While interest in headache research started early in Japan, headache cares did not develop until recently. Patients with migraine did not visit doctors for headache, and physicians were unaware of the prevalence and disability of migraine in Japan for a long time. Studies in Japan on migraine epidemiology revealed that the prevalence of migraine was 8.4% of the population, demonstrating 8.4 million people are suffering from migraine. These results gave impact to young scientists in Japan and encouraged them to do clinical and experimental studies on headache. One of the barriers for studying headache was a difficulty in communication to obtain enough information by the physicians. Patients usually suffered in silence. New medication for migraine, triptan, increased the number of patients visiting physicians. Physicians also developed such communication tools as headache diary, migraine screening tools helping physicians to obtain good amount of information on headache. The purpose of this communication is to present the author's experience in the study of mechanism and treatment of headache based on headache diary. The importance for future progress of migrainology was emphasized.

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日本神経学会は1960年に設立されましたが，当時神経学を学べる施設は，東大，新潟大，九大などに限られていました．僕は，のちに京大総長を務められた平沢興先生の錐体外路系に関する解剖講義に憧れてこの道を志し，インターン修了後すぐ渡米しましたが，1）神経系が人体のもっとも重要な，人間が人間たるゆえんである脳の機能を主要な対象としていること，2）複雑難解にもかかわらず理路整然とした学問で，解剖学の知識に基づいて病巣の局在が可能であること，3）新しい領域で，将来への展望が明るいことなどにも強く魅かれました．半世紀近くを経た今も思いは同じですが，これに加えて分子生物学をはじめとする神経科学分野の目覚しい発展により，病態の確立のみならず以前は対症療法に甘んじていた多くの疾患にも新しい治療法が続々と開発され，4）患者の治る神経内科，が神経学の新たな魅力となり，これは僕達のスローガンでもあります．神経学の国内外の進歩にともない，この分野を目指す若い先生方への期待は日増しに大きくなってきました．わが国の神経学は僕がアイオワ滞在中に飛躍的な発展を遂げ，これに貢献された多くの先達が新しい世代に求めるところは，先生方の個人的な経験を踏まえ，千差万別かと思います．この機会に日米で神経学を学んだ者の一人として，僕の次世代への期待を纏めますと，1）国際的な視野で仕事をする，2）診断に役立つ新しい技術を開発する，3）臨床に直結する基礎研究を展開する，そしてそのすべてを集結して4）患者の治る神経内科をめざすことです．いずれも実現可能な目標ですが，いうはやすく，おこなうは難しの部類です．とくに，実力に見合った国際的な評価を確立するのはわれわれがもっとも不得手とするところで，僕自身の体験でも，海外の学会活動で欧米の学者と互角にわたり合うのはかなり難しく，常に意識的な努力が必要と実感しています．国際学会での論争で，実力は伯仲しているのにいつもこちらに分が悪いのは，主に発表態度の差によるものと考えられます．我が国は儒教の影響もあり，古くから「知るを知らざるとなすは尚なり」の考えが根強く，10を知って1を語るのが良いとされます．その逆にアメリカ人は，幼稚園での「Show And Tell」を手始めに，中学校で習う「Five Paragraph Essay」で鍛え上げられ，1を知って10を語る輩が多いようです．また，日本人は完璧主義ですから，とちっても平気な欧米人とはちがいアドリブの発表が苦手です．英語でも上手く話せなければ，我は黙して語らずと達観している人もありますが，外国語ですからBrokenでも当たり前です．僕の国際性の定義は，1）実力をつけて，あとは対等と自信をもつ，2）知ってることはどんどんいう，3）失敗しても愛嬌と思って気にしない，4）英語は意味がわかればよいので，あえて流暢に喋ろうとしない，ことです．若い先生方がこれからの国際舞台でますます活躍されることを願って止みません．

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During over 50 years of my career in Neuropathology at Montefiore Medical Center in New York, I have come across certain interesting neuropathological findings. In this communication, some photographs showing macroscopic, microscopic and electron microscopic significant findings are selected to illustrate the usefulness, not only for the diagnosis but also for the understanding of the nervous system. The 11 topics presented in this paper are: (1) alteration of dura mater associated with advanced aging; (2) orderly arrangement of tumor cells in leptomeningeal carcinomatosis; (3) horizontal section of brain with border zone infarct; (4) neurofibrillary tangle formation in the nucleus basalis Meynert ipsilateral to a massive cerebral infarct; (5) extracellular spread of hematogenous edema fluid in the white matter; (6) unrolled myelin sheath; (7) unattached presynaptic terminals in cerebellar neuroblastoma; (8) unattached post synaptic terminals in agranular cerebellar degeneration; (9) neurofibrillary tangles and Lewy bodes in a single neuron; (10) Cu/Zu superoxide dismutase positive Lewy body-like hyaline inclusions in anterior horn cells in familial motor neuron disease; (11) Hirano body. Analysis of these findings are presented for an educational purpose.

