Neurological diseases have long been thought to be difficult or intractable to be cured. Recent progress in researches on etiologies and pathogeneses of many neurological diseases, however, has made it become possible to treat some diseases such as bulbo-spinal muscular atrophy and Alzheimer’s disease not only symptomatically but also in the sense of disease modification. We may be at the entrance of a new era where many neurological diseases would become treatable and overcome. My individual experiences studying 3 diseases, namely, distal myopathy with rimmed vacuoles, amyotrophic lateral sclerosis and spinocerebellar ataxia were presented and through them the following massages were conveyed to young neurologists of the Japanese Society of Neurology (JSN); To tackle the case even there is no similar case in the literature because you are the only one who could help the patient and some clues must be found, To cooperate with other colleagues and patients because you are not alone, To be reasonable, logical or scientific, To always be innovative or seek better situations, and To be global or international sharing real time information with other peoples in the world. JSN will make great leaps to the goals under the mission to contribute happiness of peoples in Japan and other countries through neurology including neurological practice, education and research.

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Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system (CNS) and the pathogenesis leading to demyelination includes 3 major processes. The first step is establishment of autoimmunity to CNS myelin components, with molecular mimicry between a portion of the infectious agents and that of myelin, which is an important feature. The second step is entry of immune cells into the CNS via the blood-brain barrier (BBB). Activated T cells can easily cross the BBB using surface LFA-1 and VLA-4 as ligands to ICAM-1 and VCAM-1, respectively, which are expressed on endothelial cells in the CNS. As the third step, immune reactions occur within the CNS when activated T cells encounter specific antigens presented by microglia. Of the helper T cells re-stimulated by autoantigens, Th1 cells producing interferon-γ and Th17 cells secreting interleukin-17 play major roles in propagating inflammation, while Th2 cells producing IL-4, and regulatory T cells secreting IL-10 and TGF-β suppress pathological processes. Final demyelination is rendered either by macrophages recruited from the bloodstream across the BBB, or by TNF-α and nitric oxide, which are secreted by Th1 cells and macrophages, and toxic to CNS myelin.

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The advance of sequencing technology, the exome analysis using next-generation sequencing (NGS), of the human genome has dramatically accelerated biomedical research and about 2,900 causative gene tests are now available. The discoveries of the causative genes for hereditary neurodegenerative diseases accelerated the studies on the pathophysiologic mechanisms of diseases and therapeutic strategies. Genome-wide association studies (GWAS) have successfully revealed numerous susceptibility genes for “common diseases” and neurodegenerative diseases with low odds ratios associated with risk alleles. It is expected that the dramatic advance of genome analysis and regenerative medicine by ES and iPS research bring a paradigm shift in clinical practice. The nationwide discussion for biomedical ethics in this personal genome era is absolutely needed.

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In the last 30 years, a lot of drugs to treat neurological disorders have been developed. Now neurology is one of the fields where the medication is the most important factor deciding the prognosis of the treated patients. Neurologists are now required to have precise knowledge of drug metabolisms and interactions on the medication to treat neurological disorders. Insert Packages contain most useful and important information for medications, however, information for the drugs are not enough to prescribe some drugs, and even though in the same drugs, information offered is different especially on drug interactions. Pharmacists and physicians should choose the drugs which offer proper and useful drug information to treat patients.
Developments of drugs to treat patients are important as a physician in Japan. It can also contribute to treat patients in the all of the world. The role of neurologists is especially big because the drugs of the brain are rapidly developed than any other fields in medicine.

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Deep brain stimulation (DBS) has been widely performed for various medically refractory movement disorders. For Parkinson disease (PD), target of DBS is subthalamic nucleus (STN) or globus pallidus internus (GPi). There are some evidences to demonstrate its effectiveness on motor function and QOL. DBS effectively improves levodopa-responsive motor symptoms, and significantly reduces dyskinesia and motor fluctuations. STN DBS particularly decreases the need for dopaminergic medication. A combination of medical treatment and DBS would provide longer relief of motor symptoms than medical treatment only. Currently new evidence supporting early introduction of DBS for better future outcome is published. DBS of Vim thalamus has been indicated for intractable tremor with various etiologies. Recently posterior subthalamic area (PSA) is introduced as an alternative target to Vim for tremor. GPi DBS is also effective treatment option for generalized dystonia.

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Dementia due to both Alzheimer’s disease (AD) and cerebrovascular disease (CVD) is designated as mixed dementia, or alternatively, AD with CVD. Cerebral amyloid angiopathy almost always accompanies AD, and causes lobar microbleeds, cortical subarachnoid hemorrhage and cortical microinfarctions. Dementia exclusively with cerebral amyloid angiopathy is a form of vascular dementia, while it is classified to AD when significant Alzheimer’s pathology coexists. Between AD and vascular dementia there are common and overlapping pathologies, which is important for differential diagnosis of these diseases.

