Although recent advancements in molecular biology have provided increasing insights into the pathophysiology of neurodegenerative diseases, there is almost no disease-modifying therapy for which the efficacy has been verified in clinical trials. Spinal and bulbar muscular atrophy (SBMA) is an adult-onset motor neuron disease caused by the expansion of a trinucleotide CAG repeat in the androgen receptor (AR) gene. SBMA exclusively affects males, whereas does not manifest in the females homozygous for the AR mutation. The ligand-dependent nuclear accumulation of pathogenic AR protein is central to the pathogenesis, although additional steps such as inter- and intra-molecular interaction are also required for toxicity. Leuprorelin, a luteinizing hormone-releasing hormone (LHRH) analogue that suppresses testosterone production from testis, inhibits toxic accumulation of pathogenic AR, thereby mitigating histopathological and behavioral impairments in a mouse model of SBMA. Although a randomized placebo-controlled multi-centric clinical trial showed no definite effect of the drug on motor functions, there was the improvement of swallowing function in a subgroup of patients whose disease duration was less than 10 years. These results indicate a need to elucidate the entire disease mechanism, clarify the natural history, initiate therapeutic intervention at an early stage, and develop sensitive outcome measures to evaluate drug effect.

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Mediation offers a process by which two parties work towards an agreement with the aid of a neutral third party. Physicians and nurses can apply healthcare mediation model to ordinary medical practice for preventing conflict. Communication using mediation skills improves patient-physician relationship, and prevents medical malpractice and conflict.

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Clinical research is guided by ethical principles promulgated in several statements, principally the Nuremberg Code, the Helsinki Declaration of the World Medical Association etc. In Japan, clinical research of medical products, principally trial of new pharmaceutical products is regulated by GCP (good clinical practice). Other types of clinical research are regulated by some ethical guidelines for clinical researches. The result is a regulatory position that is a complex combination of legislation and ethical guidelines. In the Ethical Guideline for Clinical Studies revised in 2008, clinical research is classified into intervention research and observational research. When researchers plan clinical research, they must determine the type of clinical research and appropriate ethical guideline for the type of clinical research.
Advances in health informatics and genetic research have produced a new and very rich body of raw material for clinical research in the form of gene banks and genome-wide association study etc. The use of human tissue and medical information in the course of clinical research raises issues under the ethical regulations for research with human subjects.

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Paraneoplastic neurological syndrome (PNS) is a rare disorder caused by the remote effects of cancer and is considered as immune-responses to the molecules on cancer which cross-react with self-antigens in the nervous system. Since the 1980s, several specific anti onconeural antibodies have been reported, which are useful diagnostic markers of PNS and occult cancer. Only a few onconeural antibodies have been identified as primary effectors of neurological damage. Recently sophisticated methods for the detection of new or low titer antibodies have been developed. Several new auto-antibodies against receptors or ion channels on the surface of neuronal membrane, such as NMDA receptors, AMPA receptors, GABA_B receptors and VGKC complexes, have been reported in the patients with encephalopathy including limbic encephalitis. These diseases can be associated with tumor, but they are more often non-paraneoplastic. These antibodies are generally good biomarkers for effective immunomodulatory treatment for immune-mediated encephalitis with not only consciousness disturbance but also dementia, seizures and psychiatric symptoms which sometimes mimic schizophrenia. Further studies are required to clarify the exact mechanisms underlying neuronal damage in immune-mediated neurological diseases including PNS, which may lead to the development of more rational therapies and greater understanding of immunology in the nervous system.