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Brain is highly organized organ important for learning and memory, emotion and behavior in social life. We are confronted to suffering from various brain disorders. I here present some of the research strategy for the analysis of brain disorder by molecular technique to find ways to cure the disorders. It is surprising to know that the important molecules involved in development and differentiation of the brain are all involved in the neurodegenerative disorder or neuropsychiatric disorders. I here stress the importance of the collaborative approach with other fields to analyze the brain structure and function at various levels at molecule-cell-tissue-organ-body-society.

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脊髄小脳失調症10型（spinocerebellar ataxia type 10：SCA10）は小脳失調とてんかんを主徴とする優性遺伝性神経変性疾患であり，臨床症状は多様性に富む．その遺伝子変異は，ATXN10遺伝子のイントロン9にあるATTCT5塩基リピートの不安定異常伸長である．5塩基病としてヒト唯一のものであり，リピート病として最大の変異を示すものの一つである．SCA10 ATTCTリピートは，他のリピート病とことなる特有の不安定性を示す．その病態メカニズムは，RNAレベルでおきている可能性が強い．SCA10研究が，病態が依然として明らかでない優性遺伝性非翻訳領域リピート病解明の一助になることを期待している．

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1965年新設の新潟大学脳研究所神経内科に入局して以来，根本的な治療法が無く，進行すれば生活障害をきたし，通院も困難になる神経難病等重症神経疾患患者の退院後の在宅ケアは，「臨床科としての神経内科」に課せられた一つの課題と思われた．1978年新潟市の信楽園病院で継続医療室を開設，訪問看護と往診を開始，地域の保健師，ホームドクター，ヘルパーと協働して医療依存度の高い神経疾患患者の在宅ケアを提供した．1987年在宅人工呼吸管理を開始，日本ALS協会の陳情を支援して1990年新潟県の特定疾患在宅患者医療機器購入補助事業を引き出し，新潟市でも難病対策連絡会とその下部組織の新潟市難病ケース検討会が始まり，医療職，介護職の教育の機会となり，種々の有用な制度を生み出した．著者は1997年から訪問看護ステーションと在宅介護支援センターを併設した複合体診療所を開設，退院後の患者の受け皿となり，2000年に発足した介護保険制度を軸に種々の現行制度を駆使して治療困難な患者の在宅療養を支援している．

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レヴィ小体病では，病早期より始まる心臓交感神経の変性により心臓のMIBG集積が低下し，これは他のパーキンソニズム，Parkin関連パーキンソン病，アルツハイマー病との鑑別の一助になる．心臓交感神経の変性をとらえうるMIBG集積低下とレヴィ小体の存在は非常に密接に関連していることより，MIBG集積の明らかな低下は，レヴィ小体存在のバイオマーカーであると考えられる．さらにαシヌクレイン凝集物は心臓交感神経変性に先立って沈着しており，αシヌクレイン凝集物と心臓交感神経の変性が密接に関連しているものと思われる．

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The year of 2007 was a turning point of the treatment of Parkinson's disease (PD) in Japan. Severe adverse effects of dopamine agonists including valvular heart disease induced by ergots and sudden onset of sleep attacks induced by non-ergots, were disclosed, and treatments with agonists were reassessed. Good news were marketing of ropinirole, a new non-ergot agonist, in December 2006 and entacapone, the first catechol-O-methyl transferase (COMT) inhibitor in Japan in April 2007. Having faced these new situations, Japanese Neurological Association has started revising "the Guideline 2002 for the treatment of Parkinson's disease".
Clinical trials of translational gene therapy for Parkinson's disease with adeno-associated virus (AAV) vector are now going on in four approaches; restoring dopamine synthetic capacity, protecting against cell death with trophic factors, interfering with the aberrant protein aggregation, and converting the subthalamic nucleus into an inhibitory, rather than an excitatory, structure. In Japan, gene delivery of the dopamine synthesizing enzyme aromatic amino acid decarboxylase (AADC) to the striatum of PD patients is going on in Jichi Medical University. New findings of the causative genes, environmental factors and molecular mechanism of PD have provided with new tools for developing new treatments. The big success of induction of induced pluripotent stem (iPS) cells from fibroblast has given an impact on cell therapy research of PD.

