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imagings, hyperperfusion is usually identified as visually perceivable regions with patchy increased CBF when compared with the homologous contralateral hemi- sphere [28] (Fig. 4.2).
Yu et al. studied 221 acute ischemic stroke patients due to middle cerebral artery occlusion, with a total of 361 ASL scans and found that postischemic hyperperfu- sion was more likely to appear in the patients who received reperfusion therapies, and was more prone to become HT [28]. Approximately 48% of patients who treated with reperfusion therapy had significant higher blood flow velocity (1.7 times on average) within or around the ischemic core areas than the contralateral side. During follow-up period, a correlation between HT and postischemic hyperperfusion was observed (OR = 3.5, 95% CI = 2.0–6.3, p < 0.001). About 47.6% of patients devel- oped postischemic hyperperfusion and hemorrhagic transformation that occurred at the same time point. Late HT in hyperperfusion areas occurred in 35.7% of patients.
The later time of hyperperfusion was related with the risk of higher grade of HT (Spearman’s rank correlation of 0.44, p = 0.003).
Fig. 4.2 Postischemic hyperperfusion with different clinical outcomes. A 38-year-old man pre- sented with aphasia, right paralysis and was found to have a left MCA stroke with a baseline NIHSS of 20. IV tPA was given 6 h after onset and then clot retrieval was performed. Initial CTP (panel a) showed hypoperfusion in the left MCA region, with a follow-up DWI and CBF (panel b, c) showed left MCA hyperperfusion and HT. A 43-year-old man presented with slight coma, apha- sia, right paralysis and was found to have a left MCA stroke with a baseline NIHSS of 25. IV tPA was given 3 h after onset. Initial DWI (panel d) showed right infarction in insular cortex, with a follow-up DWI and CBF (panel e, f) showed left MCA hyperperfusion and infarction growth. A 63-year-old man presented with slight coma, left paralysis and was found to have a right ICA stroke with a baseline NIHSS of 19. IV tPA was given 3.3 h after onset and then clot retrieval was per- formed. Initial CTP (panel g) showed hypoperfusion in the right ICA region, with a follow-up CTP (panel h, i) showed right MCA hyperperfusion and infarction and brain edema. MCA middle cere- bral artery, ICA internal carotid artery, NIHSS National institutes of health stroke scale, IV intrave- nous, tPA tissue-type plasminogen activator, CTP computed tomography perfusion, DWI diffused weighted image, CBF cerebral blood flow
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2.1.2 Neutrophil Infiltration and Immune Inflammation
Significant neutrophil accumulation is observed at 6 h after established recircula- tion in ischemic tissue [32]. A large number of active leukocytes flow into the brain tissue, interact with endothelial cells, resulting in a great accumulation of white blood cells, red blood cells and platelets in the microvascular bed. The obvious microvascular obstruction can generate the “no-reflow phenomenon” and give birth to secondary cerebral ischemia [32, 33]. Neutrophil infiltration exacer- bates ischemic cells, until reaching the maximum of infarct expansion. Zhang et al. demonstrated that infarct growth and neutrophil infiltration were more dra- matic in transient ischemia rats with 6 h and 24 h of reperfusion than those with 48 h permanent occlusion of middle cerebral artery [32]. In addition, other inves- tigators obtained similar findings that during ischemia/reperfusion, neutrophil depletion had better recovery of regional blood flow and smaller infarct size in animal models induced by anti- neutrophil antibodies, compared to non-neutrope- nic groups [34].
T cells also play an important role in ischemia/reperfusion injury. Studies have shown that anti-α4 integrin antibodies and vascular cell adhesion molecule 1 (VCAM 1) siRNA inhibited T-cell infiltration, so as to reduce infarct volume [35, 36]. Although early reports pointed out that in severe combined immunodeficient mice, lack of both T and B cells can decrease 40–70% of infarct size [3], there was no extra infarct volume in Rag1−/− mice (completely T- and B-cells deficient) with transplanted B cells. Infusion of wild type CD3+ T cells into Rag1−/− mice made it vulnerable to ischemia/reperfusion injury [37]. Hence, B cells did not enhance reperfusion injury alone. Moreover, complement system (e.g. C3, C1q) also takes part in this process.
2.2 Predictive Imaging Markers
2.2.1 No-Reflow Phenomenon
In addition to the mechanisms mentioned above, reperfusion therapy may lead to a specific pathway to aggravate the reperfusion injury. In real world, it would be perceivable as lack of appropriate capillary reperfusion despite of large vessel recanalization [38]. Diogo et al. retrospectively reviewed 60 acute ischemic stroke patients who achieved full reperfusion, defined as grade 3 or 2c of modified Thrombolysis In Cerebral Infarction (mTICI) and eventually found that 35% of patients had significant infarct growth, with an absolute infarct growth (30.6 ± 77.7 ml). It was suggested that initial embolus might crack into numerous particles after reperfusion therapy, and then obstruct the downstream small blood vessels and capillaries [39].
4 CIRI After Early Recanalization
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2.2.2 Cerebral Neutrophil Recruitment
C.J.S Price et al. [40] studied cerebral neutrophil recruitment of 15 acute ischemic stroke patients within 24 h of clinical onset. Indium-111 (111In) troponolate-labeled neutrophils accumulation can be observed though single-photon emission com- puted tomography (SPECT), and the attenuating recruitment along with time is con- firmed histologically by postmortem examination. In an exploratory analysis, neutrophil accumulation is found significantly related to infarct expansion, which needs further clinic practice.
2.2.3 Vascular Inflammation
According to the different ligand-conjugated microparticles of iron oxide (MPIO), different pathological mechanisms can be visualized and explained by molecular imaging. Thus, it makes molecular imaging a more accurate method to depict vas- cular inflammation [41], which is a vital characteristic mechanism of ischemia/
reperfusion injury in stroke. In experimental stroke rat models, ligand-targeted MPIO such as VCAM-MPIO for VCAM, Gd-DTPA-sLexA at both P- and E-selection [42] are commonly used to indicate vascular inflammation in vivo.
Unfortunately, because of low sensitivity of contrast, molecular imaging has its own limitation when depicting the status of endothelial inflammation following isch- emia/reperfusion injury [42]
2.2.4 Postischemic Hyperperfusion
Kidwell et al. reported that postischemic hyperperfusion areas developed into the final infarction during serial diffusion-perfusion MR studies [43]. Hyperperfusion was demonstrated in 5 of 12 patients within several hours after recanalization (mean volume, 18 ml) and in 6 of 11 patients at day 7 (mean volume, 28 ml), and 79% of voxels with hyperperfusion went into infarction at day 7 (Fig. 4.2).