We investigated the perioperative complications, clinical course, and outcomes of four consecutive patients who underwent superficial temporal artery to middle cerebral artery (STA-MCA) bypass for symptomatic internal carotid artery (IC) occlusion with a contralateral severe stenotic or occlusive IC lesion. All patients experienced neurological deterioration in the perioperative period. Perioperative cerebral infarction occurred in three patients. Among these patients, two developed cerebral infarction in the territory of the anterior cerebral artery. It was considered that so-called “watershed shift” hemodynamic phenomenon was involved. Moreover, due to severe cerebrovascular insufficiency, postoperative hyperperfusion occurred in two patients. Prognostic evaluation just before the surgery compared with that at 3 months after the surgery showed improvement in one patient, no change in another, and worsening in two. None of the patients developed recurrent stroke during the follow-up period. Outcomes were regarded as unsatisfactory due to frequent perioperative complications, although most of the neurological deteriorations were transient. In patients undergoing STA-MCA bypass for symptomatic IC occlusion with a contralateral severe stenotic or occlusive IC lesion, a better understanding of the pathogenesis of perioperative cerebral infarction and postoperative hyperperfusion might promote the development of measures to improve patient outcomes.
The importance of body temperature (BT) managements for preventing exacerbation of brain injury by hyperthermia is accepted. In this study, we examined the effects of BT for delayed cerebral ischemia (DCI) and outcome after subarachnoid hemorrhage (SAH). Forty four patients were measured BT in the period on 4th to 14th day after SAH. BT had no significant differences depend on therapeutic methods or severity of SAH. BT in patients with DCI or poor outcome were significantly higher than patients with no DCI or favorable outcome during all examinated days. BT management during perioperative period of SAH was important.
Purpose: To determine risk and management after carotid endarterectomy (CEA) or carotid artery stenting (CAS) to treat acute or subacute (AS) carotid stenosis. Methods: We treated 238 consecutive patients by CEA (n=104) or CAS (n=134) and then assigned them to groups treated at the AS (n=17; CEA, n=9; CAS, n=8) or chronic (C) (n=221; CEA, n=95; CAS, n=126) stages. We then evaluated the surgical results of all of these groups. Results: The occurrence rates of transient or permanent ischemic symptoms did not significantly differ between in the AS (permanent, n=1 [6%]) and C (transient, n=3 [1%]; permanent, n=4 [2%]) groups. The occurrence rates of DWI lesions after surgery also did not significantly differ between these groups (AS, n=3 of 14 [21%]; C, 46 of 191 [24%]). More patients had infarction after CAS than CEA in the C group (p<0.01). Hyper-perfusion syndrome was evident in 5 (29%) of the AS group and in 2 (1%) of the C group. Symptoms were permanent in 1 (6%) of the AS group (7%), although none of the patients died. The two groups significantly differed (p<0.01). Prediction and blood pressure (BP) control determined by cerebral blood flow measurements could prevent fatal intracranial bleeding. Conclusion: Hyper-perfusion syndrome frequently occurred in patients treated at the AS stage and the control of BP was necessary for prevention of fatal complication.
Aims: Previous studies suggest that both statins and calcium-channel blockers inhibit cardiovascular and cerebrovascular diseases by their pleiotropic effects, such as antioxidation and anti-inflammatory actions. By using stroke-prone spontaneously hypertensive rats (SHRSPs), the isolated effect of each pharmaceutical has been reported, but the effect of a combination of both pharmaceuticals has not been reported. In this study, we evaluated combination therapy of atorvastatin and amlodipine for its efficacy in preventing stroke in the SHRSP model. Main Methods: We initiated treatment of SHRSPs at 8 weeks of age with atorvastatin (2 mg/kg), amlodipine (1 mg/kg), a combination of atorvastatin (2 mg/kg) and amlodipine (1 mg/kg), or vehicle. Measurement of physiological parameters and immunohistochemical assessments for oxidative stress and inflammation were done at each group. Key findings: At 13 weeks of age, the combination therapy group showed greater inhibition of an antioxidation and anti-inflammatory marker than the vehicle group, although there were no differences in blood pressure. Significance: Our study suggests that the combination therapy of atorvastatin and amlodipine may protect against hypertension-induced stroke by the additive effect of the antioxidation and the anti-inflammatory action of the both agents.