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Diagnosis of dystonia is not difficult by recognizing the pattern of clinical presentation. Dopa-responsive dystonia (DRD) and Wilson disease are important in differential diagnosis because of their specific treatment. The most common are the focal dystonias, including blepharospasm and spasmodic torticollis. Dystonia comprises mobile involuntary movements and abnormal postures, the latter is better described as hypokinetic disorder. The pathogenesis of dystonia is now being clarified, and includes abnormal neuroplasticity caused by the relative excess of dopamine in the matrix compartment of the striatum, the possible primary lesion being the striosome. In a dopa-responsive dystonia model, dopaminergic projection is more deficient to the striosome than to the matrix, which could produce imbalance between the direct versus. indirect pathway activities. The treatment options include trihexyphenidyl, minor tranquilizers, botulinum toxin injection, and deep brain stimulation.

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Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system (CNS). Fortunately, progress has been made for patients with this devastating disorder thanks to the induction of novel treatment strategies. In the 1990s, autoimmunity against myelin-related proteins was verified in humans, while the molecular mechanisms of the pathological process resulting in CNS demyelination were also studied in depth using experimental autoimmune encephalomyelitis (EAE). In the present decade, those achievements led to clinical trials of a variety of monoclonal antibody reagents for preventing disease relapse. Although such treatment seems to be ideal, as it targets a specific harmful immune reaction on the basis of findings from EAE studies, it has yet to become a first-line strategy, because of, in part, unexpected serious adverse reactions. As a result, interferon-beta therapy, the efficacy of which was first reported in 1993, has maintained a good position among treatment options for suppressing disease activity. Interferon-beta is considered to exert its anti-inflammatory effect via a Th2 shift in immune responses. In addition to aberrant cellular immunity, recent progress in MS research has shed light on the involvement of disturbances in humoral immunity, including the presence of NMO-IgG and anti-aquaporin-4 antibodies. Thus, it is important to elucidate the pathological significance of those autoantibodies, as well as establish treatment strategies for patients who are positive for them. However, since the above-mentioned treatments have been developed only for patients with relapsing-remitting MS, it is also important to consider the pathogenesis of primary progressive MS, which constitutes 10-15% of the patient population. Neurologists cannot be indifferent to current studies on MS, as even viral etiologies long ago abandoned have been recently revisited. In this field of neurology, every step of progress may readily lead to the establishment of a new treatment options.

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In terms of practical view, the type of aphasia can be classified by four elementary symptoms: anarthria (apraxia of speech), phonemic paraphasia, word comprehension impairment, word finding difficulty. Each elementary symptom has been established by causative lesion: anarthria for lowed posterior part of the left precentral gyrus, phonemic paraphasia for the left marginal gyrus and underlying white matter, word comprehension impairment for the left middle frontal gyrus or the posterior part of superior and middle temporal gyrus (the area called Wernickle's area), word finding difficulty for the left inferior frontal gyrus or the left angular gyrus or the left posterior part of the inferior temporal gyrus. In addition to ordinary estimation of language some devised examination enables distinction of the symptoms due to frontal lesion and the symptom due to the posterior lesion. This methods taking advantage of the symptoms related apahasia is also useful for making diagnosis and knowing prognosis of progressive aphasia.

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Migraine is an episodic and popular headache disorder. Migraine arises from a primary cerebral dysfunction that leads to activation of trigeminovascualr system. In the 1940s cerebral arterial constriction and the following enhanced dilatation was considered to induce migraine attack. Next, the cortical neuronal change that is well linked to the migraine aura was considered to be primary mechanism of migraine attack. Recently, the trigeminovascular system has a main role in the pathophysiological mechanism of the migraine. From the animal studies, cortical spreading depression (CSD) may induce the activation of the trigeminovascular system and may be a trigger of the migraine pathological mechanism. Also the activation or the functional change of brainstem nuclei, involving periaqueductal grey matter, raphe nuclei, and locus ceruleus, may be a trigger of the migraine attack. We have showed that the level of plasma orexin-A in the migraine patients during headache free period is lower than that of control. From the animal experiments, we also showed that intracerebroventricular injection of orexin induces the increase in the cerebral cortical blood flow, and that the intraarterial application of orexin cannot increase the cerebral blood flow. We consider that orexinegic neurons in the lateral hypothalamus may be a generator of migraine.

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There have been identified 1051 cases of prion dsease in Japan since 1999 by the surveillance committee, of which idiopathic prion disease held 77.8%, hereditary 15.9% and infectious 6.6%. Idiopathic prion disease is sporadic Creutzfeldt-Jakob disease (sCJD) and most sCJD cases were classified into MM1 presenting with classical clinical features. MM2, MV2, VV1 and VV2 sCJD cases were rare and showed atypical features including prolonged course, lack of myoclonus and absence of PSD. In such occasions, high signal intensities on DW-MRI as well as increased 14-3-3 and tau proteins in CSF were very helpful. MM2 tharamic sCJD may lack all these laboratory findings but reduction of tharamic CBF in SPECT or PET would support the diagnosis. Hereditary prion disease are classified into 3 major phenotypes such as familial CJD, Gerstmann-Straeussler-Scheinker disease (GSS) mainly showing spinocerebellar ataxia, and fatal familial insomunia. While there have been known many mutations of prion protein gene, only V180I (fCJD), E200K (fCJD), M232R (fCJD) and P102L (GSS) mutations were common. Because most cases did not have family history, genetic test is mandatory in all the cases of prion disease including seemingly "sporadic" CJD. All the cases but 1 case of variant CJD were dura-grafted CJD in infectious prion disease.

