The purpose of this lecture is to introduce the results of researches concerning the pathophysiology of ischemic cerebrovascular disease (CVD) in my department and to consider its clinical application.
We found that gradual activation of voltage-sensitive Ca channel activity, a sensitive indicator of brain ischemia, occurs when CBF is reduced to 50%. This indicates the brain is more vulnerable to ischemia than had previously been believed.
Fig. 1 is a schema showing the release of glutamate, Ca influx, activation of NOS, etc. on ischemia. Administration of an N-type Ca channel blocker or K channel opener could decrease the concentration of glutamate and reduce the infarct volume produced by MCA occlusion in rats. We estimated NOS activity during brain ischemia by measuring nitrotyrosine, which is a footprint of peroxynitrite. nNOS was active in the early phase of ischemia and iNOS became predominant in the later phase of the acute stage of ischemia. Aminoguanidine, a relatively selective iNOS inhibitor, could reduce infarct volume if administered 12 hours after MCA ligation in rats. Cytoxic edema is an other important issue in ischemia. An NOS inhibitor, as well as L-type Ca channel blockers, could delay the shift of water from extra- to intracellular space. Increase in blood viscosity produced by increase in Ht, decrease in RBC deformability, accelerated RBC aggregation time and increase in plasma viscosity, as well as accelerated platelet aggregation, are important factors causing secondary circulatory disturbance after ischemia or inducing reattack.
The results are summarized in Fig. 11, and Fig. 10 shows various types of neuronal death after ischemia.
Because of the diversity in the pathophysiology, effective treatment may require a cocktail of drugs, but so far we have no idea what would be the best cocktail.

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More than 80 unrelated patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), originated from various communities around the world, have been molecularly identified, but all were white. The occurrence of CADASIL in Orientals is uncertain. We genetically identified two unrelated Japanese family with CADASIL, including 5 affected members through 2 generations. Each affected individuals developed recurrent strokes without risk factors resulted in progressive dementia, pseudobulber palsy, and gait disturbance started after the fifth decade of life. Although affected individuals had no vascular risk factors, they revealed varying degrees narrowing of retinal arteries. Their MRI /CT showed characteristics of the disease; bilateral small infarcts in the thalamus, basal ganglia, brain stem, and deep white matter in addition to the findings of leukoaraiosis. On SPECT imaging, there was severe hypoperfusion of blood flow in the cortex as well as in the white matter. Ultrastructural studies revealed an abnormal deposition of granular osmiophilic materials, within the basal lamina of pericytes in muscular capillaries. A heterozygous Arg133Cys mutation was present in affected individuals, in exon 4 of Notch3 gene, where is the hot spot region for CADASIL mutations in Caucasian families. None of non-affected members nor 50 Japanese normal controls revealed this mutation. Thus, our results confirm that CADASIL is a geographical widespread disorder caused by Notch3 mutation, and GOM may be the specific morphologic hallmark.

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We have already reported a variant αl-antichymotrypsin (ACT) (ACT Isehara-1, Met389Val, A1252G), which was frequently found in the patients with cerebrovascular disease (CVD). To clarify whether this mutant variant in a novel risk factor in CVD, we studied 87 patients with documented CVD (age 58±13 years) and 443 control subjects (age 54±9 years). CVD was diagnosed using by clinical manifestations and magnetic resonance imaging (MRI) for brain. To rule out the effects of specific extracranial and systemic factors were excluded. Genomic leucocyte DNA was used for DNA analyses including PCR-single strand conformation polymorphism (PCR-SSCP) and PCR-RFLP methods.
The frequency of ACT Isehara-1 (heterozygote) was significantly higher in the CVD subjects (12.6%) than in control subjects (5.6%, odds ratio = 2.42, 95% CI =1.14-5.12, p = 0.018). This result implies that ACT Isehara-1 is a CVD risk factor. Analysis by subtypes of CVD showed that 8 of 11 subjects with ACT Isehara-1 (72.7%) had lacunar stroke. This result was suggesting the association of ACT Isehara-1 with lacunar stroke. We concluded that ACT Isehara-1 is a possible genetic risk factor of CVD. Determination of A 1252 G genotype may be useful in assessment of CVD risk and prevention of a part of CVD.