Cerebrovascular autoregulation is the process whereby an elevation of systemic blood pressure is counteracted by a reduction in the volume of the cerebrovascular beds in order to maintain a consistent level of cerebral blood flow (CBF). This reduction in the cerebrovascular bed volume subsequently causes a reduction in intracranial pressure (ICP); therefore, ICP is negatively correlated with systemic blood pressure. Cases of severe brain damage with dysfunctional cerebrovascular autoregulation show elevated ICP along with increased blood pressure, which means that a positive correlation exists between both parameters. The pressure reactivity index (PRx) is a moving correlation coefficient between the mean arterial blood pressure (MABP) and ICP, and has recently been reported to be useful for clinical monitoring of patients with severe subarachnoid hemorrhage (SAH) and traumatic brain injury. In this study, we investigated the preservation of cerebrovascular autoregulation using PRx monitoring in patients with poor grade SAH. Ten patients with severe aneurysmal SAH were recruited; the mean age was 65.0 ± 12.0, and the mean value of the Glasgow Coma Scale (GCS) score was 4.3 ± 1.7. All patients had a grade V for the World Federation of Neurosurgeons (WFNS) score. Three of the ten cases underwent open surgery consisting of neck clipping of the ruptured cerebral aneurysm. The remaining patients underwent coil embolization of the ruptured aneurysms. Decompressive hemicraniectomy was also achieved for five cases, in an effort to control intracranial hypertension. Three months after the onset of SAH, two cases had favorable outcomes for Good Recovery (GR) and Moderately Disabled (MD) on the Glasgow Outcome Scale (GOS), while the other eight cases had unfavorable outcomes, including one death. The mean value of PRx during the acute stage was 0.047 ± 0.0002 in the favorable outcome cases, and 0.230 ± 0.184 in the unfavorable outcome cases. Cerebral vasomotor reaction resulted in a reduced response in the unfavorable outcome group, and this result was considered to reflect a strong positive correlation between ICP and MABP in the unfavorable outcome group. In six patients with delayed cerebral infarction following cerebral vasospasm after SAH, the mean value of PRx during the acute stage was 0.309 ± 0.13, while it was 0.019 ± 0.03 in the other 4 patients without cerebral infarction. Statistical analysis showed a significant difference in the PRx value between the patients with delayed cerebral infarction and the others (p<0.05). We discuss the usefulness of PRx monitoring, taking into consideration the available literature.
It has been even difficult to delineate a local atherosclerotic focus in cerebral artery stenosis, because of its smallness of relevant arteries and thinness of that vessel wall. Recently 3T MRI has shown up, which has a superior S/N ratio and a frequency resolution, enabling main cerebral arteries to be more clearly delineated. Thus, we have tried to visualize the arterial wall and the atherosclerotic local lesion with use of a brand-new sequence of 3T MRI. Twelve cases suspected to have a stenosis of unilateral middle cerebral artery (MCA) on TOF-MR angiography (MRA) were collected as a stenosis group. For the vessel wall analysis, all cases underwent a new sequence of T1-CUBE using 3T MRI (SIGNA HDxt: GE healthcare), and images were reformatted to observe both short and long axis directions of bilateral M1 portion of MCA, on which the maximal wall thickness on a short axis following after the observation on a long axis in each case was measured. And 10 cases without cerebral artery stenosis were recruited as a normal group for control. Besides, in the stenosis group the comparison between stenosis ratio on MRA and mean wall thickness was also performed. The arterial wall was apparently delineated as high signal intensity on the image obtained with T1-CUBE sequence. In a stenosis group, mean thickness of the arterial wall in a healthy side was 1.19 ± 0.08 mm, whereas that in a lesion side was 1.57 ± 0.27 mm, where a significant difference was seen between both sides (p<0.05). Meanwhile, the mean arterial wall thickness in a normal group was 0.85 ± 0.23 mm, which was significantly smaller than that in both healthy and lesion side of a stenosis group (p<0.05, p<0.001, respectively). Moreover, there was significant correlation between stenosis ratio and mean wall thickness in stenosis group (R=0.69, p=0.019). Given our results the arterial wall in cases with a stenosis of intracranial main artery should have an atherosclerotic change, which was shown in T1-CUBE image as a high signal lumen, like carotid artery stenosis. Accordingly, for the next step, it would be crucial to evaluate contents of the atherosclerotic plaque in that stenotic lesion.