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脳梗塞治療の基本は，各々の患者の脳動脈の閉塞起序と病態を把握し，病態にあった治療をおこなうことである．患者の到着後直ちに現病歴を聴取しながら，バイタルサイン，一般身体所見と神経学的所見を取り，頭部CT・MRIおよび神経超音波検査をおこなう．脳血管病変の評価は必須であり，頭部MRA，経頭蓋ドプラ検査，CT angiographyもしくは脳血管造影検査などを施行する．塞栓源不明な脳梗塞のばあいは，塞栓源の検索のために経食道心エコー検査や経胸壁心エコー検査をおこなう．発症3時間以内であれば，t-PA静注療法をおこなうことを前提とした診療を始める．急性期から多職種によるチームが，脳卒中患者専用の病棟で組織的に計画性を持って治療をおこなうことにより，死亡率の減少，在院期間の短縮，自宅退院率の増加，長期的なADLとQOLの改善を図ることができる．このように脳卒中急性期診療は大きく変貌している．

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Limbic encephalitis refers to an inflammatory process involving the hippocampi, amygdala and less frequently frontobasal and insular regions. This disorder used to be considered extremely rare, invariably associated with cancer, and unresponsive to treatment. However, recent studies suggest that limbic encephalitis is more frequent than it was previously thought, and a substantial number of patients may recover. This is due in part to the development of clinical diagnostic criteria and identification of antibodies directed against two broad categories of antigens: 1) intracellular or classical paraneoplastic antigens, including Hu, Ma2, and CV2/CRMP5, among others, and 2) cell surface antigens including, voltage-gated potassium channels (VGKC), N-methyl-D-aspartate receptor (NMDAR), and others expressed in the neuropil of the hippocampus. While the disorders related to the first category of antibodies associate with cancer (lung, testis and other), prominent brain infiltrates of T-cells, and limited response to treatment, the disorders related to the second category of antibodies associate with other tumors (thymoma, teratoma, Hodgkin's lymphoma), appear to be antibody-mediated, and respond better to immunotherapy. Of particular interest in the later group is the disorder that associates with antibodies to extracellular epitopes of NR1/NR2 heteromers of the NMDA receptor. Patients with this syndrome may present as limbic encephalitis but more frequently manifest severe psychiatric symptoms, seizures, dyskinesias, autonomic instability or hypoventilation. In all, the study of these disorders provides a link between immunologic processes and neuronal events involved in memory, cognition, seizures, and neuronal degeneration.

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Recently, many medical professionals become to realize eating problem affect deeply patient's quality of life (QOL), and they are very interested in dysphagia rehabilitation. I overviewed dysphagia rehabilitation along with the followings; 1) impact of dysphagia, 2) assessment of dysphagia, and 3) management of dysphagia.
Eating is the most enjoyable activity. Dysphagia changes this enjoyable activity to the most fearful one. Dysphagia makes three major problems: risk of aspiration pneumonia and suffocation, risk of dehydration and malnutrition, and depriving enjoyable activity. As a recent conceptualization of eating, the Process model is the most important, that reveals eating (chew-swallow) is very different from just chewing plus swallowing in physiologically.
In assessment, standardized functional tests such as the Repetitive saliva swallowing test, the Modified water swallowing test, and the Graded food test are used. The most important point in clinical assessment is identifying indication of direct therapy using food or starting period of oral feeding. Videofluorographic and videoendoscopic examinations are used as precise diagnostic and management-oriented assessment tools.
In management, exercise, posture adjustment, and modification of food promote eating possibility. Oral care is essential in dysphagic patients. Surgical intervention is effective method if a patient has severe dysphagia.