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Neuropathological diagnosis is essential in neurological disorders. Neurological signs and neuroimaging play a major role in clinical diagnosis. Although neuroimaging indicates the location and size of lesions, which is useful to longitudinal evaluation of edema or atrophy, pathological diagnosis is absolutely necessary to qualitative diagnosis. The first step of pathological diagnosis starts to observe macroscopic findings of brains, which reveal the distribution of lesions specific to individual disorders. Since the macroscopic abnormal findings are based on the microscopic degenerative findings, it may be no exaggeration to say that macroscopic findings enable to make neuropathological diagnosis. Accuracy of macroscopic finding is corrected or revised with microscopic findings and finally compared with neuroimaging and clinical diagnosis. Therefore it is very important and useful to learn macroscopic findings of neurological disorders.

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In order to tackle with the high price of new technology and new therapeutic drugs, Central Social Insurance Medical Council in Japan has begun to discuss the possibility to introduce technology assessment in the actual public health insurance system. It is indispensable to minimize the economic burden of patients to deliver technological advances in treatment. It is important for the physician to recognize the economic burden of patients and to reduce this burden as much as possible. Around 69% of the cancer patients had economic worries (n = 2037) in our survey “Economic burden of patient with cancer from the viewpoint of cancer economics”. The mean out-of-pocket expense (752,000 yen) of the patients without economic worries was three-fourths that of the patients (987,000 yen) with economic worries. The out-ofpocket expenses and the refunds/benefits were 1,217,000 yen and 652,000 yen for molecular targeted treatment (n = 494). The Intractable Diseases Control Act is to be enacted in 2016–17 to promote work on nanbyo control using all the resources of the nation, and this act should surely entail financial support.

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Modern Western medicine was introduced into Japan by a Dutch doctor Pompe van Meerdervoort in 1855. A German physician Erwin von Baelz devoted himself to educating medicine for 25 years at Tokyo Medical School, the predecessor of the present University of Tokyo. Hiroshi Kawahara and Kinnosuke Miura, pioneers of Japan Neurology, received their education by him. Kawahara first described X-linked bulvo-spinal muscular atrophy, and published the first Japanese textbook of clinical neurology in 1897. In 1902, Miura and others founded the Japanese Society of Neuro-Psychiatry, the forerunner of the present “Japanese Society of Neurology”. Both Seizo Katsunuma, Professor of Nagoya University, and Junjiro Kato, Professor of Tohoku University, succeeded Miura’s neurology. Miura investigated the cause of beriberi, but ended in failure. Hasegawa’s proposal at the Diet in 1894 that the Japan Government should found an independent department of neurology in the University of Tokyo was unfortunately rejected. There was no foundation of independent institute, department and clinic of neurology before World War II. Consequently Japanese neurology was on the ebb at that time.

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It remains to be elucidated whether there is a use- or dose-dependent effect of rehabilitative intervention on impairment and disability of spinocerebellar degeneration since the disease progressively damages cerebellar structure that plays a crucial role in motor learning. Moreover there is a trade-off between functional improvement after rehabilitation and functional deterioration due to disease progression. Recent clinical trials from Germany and Japan have demonstrated that comprehensive intensive rehabilitation focusing on balance function have immediate and lasting effect up to 1 year on ataxia and gait disorder in patients with spinocerebellar degeneration. For sustained gain after the intensive rehabilitation, customized attempts to boost patients’ daily activities according to their ability appears to be important.

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Kampo is a traditional form of medicine in Japan. The individual formulas of the Kampo medicines consist mainly of plant-derived crude drugs. Recently, extract products that maintain specific levels of quality have been commonly used for dosage formulation instead of decoction. Although severe side effects, including pseudoaldosteronism, interstitial pneumonitis, liver damage and mesenteric phlebosclerosis may occasionally arise in some patients, herbal formulations are generally safe compared with potent western medicines. Since the complicated interaction of a Kampo formulation is difficult to analyze pharmacologically, the use of each Kampo formula has been based on the empirical rules described in classical writings by clinicians. Currently, formula selection is not always based on the pathological recognition from the Oriental medicine perspective, because these ancient theories are not necessarily amenable to current clinical practice. Nevertheless, formula selection would be more appropriate, and the therapeutic efficacy would increase if the physicians understood the basic concepts of ki, ketsu, sui, yin-yang, hypofunction and hyperfunction, heat and cold, superficies and interior, the five parenchymatous viscera and the six stages of disease. Regardless of the primary diseases, many Kampo formulas are considered to be indicated for patients complaining of headache, dizziness and numbness, which are common symptoms in everyday practice in neurology.