Several reports showed cerebral blood flow (CBF) autoreguration was not persistent. The individual responses of autoreguration in rats might be interpreted by a mathematical model of rat brain blood vessels. We have run a simulation of the mathematical model reported by Ursino. The parameters of the simulation were fitted for experimental results on rats. The simulation shows a variation of CBF autoregulation with a parameter of arteriole in the physiological range. It might be indicated CBF autoregulatory curve was distinct in rats.
In the present study we examine whether the intra-arterial infusion of liposome-encapsulated hemoglobin (LEH) via the recanalized internal carotid artery can have the neuroprotective effect on ischemia-reperfusion (I/R) injury by using transient middle cerebral artery occlusion model of rats. Neurological function was significantly improved and infarct and edema area were significantly reduced in the LEH treatment group. LEH was distributed in more microvessels compared with rat erythrocyte. Because of its small size, LEH can effectively deliver oxygen to narrow microvessels. This advantage may contribute to the inhibition of endothelial damage, and, moreover, the inhibition of neutrophil activation, neutrophil-derived matrix metalloprotease-9 production, and the breakdown of blood-brain barrier. The intra-arterial infusion of LEH may be a promising candidate to prevent I/R injury after thrombolysis and/or thrombectomy.
The establishment of the treatment for warfarin-induced hemorrhagic infarction is essential because there is no effective treatment for hemorrhagic infarction at present and an exacerbation of hemorrhagic infarction with warfarin is mortal. Cilostazol, an antiplatelet agent, have various protective effects, including neuroprotective effect and protective effects on vascular endothelial cells, however it is careful administration for warfarin treatment patients. In the present study, we found that cilostazol suppressed the exacerbation of warfarin-induced hemorrhagic infarction by the enhancement of tight junction proteins and VE-cadherin. Furthermore, we suggested that this combination treatment is available clinically because this combination treatment was not extend bleeding time from the murine tail vein.
The current difficulty of predicting the progression of cerebral degeneration and recovery after head injury hampers making appropriate treatment. The lack of clinically relevant animal model is the most significant problem in the basic research of head injury. Even mechanical impact without skull fracture leads to contusion in human brain, however this process is hardly mimicked in rodents. Thus, classical head-injury models have been created by giving impact to brain parenchyma through craniotomy. Most models show long-term degeneration and lack recovery, largely due to craniotomy, which activates glial cells by itself. In order to address this problem, we have developed a novel method to create injury by strong light exposure through small thinned-skull region. This intact skull injury have shown hemorrhage within 24 hours and significant shrinkage of initial injured region to form small contusion. This cerebral recovery has been accompanied by the accumulation of CD68-positive microglia and nestin-positive astrocyte in the center and periphery of lesion, respectively. The process of nestin-positive reactive astrocyte covered recovering region, whereas reactive astrocyte distal to lesion lacked nestin expression. Since fatty acid has accumulated in the nestin-expressing reactive astrocytes, these cells may facilitate tissue recovery by maintaining energy metabolism in lesion.