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痴呆性神経疾患の診断において，有効な診断マーカーを未だ持たない中で，神経画像はもっとも有力な補助診断法である．萎縮やグリオーシスなど病理学的・構造的変化をみるMRIは時にpathognomonicであり，機能的変化をみるPETやSPECTはより鋭敏に変化を捕捉することができる．アルツハイマー病（AD）の神経画像の特徴をレビューし，それを対照にしながら重要性の高い疾患の画像診断の要点をまとめる．

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With an expanding knowledge about the genetic bases of diseases, genetic testing has become popular in clinical practice. There is no doubt that genetic testing is a powerful diagnostic tool for neurodegenerative diseases, but patient's test results can have a psychosocial impact on both the patient and their relatives. Test results may reveal a genetic risk to family members, and prompt them to have predictive or prenatal genetic testing. Thus, genetic counseling should be carefully conducted along with genetic testing, even for symptomatic individuals. During pre-test counseling sessions, we should clarify the clinical benefits and disadvantages of testing and whom the test results are disclosed to. Post-test follow-up will be needed to help the patient and their relatives cope with the test results. To provide effective psychosocial support, neurologists need to cooperate with clinical psychologists and genetic counselors. Furthermore, neurologists involved in genetic testing are required to have much more information on disease frequency, natural course, and therapeutic options for neurodegenerative diseases in order to enhance the clinical benefits of genetic testing. The guideline for the genetic testing for neurological diseases will shortly be recommended by the Japanese Society of Neurology to its members.

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Japan Alteplase Clinical Trial (J-ACT), a prospective multicenter clinical trial, demonstrated good clinical outcome in patients treated with 0.6mg/kg of alteplase, being similar to that with 0.9mg/kg of alteplase in the National Institute of Neurological Disorders and Stroke (NINDS) study. On that basis, intravenous aplteplase therapy was approved in Japan in October, 2005. This therapy resulted in better efficacy and similar safety in our stroke care unit (SCU) as compared to J-ACT or other clinical studies performed outside Japan. Our nation-wide survey demonstrated that the approval of the therapy resulted in dramatic changes in the processes of management for acute stroke patients. Preliminary results of the post-marketing surveillance study of alteplase in Japan suggested similar efficacy and safety profiles of the therapy to those reported by a European study, Safe Implementation of Thrombolysis in Stroke-Monitoring Study (SITS-MOST).
There are several limitations and problems in the therapy that will be overcome by new therapeutic strategies including the development of new-generation therombolytic agents having longer therapeutic time window, applications of magnetic resonance imaging techniques, and combination therapies with neuroprotective agents, sonothrombolysis, intraarterial application of the agent, or mechanical thrombectomy.

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The underlying pathogenesis of stroke is mediated by a variety of environmental risk factors as well as genetic ones. Thus, we have to evaluate the environmental factors precisely to identify the stroke-related gene polymorphisms. The Hisayama study, an epidemiological study of cardiovascular diseases, was established in 1961 in Hisayama, Japan. In 2002, a screening survey for the genetic study was performed in Hisayama. The Fukuoka Stroke Registry (FSR) is a hospital-based registration of stroke patients. Stroke specialists from eight medical centers in southern Japan have participated in FSR. In the present study, control and case subjects were recruited from the Hisayama study and FSR, respectively.
We performed a genome-wide case-control study and found that a nonsynonymous SNP in PRKCH encoding a member of protein kinase C (PKCη) was significantly associated with brain infarction. As a candidate gene analysis, we investigated the role of NAD (P) H oxidase C242T polymorphism in the development of brain infarction. The C242T polymorphism was not associated with lacunar and atherothrombotic infarction; however, the presence of T-allele may have a protective role in the occurrence of atrial fibrillation and cardioembolic brain infarction. These studies may provide important information for the development of the therapeutic strategies against stroke.

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A free radical scavenger Edaravone is the first clinical drug for neuroprotection in the world which has been used from 2001 in most ischemic stroke patients in Japan, and is especially useful in thrombolytic therapy with tissue plasminogen activator (tPA). Of great importance for regenerative therapy and gene therapy are the neural stem cells which are intrinsically activated or exogenously transplanted. Addition of NTFs greatly enhanced an intrinsic migration or invasion of stem cells into the scaffold, which could provide a future regenerative potential against ischemic brain damage at chronic stage.

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Stroke patients receive acute care and a variable period of rehabilitation in community hospitals. Some patients also receive long-term care in nursing homes. Quality assessment of each hospital and nursing home does not necessarily reflect quality of total stroke care providing in the community. Clinical indicators representing total stroke care are needed for the continuous improvement of stroke care. In several countries, measurement of quality of stroke care had recently been started. Since 1998, National Sentinel Stroke Audit had been performed every two years using simple 12 clinical indicators in England. In 2000, a nation-wide audit system named "Nationale Indikator Projekt Apopleksi" was developed in Denmark. In 2006, the quality indicator board of the German Stroke Registers Group published indicators for measuring quality of acute stroke care. In 2007, the first issue of the National Sentinel Stoke Audit was published in Australia.
Clinical indicators must be meaningful, valid, and evidence-based. Inter-rater reliability, internal consistency, and test-retest reliability should be tested to serve as a useful marker of healthcare quality in the community. It is urgently need to develop adequate indicators for measuring quality of stroke care in Japan.