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Doctors in any department should have at least minimum knowledge of Kampo medicines. However, doctors who specialize in neurology often have inadequate knowledge of Kampo medicines. The efficacy of Kampo medicines in treating intractable diseases such as neurodegenerative diseases is not adequately understood and needs to be investigated in the future．On the other hand, Kampo medicines are often effective for treating common symptoms such as headache, dysesthesia, pain, and vertigo, encountered in daily medical practice. Because many patients suffer from these symptoms, the impact of these symptoms on our society is not small, even though the causes of these symptoms are not crucial. Having the skill to prescribe even a dozen or so Kampo medicines (for example, goshuyuto, goreisan, goshajinkigan, sokeikakketsuto) increases the treatment options and may be very beneficial in daily medical practice. In this article, I provide instructions on the use of representative Kampo medicines and present some case reports to elucidate their use. Amassing and sharing clinical experiences regarding the use of Kampo medicines would strengthen the medical evidences of Kampo medicines.

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MicroRNAs (miRNAs) bind to the 3'-untranslated region of mRNA, and thereby suppress the gene expression. Recent studies suggest that miRNAs modify the pathogenesis of cancer and neurodegeneration. Our study demonstrated that the expression levels of miR-196a is increased in a mouse model of spinal and bulbar muscular atrophy (SBMA), a neurodegenerative disease caused by the expansion of polyglutamine in androgen receptor (AR). In cultured neuronal cells, miR-196a decayed the mutant AR mRNA via silencing CUG triplet repeat RNA binding protein 2, a potent miR-196a targeting mRNA, which contributed to stabilize the mutant AR mRNA. Adeno-associated virus vector-mediated delivery of this miRNA attenuates the expression of the mutant AR, resulting in the mitigation of motor neuron degeneration in the SBMA mice. Introduction of miRNA appears to be a novel therapeutic strategy for devastating neurodegenerative diseases.

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Inclusion body myopathy with Paget’s disease of bone and frontotemporal dementia (IBMPFD) is an autosomal dominant disease caused by mutations in the VCP gene. VCP encodes a well-conserved multifunctional protein, valosin containing protein (VCP), which has important roles in protein quality control via proteasome and autophagy, protein aggregation, quality control of mitochondria, cell proliferation, and so on. Clinically, muscle weakness is the most common symptom of which disease onset is around 40 years. Affected muscles are variable, and the patients are sometimes diagnosed as limb girdle muscular dystrophy or GNE myopathy. Muscle pathology shows characteristic features including cytoplasmic/nuclear inclusions, rimmed vacuoles, and disorganized myofibrills, together with neurogenic changes. Paget’s disease of bone is reported to be observed in a half of the patients around the age of 40 years, but less common in Japanese patients. Frontotemporal dementia is seen around one third of the patients which appears nearly 10 years later than muscle or bone disease. In addition to cognitive dysfunctions, motor neuron involvement and cerebellar signs were also seen in our series. IBMPFD is not so rare disease as previously thought, but complicate clinical findings may make its diagnosis difficult.

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Neuroendovascular therapy is a rapidly evolving clinical subspecialty because of its minimal invasiveness and novel device development. In Japan, neurosurgeons perform a substantial portion of neuroendovascular procedures, however, the number of neurologists who certified by the Japanese Society for Neuroendovascular Therapy (interventional neurologist) is gradually increasing.
Neurologists tend to deal with medical treatment in the acute stage and prevention of ischemic stroke, in addition, neuroendovascular procedures for ischemic cerebrovascular diseases performed by neurologists themselves, such as acute revascularization therapy for acute intracranial major artery occlusion or carotid artery stenting, might provide various benefits to ischemic stroke patients because of the smooth, seamless and close management from admission, to intervention, to discharge and after discharge.
Because of insufficient number of interventionists to perform emergent neurointerventional procedures in the clinical setting of acute ischemic stroke in Japan, we wish that more neurologists get interested in and receive training in the neuroendovascular therapy.

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The development of next-generation sequences has brought not only high-throughput sequencing but also new possibilities for various kinds of analysis methods of genetic information. Dr. Hayashizaki et al. developed new technologies to construct the full-length cDNA library and applied them to high-throughput sequencing technologies for large-scale transcriptome analysis. These analysis results overturned the conventional assumption the 2% of the genome is transcribed by showing that 70% or more of the genome is transcribed as RNA through FANTOM activities which was founded in 2000 on their initiative. Further, the existence of 23,000 non-protein coding RNAs was confirmed. These new findings redefine the central dogma into a new picture containing new interaction cascade and the unexpected complexity of combined omics. The neo central dogma shows that there are three types of final products derived from genes; long ncRNA, small ncRNA, and protein. They play essential roles by forming complexes with each other to maintain life. Long ncRNA and small ncRNA play a role as a ligand with sequence information. Long ncRNA and protein play a role as a functional molecule. Here, I would like to introduce the neo central dogma concept and some of the mechanisms of ncRNAs.

