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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The Japanese Society of Neurology (JSN), founded in 1960, gained the momentum after the 12th World Congress of Neurology (WCN) held in Kyoto (1981) and currently enjoys an indisputable reputation as a major contributor to neuroscience. Despite this achievement, we often find it difficult to debate with an English-speaking opponent. Our traditional teaching emphasizes silence rather than eloquence as the virtue with the dictum not to dwell upon your knowledge base (learn 10, speak 1). This practice would make it difficult for us to compete against those trained to elaborate even on limited information (learn 1, speak 10). To counter our timidity, we must develop self-confidence, learn to express our views fully and abandon the impractical spirit of perfection in favor of candor. From my vantage point working with the World Federation of Neurology (WFN), science talks "broken" English at an international conference such as WCN. Thus, it suffices that we speak clearly, if not fluently, to effectively participate in global affairs. Last but not least, we must seek the sovereignty of neurology world wide as advocated by WFN. I hope members of the JSN will have a continued success in their pursuit of international recognition, which they so justifiably deserve.

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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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Spinocerebellar ataxia type 10 (SCA10) is a dominantly inherited neurodegenerative disease caused by expansion of the ATTCT pentanucleotide repeat in intron 9 of a novel gene, ATXN10, on chromosome 22q13.3. It is clinically characterized by progressive ataxia, seizures, and anticipation, which can vary within and between families. The length of the expanded ATTCT repeats is highly unstable on paternal transmission and shows a variable degree of somatic and germline instabilty, revealing complex SCA10 genetic mechanisms. How this untranslated ATTCT expansion leads to neurodegeneration has been still controversial. Growing number of evidence indicates a gain-of-function RNA mechanism, similar to the myotonic dystrophies caused by non-coding CTG or CCTG repeat expansions.

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In 1965 I became a member of the newly-established department of neurology in Brain Research Institute of Niigata University. One of the most important theme for clinical neurologist was to offer medical care after discharge from hospital for serious or intractable neurological disease patients who would soon become unable to come to outpatient clinic. In 1978 Shinrakuen hospital in Niigata City launched the Continuing Medical Care Section providing home visit by doctors and periodical home nursing for medically dependent homecare patients. The stuff of that section started home care program for TPPV patient suffering from ALS from 1987. In 1990, they promoted with the members of Japan ALS Association the establishment the public rental system of Niigata prefecture of ventilator and the accessory medical instruments. They also collaborated with the stuff of the city office to establish the liaison conference for care of the intractable disease patients in Niigata City, which resulted in improvement of education and produced many useful system. The author opened in 1997 an organized clinic of internal and neurological medicine and on the basis of long term care insurance program in 2000 put into practice the home care system of cooperation between municipal administration, medicine and nursing.

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Cardiac uptake of meta-iodobenzylguanidine (MIBG) is specifically reduced in Lewy body disease (LBD). To see pathological basis of the reduced cardiac uptake of MIBG in LBD, we immunohistichemically examined cardiac tissues from patients with LBD, related movement disorders and Alzheimer's disease (AD). In LBD, cardiac sympathetic denervation occurs, which accounts for the reduced cardiac uptake of MIBG. Patients with LBD have Lewy bodies (LBs) in the nervous system, whereas patients with the other neurodegenerative parkinsonism, parkin-associated Parkinson's disease (PD) and AD and have no LBs. Therefore, cardiac sympathetic denervation is closely related to the presence of LBs in a wide range of neurodegenerative processes. We further investigate how α-synuclein aggregates are involved in degeneration of the cardiac sympathetic nerve in PD. Accumulation of α-synuclein aggregates in the distal axons of the cardiac sympathetic nervous system precedes that of neuronal somata or neurites in the paravertebral sympathetic ganglia and that it heralds centripetal degeneration of the cardiac sympathetic nerve in PD. This chronological and dynamic relationship between α-synuclein aggregates and degeneration of the cardiac sympathetic nervous system may represent the pathological mechanism underlying a common degenerative process in PD.

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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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The management for acute stroke has been changed greatly in Japan. Because use of intravenous administration of tissue plasminogen activator (IV-t-PA) for acute brain infarction within 3 hours of onset has been approved by Japanese government from October, 2005. Now, if acute stroke patient arrivals at hospital within 3 hours of onset, we consider that such patients should be treated with t-PA therapy. The accurate diagnosis should be made by systematic evaluation using CT/MRI, neurosonology including transcranial Doppler, carotid echography, and echocardiography (TEE and TTE), SPECT, and angiography. In particular, it is important to assess the arteries from heart and brain. The grad A for treatment of acute stroke is recommended as IV-t-PA therapy, aspirin administration within 48 hours of stroke onset, and the management in stroke unit. In particular, stroke unit can improve functional outcome and to reduce the length of hospital stay. The evidence directing therapy for acute stroke is changing rapidly.

