Cerebrovascular disease and Alzheimer's disease (AD) are the most frequent causes of dementia in the elderly. Pathological backgrounds for vascular dementia (VaD) are heterogenous. Cerebral white matter is mostly involved in dementia due to small-vessel disease and Binswanger's diease. In Binswanger's disease, a quantitative electron microscopic study showed the reduction of nerve fibers, oligodendrocytes and astrocytes in the white matter. These changes are associated mainly with lipohyalinosis (angionecrosis) of small intraparechymal arteries as well as atherosclerosis of main cerebral arteries. The changes in arterioles are believed to cause blood-brain barrier impairments, activation of microglia, and increased production of cytokines and free radicals, all of which may lead to white matter damage. Clinical, pathological and neuroimaging features are different between typical cases with VaD and AD. However, recent studies have reported that VaD has also characteristic features of AD, including hippocampal atrophy, the reduction in acetylcholine concentration in the bain, and possible beneficial effect of acetylcholine esterase inhibitors. Like VaD, AD also shows carebral white matter changes and changes in cerebral blood flow and oxygen metaboloism. Epidemiological studies have reported that almost all risk factors for cerebrovascular disease increased the risk of AD. Further clinicopathological investigation will enhance our understanding of the relation of VaD to AD and our capability to prevent and treat VaD and AD.
The Japan Statin Treatment Against Recurrent Stroke (J-STARS) Study is a prospective, randomised, open, blinded endpoint study designed to evaluate the effects of pravastatin 10 mg/day in patients who preveously experienced an ischemic stroke other than cardioembolic infarction, but who do not have any CHD requiring statin treatment. We planed to enroll a total of 3, 000 patients. aged 45-80 years who have serum cholesterol level of 180-240 mg/dl. The primary endpoint is fatal and non-fatal stroke recurrence during the follow-up period of 5 year and the data collection phase of the study is expected to be completed by April 2010. Effects of statin on hs-CRP and carotid intima-media thickness will also be investigated as substudies of J-STARS. Further, we planned a longitudinal follow-up study called J-STARS-L (J-STARS-Longitudinal), where we aquired a follow-up data from the stroke data bank developed by the Japan Standard Stroke Registry Study (JSSRS) Group, and attempted to confirm the proposed cardiovascular event rate in the ischemic stroke patients who should be enrolled in J-STARS. The present status of J-STARS-L and J-STARS have been presented in this symposium.
Since 1985, when the efficacy of the extracranial-intracranial (EC-IC) bypass surgery on stroke prevention was denied by the randomized multi-center trial, the number of bypass surgery for stroke prevention had drastically decreased all over the world. Recent development of quantitative cerebral blood flow (CBF) measurement, however, has made it possible to examine efficacy of bypass surgery for specific groups of cerebrovascular insufficiency. Japanese EC-IC bypass surgery trial (JET) focused on the efficacy of bypass for the stage II ischemia, and now established significantly lower recurrence rate in the bypass-surgery group than the medical treatment group. JET-2 study, now in progress, is designed to examine stroke recurrence rate on medical treatment for the stage I ischemia, classified into 4 subgroups based on cerebrovascular reserve capacity and rest CBF value, and will establish whether there is potential candidate in the stage I ischemia who benefit from bypass surgery for stroke prevention. Japan Adult Moyamoya (JAM) Trial is a multi-center randomized trial designed to answer the efficacy of bypass surgery for secondary prevention of hemorrhagic stroke in adult patients with moyamoya disease of hemorrhagic presentation. These Japanese multi-center studies will herald a new era of bypass surgery for stroke prevention after longstanding darkness since 1985.