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Brain-machine interface (BMI) is a new technology to receive input from the brain which is translated to operate a computer or other external device in real time.
After significant progress during the recent 10 years, this technology is now very close to the clinical use to restore neural functions of patients with severe neurologic impairment. This technology is also a strong tool to investigate the mode of neuro-signal processing in the brain and to understand the mechanism of neural dysfunction which leads to the development of novel neurotechnology for the treatment of various sorts of neurological disorders.

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Neurosurgical procedures are indispensable in management of various types of movement disorders (MD). Stereotactic operations that have been well established include deep brain stimulation for tremor, dystonia, and Parkinsonian symptoms. Recently the actual role of stereotactic ablative procedures such as thalamotomy and pallidotomy has been re-explored, and Vo thalamotomy shows long-term improvement of taskspecific focal dystonia like writer’s cramp and musician’s dystonia. A new less invasive treatment of tremor using MR guided focused ultrasound has started and is promising. Intrathecal administration of baclofen is also an established treatment for severe spasticity, but other ablative procedures such as peripheral neurotomy and dorsal rhizotomy are also important in spasticity treatment.
It seems that most neurologists are unfamiliar, at least in Japan, with such neurosurgical procedures. However, neurologists involved in management of MD should understand the important roles of neurosurgical management of intractable MD and should refer such patients to appropriate neurosurgeons before permanent contracture and deformity develop.

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Neuralgic amyotrophy (NA, also known as Parsonage-Turner syndrome) is a distinct peripheral nervous system (PNS) disorder, characterized by sudden attacks of severe neuropathic pain usually in the shoulder and/or arm. The neuralgia commonly disappears after a few days to weeks, and consequently patchy paresis with amyotrophy appears. The available evidence suggests that NA is essentially idiopathic immune-mediated neuritis of the brachial plexus, and also has a complex pathogenesis that includes an underlying predisposition, susceptibility to dysfunction of some PNS structure, and a trigger for the attacks, such as viral infection, vaccination, trauma, surgery, and strenuous exercise. Genetic factors also contribute to the pathogenesis of NA, and thus, this disorder occurs in both idiopathic and hereditary forms, but hereditary one is considered to be 10 times less common than idiopathic one. NA has been considered to be self-limiting, benign disorder showing good recovery without specific treatments. However, recent studies have indicated that the long-term prognosis of NA is less favorable than has been assumed. In 2009, a Cochrane review identified one open label, retrospective series, the results of which suggested that administration of corticosteroids in the acute phase of NA could shorten the duration of painful symptoms and also accelerate recovery in some patients. We recently have reported that intravenous immunoglobulin (IVIg) with methylpredonisolone pulse therapy is effective for motor impairment of NA.

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Non-motor symptoms are common in patients with newly diagnosed Parkinson’s disease (PD), and some even predate the emergence of the classic motor features. The premotor phase of PD is characterized by several important non-motor features, including constipation, olfactory dysfunction, REM sleep behavior disorder (RBD), depression, etc. The basis of this prodromal stage is that the pathological process related to Lewy bodies, may start outside of the substantia nigra. We investigated 469 Japanese PD patients in our multicenter study, using the Japanese version of the RBD screening questionnaire. Probable RBD was detected in 146 patients (31%) and the RBD symptoms of 53 patients preceded the onset of PD motor symptoms. With the probable exception of RBD, non-motor clinical markers can be sensitive for an impending diagnosis of PD, but these features are common and non-specific. The combination of non-motor clinical markers and more specific markers (e.g., imaging or genetic markers) may achieve sufficient utility in PD diagnosis and prediction in future. Being able to diagnose that a patient has PD at an earlier time point than is currently possible, would be allowed to introduce potential disease-modifying therapies at a time when it could have fundamental and long-lasting effects.

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Brain MRI is essential for differentiating Parkinson’s disease (PD) from other parkinsonian syndromes. The purpose of performing brain MRI is not to make a diagnosis of PD but is to exclude other parkinsonian syndromes. Recently, several new MRI techniques such as voxel based morphometry, relaxometry, magnetization transfer, spectroscopy, tractography, and functional MRI have been introduced in the diagnosis of PD. Neuromelanin imaging is one of the new techniques and can be useful to make an initial diagnosis of PD. MIBG myocardial scintigraphy is a sensitive imaging tool to differentiate PD from other parkinsonian syndromes and is one of the good tools to make an initial diagnosis of PD. Brain perfusion imaging is sometimes useful to make an initial diagnosis of PD, because reduced brain perfusion area can be detected before brain MRI detects morphological changes of the brain. Dopamine transporter imaging, not available in Japan, is a sensitive tool to detect very early parkinsonism and is useful to make an initial diagnosis of PD. However, it is difficult to differentiate PD from other parkinsonian syndromes.