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The association between angiotensin-converting enzyme (ACE) gene insertion (I) /deletion (D) polymorphism and cerebrovascular disease (CVD) is controversial. The aim of our study is to elucidate this association. ACE genotype was analyzed using PCR. The frequencies of DD genotype and D allele were significantly higher in hypertensives with CVD than those without CVD and normotensives. The frequencies of DD genotype and D allele were also higher in hypertensives with parental history of stroke (PHS) compared with those without PHS. However, casual and ambulatory blood pressure levels and plasma levels of plasminogen activator inhibitor 1 (PAI-1) were not different in ACE genotype. These findings suggest the ACE genotype is one of the risk factors of CVD independent of blood pressure levels and PAI-1 levels.

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Silent brain infarction (SBI) is often found with white matter hyperintensity (WMH). A recent genetic study on elderly twins indicated that the susceptibility to WMH was largely determined by genetic factors, implying the existence of genetic susceptibility for SBI as well. We therefore studied three genetic polymorphisms in SBI, the D/I polymorphism of angiotensin-converting enzyme (ACE) gene, the apolipoprotein (a) [apo (a)] phenotype and the T677C polymorphism of methylenetetrahydrofolate reductase (MTHFR) gene, by a case-control study.
By MRI, 147 subjects with SBI [SBI group] and 214 without cerebral infarctions [Control group] were selected from participants of a health examination of the brain. Eighty-five patients with symptomatic subcortical infarction (SSI group) from the same area were also included in the study. In addition to the Control, two more reference populations were recruited.
Typing of the apo (a) phenotype was done by western blotting using an anti-apo (a) antibody. Genotypes of ACE and MTHFR were determined by PCR amplification of the genomic DNA and subsequent restriction enzyme digestion.
The ACE polymorphism was not associated either with SBI or with SSI. In contrast, the small-sized apo (a) was associated both with SSI and SBI. The MTHFR polymorphism was associated only with SSI. The association of MTHFR and apo (a) was greater in the younger subjects. Among the three genetic polymorphisms studied, only the apo (a) phenotype is a risk factor for SBI.

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There is always a fear being attacked by subarachnoid hemorrhage (SAH) for a member of the family with a history of SAH. I have reported a significant correlation between a family history of SAH and the discovery of an unruptured aneurysm in a group of healthy volunteers at my Brain Dock. This time, in order to confirm such a correlation, an incidence of asymptomatic, unruptured cerebral aneurysms was studied among the outpatients and inpatients with a family history of SAH within the second degree of consanguinity. The result was compared with the updated data gathered from 1, 000 healthy volunteers at the Brain Dock. Fortyone unruptured cerebral aneurysms were found in 34 (13.3%) of 244 patients. This incidence was significantly higher than that found at the Brain Dock of healthy volunteers (6%). Furthermore, patients who had a family history of SAH combined with multiple systemic risk factors were found to have the highest incidence of unruptured aneurysms statistically (32% ; odds ratio 3.49, 95% confidence interval 1.37-8.9). These findings suggest that a family history of SAH, especially with the addition of more than one systemic risk factor, should identify a high-risk group of patients with possible cerebral aneurysms. Aggressively screening these highrisk patients combined with optimum surgical treatment of unruptured aneurysms should decrease the incidence of SAH in the future. There were four cases (0.4%) of AVM found at the Brain Dock and none of them have a family history of AVM.

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Recently, several clinical trials in acute stroke have failed to produce efficacy. This suggests that there is a large gap between results in human trials and in animal. Animal models may present on aspect of pathophysiology in patients. We have to know how similar and what aspect of animal models can be extrapolated to patients. It is a big question whether or not therapeutic time window between animal models and patients is similar. In some animal models, cerebral damage establishes within 6 hours of the MCA occlusion, and this indicates that it is impossible to cure cerebral damage when drug injection is administrered over a 6 hour pe-riod. Recently, some investigators demonstrated that in human penumbra disappears within 6 hours after ischemia and therapeutic time window is as narrow as that in animal models. Finally, in animal studies, effects of neuroprotective agents are evaluated by the size of cerebral damage and neurological deficits. In human trials, effects of these agents are evaluated by stroke scores in including Japan stroke scores. In stroke scores, consciousness, language ana paralysis are examined, but in animal models, only paralysis is examined. Data of neurological symptoms of animal studies do not accord with those in human trials.