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Multiple system atrophy (MSA) is a sporadic neurodegenerative disorder that encompasses olivopontocerebellar atrophy (OPCA), striatonigral degeneration (SND) and Shy-Drager syndrome (SDS). The histopathological hallmarks are α-synuclein (AS) positive glial cytoplasmic inclusions (GCIs) in oligodendroglias. AS aggregation is also found in glial nuclear inclusions (GNIs), neuronal cytoplasmic inclusions (NCIs), neuronal nuclear inclusions (NNIs) and dystrophic neurties. Reviewing the pathological features of 102 MSA cases, OPCA-type was relatively more frequent and SND-type was less frequent in Japanese MSA cases, which suggested different phenotypic pattern of MSA might exist between races, compared to the relatively high frequency of SND-type in western countries. In early stage of MSA, NNIs, NCIs and diffuse homogenous stain of AS in neuronal nuclei and cytoplasm were observed in various vulnerable lesions including the pontine nuclei, putamen, substantia nigra, locus ceruleus, inferior olivary nucleus, intermediolateral column of thoracic cord, lower motor neurons and cortical pyramidal neurons, in additions to GCIs. These findings indicated that the primary nonfibrillar and fibrillar AS aggregation also occurred in neurons. Therefore both the direct involvement of neurons themselves and the oligodendroglia-myelin-axon mechanism may synergistically accelerate the degenerative process of MSA.

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FTLD is a neuroanatomical disease concept defined only by the presence of degeneration of the frontal and temporal lobes regardless of the underlying histopathological features, and therefore inevitably includes heterogeneous diseases that affect those cerebral regions. The ambiguous idea of Pick disease, the prototype of FTLD, constantly caused great nosological confusion as to FTLD. Progress in molecular neuropathology aimed at clarification of the protein constituents of the inclusion bodies seen in conditions causing FTLD, however, has resolved this problem by providing FTLD with a new concise nomenclature and classification based on the inclusion body proteins. The substances in inclusions in FTLD with ubiquitin-only inclusions (FTLD-U) have been discovered one after another; TDP-43 was the first, being found in inclusions in ALS and ALS with dementia (ALSD) too, and soon FUS/TLS was identified in some TDP-43-negative FTLD-U groups. Thus, FTLD has been divided into three main subgroups; 1) FTLD-tau, which includes Pick disease, PSP, CBD, etc., 2) FTLD-TDP, which is further divided to types A-D, ALSD belonging to type B, and 3) FTLD-FUS, which includes aFTLD-U, NIFID, and BIBD. Further deciphering of yet-unidentified proteins of some FTLD-U subsets will add more subclasses.

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Many researchers now recognize the importance of glycobiological research achievements. Glycoside-containing substances such as proteins (glycoproteins) and lipids (glycosphingolipids) have been involved in many important and essential events for normal life. The production of glycoside residues of the proteins is only partially regulated by the genes. In this talk, I will make a brief description of what glycobiology can influence the future of neurological research arena and how glycoproteins and glycolipids affect the normal biology of the neurons. Furthermore, I will introduce you some evidences that many neurological disorders such as Alzheimer's disease and immune-mediated encephalitis have special relationships with glycobiological abnormalities. I also explain the structures and functions of lipid rafts, caveolae, and glycosynapse and their roles in the intracellular signal transduction and cell motility.

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Gliomas account for approximately 40% of all brain tumors and are thus the most common primary tumors of the central nervous system (CNS). High-grade (WHO grades III and IV) malignant gliomas that include anaplastic astrocytoma (AA), anaplastic oligodendroglioma (AO), anaplastic oligoastrocytoma (AOA), and glioblastoma multiforme (GBM) are often resistant to treatment; especially, GBM, the most common glioma in adults, kills patients within a median time span of a year after diagnosis despite treatment with aggressive surgical resection, chemotherapy, and radiotherapy. In 2006, Temozolomide (TMZ) was certified as the treatment agent for malignant gliomas in Japan, and it is now used as the first-line therapy. However, its clinical outcomes depend on the O⁶-methylguanine-DNA methyltransferase (MGMT) status, and MGMT modification is one of the key factors to obtain greater clinical benefits. Previously, we demonstrated that Interferon-β (IFN-β) markedly enhanced chemosensitivity to TMZ in an in vitro study of human glioma cells; this finding suggested that one of the major mechanisms by which IFN-β enhances chemosensitivity is the downregulation of MGMT transcription via p53 induction. Previously, we tried clinical trial of gene therapy by means of IFN-β gene in order to evaluate the safety, feasibility, and preliminary clinical effectiveness, and reasonable results could be obtained. As a next step, we are conducting a clinical trial study, namely, genomic therapy using with siRNA-MGMT. We hope that these new regimen will be safe and well tolerated, and may prolong survival in patients with GBM.