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Although the pathogenetic mechanisms underlying neurodegenerative diseases have been long elusive, recent progress in molecular neurogenetics and neurobiology has suggested that accumulation of misfolded protein leads to dysfunction and degeneration of neurons. Misfolded proteins have propensities to form fibrils termed amyloid fibrils. In the process of amyloid fibrils, intermediate forms such as oligomers and protofibrils are produced and thought to have cytotoxic effects to neurons. Neurotoxicity mediated by misfolded proteins are also caused by stress response such as unfolded protein response. Moreover, recent findings indicate that non-neuronal cells surrounding neurons or extracellular misfolded proteins promote neurodegeneration. To eliminate toxic proteins would constitute promising future therapy for neurodegenerative disorders.

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遺伝学・生化学的解析から，アミロイドβ蛋白（Aβ）産生および蓄積過程がアルツハイマー病発症機序に深く関与していることが示唆されており，脳内におけるAβの存在量および蓄積過程の制御は，発症機序に基づいたdisease-modifying therapyとなることが期待されている．γ-セクレターゼはAβ産生経路においてC末端側の切断に関与し，Aβの凝集性を決定することから，重要な創薬標的分子と考えられてきた．近年になり，γ-セクレターゼの分子的な実態が明らかとなり，その酵素学的な解析と相まって，特異的な阻害剤がAD治療薬として開発され始めている．したがってγ-セクレターゼの構造活性相関の理解は特異的な活性を持つ化合物のラショナルデザインにつながる可能性があると考えられる．

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Filamentous tau inclusions are hallmarks of Alzheimer's disease (AD) and related tauopathies, and the discovery of mutations in the tau gene in frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) constitutes convincing evidence that tau proteins play a key role in the pathogenesis of neurodegenerative disorders. To investigate the pathomechanism of tauopathies, we generated and studied P301S mutant human tau transgenic mice (line PS19). Filamentous tau lesions developed in PS19 mice at 6-months of age, and progressively accumulated in association with striking neuron loss as well as hippocampal and entorhinal cortical atrophy by 9-12 months of age. Remarkably, hippocampal synapse loss and impaired synaptic function were detected in 3 month old PS19 mice before fibrillary tau tangles emerged. Prominent microglial activation and proinflammatory cytokine expressions in neurons also preceded tangle formation. Importantly, immunosuppression of young PS19 mice with FK506 attenuated tau pathology, thereby linking neuroinflammation to early progression of tauopathies. Recently, an anti-inflammatory function of acetylcholine (ACh) has been reported, suggesting that synaptic dysfunction might accelerate neuroinflammatory reaction by depletion of ACH. To investigate this, we administered donepezil (DZ), an ACh-esterase inhibitor, and trihexiphenidyl (TP), an anti-cholinergic agent to PS19 mice. Interestingly, DZ ameliorated but TP deteriorated microglial activation, tau pathology and neuronal loss, indicating the ACh level in the brain might play roles in not only neurotransmission, but also suppressing neuroinflammation in the brain.

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The pathomechanism of neurodegenerative disorders are not fully elucidated yet. In Huntington Disease (HD) and some hereditary spinocerebellar ataxias, expanded polyglutamine (polyQ) accumulates and forms aggregates in neuronal nuclei. We have been studying the pathological process by which the mutation induces the misfolding and accumulation of the gene product leading to neuronal degeneration using cell biological and structural biological approaches. We analyzed the pathological process in polyQ disease cellular model and the structural changes of polyQ-induced protein misfolding using our polyQ-bearing myoglobin model system. Using these models, we found that expanded polyQ forms a beta-sheet structure and causes proteasome inhibition. We further analyzed the structural basis of toxic aggregates, which suggested the polyglutamine exposed form may be more toxic to sequester several important functional molecules. We also established the method for analyzing aggregate interacting proteins (AIPs) and reported several AIPs including transcription factor NF-Y.
Based on the pathomechanism, which we revealed, we developed several experimental therapies, including stabilizing abnormal protein, activating proteasomal function and enhancing the selective degradation of abnormal protein through chaperone-mediated autophagy.