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Several stroke scales, such as the National Institutes of Health Stroke Scale (NIHSS), The Scandinavian Stroke Scale (SSS), The European Stroke Scale (ESS), have been used in clinical measurements of the severity in patients with acute stroke. But all these scales are ordinal scales, so level of data of them in not high than that of ratio scale.
Recently, Japan Stroke Scale (JSS) is established, which is a ratio scale and a quantitative measure of the severity in acute stroke by use of conjoint analysis, with 10-item neurologic examinations. The examinations can be performed easily, and JSS has proven inter-rater reliability and has predictive validity for stroke outcome.
For estimating usefulness and problem of JSS for clinical use in acute stroke, we investigated total score and each scale item in 50 patients with acute stroke. Several notice were recognized in some cases, for the specific items of the scale : level of consciousness, sensory system and motor system.

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Stroke patients admitted to neurosurgical departments first undergo a decision making process whether medical or surgical treatment is needed. Besides various imaging studies, patients' neurological symptoms hold a significant role for the decision. The purpose of this investigation was to test if the Japan Stroke Scale (JSS) is useful in neurosurgical decision making for acute stroke patients. Forty nine acute stroke patients, 15 intracrebral hemorrhages, 18 cerebral infarctions and 16 subarachnoid hemorrhages, were examined by four neurosurgeons using JSS. Although the reproducibility among investigators was high, several problems were pointed out including 1) several items were not applicable to patients with signigicant consciousness distur-bance, 2) making borderlines between medical treatment and surgical treatment was often difficult using JSS. probably because poor discrimination among patients with significant consciousness disturbance and 3) more specifically, it might be a problem that the Japan coma scales 1 and 30, and 100 and 300 were grouped in the same grade respectively in the JSS. In conclusion, JSS, which seems more suitable to patients with less consciousness disturbance, appeared sometimes difficult to apply to acute stroke patients with more severe consciousness disturbance. Future investigation is necessary to clarify if the JSS in applicable to decide indications of neurosurgical interventions.

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Japan Stroke Scale (JSS, acute stage) is already being used in Japan. In this scale, an emphasis is placed in the consciousness disturbance, because it is a quantitative scale for the acute stage of stroke. On the other hand, in the chronic stage, the motor function disturbance becomes one of the substantial problems. Therefore, the Stroke Scale Committee of the Japan Stroke Society has developed a novel stroke scale (Japan Stroke Scale-Motor Function, JSS-M) with which it is possible to specifically evaluate motor disturbance quantitatively. An official and detailed report from the committee will be published in the near future.

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To clarify the possible usefulness of Japan Stroke Scale (JSS), we applied this scale to acute ischemic stroke patients and compared with the Hemispheric Stroke Scale (HSS) as physical deficit scale and the Barthel Index (BI) as functional scale. Forty-seven patients with acute (<3 days) ischemic stroke were included. The rating scale was tested before and 1, 3, 7, 14 and 28 days after the treatment. The JSS score correlated well with the HSS (r=0.92) and the BI score (r=-0.80). The JSS and HSS scores were significantly decreased with the process of time. Significant decrease in the JSS score was found at 3 days after the treatment, while the HSS score was not significantly changed until 7 days after treatment. Both groups treated with argatroban and with ozagrel Na showed significant decrease in the JSS and the HSS scores, although there wan no significant difference in the rate of score reduction with the process of time between the two treatment groups. The JSS should prove useful in quantifying neurologic deficits in ischemic stroke and in following changes in neurological status.