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Behavioral and psychological symptoms of dementia (BPSD) is the term defined as symptoms of disturbed perception, thought content, mood or behavior that frequently occur in patients with dementia. As BPSD can cause remarkable distress for both the patient and the caregiver, clinicians are required to treat the symptoms effectively.
Before undertaking an intervention to BPSD, patients should be assessed in a detailed clinical interview to establish symptoms causing distress to the patient and/or caregiver. Initial intervention should focus on nonpharmacologic measures. However, pharmacologic intervention is necessary in many cases. There are many classes of medications to choose from for treating BPSD, but the evidence behind treatment is varied and confusing. Clinicians should discuss the potential risks and benefits of treatment with patients, and must ensure a balance between side effects and tolerability compared with clinical benefit and QOL.
To provide medical care to the patients with dementia represents the comprehensive management of them, including differential diagnosis, treatment of BPSD and education of caregivers. Almost all of the patients with dementia develop BPSD during the course of the disease. As long as dementia is a neurological disorder, both neurologists and psychiatrists should work cooperatively in the treatment of dementia.

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Diffusion tensor imaging and voxel based morphometry are efficient in the diagnosis of neurodegenerative disorders, however, these technologies are available at a limited number of facilities. Thus, conventional MRI remains important in the diagnosis of neurodegenerative disorders.
Dorsolateral putaminal hyperintensity (DPH) and hot cross bun sign discriminate Parkinson's disease from multiple system atrophy (MSA). However, differences in magnetic field strength and sequence affect the sensitivity of DPH, and mild DPH may be observed in normal elderly subjects.
Patients with progressive supranuclear palsy (PSP) presenting Richardson's syndrome show midbrain tegmentum atrophy, but Parkinsonian PSP (PSP-P) and pure akinesia with gait freezing, which are other phenotypes of PSP, may not show especially during early course of illness. In patients with corticobasal degeneration (CBD), asymmetrical cerebral atrophy corresponding with corticobasal syndrome (CBS) may be a characteristic finding. However, at autopsy, CBS patients presenting asymmetrical cerebral atrophy have CBD as the underlying pathology in approximately 50% of PSP patients.
The sensitivity and specificity of MRI for the diagnosis of MSA, PSP, and CBD is based generally on clinical diagnostic criteria. Diagnosis based on MRI has limitations, and, therefore, we should reconsider our diagnoses, particularly during the early course of illness.

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With the increasing knowledge of the molecular bases for neurological disorders, neurologists are now often required to administer genetic testing and to present the resulting information effectively in clinical practice. In the neurologic clinical setting, genetic testing of affected individuals is usually taken into consideration for a correct diagnosis, but is rarely undertaken in healthy individuals to determine genetic risks for their life planning. Genetic counseling is indispensable for genetic testing because test results may cause serious distress for patients and their family members (referred to as "clients" in the counseling session). Genetic counseling is the medical process of communication that helps clients understand the nature of the genetic disorder and the options open to them in management and family planning. Through the counseling process, clients are given both the medical information and psychosocial support necessary for their own decision-making. Thus, the aim of genetic counseling is to support the client's decision-making process regarding genetic testing, and to avoid unfavorable actions after disclosure of test results. In the broad sense, genetic counseling is a part of ordinary clinical practice for patients with hereditary neurological disorders because neurologic clinical practice includes education and psychosocial support for patients. But clients seeking predictive genetic testing, which includes complicated ethical and psychosocial issues, should be referred to more specialized genetic counseling clinics that take a multi-disciplinary approach. The counseling process is not a one-way transmission of medical information by neurologists, but consists of two-way communication between patients and neurologists. It is therefore crucial for neurologists to master communication skills, particularly those involving active listening and empathic understanding, in order to conduct effective genetic counseling in clinical practice.