Randomized trials (NASCET, ECAS, ACAS) have shown absolute benefit of carotid endarterectomy (CEA) for patients with high grade stenosis. For carotid stenting (CAS), safety and efficacy (and durability) as first-choice treatment have not been established. The present prospective, multicenter (not-randermized) trial ; Japan Carotid Atherosclerosis Study (JCAS) has started to analyze present practice and propose treatment guidelines for Japanese patients. Until the end of September 2004, 1, 013 patients ; 882 males (87%) and 131 female (13%), and mean age was 69.8 years (52-89 years), have been registered. 510 patients (51%) had any neurological symptoms : cerebral stroke (29%), TIA (17%), ocular symptoms (5%), and 503 (49%) patients are asymptomatic. Sixtypercent of these patients had hypertension, 30% had diabetes mellitus and 30% had a previous coronary disease. Sexual difference was not observed in the incidence of thse previous diseases and medical risks. Of these 1, 014 patients, 444 CEAs (44%) and 317 CASs (31%) were performed. Total complication rate, including neurologic and nonneurologic ones, were 10.6% in CEA and 9, 6% in CAS. Morbidity and mortality rates during one month after surgical treatment were 2.7% (12 cases) in CEA and 3.5% (11 cases) in CAS. Of 12 patients with persistent complication after CEAs, 7 ischemic cerebral symptoms mainly due to distal embolism, 3 hemorrhagic stroke/neurologic deficits due to hyperperfusion syndrome, 2 cranial palsy, and 1 fatal cardiac failure were included. Of 317 CASs, 6 persistent ischemic symptoms due to distal emblism, 2 hemorrhagic stroke, 1 long term hypotention, and 2 technical complication related to angiography were observed.
In this country, enormous amount of effort was devoted to the promotion of basic science, whereas much less has been paid to clinical science. Consequently, clinical introduction of new therapeutic technologies is hampered, with a paucity of medical innovations derived from our country. To put back the fruit of scientific achievements to patients, we are urged to construct an intellectual and practical infrastructure of clinical studies/trials. Under such conditions, Translational Research Informatics Center was founded in 2002, given financial supports from the Japanese government. The center is committed to the innovation of medical technologies, by facilitating the transfer of basic research findings to clinical practice. Our goal is to improve prognoses of intractable human diseases, including cancer, heart disease and stroke. For the goal, our missions are to establish standard treatments that are tentatively or empirically practiced in the clinic, and to explore new diagnostic, therapeutic and preventive strategies. Given such missions, we plan and help conduct every phase of translational researches and clinical trials, currently supporting more than 50 clinical studies, to scientifically, ethically and safely carry them out. Also, to allow for more efficient accomplishments in such studies, we are continuously optimizing our research management systems, with the help of information technology.
Neuroprotective therapy is crucial to salvage the penumbra surrounding the core of ischemia in the acute phase of ischemic stroke. Cumulative evidence suggests that apoptosis plays a pivotal role in neuronal cell death after cerebral ischemia in various experimental animal models. The time-dependent molecular and biochemical sequelae that lead to apoptotic cell death after the interruption of cerebral blood flow have been established. Therefore, various kinds of neuroprotective agents have been developed. In this symposium we introduced the ischemic cell death pathway, especially intrinsic mitochondriadependent and extrinsic receptor-mediated pathway of apoptosis after ischemia, and also introduced our experimental studies on several kinds of brand-new neuroprotective compounds after focal ischemia. Moreover, extra-mild hypothermic therapy (35°C) enhanced that neuroprotective effect and prolonged that therapeutic time window, was introduced.°C These present data show that these newly developed neuroprotective agents and the combination treatment with extra-mild hypothermia (35°C) are effective for neuroprotection in acute cerebral ischemia. These studies provide an impetus for novel therapeutic targets in neuroprotective strategies in acute ischemic stroke. These combined therapy may be useful in clinical medical care for acute ischemic stroke in human.
Advanced systemic atherosclerotic disease is increasing in Japan. The patients with severe carotid steno-tic lesion have frequently (30-40%) associated with coronary artery disease, especially in those with diabetes mellitus and peripheral arterial disease. The new concept of acute neurovascular syndrome is similar to that of acute coronary syndrome, and both are based on the therapeutic standpoint. It becomes more important to protect the advanced atherosclerotic patients from both cerebral and myocardial ischemia/infarction, although the technology and safety of the surgery and stenting for carotid and coronary artery is remarkably improving. Clinical evidence from Japanese large clinical research should be clarified near future. The various approaches to carotid and coronary atherosclerosis tend to be less invasive.