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Recent advances in basic research toward neuroprotective strategies of Parkinson’s disease (PD) are increasingly highlighting the need for early diagnosis of PD. Substantia nigra (SN) hyperechogenicity, as visualized by transcranial sonography, has been heralded as a particularly useful diagnostic marker, as it is stable and remains unchanged with advancing stages of PD. In addition, SN hyperechogenicity is observable in patients in the very early stage, or even premorbid stages of PD. Prior studies have shown that SN hyperechogenicity is observable in approximately 90% of patients with PD and up to 10% of healthy controls. It has been hypothetically proposed that may be a vulnerability marker for nigrostriatal dopamine neuronds and may be related to an increase in iron content. It is expected that transcranial sonography of SN will be a feasible method for more accurate diagnosis of PD.

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Although α-synuclein protein (αS) aggregates from a monomer to assemblies such as oligomer, protofibril and mature fibril, the early intermediate aggregate, that is, oligomer has been considered to be most toxic species in recent reports. While it was reported that αS concentration in cerebrospinal fluid was decreased significantly in the patients with Parkinson’s disease (PD) and dementia with Lewy bodies, there were reports that αS oligomer concentration was elevated in cerebrospinal fluid of PD patients. Moreover, it was supposed that αS oligomer concentration was also elevated in blood of PD patients. Further studies of αS in cerebrospinal fluid and blood would lead to establishment of the significance of αS as a biomarker for α-synucleinopathies including PD.

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Mural thrombus due to blood stasis develops in the left atrium as atrial fibrillation (AF) persists longer. Characteristically, its development depends on the endothelial function of the atrium, and the prevention and control of each component of CHADS₂ score are thus important. Treatment of hypertension is essential in the primary prevention of AF, but once AF develops, its suppression will be the next step to address and catheter ablation is a useful intervention for this purpose. If these efforts fail, anticoagulation therapy for those with a substantial risk is mandatory. After the duration of AF and the bleeding risk are carefully taken into account, new oral anticoagulants with the risk of cerebral bleeding much less than warfarin are indicated.

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Cardioembolic stroke is approximately 30% of brain infarction, and most of the embolus sources are atrial fibrillation (AF). Brain infarction with AF was associated with an elderly woman, main brain arterial occlusion, and large infarcts. Therefore, patient outcome is so sever, and mortality is very high compared with other stroke types. Use of the anticoagulant before stroke onset is only 32%, and less than 1.6 of PT-INR was 58.4%. The hospitalized recurrence was 7.5%, which was not higher than stroke patients without AF. For detection of the intracardiac tthrombus, transesophageal cardiac-echogram detected thrombus in 16.4%. Within five years after discharge, mortality rate was higher in stroke patients with AF than those without AF. Brain infarction with AF should be knock-out stroke.

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Novel oral anticoagulants (NOAC) such as the direct thrombin inhibitor, dabigatran, and oral factor Xa inhibitors, rivaroxaban and apixaban, have recently approved for prevention of stroke in nonvalvular atrial fibrillation (NVAF). Phase III trials have compared each of these agents to warfarin. Dabigatran was more efficacious than warfarin in reducing the risk of stroke when given at a dose of 150 mg BID to patients with NVAF. Rivaroxaban 20 mg QD was superior to warfarin in on-treatment analysis. Apixaban 5 mg BID was also found to be superior to warfarin in reducing stroke in NVAF patients. Of note, the rate of hemorrhagic stroke was much smaller in the patients treated with NOAC than those with warfarin. NOAC offer a good therapeutic option for prevention of stroke in NVAF patients.

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Warfarin has unmet medical needs such as blood coagulation monitoring, limitation of vitamin K intake, and interaction with other drugs, while novel oral anticoagulants (NOACs) do not have such kind of unmet medical needs. Therefore, NOACs are recommended to busy patients or patients far from hospitals, or who do not want to limit vitamin K or use many other drugs concomitantly. NOACs are also recommended to patients with low time in therapeutic range (TTR). NOACs are also recommended to warfarin-naïve patients. Warfarin is recommended to patients with economical difficulty because it is much cheaper than NOACs. If needed, warfarin should be selected in patients with renal insufficiency or under hemodialysis because NOACs are contraindicated. New guidelines by the European Society of Cardiology recommend NOACs to low risk patients with CHA₂DS₂-VASc score 1, and also as the first line to those with CHA₂DS₂-VASc 2 or more. Finally, drug should be determined by patients’ preference. Doctors should give adequate information helpful for patients’ selection.