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The relationships between AJFNHE (Kamei S: 2004) and anti-N-methyl-d-aspartate receptor (NMDAR) encephalitis (Dalmau J et al: 2007) is discussed. The comparative clinical features in both reports revealed that most were young adult women, a prodrome was presented in 80%, the first neurological symptom was psychosis, the main symptoms included convulsions, consciousness disturbance, and involuntary movements, and mechanical ventilation was required in 80%. Dalmau reported that ovarian teratoma was demonstrated in 11 out of 12 patients, and mediastinal teratoma in 1 patient. We had yet to examine these conditions at the time of publication. AJFNHE and anti-NMDAR encephalitis are thus considered to be the same condition. AJFNHE represents a clinical concept based on the specific clinical features, and anti-NMDAR encephalitis represents a clinical entity based on the neuro-oncological findings. A nationwide survey of AJFNHE was undertaken in Japan. Collected patients predominantly were young adult women. Their clinical features were uniform and also in concordance with those previously reported as AJFNHE. This survey revealed that the annual incidence was 0.33/10⁶ population, respiratory failure was observed in 70% and required care with mechanical ventilation, associated tumors were demonstrated in 40% and ovarian teratoma was the most frequent.

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Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is a new category of treatment-responsive encephalitis associated with "anti-NMDAR antibodies," which bind to extracellular conformal epitope in the NR1/NR2 heteromers of the NMDAR. The antibodies are usually detected in CSF/serum of young women with ovarian teratoma, who typically developed schizophrenia-like psychiatric symptoms, usually preceded by viral infection-like illness. Most cases developed seizures, followed by unresponsive/catatonic state, decreased level of consciousness, central hypoventilation, orofacial-limb dyskinesias, and autonomic symptoms. Brain MRI is often unremarkable. CSF reveals nonspecific changes. EEG shows diffuse delta slowing.
The pathogenesis remains unknown, however this disorder is considered as an antibodies-mediated encephalitis. The prodromal"viral-like"disorder by itself or in combination with a teratoma sets off the autoimmune response. The antibodies bind to the common autoantigens expressed on the cell membrane of the neurons in the forebrain/hippocampus. Based on the current NMDAR hypofunction hypothesis of schizophrenia, we speculate that the antibodies may cause inhibition of NMDAR, rather than stimulation, in presynaptic GABAergic interneurons, causing a reduction of release of GABA. This results in disinhibition of postsynaptic glutamatergic transmission, excessive release of glutamate in the prefrontal/subcortical structures, and glutamate and dopamine dysregulation that might contribute to development of schizophrenia-like psychosis and bizarre dyskinesias.

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Anti-NMDAR encephalopathy is included in paraneoplastic limbic encephalopathy and show the good response to treatment compared to other paraneoplastic syndromes. Treatment of anti-NMDAR encephalopathy includes immunotherapy and/or tumor removal. About 65% of patients with anti-NMDAR encephalopathy had fully or near-full recovery. Immunotherapy is principally necessary and effective in patients with and without tumor. Corticosteroids and intravenous immunoglobulin are most frequently used. It is likely that patients who do not respond to one form of immunotherapy might respond to others regimens including plasmapheresis, cyclophosphamide, and rituximab. A tumor was found in 58% of patients with anti-NMDAR encephalopathy. Early removal of tumor should be considered based on following reasons. First, patients with ovarian teratoma showed higher mortality and higher titer of anti-NMDAR antibody compared with those without. Second, relapsing neurological symptoms occurred in 13% of patients, usually related to a delay in tumor diagnosis. Third, when a tumor was found and removed, recovery was faster and predictable. However, early removal of tumor cannot be conducted because of unstable conditions such as hypoventilation and dyskinesias. In supportive cares, severe central hypoventilation requires mechanical ventilation. The involuntary movements and facial dyskinesias are refractory to anti-epileptic drugs. In conclusion, search for and removal of an ovarian teratoma should be promptly considered after the diagnosis of anti-NMDAR encephalopathy.

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非傍腫瘍性非ヘルペス性急性辺縁系脳炎・脳症（NPNHALE）（成人69例+小児26例）と，卵巣奇形腫を合併する脳炎・脳症症例（NHAE-OT）（19例）を比較検討した．NHAE-OTの臨床特徴は，発病年齢，先行因子から脳炎発病までの日数，初発神経症状，急性期神経症状，髄液所見などの点で，成人のNPNHALEときわめてよく似ていることがわかり，卵巣奇形腫に合併する脳炎・脳症は，急性辺縁系脳炎の特徴を示すことがわかった．抗GluRε2抗体についても，共通性がみられ，両群とも高率に，NMDA型GluRのうちのGluRε2（NR2B）の細胞外ドメイン（N末）をエピトープとする自己抗体を有していた．

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多発性硬化症（Multiple sclerosis, MS）は，中枢神経髄鞘抗原を標的とする臓器特異的な自己免疫疾患とされる．病態の進行は，神経抗原に対する自己免疫としてのantigen-driven diseaseという面と，抗原に無関係に進行するprocess-driven diseaseとしての面がある．MSの病態研究はTh17細胞の発見と抗aquaporin-4（AQP4）抗体の発見により，分子レベルでの解明が急速に進みつつある．Mayo Clinicおよび東北大学からは，NMOはNMO-IgG/抗AQP4抗体がアストロサイトを障害し二次的に脱髄をおこしており，MSとはまったくことなるものであるという仮説が出されている．もう一つの考え方は，Th17細胞（あるいはTh1細胞）が寄与するT細胞性炎症により選択的で壊死性の病巣が形成され，抗AQP4抗体は病態を修飾しているのではないかというものである．今後，T細胞性免疫の立場と液性免疫の立場の両者から病態解明が進んでいくことが期待される．