Several experimental and clinical studies have reported intravenous transplantation of mesenchymal stem cells (MSCs) derived from bone marrow ameliorates functional deficits in cerebral infarction. However, functional recovery is not always correlated with lesion volume assessed by T2 weighted image in MRI. In this study, we reported the relationship between fMRI patterns and functional recovery of ischemic stroke model rats transplanted intravenously MSCs. In medium infused group, electrical stimulation of the left forepaw elicited a unilateral (right cortex) activated signal detected by fMRI in the infarcted somatosensory cortex. In the MSCs infused group, their motor function were significantly improved compared to the medium infused group, and two fMRI patterns were observed: unilateral and bilateral activation of sensorimotor cortex. The bilateral activated pattern in the MSCs group showed the greatest functional recovery in spite of the same lesion volume compared to unilateral activated pattern. These results suggest that the detection of a bilateral signal in sensorimotor cortex by fMRI was more predictive of improved functional outcome than lesion volume alone. Further evaluation of these results in the ongoing randomize clinical trial (phase 3) using auto serum-expanded autologous MSCs in the stroke patients is warranted.
Cell replacement therapy is attractive as a novel strategy for neurological diseases such as stroke. To realize this therapy, safer and more therapeutic effective cell resources are now needed. Induced pluripotent stem (iPS) cells can retain high replication competence and pluripotency when they differentiate into various kinds of cells, then they are regarded as a promising cell resource for cell transplantation therapy. However, high tumorigenesis of iPS has to be overcome for clinical applications. Recently it was reported that novel combination of transcriptional factors can convert somatic cells to various kinds of mature neuronal cells and neural stem cells without requiring iPS cell fate. Some evidence indicated that these directly induced neuronal (iN) cells have little tumorigenic potential. We discuss the advantage, issues, and possibility of clinical application of iN cells for cell replacement therapy.
Symposium 3 Surgical Intervention and Cerebral Blood Flow
The purpose of this study was to evaluate the feasibility of regional cerebral blood flow monitoring using near-infrared spectroscopy (NIRS) and indocyanine green (ICG) as an intravascular tracer in carotid artery stenting (CAS) with a filter protection device. Thirty four patients underwent CAS under local anesthesia. We assessed the change of blood flow index (BFI) and mean transit time (MTT) parameter measured by NIRO 200NX (Hamamatsu Photonics) during CAS procedure. Angiographic success was obtained in all procedure. Two patients presented hyperperfusion syndrome and they managed under sedation and hypotension therapy by reference to NIRS values. There were no major/minor embolic strokes and intracranial hemorrhage associated with hyperperfusion syndrome. BFI ratio was increased and MTT ratio was shortened after stent placement in HPS group compared with non HPS group. These results suggest that NIRS using ICG as a intravascular tracer can provide valuable information on cerebral hemodynamic changes during perioperative management.
Exact mechanisms of early brain injury after subarachnoid hemorrhage (SAH) is still undetermined. We showed that reduction in oxidative stress may attenuate early brain injury after SAH via activation of Akt/GSK3β survival signaling in rat SAH model. We also showed that diffusion weighted imaging (DWI) is useful tool to detect early brain injury after SAH in the clinical setting. DWI can provide an objective means to estimate the outcome of poor-grade SAH. These research about early brain injury after SAH could provide new therapeutic approach.