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To prevent major hemorrhage during anticoagulation, it is quite important to manage controllable risk factors such as hypertension, diabetes mellitus, smoking habit, and too much alcohol intake. It is also important to avoid dual antithrombotic therapy as long as possible, which increases severe bleeding events. For patients with major bleeding during anticoagulation, we should stop oral medication, stop bleeding by mechanical compression or surgical interventions, and maintain circulation blood volume and blood pressure by appropriate intravenous drip infusion. When intracranial hemorrhage happens, adequate treatment to suppress blood pressure should be provided. Administration of prothrombin complex concentrate (PCC) and vitamin K is effective for urgent reversal of anticoagulation by warfarin. The PCC may be also useful for that by novel oral anticoagulants.

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Genetic tests for asymptomatic persons, who have family members with hereditary neuromuscular diseases, should be done carefully by following strict rules. For example, an examinee should be given a clear plan for clinico-psychological and social support services in case of testing positive. It is very important to assess the potential impact of genetic test results, so the anticipatory guidance should be provided times without number.
It is difficult for local hospitals however, to fulfill such conditions during a primary genetic counseling, as they have limited staff. Our hospital is a case in point, where just one neurologist, who is also a certified clinical geneticist, provides the counseling, with the help of nurses, and social workers.
The availability of second and third level genetic counseling systems have made it possible for us to carry out primary counseling, and we make every effort to ensure that clients and patients can avail our services any time, and without any constraints.
In my opinion, a comprehensive education system to train primary care physicians in genetic testing and primary genetic counseling would prove beneficial for a lot of clients and also reduce the burden on neurologists.

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For neuromuscular disease the best diagnosis is by genetic testing. Genetic testing is very important, however, the influence which a positive result can have on a family is very considerable. It can affect the family’s lifestyle a lot. For example presymptomatic and prenatal genetic testing may be necessary for the family’s children when they become adults themselves.
We did qualitative research with five people who received presymptomatic genetic testing because of a family member with familial amyloidic polyneropathy. Heredity problems had a big influence on their life and on family dynamics.
In order to support hereditary disease patients and their families, it is important to make a system which all medical institutions can use to help them cooperate together and deal with the treatment of hereditary diseases.

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Although genetic reserch in neurological diseases has been dramatically advanced, its application to clinical neurology is still limited. Given the increased awareness of genetic testing in neurological diseases such as spinocerebellar ataxia, patients and their relatives’ requests for information is increasing. In this report, we provide a framework for assessing genetic risk of neurological diseases in at-risk relatives baesd on our experience in TMDU medical hospital. Reagrding asymptomatic individuals, there are concerns that prerictive testing may trigger some unexpected psychological responses, such as severe depression and anxiety. Thus we also conducted a questionnaire for neurologists about predictive genetic testing in their clinic. Thre obtained results contained the complexed difficulties which can be shared among broader communities of medical specialists.

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The aim of stem cell therapy for Parkinson’s disease (PD) is to reconstruct local synapse formation and/or induce the release of dopamine and cytokines from grafted cells in the putamen. Fetal ventral-midbrain cells are reported to relieve the neurological symptoms of PD patients. However, not only embryonic stem cells (ESCs), but also induced pluripotent stem cells (iPSCs) are expected to provide an alternative donor cell population because of their capacity for self-renewal and pluripotency. A protocol to generate dopaminergic (DA) neurons from ESCs and iPSCs has been developed, and human ESCs were proven to function in the brain of rat and monkey PD models. The next step will be the isolation of DA neurons as a donor cell population for a safe and efficient transplantation.

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Stimulated by the 2012 Nobel Prize in Physiology or Medicine awarded for Shinya Yamanaka and Sir John Gurdon, there is an increasing interest in the iPS cells and reprogramming technologies in medical science. While iPS cells are expected to open new era providing enormous opportunities in the biomedical sciences in terms of cell therapies for regenerative medicine, safety-related concerns for iPS cell-based cell therapy should be resolved prior to the clinical application of iPS cells. In this symposium, the pre-clinical investigations of cell therapy for SCI using neural stem/progenitor cells derived from iPS cells, and their safety issues in vivo are outlined.

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Recently, several stem cell-based approaches have been considered as a novel treatment for stroke, such as delivery of non neural stem cells, stimulation of endogenous neural stem cells, and transplantation of neural stem cells. Among them, transplantation of neural stem cells is thought to have an advantage for functional recovery through neuronal replacement rather than other mechanisms. We demonstrated that human iPS cells derived neural stem cells form functional neurons and improve recovery after grafting in stroke-damaged rodents without tumor formation. Here we discuss about the potential and clinical application of iPS cells for stroke therapy.