Blood vessels are the huge organ, which connects a heart with general organs. Therefore, coronary artery disease and cerebrovasucular disease share common risk factors and pathlogical mechanisims. In other words, coronary artery and cerebrovasucular disease express end-stage of life-style related disease. We, especially cardiologists. should be aggressive in anti-coagulation therapy in patients with atrial fibrillation. Although many large-scale clinical trials about anti-hypertensive therapy in patients with cerebrovascular disease, doctors of cerebrovascular disease may be not forward enough to decrease their blood pressure. We can select from a menu of some options including drug eluting STENT and off-pump coronary artery bypass for ischemic heart disease patients with cerebrovascular lesions. However, there is much room for discussion whether therapy to coronary artery lesions should be prioritized or therapy to cerebral artery lesions should be prioritized. Moreover, the most important thing is that cardiologists and doctors of cerebrovascular disease build patient-oriented medical cooperation. Because unrecognized coronary artery disease is prevalent in patients with cerebrovascular disease, selected patients with high cardiovascular risk profiles and symptoms of brain ischemia in the presence of significant cerebrovascular disease should be considered for evaluation for coronary artery disease. for early diagnosis to care patients with coronary or cerebral artery disease.
Echocardiography is a noninvasive and useful tool to detect cardiovascular source of cerebral embolism. Although transthoracic echocardiography is easy to detect cardiovascular abnormalities, transesophageal echocardiography is superior to transthoracic approach in terms of the image quality. We should use both of transthoracic and transesophageal echocardiography in a complementary way. Left ventricular thrombus is occasionally found in patients with myocardial infarction and dilated cardiomyopathy and is usually well ob-served by transthoracic echocardiography. Left atrial thrombus is a major source of embolism and trans-esophageal echocardiography is indispensable to detect it. Transesophageal echocardiography is also useful to detect aortic atheroma and vegetation in infective endocarditis. Atrial aneurysm is associated with paradoxical embolism. The presence of right-to-left shunting can be confirmed by contrast echocardiography and the Valsalva maneuver. Therefore, if a patient has stroke of unknown origin, this procedure should be done. Cardiac tumors also cause cerebral embolism. Myxoma is most common among cardiac tumors and soft and polypoid one with irregular surface is at a high risk of embolism. Papillary fibroelastoma incidentally found on the mitral or aortic valve in asymptomatic aged people may also be a source of cerebral embolism.
A nonvalvular atrial fibrillation (NVAF) is the most important risk factor in patients with cardioembolic stroke, however the antithrombotic strategy for this arrhythmia is not sufficient in Japan. Because of the high bleeding complication, one of the major impediments in Japanese patients is to indicate anticoagulation. The penetration rate of the treatment is still low. To avoid the hemorrhagic complication, it is very important to include and limit the cases with higher risk for thrombosis. We put our hopes on enhanced multi-slice chest computed tomography and several hemostatic molecular markers to evaluate the embolic risk. In the case of secondary prevention therapy, custom-tailored anticoagulation, and careful control of this is a special concern. The occurrence of cardioembolic stroke can be reduced to one-half, if we perform the ideal prevention strategy for NVAF.
Increasing evidences strongly indicated that genetic backgrounds for deep vein thrombosis show an ethnic difference. The most prominent and well-known evidences are factor V Leiden mutation and prothrombin G20210 mutation. They are prevalent in Caucasian population but not in Orientals. Using a Japanese general population, we clarified the prevalence of deficiency of plasminogen (4.29%), antithombin (0.15%), protein C (0.13%), and protein S (1.12%), by measuring their activities in plasma. The prevalence of plasminogen and protein S deficiencies in Japanese was higher than those in Caucasian population. Comparison of the prevalence of deficiencies between the deep vein thrombosis group and population-based controls indicated that de-ficiencies of protein C and antithrombin were risk for deep vein thrombosis but plasminogen deficiency was not. Protein S activity in the deep vein thrombosis group was not measured but was actually risk for deep vein thrombosis in Caucasian population. Taken together, our study indicated the significance of deficiencies with deep vein thrombosis in Japanese population.