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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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[in Japanese]

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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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Genetic and biological studies provide evidence that the production and deposition of amyloid-β peptides (Aβ) contribute to the etiology of Alzheimer's disease. Thus, β- and γ-secretases, that are involved in the Aβ generation, are plausible molecular targets for Alzheimer's disease treatment. γ-Secretase is an unusual aspartic protease that cleaves the scissile bond within the transmembrane domain. This unusual enzyme is composed of a high molecular weight membrane protein complex containing presenilin, nicastrin, Aph-1 and Pen-2. Drugs that regulate the production of Aβ by inhibiting or modulating γ-secretase activity could provide a disease-modifying effect on AD, although recent studies suggest that γ-secretase plays important roles in cellular signaling including Notch pathway. Thus, understanding the molecular mechanism whereby γ-secretase recognizes and cleaves its substrate is a critical issue for the development of compounds that specifically regulate Aβ-generating γ-secretase activity. I will review our structural studies on the γ-secretase complex, and envision the direction for developing effective and selective γ-secretase inhibitors as therapeutics for AD.

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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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We compared clinical characteristics and autoantibodies against GluRε2 between 95 patients with non-paraneoplastic non-herpetic acute limbic encephalitis (NPNHALE) and 19 patients with non-herpetic acute encephalitis accompanying ovarian teratoma (NHAE-OT).
Onset age (mean±SD) was 27.7±18.6 years old in NPNHALE, 27.5±6.5 in NHALE-OT. Preceding factors were found in 63.8% of patients with NPNHALE and 89.5% of patients with NHALE-OT (Fisher's exact test, p=0.025), and major preceding factors were upper respiratory infections or fever in both groups. Symptoms at the onset were disorder of behavior and talk > seizures > impairment of consciousness in NPNHALE, and disorder of behavior and talk > seizures > disorientation in NHALE-OT. Symptoms at the acute stage were similar between NPNHALE and NHAE-OT, but duration of hospital stay was longer in NHAE-OT (209.0 days) than NPNHALE (87.5 days)(Mann Whitney test, p<0.0001). At the onset, cell counts in CSF were 51.6±66.4/mm³ and protein levels were 35.4±14.7mg/dl, and IgG levels were 6.6±4.2mg/dl in NHAE-OT, and these data were not significantly different between NPNHALE and NHAE-OT.
In acute stage, autoantibodies against whole molecule of GluRε2 in CSF were detected in 51.8% (29/56) of adult NPNHALE, and 40% (6/15) of NHAE-OT patients by immunoblot. These autoantibodies in both groups included epitopes to n-terminal of GluRε2. Antibodies against NMDAR complex (Dalmau's method) in CSF were detected in 90.9% (10/11) of NHAE-OT patients.

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Multiple sclerosis (MS) is a chronic demyelinating disease of the central nervous system (CNS), whereas neuromyelitis optica (NMO) is an inflammatory disease of the CNS selectively affecting the optic nerves and the spinal cord. The pathological hallmark of MS is sharply demarcated demyelinating plaque with axons relatively preserved, while in NMO both axons and myelin are involved, resulting in necrotic cavitation. The nosological position of NMO has long been a matter of debate. MS has aspects of an antigen-driven disease as well as those of a process-driven disease that is unrelated to any specific autoantigens. Research into the mechanisms of MS is rapidly progressing because of the discovery of Th17 cells producing autoimmune diseases and of NMO-IgG targeting aquaporin-4 (AQP4) on the astrocyte foot process. One hypothesis is that NMO is caused by anti-AQP4 antibodies destroying astrocyte foot processes and that it is distinct from MS. Another is that MS/NMO is caused by myelin-specific Th17 cells (or Th1 cells) and that the emergence of CNS antigen-specific autoantibodies modifies the disease. Anti-myelin antibody produces widespread demyelination whereas anti-AQP4 antibody induces astrocyte foot process injury, resulting in profuse vasogenic edema and tissue necrosis. Future research on both T cells and humoral immunity is expected to disclose the pathophysiology of MS.

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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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