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In medical research, remarkable increase in collaboration with industry, public organizations such as universities, research institutions, and academic societies makes researchers to be more deeply involved with the activities of commercial entities. Activities of education and research, which are the responsibilities of academic institutions and societies, conflict with the interests of individuals associated with industrial-academic collaboration. Management of such conflict of interest (COI) is of much importance for academic institutions and societies to appropriately promote industrial-academic collaborative activities. Particularly, participation not only by healthy individuals, but also patients, is essential in the medical field as subjects of clinical research. For those involved in medical research, the deeper the level of COI with commercial entities, who are the financial or benefit provider, becomes serious, the more human rights of subjects could be violated, safety of life could be endangered, and research methods, data analysis and interpretation of results could be distorted. It is also possible that research may be unfairly evaluated or not published, even if the results are accurate, sometimes resulting in the ascertained effects of reporting bias included the overestimation of efficacy and the underestimation of safety risks of interventions. According to the COI management guideline of the Japanese Association of Medical Science (JAMS), significance of COI management is discussed.

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The neuromuscular junction lacks the protection of the blood-nerve barrier and is vulnerable to antibody-mediated disorders. Myasthenia gravis (MG) is caused by the failure of neuromuscular transmission mediated by autoantibodies against acetylcholine receptors (AChR) and muscle-specific receptor tyrosine kinase (MuSK)/LDL-receptor related protein 4 which are AChR-associated transmembrane post-synaptic proteins involved in AChR aggregation. The seropositivity rates for AChR positive and MuSK positive MG in Japan are 80-85% and 5-10%/less than 1%,respectively. The incidence of late-onset MG, defined as onset after age 50 years, has been increasing worldwide. A nationwide epidemiological survey in Japan also revealed that the rates of late-onset MG had increased from 20% in 1987 to 42% in 2006. In 2010, a guideline for standard treatments of late-onset MG was published by the Japanese Society of Neurological Therapeutics. Lambert-Eaton myasthenic syndrome (LEMS) is an autoimmune disease of the neuromuscular junction and approximately 60% of LEMS patients have a tumor, mostly small cell lung cancer (SCLC), as a paraneoplastic neurological syndrome. The clinical pictures of Japanese LEMS patients are as follows; male dominant sex ratio (3 : 1), mean age 62 years (17-80 years), 61% of LEMS have SCLC, and the remaining are without cancer. In less than 10% of cases there are signs of cerebellar dysfunctions (paraneoplastic cerebellar degeneration with LEMS; PCD-LEMS) as well, often associated with SCLC. Most patients benefit from 3, 4-diaminopyridine plus pyridostigmine. In paraneoplastic LEMS, treatment of the tumor often results in neurological improvement. In non-paraneoplastic LEMS, prednisone alone or combined with immunosuppressants are treatment options. In both MG and LEMS, where weakness is severe, plasma exchange or intravenous immunoglobulin treatment may provide short-term benefit.

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It is well known that some migraine patients recognize the change of their migraine characteristics over time. These patients often complain chronic daily headaches instead of episodic attacks of migraine. Such chronic headaches are resistant to medication, and called refractory or intractable migraine. Refractory migraine is a term, which has been used for many years, but until recently, there has been little attention paid to its definition. The criteria used for diagnosis of refractory migraine have varied considerably. In most circumstances, however, the definition has included a poor response to "standard" preventive medications. This review article introduces the proposed criteria for definition of refractory migraine and the therapeutic strategies against refractory migraine.

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Alzheimer's disease (AD) is the major cause of dementia in the elderly people. In the molecular pathogenesis of AD, toxicity of secreted amyloid-β protein (Aβ), especially Aβ oligomers, is considered to play a pivotal role. While, we have long been focused on intraneuronal Aβ as a therapeutic target in AD. Intraneuronal Aβ accumulation is found in the early stage of AD neurons, and may be quite toxic and pathogenic. Recently, we have found apomorphine (APO), a kind of dopamine receptor agonists, to promote the intracellular Aβ degradation activating the Aβ-degrading enzymes, proteasome and insulin-degrading enzyme (IDE). We then found that APO treatment improved memory function and AD-related pathology in an AD mouse model, 3xTg-AD mice. Moreover, APO protected against oxidative stress in vitro and in vivo. We further investigated effects of APO on cellular anti-oxidative stress system, and found that APO activated glutathione peroxidase (GPx) specifically. Thus, APO may be a promising drug for the cure of AD and clinical trials are necessary in the future. In addition, further investigation to understand the molecular mechanism associated with the APO effect greatly contributes to the development of new drugs for AD.