Antiphospholipid syndrome (APS) and Trousseau's syndrome are clinically important because they are common among coagulation abnormalities as causes of cryptogenic stroke or stroke in young adults, and are treatable with antithrombotic therapy. Antiphospholipid antibodies (APLs) such as antiphosphatidyl serine or antiprothrombin antibody other than anticaldiolipin antibody or lupus anticoagulant should be measured in patients strongly suspected of APS. Disruption of annexin V shield by APLs is the first hypothesis to simultaneously explain prolongation of coagulation time and thrombophilia in APS patients. In our stroke patients with APLs, females are more common, stroke occurs earlier and preferentially involves vertebrobasilar system, and valvular heart diseases, neurological diseases, coagulation abnormalities, and venous thrombosis are frequent, but vascular risk fac-tors and large vessel lesions are less frequent, and levels of thrombin-antithrombin III complex are lower. Trousseau's syndrome is a paraneoplastic neurologic syndrome which is caused by remote effects of can-cers. Tumor cells express cellular procoagulants and fibrinolytic proteins as well as their inhibitors and recep-tors. They also release cytokines and interact with endothelial cells, monocytes and platelets to further enhance activation of coagulation cascade. Clinical characteristics of our patients with Trousseau's syndrome are at wide range of age, female-predominant, commonly associated with solid gynecological cancers, frequently suffer from multiple bland or hemorrhagic cortical infarcts, usually associated with compensated platelet counts and fibrinogen levels, and always associated with increased levels of coagulation and fibrinolysis markers.
Backgrounds; We investigated the incidence and clinical significance of hyperhomocysteinemia in cerebral infarction (study 1) and dementia (study 2) in relation to the clinical findings. Subjects and Methods; Blood levels of homocysteine (HC) and related coenzymes, that is, folic acid, vitamin B12, and 136, were determined in patients with cerebral infarction in the chronic stage, dementia, and controls. Data were analyzed retrospectively (study 1; n = 145, study 2; n= 143). Grades of cerebral white matter lesions (periventricular hyperintensity and/or deep and subcortical white matter hyperintensity) were evalu-ated by using Shinohara's grading (2003). Binswanger type dementia (Binswanger's disease) was diagnosed based on the criteria by Bennett DA, et al. (1990). Results; In study 1, increased levels of HC and Lp (a) as well as decreased levels of HC-related coenzymes were observed in patients with atherothrombotic infarction or white matter lesions. In study 2, increased lev-els of HC and Lp (a), and also, decreased levels of HC-related coenzymes were observed in patients with vascular dementia, mixed dementia, and Binswanger's disease. Conclusions; HC, Lp (a), and HC-related coenzymes are involved in the pathogenesis not only of cerebral infarction but also of vascular dementia including Binswanger type.
Inflammation has been shown to be important in the process of atherothrombotic events including myo-cardial infarction and stroke. We have clarified the value of inflammatory markers such as high-sensitivity CRP (hs-CRP) and soluble ICAM-1 for prediction of atherosclerosis progression with carotid ultrasound. Furthermore, we have demonstrated the association between serum levels of inflammatory cytokine, inter-leukin-6 and plaque echogenecity, suggesting the involvement of inflammation in plaque stability. In patients with obesity and metabolic syndrome, both hs-CRP and plasminogen activator inhibitor-1 levels increased, suggesting upregulation of inflammation and thromobosis activity in those patients. Furthermore, in patients with small vessel diseases such as silent brain infarction and white matter lesion, hs-CRP has been shown to be associated with the presence of silent infarction or the degree of white matter lesion. Those findings highlighted the inflammatory process in the vascular lesion underlying atherothromobotic and lacunar infarction. Recent studies have clarified the CD40 pathway connecting the inflammation and thrombosis in the athero-motous plaque. Therapeutic strategy to inhibit both inflammation and thrombosis will be potential for pre-venting ischemic stroke.
Non-contrast CT and diffusion-weighted images (DWI) are widely applied for accessing patients with acute ischemic stroke including candidates for thrombolytic therapy. Although early CT signs still remain a gold standard as the diagnostic measure for thrombolysis, their changes are subtle and strongly depend on image quality. Standardization and optimization of non-contrast CT performed by MELT-Japan trial have successfully improve its diagnostic performance. Display conditions of DWI are different among institutions or operators, so that objective evaluation of diffusion abnormalities seems to be difficult in multicenter trials. ASIST-Japan group recently proposed a technique to determine appropriate display conditions, which can be utilized as a standard protocol in clinical trials. The 1/3 MCA rule seems to be relatively unreliable to evaluate ischemic areas, so that more objective markers, such as ASPECTS, would be favorable. Standardization of imaging techniques is considered to be necessary to improve the reliability of clinical trials for acute stroke man-agements.