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Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder in which motor neuron (MN) loss in the spinal cord leads to progressive paralysis and death. Cytosolic aggregations in ALS MNs are composed of Tar DNA-binding protein-43 (TDP-43). Genetic analysis has identified more than twenty mutations of TDP-43 in ALS cases. Although accumulating evidence provides several hypotheses of disease mechanism, it is still needed to discover effective cure for ALS. We aimed to reveal cellular phenotypes in ALS MNs for identifying a drug-screening target for ALS using patient-specific induced pluripotent stem cells (iPSCs). To generate patient-specific iPSCs, dermal fibroblasts were obtained by biopsy from ALS patients carrying mutant TDP-43. The fibroblasts were reprogrammed by retrovirus or episomal vectors. Disease-specific iPSCs were differentiated into MNs expressing HB9 and SMI-32. Despite short culture period, ALS MNs recapitulated several disease phenotypes including detergent-insoluble TDP-43, shortened neurites and cellular vulnerability that observed in patient and animal models. Anacardic acid treatment reverted those phenotypes. Disease-specific iPSCs might provide a first step for drug-screening platform for ALS using patient-specific iPSCs.

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Corticobasal degeneration (CBD) is a distinct neurodegenerative disorder characterized by neuronal and glial accumulation of abnormal tau protein. The core characteristic clinical features of the disorder include progressive asymmetric akinetic-rigid syndrome with apraxia. Pathological examinations of patients presenting such clinical presentations have indicated that several proteinopathies, including tauopathies, amyloidopathies, TDP-opathies, α-synucleinopathies, and prionopathies may underlie the same clinical phenotype. Because of this considerable clinicopathologic heterogeneity, experts use the term corticobasal syndrome (CBS) for patients with a clinical diagnosis of CBD, and reserve CBD for those whose conditions have been diagnosed on the basis of neuropathological analyses. In this review, we have focused on the clinical aspects of CBS, including its clinical presentation, diagnostic criteria, and pathological backgrounds.

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Corticobasal syndrome (CBS) is associated with different pathologies including FTLD-tau (corticobasal degeneration; CBD, progressive supranuclear palsy, and Pick disease), FTLD-TDP, Alzheimer disease, Creutzfeldt-Jakob disease, and Parkinson disease/dementia with Lewy bodies. Genetic causes of CBS are also various reflecting diverse pathology. In familial and sporadic FTLD, MAPT, GRN and C9ORF72 mutations are three major causes of the disease. A part of patients harboring these mutations could exhibit CBS. In addition, the patients with TARDBP, FUS, LRRK2 or CSF1R mutations also have potential to exhibit CBS. In sporadic cases, H1 haplotype of MAPT is known to be associated with FTLD-tau, including CBS/CBD. Despite major advances in recent years, the majority of familial and sporadic CBS cases are genetically unsolved. In particular, little is known about both familial and sporadic cases of CBS in Japanese. Further studies are needed to unveil the genetic background of CBS.

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Recently, several attempts have been made to characterize clinical symptoms and brain atrophy patterns in pathology-proven corticobasal degeneration (CBD) and corticobasal syndrome (CBS). Voxel-based morphometry (VBM) analysis of MRI revealed that frontal lobe involvement is characteristic of CBD. CBS was associated with perirolandic atrophy irrespective of underlying pathology. In CBS due to frontotemporal lobar degeneration (FTLD), atrophy extended into prefrontal cortex, striatum, and brainstem, whereas in CBS due to Alzheimer’s disease (AD), atrophy extended into temporoparietal cortex and precuneus.
No functional imaging study in pathology-proven CBD or CBS with known histopathology has been published today. PET and SPECT studies demonstrated that decreased glucose metabolism and cerebral blood flow in the fronto-parietal cortex, especially contralateral to the dominant symptoms in patients with CBS. [¹⁸F]6-fluorodopa PET and dopamine transporter SPECT studies demonstrated dysfunction of nigrostriatal dopaminergic function in CBS. A PET study showed decreased acetylcholinesterase activity (AChE) in the fronto-parietal cortex, and a correlation between cortical AChE activity and mini-mental state examination score in patients with CBS.
Amyloid imaging agent is useful for detection of AD pathology in CBS. The recent development of tau imaging agent has made it possible to image distribution of neurofibrillary tangles in the brain in vivo.