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Microglia play a crucial role in the development of inflammatory demyelinating lesions in multiple sclerosis (MS). Microglia act on inflammatory lymphocytes as antigen presenting cells, and produce inflammatory cytokines, glutamate, and reactive oxygen species (ROS). Neurodegeneration, which is observed in the demyelinating lesions, affects the prognosis in MS. Neuritic beading, focal bead-like swellings of the dendrites and axons, is a neuropathological sign in the early phase of neurodegeneration in MS. Microglia-derived glutamate and ROS initiate beading formation.
Microglia can exert neuroprotective effect by deprivation of dead cells and induction of neurotrophic factors, anti-inflammatory cytokines, and anti-oxidant enzyme in MS.
Neurons are thought to be not merely passive targets of microglia but rather control microglial activity through various signals including cytokines and chemokines. Soluble fractalkine (sFKN), which is secreted from damaged neurons by glutamate, promotes microglial phagocytosis of neuronal debris, and induces the antioxidant enzyme heme oxygenase-1 in microglia. IL-34 secreted from neurons also induces microglial neuroprotection.
Astrocytes exert neuroprotective effect. However, toll-like receptor ligands induce neurotoxic molecules in astrocytes. IL-33 produced by astrocytes induces microglial activation. Thus, disruption of beneficial interaction between glia and neurons is crucial for the pathogenesis of MS.

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The immune and nervous systems have similar functional characteristics. Both have an intricate network of synaptic connections and an exquisite communication system that enable to maintain homeostasis. Although semaphorins were originally identified as guidance cues in neural development, several semaphorins such as Sema4A and 4D are involved in various phases of the immune response by regulating immune cell-cell contacts, immune cell migration and immune cell-neural cell interaction. Inappropriate expression of Sema4A, 4D, and their receptors Plexin-Bs by undetermined mechanisms causes neuroinflammation that leads to demyelination. The pathogenic role of the anti-AQP4 antibody in NMO has been speculated based on studies in vitro. The fact that passive transferred IgG collected from NMO patients who underwent therapeutic plasmapheresis exacerbated EAE indicates the pathogenicity in vivo. When the antibody once penetrates the blood-brain barrier probably under an inflammatory condition primarily causes complement-dependent astrocyte damage.

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Multiple sclerosis (MS) is a demyelinating disease of the central nervous system (CNS) while neuromyelitis optica (NMO) is an inflammatory disease of the CNS that selectively affects the optic nerves and spinal cord. An antibody for aquaporin-4 (AQP4), which is a water channel located in astrocyte foot process, is specifically positive for NMO and antibody and complement dependent astrocytic damage is thought to be a main cause of NMO. Baló's disease is characterized by alternating rings of demyelination and preserved myelin. We pathologically compared the astrocytic changes among autopsied cases with these CNS demyelinating diseases. NMO, MS and Baló's disease shared with reduced AQP4 immunoreactivity independent of antibodies and complements. The pathological finding was accompanied with a reduced immunoreactivity of connexin 43 and perivascular lymphocytic cuffing predominantly composed by T cells. The loss of astrocytic proteins such as AQP4 and connexin 43 preceded the loss of myelin proteins in some lesions. These features suggest astrocyte damages resulting in the loss of connexin 43 cause demyelination through the impairment of interaction between astrocytes and oligodendrocytes and the pathomechanism involves a T cell reaction.