CT and MR perfusion imaging are useful tools in evaluation of regional blood flow in acute ischemic stroke. However, quantitative results show fluctuations, because scan protocol and analysis method are not standardized. In addition, inadequate settings of scan parameters can induce unnecessary radiation exposure in CT perfusion. Therefore, standardization of scan protocol, analysis methods, and evaluation methods are needed. It is important to standardize scan parameters, in order to assure safety of the patients. Standardization of scan parameters and analysis methods is also important to minimize variations of quantitative values. In order to evaluate the degree of ischemia correctly, defining a universal index for the ischemic lesion, such as DWI-PWI mismatch, is required. In summary, the goal of the standardization is to assure the safety of patients, to ensure the reliability of results, and to establish universal evaluation methods. In Japan, standardization of perfusion imaging, as well as other stroke imaging, is being carried out by ASIST-Japan (Acute Stroke Imaging Standardization).
Recent Japanese EC-IC Bypass Trial (JET Study) showed that the EC-IC Bypass was beneficial for stroke prevention in patients with Stage II hemodynamic cerebral ischemia determined by quantified CBF-SPECT imaging. Standardization of quantified stratification of hemodynamic cerebral ischemia using CBF-SPECT imaging will be important issue in decision-making of indication of EC-IC Bypass surgery for cerebral ischemia. In this article, we proposed newly developed two CBF-SPECT analysis for improving measurement accuracy and judgment accuracy. Dual table ARG (DTARG) analysis provided same-day quantification of both resting CBF and acetazolamide-activated CBF using split dose of CBF tracer (IMP) and common arterial input function for im-proving measurement accuracy. In this method, resting and acetazolamide-activated CBF-SPECT could be quantified pixel-by-pixel using dual table look-up method without error of input functions. Segmental extraction estimation (SEE) analysis presented resting CBF, acetazolamide-activated CBF, VR, and stratification of hemodynamic cerebral ischemia unfolded on the standardized brain surface coordinate using 3-dimensional stereotactic surface projections (3D-SSP) for improving judgment accuracy. In this analysis, severity of hemodynamic cerebral ischemia could be estimated from both stereotactic and quantitative viewpoints based on standardized vascular territories. Standardization of quantified stratification of hemodynamic cerebral ischemia using CBF-SPECT imaging will be progressed by introduction of DTARG and SEE analysis.
For multi-institution clinical research on cerebrovascular disease, the standardization of MR imaging conditions is required. Firstly, the magnetic field strength must be the same in all the facilities, and it is at least necessary for a chronological sequence of observations of the same patient to be conducted on the same machine at the same facility. Further, the angle and width of brain slices in MRI must be the same. Secondly, in addition to T1WI, T2WI and FLAIR, T2WI is recommended for detection of micro-bleeding in the brain. Thirdly, perivascular spaces, number and areas of infarcts, and deep white matter and periventricular white matter hyperintensities must be evaluated according to specified criteria. Such standardization of MR imaging among different institutions should provide high-quality evidence to elucidate the pathophysiology of cerebrovascular disease and to develop therapeutic strategies.
In the process of human genome sequencing, many polymorphisms of genes, which might include disease specific or disease sensitive genes, have been revealed. We examined whether these polymorphisms contributed to the onset of cerebral infarction by means of case-control studies, although ischemic stroke is recognized as a multi-factorial disease. The subjects of this study were approximately 226 symptomatic ischemic stroke patients being treated at the Department of Neurology of Keio University Hospital and approximately 312 control subjects who were employees of Keio University Hospital undergoing regular health check-ups, We selected 20 candidate genes and analyzed their polymorphisms by means of the polymerase chain reaction and restriction fragment length polymorphisms. Four gene polymorphisms among the 20 were significantly frequent in those who had suffered cerebral infarctions. The four polymorphisms were found in the Met allele of Thr145Met of platelet glycoprotein Iba, the T allele of the C242T NADPH oxidase p22 PHOX. the T allele of the C1019T of connexin37, and the C allele of the A561C of E-selectin. Our studies suggest that polymorphisms of genes related to platelets, leukocytes, and cell adhesion molecules may be risk factors for ischemic stroke.