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Immunomodulatory drugs such as interferon beta (IFN-β) have modestly effective in relapsing remitting multiple sclerosis (RRMS). However, all current therapies are partially effective. The cause of MS and the determinants of heterogeneity in the clinical phenotype of MS remain largely unknown and new therapeutic approaches in MS are emerging. Even now, "bench to bed" is the only approach to find new therapies. However, we need to take part in exploring new therapies with the approach of "bench to bed and back". In the near future, studies on susceptibility genes and pharmacogenetics will provide invaluable information concerning new drugs for the treatment of MS and better therapeutic regimens for MS patients.

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The pathogenesis of multiple sclerosis (MS) remains to be elucidated and there is no curative therapy against MS, though we have several disease modifying drugs. In this symposium, I introduce several new strategies against development of autoimmune processes and axonal degeneration in MS. Several mechanisms regulate immune system not to attack self components. One of the most potent regulatory cells is CD4+CD25+FoxP+regulatory T cells (Treg), which suppress development of both T helper 1 and 2. Thus, to increase the number and function of Treg is an approach to suppress autoimmune diseases. We have found recently that midkine suppresses the development of Treg, and that suppression of midkine by RNA aptamer alleviates symptoms of experimental autoimmune encephalomyetitis, an animal model of MS, by expanding Treg. Another important strategy against MS is to suppress axonal degeneration which reportedly occurs from an early stage of MS. We have found that the most toxic agent from activated macrophages and microglia is glutamate that was produced by glutaminase and released through gap-junction. Thus, inhibitor for glutaminase and gap-junction may be other candidates to treat MS. Interferon-β also effectively suppress glutamate production by these cells and subsequently suppress development of axonal degeneration.

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In human body, there are thirteen water channels but their expression patterns are tissue specific. Aquaporin-4 (AQP4) is a predominantly expressed water channel in the mammalian brain and an important drug target for treatment of cerebral edema, bipolar disorder, and mesial temporal lobe epilepsy. Recently it was reported that IgG of optic-spinal multiple sclerosis patients bound to AQP4. In order to reveal the function of AQP4, we determined the atomic structure of AQP4 by electron crystallography of double layered two-dimensional crystals. In double layered crystal, each single layered crystal contacts by a short 3₁₀ helix in the extracellular loop C. It would suggest that AQP4 shows the weak adhesive activity between adjoining membranes. This is correlated to immunogold labeling of AQP4 in glial lamellae localizing the protein areas where the membranes are separated but also all along junctional regions. Furthermore, from the freeze fracture replica labeling and the mutational experiment, the palmitoylation of N-terminal cysteine residues makes orthogonal array structure unstable on Chinese hamster Ovary (CHO) cell membrane. These findings suggest that there must be the complicated mechanism for control of water content relevant to AQP4 within the brain.

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Diffusion tensor imaging of magnetic resonance imaging, including diffusion tensor tractography, is a unique tool to visualize and segment the white matter pathways in vivo and one can evaluate the segmented trace quantitatively. Three dimensional visualization of the white matter fibers, such as corticospinal (pyramidal) tracts, with relationship to brain lesions (infarcts, vascular malformations and brain tumors) is extremely helpful for stereotactic radiosurgery, preoperative evaluation and intraoperative navigation. Quantitative measurement of the tract is a very sensitive method to detect differences in the tract in neurodegenerative/neurocognitive/psychiatric patients such as amyotrophic lateral sclerosis, schizophrenia and Alzheimer diseases. Importance of this tool will become more significant in clinical and neuroscience fields in the future.

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White matter lesions are frequently observed in the elderly, and have been postulated to be responsible for dementia and parkinsonism. At first, we revealed that cholinergic pathways are damaged in the external capsule due to white matter lesions in Binswanger's disease. In addition, a flumazenil (FMZ)-PET study, a marker of benzodiazepine/GABA_A receptors, revealed that FMZ-binding was decreased in the prefrontal cortex and the insular cortex in demented patients with extensive white matter lesions. In contrast, FMZ-binding was decreased in the premotor cortex and the striatum in the patients with extensive white matter lesions and parkinsonism, as compared to those with white matter lesions but without parkinsonism. These results indicate that subcortical nerve fiber damages may impair neural networks and hence, the neural function in the corresponding gray matter.

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