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The apolipoprotein (a) [apo(a)] gene encodes a protein component of lipoprotein (a) [Lp(a)] . To study the implications of Lp (a), we examined plasma Lp (a) levels and molecular weights (MW) of apo (a) in patients with cerebrovascular disease (CVD), or central retinal artery occlusion (CRAO). Mean Lp (a) concentrations were higher in the CVD cases with atherothrombotic brain infarction than in those with brain hemorrhage and lacunar infarction. Mean Lp (a) concentrations were also significantly higher in the CRAO cases than in the controls. Lp (a) levels higher than 30 mg/dl were more frequent in the CRAO cases than in the controls. Lp (a) concentrations correlated significantly with low-MW isoforms of apo (a) in these patients. We subclassified the apo (a) gene into four types (A-D) by polymorphisms in the 5'-flanking region, measured plasma Lp (a) concentrations, and examined the expression of the gene by in vitro assay. Homozygotes of type C had higher Lp (a) levels than those of type D in vivo, and the relative expression of type C was higher than that of type D in vitro. Thus, Lp (a) concentrations are genetically determined by extensive polymorphisms in both the 5'-alleles and the numbers of Kringle 4 repeats, and hyper-Lp (a) -emia is a risk factor for thrombosis of various types of vessels.

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The association of insulin with atherosclerosis has been a subject of research for more than 3 decades. Several studies have shown that hyperinsulinemia is associated with the risk of coronary heart diseas, but information on the association of hyperinsulinemia with the risk of ischemic stroke is limited. According to recent prospective epidemiological studies, such as the Kuopio study and the Helsinki policemen study, fasting insulin level appears to be a risk factor for ischemic stroke. Furthermore, cross-sectional studies have shown that hyperinsulinemia or insulin resistance is associted with ultrasonographically assessed atherosclerosis in carotid arteries. Concerning the stroke type, insulin resistance and compensatory hyperinsulinemia seems to be an important pathogenetic factor underlying the development of atherothrombotic cerebral infarction in Japanese. However, in another German study, elevated insulin levels represent a pathogenetic factor in the development of cerebral small vessel disease, predominantly in patients presenting with lacunes. These diffenence may indicates racial difference. In relation to the insulin level, significance of fibrinogen and leptin is noticed. On the treatment of the stroke patients with hyperinsulinemia, calorie restriction, weight loss and exercise training is important. Antihypertensive drugs with improving insulin sensitivity are indicated for hypertensive patients.

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The role of cell adhesion molecules and tissue factor as risk factor for brain infarction has been emphasized. By primate models of middle cerebral artery occlusion and reperfusion (MCA : O/R), we have tested the potential role of these molecules in the microvasculature in ischemic brain tissue. Significant increase of cell adhesion molecules (P-selectin, E-selectin, ICAM-1, and GP IIb/IIIa) of immunoreactive expression was recognized in the affected site of MCA : O/R. Infusion of monoclonal antibody of β 2 integrin subunit (CD 11 b), IB 4 produced significant increase in reflow. Preischemia infusion of the anti-tissue factor monoclonal anti-body, TF 9-6 B 4 resulted in significant reduction of intramicrovascular fibrin in MCA : O/R. These results in-dicate that cell adhesion molecules and tissue factor-mediated events may play an important role in the proc-esses of brain ischemia, coagulation system activation and inflammation, which are interrelated each other.

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TIA and atherothrombotic stroke are platelet-dependent disease states since they are attributable to platelet-rich thrombi formed on an atheromatous plaque in major arteries. Cadioembolic stroke is attributable to fibrin-rich thrombi, although platelets might be strongly activated by thrombin generated as well. Recent studies have clarified that microatheroma, branch atheroma, and microemboli originated from major arteries, which might be platelet-dependent disease processes, contribute to the pathogenesis of lacunar stroke. In addition, it has been well known that platelet aggregation, release reaction, and procoagulant activity play important roles in the pathophysiology of acute ischemic stroke.
Findings of platelet activation were frequent in patients with atherothrombotic stroke or TIA. Platelet consumption and destruction were most prominent in patients with cardioembolic stroke. Mild platelet activation or consumption was also observed in some patients with lacunar stroke. Polymorphisms of platelet membrane glycoproteins have recently been reported to be a risk factor of stroke.
It might be finally proven by the efficacy of antiplatelet therapy whether platelet activation can be a risk factor of stroke. Meta-analyses by Antiplatelet and Antithrombotic Trialists' Collaborations have established the risk reduction by antiplatelet therapy in patients with atherothrombotic diseases. Clinical applications of more potent antiplatelet agents including platelet glycoprotein IIb/IIIa inhibitors may more clarify what disease states are platelet-dependent.