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The development of orphan medicines presents many challenges. Clinical trials with new therapeutic strategies are now being planned and conducted for many orphan diseases such as Duchenne and Becker muscular dystrophy (DMD/BMD). However, since adequate numbers of patients are needed to achieve significant results for clinical trials, patient registries are an important infrastructure worldwide, especially in the case of rare diseases. We developed a national registry of Japanese DMD/BMD patients in collaboration with European research network, TREAT-NMD. Japanese registry adopts a self-report system and this database includes clinical data and molecular genetic data. The main purpose of this registry is the effective recruitment of eligible patients for a clinical trial and may provide timely information to individual patients. The registry data gives us more detailed knowledge of natural history, epidemiology, and clinical care. This registry will gain trial readiness in Japan and accelerate more effectively harmonization with other countries to fight orphan diseases.

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To investigate the longitudinal course of Japanese patients with Amyotrophic Lateral Sclerosis (ALS), we constructed a multicenter registration and follow-up system called Japanese Consortium for Amyotrophic Lateral Sclerosis research (JaCALS). Genomic DNA samples of ALS patients were stored and linked to the clinical information. We designed a telephone survey system using a clinical research coordinator (CRC) to check the score of the ALS Functional Rating Scale-R (ALSFRS-R) and the prognosis every 3 months. In January 2006, we began registering ALS patients, and, at present, 22 neurology facilities are participating in the JaCALS. Currently, 571 Japanese ALS patients are registered.
From the longitudinal data of the 279 patients who were registered before September 2009, the older age at onset was a significant risk factor for not only earlier death or introduction of mechanical ventilation, but also earlier loss of speech, loss of swallowing function and loss of upper limb function.
In collaboration with the RIKEN Center for Genomic Medicine, genome-wide association studies (GWAS) using 1,305 ALS samples from the JaCALS and BioBank Japan were conducted, which showed that ZNF512B gene was associated with susceptibility to ALS.
The JaCALS has established an efficient registration and follow-up system with genomic DNA resources of ALS patients, and will contribute to identify ALS-associated genes and to promote clinical researches.

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An accurate population-based cohort study of dementia was begun in 1985 in the town of Hisayama, Japan. To examine secular trends in the prevalence of dementia and its subtypes, four cross-sectional surveys were conducted among Hisayama residents aged 65 years or older in 1985, 1992, 1998, and 2005. The prevalence of Alzheimer's disease (AD) significantly increased with time, while the prevalence of vascular dementia (VaD) decreased from the 1985 survey to the 1998 survey and then increased in the 2005 survey. In a 17-year prospective study of a total of 668 elder residents without dementia, elevated midlife and late-life blood pressure were significant risk factors for the late-life onset of VaD, but not for that of AD. A 15-year prospective study of 1,017 elder subjects, who underwent a 75-g oral glucose tolerance test, revealed that the age- and sex-adjusted incidence of VaD and AD significantly increased in subjects with diabetes than in those with normal glucose tolerance. Moreover, 2-hour post-load plasma glucose levels were closely associated with increased risk of VaD and AD. In a pathological study of Hisayama residents, higher levels of 2-hour post-load plasma glucose, fasting insulin, and HOMA-IR were significantly associated with increased likelihood of neuritic plaques.

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Multiple system atrophy (MSA) is an adult-onset, progressive neurodegenerative disorder which is clinically characterized by various combinations of cerebellar ataxia, Parkinsonism, autonomic dysfunction and pyramidal signs. MSA is known as a sporadic disease, however, multiplex families with MSA suggest a genetic predisposition to MSA. The advanced genome research will clarify the pathogenetic mechanisms of MSA, and the disease-modifying therapy of MSA may be available in the future.
To clarify the natural history of MSA for the future therapeutic trials, and to elucidate the molecular pathogenetic mechanisms of MSA, JAMSAC (Japan MSA research consortium), a nationwide consortium, was established in 2003. In the view of the future therapeutic trial for MSA, it is essential to design appropriate end point, sample size, duration of the trial. And inclusion criteria are also important for effective therapeutic trial. We conducted a cross-sectional study on 225 MSA patients using unified multiple system atrophy rating scale (UMSARS). As inclusion criteria, we employed additional criteria based on specific MRI findings to recruit earlier stage patients. Sample size estimation from the longitudinal study suggested we need sensitive outcome measures beside UMSARS.
JAMSAC is planning to a longitudinal study for natural history of MSA in Japan.