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Corticobasal degeneration (CBD) was initially thought to represent a clinicopathological entity, but recent studies have shown its considerable clinicopathological heterogeneity. Thus, the constellation of the findings initially considered characteristic of CBD is now named “corticobasal syndrome” (CBS), while the term “CBD” is used for the histopathological disorder. Multiple phenotypes associated with CBD pathology and multiple diseases associated with CBS, the latter of which are called “CBD mimickers,” make the correct diagnosis of these conditions on the basis of only clinical symptoms and signs difficult. Therefore, the development of specific biomarkers for diagnosing each causative disease of CBS is extremely important. Abnormal accumulations of the microtubule-associated tau protein are found in both neurons and glia, and CBD is thus considered one of the tauopathies. Although some studies have measured total and phosphorylated tau in the CSF of patients with CBS, their results are inconclusive. Disease-specific truncation and/or phosphorylation of tau protein and its fragments in the CSF would be a promising biomarker candidate; however, its effectiveness still needs to be confirmed by further studies. Progress in biomarker development to differentiate CBD from CBD mimickers has been slow, but it is essential to improve diagnostic accuracy and to develop disease-modifying therapies.

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Numerous approaches have been explored to treat individuals with Alzheimer’s disease (AD). General approaches include the following treatment; treatment of cognitive symptoms, slowing decline, delaying onset of disease, and primary prevention. 2011 is the new era for the drug therapy for AD in Japan, because three anti-dementia drugs, galantamine, rivastigmine and memantine, were admitted to use for AD in addition to donepezil. Donepezil, galantamine and rivastigmine has been developed based on cholinergic hypothesis that acetylcholine (ACh) acts a chief neurotransmitter as a cognitive neurotransmitter. Donepezil a specific acetylcholinesterase inhibitor (AChEI). Galantamine acts as an allosteric potentiating ligand of nicotinic acetylcholine receptors in addition to the function of AChEI. Rivastigmine increase acetylcholine in the cholinergic synapse by inhibition of both AChE and butyrylcholinesterase. Recent study shows that these anti-dementia drugs afford symptomatic effect and also act as disease-modifiers which inhibit neuronal death and abnormal amyloid-beta deposition. These effects can slow the rate of decline of the disease. While in the past many of our attempts have been to treat secondary symptoms or improve the cognitive deficits, future attempts are likely to focus on slowing the rate of decline, delaying the onset of appearance, or preventing the disease.

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Neurofibrillarly tangles (NFTs) are seen most patients, who shows dementia, while β amyloid deposition observed specifically in AD patients. NFTs observe first from coeruleus and entorhinal cortex, and then spread to neocortex, which well explain clinical progression of AD, such as memory problem to dementia. Tau fibrils are the major component of NFT. Before forming tau fibrils, tau binds together, form soluble tau oligomer, and then granular tau oligomer. The soluble tau oligomer associates with synapse loss, and granular tau formation induces neuronal loss. Therefore, tau aggregation inhibitor is expected to halt the clinical progression of AD.

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Significantly increased levels of oxidized nucleic acids, proteins, and lipids have been described in the brains of subjects with Alzheimer disease (AD) and mild cognitive impairment (MCI) as well as young adults with Down syndrome, compared to age-matched controls. Therefore, it is speculated that oxidative stress (OS) and consequent cellular damage occur at an early-stage in the pathological cascade of AD. Until now, several antioxidants, mitochondrial protective agents, anti-inflammatory agents and metal chelators have been tested as possible OS-targeting therapeutics for AD. Although some of these agents have shown significant neuroprotective effects in cellular and animal models of AD, their efficacies in AD clinical trials have not been fully established. When limited efficacies of exogenous antioxidants in previous trials are taken into account, early-stage interventions aimed to activate endogenous antioxidants may be promising as OS-targeting therapeutic strategies for AD. A recent randomized controlled trial of dietary intervention for amnestic MCI is a good example of such an approach, where an OS-marker in cerebrospinal fluid is decreased and cognitive function is successfully improved by a diet with low-saturated fat and low-glycemic index. Indeed, transcriptional activators of endogenous antioxidants should be researched and tested in future clinical trials for AD.

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Rehabilitation is essential for treatment of Parkinson’s disease. New rehabilitation therapy is updated, in addition to evidence shown with “Parkinson’s disease treatment guidelines 2011”. Furthermore, a portable gait rhythmogram (acceleration sensor) is presented (not publication). Parkinsonian gait was significantly slow and the steps were small, but the cadence was not different compared as that of normal control. The strength of parkinsonian gait was apparently week compared as normal control. We also could examine consecutive changes of gait rhythm and detect freezing gait in patients. In this study, we could extract the characteristic of the parkinsonian gait and evaluate especially freeing events more objectively. This method may bring us to evaluate severity of parkinsonian gait not only in a consulting room but also daily profile even not to see directly, using the portable gait rhythmogram.

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