Intracranial aneurysms are complex in origin, involving the interaction of several genes and environmental factors, and therefore belong to a common disease. Among hereditary connective tissue diseases, only autosomal dominant polycystic kidney disease has proved to be associated with intracranial aneurysm. Two genes, PKDJ (85% of cases) and PKD2 (15% of cases), have been identified and characterized. To date no susceptibility genes related to intracranial aneurysms are found in other common types of aneurysms. Three genome-wide linkage studies have identified genetic loci for intracranial aneurysms on 7g11, 14q22, 5q22-31 in our Japanese, on 19g13.3 in a Finnish, and 17cen, 19g13, Xp22 in other Japanese study. These genetic loci include some interesting candidate genes such as ELN. These candidate genes should be confirmed in largescale association studies in different ethnic groups and roles of them should be studied further.
Recent research suggests that many genetic variants and environmental exposures might affect the occurrence and progression of common diseases including stroke. However, genetic risk factors for cerebral infarction, the most common type of stroke in developed countries, are almost unknown. We conducted a genome-wide association study using 1, 126 Japanese subjects with cerebral infarction and age-and sexmatched healthy controls selected from the participants of health examination survey of the Hisayama study in 2002 and 2003. We initially genotyped 188 cases for 52, 608 gene-based single nucleotide polymorphisms (SNPS) and compared their genotype distributions with those of 188 corresponding controls. We found 1, 098 SNPS with significant associations (p<0.01) in the initial screening and further genotyped these SNPS in the remaining cases and controls. As a result, 10 SNPs loci showed strong associations (p<0.0001) with cerebral infarction. When the subjects were examined by cerebral infarction subtypes, we found that another 2 SNPs loci were significantly associated with lacunar infarction. These loci might include susceptible genes for cerebral infarction. Further studies examining function of these genes are needed to clarify genetic risk factors for cerebral infarction in Japanese.
β2-Glyoprotein I (β2-GPI) is the most responsible antigen for antiphospholipid antibodies. At the DNA level, 4 different types of allelic polymorphism have been detected in β2-GPI. Position 247 allele is composed of either Valine (V) or Leucine (L), resulting in genotype expression of VV, VL, or LL. We investigated frequencies of either V or L presented at position 247 allele in patients with cerebral infarction. Relationships between the genotypes of β2-GPI gene and patient characteristics were studied. Method The DNA segment containing the position 247 polymorphism was amplified by the semi-nested polymerase chain reaction (PCR), and the polymorphism was detected by restriction endonuclease digestion. DNA samples from 103 patients with cerebral infarction and 98 healthy individuals (control) were analyzed. Results V allele and VL genotype were more frequent in patients with cerebral infarction than in normal control (32% vs 46%, p=0.040). VL genotype was more frequent among patients ≤ 60 years than those aged>60 years (58% vs 37%, p<0.005) .The mean values of b-thromboglobulin and platelet factor 4 in patients with VL genotype were significantly higher than those with LL genotype (p=0.019, p=0.014). Conclusion Results suggested that Valine247 β2GPI allele is one of the genetic risk factors for development of cerebral infarction.
Ischemic damage of large-scale networks between cortical regions leading to disconnection may cause cognitive impairment associated with widespread functional disturbance. However, it remains unclear to what extent this mechanism contributes to the development of cognitive impairment or dementia, because there is no way to evaluate quantitatively and precisely the amount of the disconnection in each patient. We investigated atrophy of the corpus callosum as a surrogate marker for damage of large-scale networks. In ca-rotid artery disease without cortical infarction, callosal atrophy was associated with cognitive impairment and widespread cerebral cortical hypometabolism. Ischemic loss of the pyramidal cells in layer 3 originating long association and commissural fibers, which may result in calllosal atrophy, may lead to the disconnection be-tween cortical regions. In patients with lacunar infarction and white matter lesions, callosal atrophy was a predictor of global cognitive impairment, whereas the extent of white matter lesions per se was related to impairment of frontal lobe function independent of callosal atrophy. Callosal atrophy may parallel the total loss of fibers in the white matter, the degree of which may determine the severity of disconnection. Damage of largescale networks is important for the development of cognitive impairment in ischemic stroke.
We presented our experience about cognitive changes associated with vascular reconstructive surgery in patients with ischemic cerebrovascular diseases. 1) Bypass surgery improves impaired cognitive function. Further, degree of cognitive improvement is associated with degree of an increase in CMR02 and a decrease in OEF. 2) Cerebral hyperperfusion after carotid endarterectomy, even when asymptomatic, is associated with impairment of cognitive function in patients undergoing CEA. Further, development of hyperperfusion syndrome is associated with persistence of postoperative cognitive impairment.