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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脳梗塞患者におけるα-1-antichymotrypsin(ACT)変異体であるACTIsehara-1の出現頻度について検討した.
脳梗塞患者87名(男性57名,女性30名,平均58±13歳)とコントロール群443名(男性293名,女性150名,平均54±9歳)を比較した.脳梗塞患者群87名のうち,11名でACTIsehara-1を有していた(12.6%)のに対して,コントロール群では443名中の25名(5.6%)にしか過ぎず,統計学的に有意であった(p=0.018, odds ratio=2.42, 95%CI=1.14-5.12).今回の検討では,高血圧,糖尿病および高脂質血症とACTIsehara-1は明らかな相関を示さなかった。脳梗塞の分類上,ラクナ梗塞にACTIsehara-1の出現頻度が高い傾向がみられた.以上の事から,変異ACTの量的または質的異常が脳血管障害の危険因子となる可能性が示唆された.

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【背景】アンジオテンシン変換酵素(ACE)遺伝子の欠失(D)/挿入(I)多型と脳血管障害との関連は現在のところ明らかではない.
【結果】脳梗塞を有する高血圧患者の対立遺伝子Dを持つ頻度(0.47)は,脳梗塞を持たない高血圧症患者群(0.31)や正常血圧群(0.34)よりも有意に多かった.脳血管障害の家族歴でACE遺伝子型を検討すると,対立遺伝子Dの頻度は家族歴(+)群で家族歴(-)群に比し有意に高値を示した(0.72vs.0.52).ACE遺伝子型別の随時血圧,24時間血圧,血中Plasminogen activator inhibitor 1 (PAI-1)濃度は,いずれも有意な関連を認めなかった.
【結語】ACE遺伝子型は血圧値,PAI-1とは関連せず,発症機序は明確でないが,脳血管障害のgenetic risk factorの一つとして,ACE遺伝子多型が示唆される.

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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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脳卒中の家族歴をもつ人にとって,自分も脳卒中になるのではないかという不安は消えない。著者は,健常人を対象とした脳ドックの結果から,クモ膜下出血の家族歴と未破裂脳動脈瘤発見率との重要な相互関係について報告してきた.今回は脳ドック以外で,2親等以内にクモ膜下出血の家族歴を有する外来および入院患者を対象に,無症候性未破裂脳動脈瘤の発見率を調査し,脳ドック1,000人の結果と比較した.244名中34名に41個の未破裂脳動脈瘤(13.9%)が発見された.患者を対象とした発見率は,健常人を対象とした脳ドックにおける発見率(6%)よりも有意に高かった.さらに,複数の危険因子の関与が統計学的に有意に高い発見率(32%; Odds ratio 3.49, 95% CI 1.37-8.90)を示した.この結果,SAHの家族歴を未破裂脳動脈瘤の危険因子とみなし,さらに危険因子を二つ以上有する場合には脳動脈瘤を持つ危険性が高く,このようなハイリスク群を中心にスクリーニングを進め予防的治療をすればクモ膜下出血を減少させる可能性があると考えられる.また,脳ドックにおいて,AVMは4例(0,4%)発見されたが,家族歴を有する症例はなかった.

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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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日本脳卒中学会Stroke Scale委員会により脳卒中による運動機能障害重症度を数量的に評価可能なスケールが作成された.まず,既存の代表的な7つのスケールを参考に仮スケールが作成された.このスケールを実際の患者に当てはめ,妥当性,信頼性,分布の正規性が検討された.カテゴリーの修正が行われ,修正スケールを用いて信頼性が検討された.各評価項目の重みづけを行う目的でアンケート調査を行い,Conjoint analysisの手法により評点が算出された.最終的に得られたスケールは顔面麻痺:カテゴリー数:2,嚥下障害:3,腕:3,手:3,下肢近位筋:3,足関節:2,複合運動:3,歩行:3の8つの評価項目からなり,嚥下障害と歩行に高い相対的重要度が置かれた.健常者と最重症者の評点はそれぞれ-0.26と31.29であり,統計学的に有意に区別された(p<0.00001).

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Japan Stroke Scale(JSS)の有用性を検討する目的で,急性期脳梗塞患者においてJSS,Hemispheric Stroke Scale(HSS),Barthel Index(BI)を用いて経時的に重症度を評価し,各スコアを比較検討した.対象は発症後3日以内の虚血性脳血管障害患者47例で,各重症度判定は治療前,治療開始1,3,7,14,28日後に行った.JSSはHSSと正の,BIとは負の有意な相関関係にあった.各スコアはJSSでは3日目に,HSSでは7日目に,BIでは3日目に有意な変動がみられた.非塞栓症患者36例はアルガトロバンもしくはオザグレルによる治療を受け,両群とも経時的に有意なスコアの変動がみられた.いずれの群でもJSSの方がHSSより早期にスコアの変動がみられた.JSSはHSSに比し神経学的症候の変動をより鋭敏に反映する可能性があり,経過観察,治療効果を判定するうえでより有用であることが示唆された.

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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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