Evaluation of cerebrovascular hemodynamics in patients with cerebral vascular disease (CVD) is important especially when they receive neurosurgical treatment. PET measurements of cerebral blood flow (CBF) and metabolism using 15O-tracers and 18F-fluorodeoxy glucose (FDG) have been a basic and standard method to evaluate hemodynamics and energy metabolism in the brain since development of quantitative analyses in early 1980’s. Recent development of PET/CT scanners, as well as PET/MR scanners, provides high quality images and reliable quantitative values not only for cancer studies, but also for brain imaging. Advancement of computational technology enables application of various new models for quantitative measurement of CBF and other PET parameters. PET tracers also showed substantial advancement owing to the recent development of molecular imaging technique. Ligands for receptors and transporters are good examples, which can be applied now to dopamine transporter (DAT) imaging with SPECT for clinical diagnosis of Parkinsonism. Amyloid-β imaging available recently is also a good example of the clinical application of molecular imaging. In this article, the history of PET measurement of cerebral perfusion and metabolism is reviewed, and applications of molecular imaging methods for clinical studies are overviewed.
We performed 18F-AV45 positron emission tomography (PET) on 17 patients with Alzheimer disease (AD), 6 patients with mild cognitive impairment (MCI), 6 patients with frontotemporal lobar degeneration (FTLD) and 5 healthy controls (HC). Dynamic PET was performed over approximately 90 min after tracer injection (370 MBq). Subsequently, we constructed time–activity curves. Standardized uptake values (SUVs) and cortex-to-cerebellum SUV ratios (SUVRs) were calculated with regions of interest at the cortical region (frontal, temporal, parietal, and occipital lobes) and other regions (putamen, thalamus, and pons) for all subjects. The SUVRs for patients with AD were greater than those for HC and the SUVRs for patients with MCI were intermediate. The SUVRs were higher for white matter than for gray matter in HC. However, the SUVRs were higher for gray matter than for white matter in patients with AD. The SUVRs in the frontal, parietal, and temporal regions were significantly higher for patients with AD than for HC or those with FTLD. The SUVRs in the frontal and parietal regions were significantly higher for patients with AD than those with MCI. The SUVRs in the occipital regions were not significantly different between patients with AD and other subjects. These results were consistent with those of previous reports on Aβ detection using 18F-AV45 PET and suggested that 18F-AV45 PET was probably effective in predicting the risk of onset of AD in patients with MCI, discriminating between AD dementia and non-AD dementia.
The aim of this study was to investigate whether postoperative hyperperfusion is associated with preoperative cerebral hemodynamic impairment due to chronic ischemia and with acute cerebral ischemia during clamping of the internal carotid artery (ICA) during carotid endarterectomy (CEA). Transcranial cerebral oxygen saturation (SO2) was monitored intraoperatively using near-infrared spectroscopy in 89 patients undergoing CEA for ipsilateral ICA stenosis (>70%). Cerebral blood flow (CBF) and cerebrovascular reserve capacity (CVRC) to acetazolamide were also measured using singlephoton emission computed-tomography (SPECT) before CEA. In addition, CBF was measured immediately after CEA. Hyperperfusion (CBF increase >100% compared with preoperative values) was observed immediately after CEA in 10 of 18 patients (56%) with reduced preoperative CVRC. Also, post-CEA hyperperfusion was observed in 9 of 16 patients (56%) whose SO2 during clamping of the ICA decreased to less than 90% of the pre-clamping value. Logistic regression analysis demonstrated that reduced preoperative CVRC and reduced SO2 during ICA clamping were significant independent predictors of the development of hyperperfusion immediately after CEA. In fact, all patients with reduced preoperat ive CVRC and reduced SO2 dur ing ICA clamping developed post-CEA hyperperfusion.
We examined whether concentrations of malondialdehyde-modified low-density lipoprotein (MDA-LDL), a biochemical marker of oxidative damage, in the jugular bulb during CEA correlates with development of postoperative cognitive impairment, and proved that MDA-LDL concentration in the jugular bulb during CEA correlates with development of postoperative cognitive impairment. Recently, we examined whether postoperative changes in cerebral metabolites measured using 3-tesla proton MRS were associated with changes in cognitive function after CEA, proved postoperative changes in cerebral metabolites measured using proton MRS were associated with changes in cognitive function after CEA. On the other hand, in patients with major cerebral arterial occlusive disease, a marginally adequate blood supply relative to metabolic demand (misery perfusion) in the affected hemisphere may increase the risk of cerebral infarction. Misery perfusion can be identified by demonstrating an increased oxygen extraction fraction (OEF), which is directly measured only through positron emission tomography (PET). However, the facilities performing PET are limited, and more than half of patients who underwent SPECT with acetazolamide challenge developed adverse effects after administration of the acetazolamide. We proved that SPECT methods using IMZ-SPECT and 123I-IMP SPECT (rest) can detect misery perfusion simply and safely.