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Recently, Chlamydia pneumoniae (C pneumoniae) has been noteworthy to be linked to an atherosclerotic disease and clinical evidence that C pneumoniae infection contributes to atherosclerosis is accumulating. We clarified the detail distribution of C pneumoniae infection in the atherosclerotic carotid artery by im-munohistochemistry and electron microscopy.
Twenty-seven specimens of carotid atheromatous plaque were obtained during carotid endarterectomy in 26 patients with severe carotid artery stenosis. Immunoreactivity for the C pneumoniae-specific antigen was observed in 55% of patients, and intense immunoreactivity was observed in 35% of patients. C pneumoniae infection was observed in endothelial cells, macrophages and smooth muscle cells that had migrated into the atheromatous plaque, as well as in smooth muscle cells and small arteries in the media underlying the atheromatous plaques. C pneumoniae infection was most prominently observed in smooth muscle cells. In electron microscopy, a pear-shaped elementary body of C pneumoniae was observed.
Macrophages in the intima produce some cytokines and growth factors, and elicit migration of smooth muscle cells from the media to the intima as well as an inflammatory response which subsequently leads to atherosclerosis progression. Chronic infection of C pneumoniae may enhance the proliferative and inflammatory processes of atherosclerosis by inducing some cytokines and lipoproteins through activation of transcription factors such as nuclear factor (NF)-kB.

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Successful embolization can be achieved only when the follwing three factors are correct and in cooperation : catheter tip position, flow control, ant the setting time of normal-butyl cyanoacylate (NBCA) . Otherwise, the procedure may end with unsatisfactory results or complications. The current principle of safe and efficient embolization of cerebral arteriovenous malformation (AVM) is based on superselective cannulation of every strategically important feeding pedicle and injection of liquid embolic material under flow control. This study was based upon our experiences of embolizing 96 cases with cerebral AVM performed under the above conditions at our department. Results shows very encouraging new observations with implications for further procedures : total removal of the AVM nidus after embolization was achieved in 90% of the cases, preradio-surgical embolization achieved 52% volume reduction and successfully maneuvered all cases into the gamma knife focal spot. Recently improved microcatheters with increased flexibility and minimal friction made it possible to place the tip of the microcatheter into the nidus with a higher success rate and better safety factors. In order to obliterate a substantial amount of the AVM nidus and prevent penetration into the draining veins, the creation of optimal flow status, and optimal setting time of NBCA have paramount importance. Forthcoming complete microcatheter/guidewire units and new embolic materials will enable us to perform safer and more efficient embolization even though the AVM is located distally or fed by perforating arteries.

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Stroke causes significant burden both on the individuals and on the society, which necessitates national stroke strategies. Three issues which are considered to be important from the viewpoint of national stroke strategy are mentioned in this article : effects of community prevention program in Japan, stroke unit (SU) in the UK, and Brain Attack Campaign in the US.
In Japan, community stroke prevention program has been proven to be effective in reducing stroke incifdene.
SU was proven to be effective in reducing mortality, increasing home discharge, improving ADL and QOL, and shortening length of hospital stay. In the UK, SU has been widely introduced. A survey in 1998 showed that there are 184 SUs in the UK and 52% of stroke patients were treated in SU.
In the US, Brain Attack Campaign was strated to realize thrombolytic therapy using t-PA for cerebral in-farction within 3 hours from onset. Public education on stroke warning sings and on the need of emergent response at onset is indispensable for the campaign.
Systemic approaches such as a community stroke prevention program, the introduction of SU, and Brain Attack Campaign are considered to be important cores of future Japanese stroke strategies.

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