神経治療学
Online ISSN : 2189-7824
Print ISSN : 0916-8443
33 巻 , 3 号
選択された号の論文の71件中1~50を表示しています
第33回日本神経治療学会総会特集2
教育講演
  • 辻 省次
    2016 年 33 巻 3 号 p. 297
    発行日: 2016年
    公開日: 2016/11/10
    ジャーナル フリー
  • 荻野 美恵子
    2016 年 33 巻 3 号 p. 298
    発行日: 2016年
    公開日: 2016/11/10
    ジャーナル フリー
  • 宮嶋 裕明
    2016 年 33 巻 3 号 p. 299-302
    発行日: 2016年
    公開日: 2016/11/10
    ジャーナル フリー

    Iron is a bioactive metal essential for normal cellular functions. However, excessive iron leads to cell death because iron enhances oxidative stress due to the generation of highly cytotoxic hydroxyl radicals. Therefore, the tissue iron content is critically regulated by several iron metabolic molecules.

    Neurodegeneration with brain iron accumulation (NBIA) comprises a heterogeneous group of inherited neurodegenerative disorders collectively characterized by extrapyramidal movement disorders and abnormal iron accumulation in the deep basal ganglia nuclei of the brain. Ten NBIA genes have been identified to date : eight are autosomal recessive, one is autosomal dominant, and one is X–linked dominant. Mutations in 10 genes have been associated with NBIA that include ceruloplasmin (Cp) and ferritin light chain (FTL), both directly involved in iron homeostasis, as well as pantothenate kinase–associated neurodegeneration (PKAN) [PANK2], phospholipase A2–associated neurodegeneration (PLAN) [PLA2G6], mitochondrial membrane protein–associated neurodegeneration (MPAN) [C19orf12], static encephalopathy of childhood with neurodegeneration in adulthood, beta–propeller protein–associated neurodegeneration (SENDA, BPAN) [WDR45], fatty acid hydroxylase–associated neurodegeneration (FAHN) [FA2H], Coenzyme A synthase protein–associated neurodegeneration (CoPAN) [COASY], Kufor–Rakeb syndrome [ATP13A2], Woodhouse–Sakati syndrome [DCAF17]. These genes are involved in seemingly unrelated cellular pathways, such as lipid metabolism, Coenzyme A synthesis and autophagy.

    A greater understanding of the NBIA genes and any shared cellular function will ultimately help to link common clinical presentation. In this review, I will discuss clinical findings for each NBIA–related gene, discuss proposed disease mechanisms such as mitochondrial health, oxidative damage, autophagy/mitophagy and iron homeostasis, and speculate the new targets for drug discovery (new iron chelators, zinc treatment, etc).

  • 横田 隆徳, 仁科 一隆, 桑原 宏哉
    2016 年 33 巻 3 号 p. 303-306
    発行日: 2016年
    公開日: 2016/11/10
    ジャーナル フリー

    Two major types of oligonucleotide drugs for gene silencing, short interfering RNA (siRNA) and RNase H active antisense oligonucleotides (ASOs), microRNA (miRNA) and Aptamer are being developed as therapeutic platforms orthogonal to small molecule and protein therapeutic. We outlined these oligonucleotide drugs. Despite progress in the design of new oligonucleotide chemical modifications, methods which improve potency of oligonucleotide drugs in animals are highly desirable. The insufficient delivery, poor cellular uptake and their inefficient access to target RNA during intracellular trafficking are major impediments to in vivo silencing by conventional oligonucleotide drugs. Here we developed a short DNA/RNA heteroduplex oligonucleotide (HDO) with a structure different from siRNA of double–stranded RNA and ASO of single–stranded DNA. When the DNA strand was used as 13–mer locked nucleotide acid (LNA) gapmer ASO and RNA strand was conjugated with vitamin E (α–tocopherol) (Toc–HDO), it achieved the most efficacious gene silencing in yet reported ASOs.

  • 西澤 正豊
    2016 年 33 巻 3 号 p. 307-310
    発行日: 2016年
    公開日: 2016/11/10
    ジャーナル フリー

    Even after the Japanese people experience a devastating disaster in eastern Japan in March 11, 2011, disaster medical assistance plans have not yet been effectively provided for all of individuals with intractable neurological diseases, who are living in local communities, and receiving home medical care by using such medical equipment as artificial ventilators. It is our responsibility to make necessary preparations for those who cannot take refuge by themselves in case of disasters. Recently amended “Fundamental Disaster Relief Act” defines that local government can utilize and share personal information of those with intractable diseases when natural disasters take place, and it is expected that individual planning of disaster medical assistance will progress smoothly.

  • 木多 眞也
    2016 年 33 巻 3 号 p. 311
    発行日: 2016年
    公開日: 2016/11/10
    ジャーナル フリー
  • 長谷川 成人
    2016 年 33 巻 3 号 p. 312
    発行日: 2016年
    公開日: 2016/11/10
    ジャーナル フリー
メディカルスタッフ教育講演(疾患シリーズ)
  • 柏原 建一
    2016 年 33 巻 3 号 p. 313-317
    発行日: 2016年
    公開日: 2016/11/10
    ジャーナル フリー