We had demonstrated that intravenous administration of bone marrow derived mononuclear cells or hematopoietic stem cells improves functional recovery through enhanced angiogenesis in experimental stroke model. Based on these observations, we started phase 1/2a clinical trial of cell-based therapy for patients with cardiogenic cerebral embolism (ClinicalTrials.gov ID: NCT01028794). The results of clinical trial indicated that autologous bone marrow cell transplantation at day 7–10 after onset of stroke is feasible and safe in patients with severe stroke, and patients with cell therapy had better neurological outcomes, compared with historical control group. Our results encouraged us next randomized clinical trials to confirm the effect of cell therapy for patients after stroke.
The neurovascular unit (NVU) consists of neurons, astrocytes, cerebral microvascular endothelial cells and pericytes. These component cells complicatedly interact with each other, and are responsible for the maintenance of various brain functions such as the regulation of microcirculation and blood-brain barrier. Particularly, pericytes play an important role not only in stabilization of microvessels by direct covering, but also in the maturation of microvessels and the maintenance of blood-brain barrier via the interaction with endothelial cells. In response to brain ischemia, pericytes migrate to peri-infarct area and produce various growth and trophic factors, thereby contributing to the tissue repair. Pericytes might play a central role in the protection and repair process of NVU, and thus, are expected as a new therapeutic target for various central nervous diseases, such as cerebral ischemia and dementia.
Various signaling pathways are activated after cerebral ischemia. p53 plays important roles in regulation of apoptotic pathways. p53 transcriptionally activates mitochondria-dependent apoptotic pathway that involves pro- and antiapoptotic protein binding, the release of cytochrome c and apoptosis-inducing factor, leading to neuronal death after cerebral ischemia. In this report, we summarize this signaling pathway, focusing on Bcl-2-associated X protein (Bax), p53-upregulated modulator of apoptosis (PUMA), and p53-induced protein with a death domain (PIDD).
Subarachnoid hemorrhage (SAH) is a cerebrovascular disease with high mortality and morbidity. It has been suggested that the major causes of death and disability in SAH are cerebral vasospasm and early brain injury (EBI). Although cerebral vasospasm was widely studied using a lot of drugs, the outcome was hardly improved even if the drugs were effective for reduction of arterial diameter. Therefore, now EBI is a good candidate target for future research in SAH. It would be very beneficial for SAH patients if the pathophysiology of EBI is clarified and new therapies can be used in a clinical setting. In this review, we introduce some pivotal concepts for studying EBI in SAH for translational research.
Recent changes in dietary habits and insufficient physical activity are associated with the increase of lifestyle-related risk factors such as dyslipidemia and obesity. Hypercholesterolemia is associated with endothelial dysfunction and reduced endothelial nitric oxide synthase phosphorylation in cerebral arteries. Furthermore, visceral fat accumulation is independently associates with the presence of cerebral small vessel disease. Visceral fat releases several bioactive mediators, such as adiponectin and inflammatory cytokines, that influence inflammation and coagulation, resulting in endothelial dysfunction and atherosclerosis. Because the prevalence of obesity in children and youth has increased, the role of lifestyle-related risk factors in cerebrovascular disease is expected to be more important in the future. Improvement of endothelial dysfunction caused by lifestyle-related risk factors could be one of the effective treatments for the prevention of cerebrovascular disease.