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Duchenne muscular dystrophy (DMD) is caused by the lack of dystrophin at the sarcolemma. Exon skipping by antisense oligonucleotides is a novel method to restore the reading frame of the mutated DMD gene, and rescue dystrophin expression. We recently reported that systemic delivery of Morpholino antisense oligonucleotides targeting exon 6 and 8 of the canine DMD gene, efficiently recovered functional dystrophin at the sarcolamma of dystrophic dogs, and improved phenotypes of affected dogs without serious side effects (Ann Neurol. 65: 667-676, 2009). To optimize therapeutic antisense Morpholinos for more frequent mutations of the DMD gene, we designed antisense Morpholinos targeting exon 51 of the mouse DMD gene, and injected them separately or in combination into the muscles of mdx52 mice, in which exon 52 has been deleted by a gene targeting technique. We also tried systemic delivery of antisense Morpholino to skip exon 51 in mdx 52 mice and found the amelioration of the phenotypes (Mol Ther, 2010). Clinical trials of exon 51 skipping for DMD patients is now going in our country and application of antisense strategy to other hereditary neuromuscular diseases is largely expected.

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The past decade of researches have revealed mutations of known or putative glycosyltransferases in several types of muscular dystrophy, including Fukuyama-type congenital muscular dystrophy. In these disorders, the function of α-dystroglycan is severely decreased, therefore they are called α-dystroglycanopathy. Recently, putative glycosyltransferase Large was shown to restore the defective function of α-dystroglycan, thus, it is an intriguing idea to apply this effect to the therapy of α-dystroglycanopathy. In the present study, we sought to test this possibility. Using several cultured cell lines, we confirmed that the overexpression of Large results in hyperglycosylation and marked enhancement of the function of α-dystroglycan. For this effect, the whole luminal domain of Large was shown to be necessary using several deletion constructs. We further generated transgenic mice overexpressing Large ubiquitously. In each tissue of the mice, the glycosylation of α-dystroglycan and its laminin binding activity was remarkably increased. Moreover, the morphological analyses on each tissue stained by H-E revealed no significant abnormality in the transgenic mice, suggesting no serious side effects by the overexpression of Large. Taken together, these results indicate that the restoration of the function of α-dystroglycan by Large should be an important molecular target to develop therapeutic strategies for α-dystroglycanopathy.

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Recent advance in Brain-Machine interface (BMI) technology, including analysis of brain signal, enable a real-time interaction between patients and environment bypassing their damaged neuromuscular systems. Although most of researches have focused on substituting output function, it has been growing interest in applying this technology for restoring their brain. Several studies have proved that feedback of cortical activities (neurofeedback) enable regulating brain activation voluntarily. According to this notion, we have developed a real-time neurofeedback system mediated by near-infrared spectroscopy (NIRS) as a neurofeedback tool in neurorehabilitation. First, we have evaluated whether real-time cortical oxygenated hemoglobin (OxyHb) feedback signals correlated with reference OxyHb signals analyzed off-line during a motor execution task. Our results showed high correlation between results from two analyses. Second, we investigated whether the self-assessment scores for kinesthetic motor imagery and motor imagery related cortical activation was enhanced by neurofeedback. Our experiment with right handed healthy subjects revealed significant improvement of the imagery scale, and enhanced cortical activations including the contralateral premotor area. These results suggest that the neurofeedback technique may improve the efficacy of mental practice with motor imagery.

