outstretching, (4) climbing, (5) body proprioception, and (6) response to vibrissae touch, so that 18 points indicate no neurologic deficit.…”

“…The CBF maps obtained from the control group have been published elsewhere. 17 Functional assessments were obtained before each MRI session and in addition on D7 after MCAO. Of the initially included 21 animals, eight controls and five NPA animals remained in both groups; exclusions were because of massive stroke and intolerable weight loss/behavioral abnormalities/seizures: controls n ¼ 3, NPA n ¼ 0; because of surgical complications (subarachnoid hemorrhage upon advancement of the thread): controls n ¼ 2, NPA n ¼ 1; and because of behavioral abnormalities such as reduced spontaneous activity or failure to perform baseline functional assessment within predefined range (see below): controls n ¼ 0, NPA n ¼ 2.…”