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The pathological hallmark of neurodegeneration is presence of intra- and extra neuronal inclusion bodies such as Lewy bodies in Parkinson's disease, senile plaques and neurofibrillary tangles in Alzheimer's disease. These are consisted of aggregated conformationally abnormal proteins. The precise mechanism of aggregation remains unknown, but increased expression of aggregation-prone proteins can lead to their aggregation. For example, in Down syndrome, duplication of the 21^st chromosome, which contains the amyloid beta precursor protein (APP) gene, leads to accumulation of amyloid beta and Alzheimer's disease pathology and multiplication of APP gene is shown to be the cause of familial Alzheimer's disease. Moreover, in rare cases of PD, duplication or triplication of SNCA gene leads to alpha-synuclein accumulation, with triplication producing a more severe phenotype than duplication, suggesting that SNCA expression level determines the severity of the pathology. Lastly, animal models of neurodegenerative disorders are generated by over-expression of causal genes, further supporting the conclusion that increased gene expression is related to pathogenesis. Additional evidence indicates that SNCA promoter polymorphisms increases alpha-synuclein expression and increases susceptibility to sporadic PD.
In addition to promoter polymorphisms, epigenetic modification can alter downstream gene expression. Epigenetic regulation includes histone modification and DNA methylation, of which CpG island methylation can be gene-specific; in several different cancers, CpG methylation inhibits binding of the transcription machinery, causing silencing of a specific oncogene, which leads to carcinogenesis. In central nervous system disorders, CpG methylation has been associated with psychiatric disorders, such as autism and schizophrenia. We found several cases of Parkinson's disease with epigenetic abnormality in SNCA gene.
Thus, we believe that studying epigenetics can provide previously unknown causes for dementia and other neurodegenerative disorders.

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In patients with atypical dementia, cognitive dysfunctions other than amnesia predominate. It remains to be established how to examine these cognitive dysfunctions in the systematic way. "Action" deficit in dementia can occur at any stage from perception of objects to motor control. We examined the mechanism of "action" deficit in a patient with posterior cortical atrophy and that with progressive supranuclear palsy. The former demonstrated impaired control of visual attention, which seems to be related to dysfunction of the dorsal visual pathway. The latter showed poor control of ballistic action with a tool. Dysfunction of the supplementary motor area might be related to poor control of context-dependent ballistic action in this patient. Combined use of neuropsychological and neuroradiological data could clarify the underlying functional impairment and their neuronal bases, which will help understand pathological progression of atypical dementia.

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Subcortical vascular dementia (SVD) is a subtype of vascular dementia which constitutes approximately half of vascular dementia in Japan. It is featured by hypertensive small vessel disease such as white matter lesions and lacunar infarctions. The clinical and pathological features of SVD are relatively uniform. White matter lesions may remain asymptomatic but may develop subcortical dementia and Parkinsonism, if neural network function is impaired severe enough. SVD and CAA are considered to be a subcortical and cortical counterpart of small vessel disease, respectively, and the latter is closely associated with Alzheimer's disease. Therapeutic strategy for SVD is classified to the remedies for vascular risk factors and anti-dementia treatment. Anti-choline esterase inhibitors and memantine may be beneficial for SVD patients, but are not approved as therapeutic agents for vascular dementia.

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The discovery of the causative gene for hereditary cerebral small vessel disease (CARASIL: Cerebral Autosomal Recessive Arteriopathy with Subcortical Infarcts and Leukoencephalopathy) opens a new avenue for exploring the pathogenesis of cerebral small vessel disease. The causative gene for CARASIL is HTRA1 (high-temperature requirement A1). HTRA1 is a serine protease and inhibits TGF-β signaling in their protease activity-dependent manner. The CARASIL-associated mutant HTRA1s lost their protease activity and increase the TGF-β family signaling. However the precious molecular mechanism for inhibition of TGF-β signaling by HTRA1 has not been elucidated. We have found that HTRA1 aberrantly cleaved pro-TGF-β in an endoplasmic reticulum and the cleaved products were degraded by the endoplasmic reticulum-associated degradation pathway. The result reconfirms the importance of HTRA1 for TGF-β signaling. The study for Marfan syndrome, which is caused by the increasing TGF-β signaling in aortic artery, indicates that the angiotensin I receptor antagonist, a drug already in clinical use for hypertension, inhibits TGF-β signaling and ameliorates the disease progression in model mouse as well as patients with Marfan syndrome. In human brain, angiotensin I receptor antagonist also inhibits TGF-β signaling. Therefore angiotensin I receptor antagonist warrants investigation as a therapeutic strategy for patients with CARASIL.

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