    Parkinson's disease (PD) is a progressive disorder of the nervous system that affects motor, neuropsychiatric, sleep, autonomic, and sensory functions. Motor symptoms of PD may include tremor, bradykinesia, muscle rigidity, postural instability, and speech and swallowing disturbances. Neuropsychiatric symptoms include depression, apathy, anxiety, cognitive impairment, hallucinations, and delusions. Sleep problems include insomnia, REM sleep behavioral disorder, excessive daytime sleepiness and sudden onset of sleep. Main autonomic symptoms include constipation, urinary dysfunction, orthostatic hypotension, sexual dysfunction, drenching sweat. Anosmia and sensory symptoms also are frequent complications of PD. Diagnosis of PD is determined by detecting these symptoms. The essential criterion is parkinsonism, which is defined as bradykinesia, in combination with at least 1 of rest tremor or rigidity. In addition, diagnosis of clinically established PD requires absence of absolute exclusion criteria, at least two supportive criteria, and no red flags. Exclusion criteria includes cerebellar abnormalities, downward vertical supranuclear gaze palsy, frontotemporal dementia, parkinsonism restricted to the lower limbs, treatment with dopamine receptor blocker, etc. Drugs, deep brain stimulation (DBS), and rehabilitation are measures to manage PD. Levodopa and dopamine agonists are the cardinal drugs to treat motor symptoms. Levodopa tended to induce motor complications such as wearing off and dyskinesia if used in the larger amount of more than 400 mg/day to PD patients with younger onset. Dopamine agonists induce motor complication less frequently than levodopa, but may include hallucinations, daytime sleepiness and impulse control disorders such as hypersexuality, gambling, and eating. Apomorphine is used for quick relief. DBS is a surgical procedure to treat motor symptoms of PD. Nowadays, increasing evidences support that physical activity improve motor and non-motor symptoms of PD. Global Parkinson's disease survey steering committee concluded in 2002 that “satisfaction with the explanation of the condition at diagnosis” and “current feelings of optimism” have a significant impact on health-related quality of life of PD patients.

  • 本村 政勝
    2016 年 33 巻 3 号 p. 318-322
    発行日: 2016年
    公開日: 2016/11/10
    ジャーナル フリー

    Myasthenia gravis (MG) is an autoimmune neurological disorder characterized by impaired neuromuscular transmission due to circulating pathogenic autoantibodies. MG patients produce pathogenic autoantibodies against the acetylcholine receptors (AChR), muscle–specific receptor tyrosine kinase (MuSK), and low–density lipoprotein receptor–related protein 4 (Lrp4) which are localized on the postsynaptic membrane of the neuromuscular junction. This lecture provides the overview of MG in Japan including classification, epidemiology, autoantibodies, clinical manifestation, diagnosis, treatment, and prognosis, especially focusing on the new standard treatment approach according to novel MG diagnostic criteria suggested by the MG clinical guidelines for 2014. Treatments for MG are based on immunotherapy by steroids and immunosuppressants. In Japan, treatments include cholinesterase inhibitors, thymectomy, steroids, immunosuppressants, plasma exchange, and intravenous immunoglobulin therapy. However, even when utilizing all of these treatments, the proportion of MG patients achieving complete stable remission is less than 10%. The new treatment approach suggests the combination therapy from early disease stage, to reduce the risk of crisis and disease progression. The current goal of MG treatment is firstly to treat MG patients to achieve pharmacological remission as rapidly as possible using the above therapies at onset. The therapeutic protocol according to onset age, disease type, and pathogenic autoantibodies conducted in Nagasaki University Hospital is also discussed.

  • 和田 健二
    2016 年 33 巻 3 号 p. 323-327
    発行日: 2016年
    公開日: 2016/11/10
    ジャーナル フリー

    The prevalence of dementia among elderly people aged 65 years or older in Japan, has been estimated as 15% in 2012. With the substantial aging of the population in Japan, number of the people of dementia estimated to be 20% in 2025. Issues on dementia have become not only the medicine but also social problems. A national strategy on dementia (aka, new orange plan) is devised for creating a kind community for people with dementia and their family caregivers.

    Dementia is defined by a loss of cognitive ability severe enough to interfere with normal activities of daily living. Several behavioral and psychological symptoms (BPSD) could be seen in people with dementia. Then, timely and precious diagnosis of dementia would lead to treatment or care for reduction of symptoms of people with dementia as well as of care burden of their family. In this report, after explanation of cognitive symptoms and BPSD in each dementia disorders, important points of treatment and care for dementia are described.

  • 久留 聡
    2016 年 33 巻 3 号 p. 328-331
    発行日: 2016年
    公開日: 2016/11/10
    ジャーナル フリー

    The diagnosis and treatment of muscular diseases are reviewed. For the diagnosis of muscular diseases, it is necessary to combine clinical findings with various investigations, including laboratory tests, electrophysiological assessment, muscle biopsy and genetic analysis.

    Idiopathic inflammatory myopathies (IIMs) have been classified into three distinct subsets, polymyositis, dermatomyositis and sporadic inclusion myositis. For the treatment of IIMs, corticosteroids, immunosuppressants and intravenous immunoglobulin are used.

    Duchenne muscular dystrophy (DMD) is caused by the mutation of dystrophin gene. Recently, promising genetic strategies, such as stop–codon readthrough and exon–skipping with antisense oligonucleotide, have been developed as potential therapies for DMD. There is a pressing need for a useful outcome measures to assess disease progression and the efficacy of treatment. Current clinical outcome measures include functional tests and muscle imaging, such as CT, MRI and ultrasonography.

  • 池田 佳生
    2016 年 33 巻 3 号 p. 332
    発行日: 2016年
    公開日: 2016/11/10
    ジャーナル フリー
  • 岩崎 靖
    2016 年 33 巻 3 号 p. 333-337
    発行日: 2016年
    公開日: 2016/11/10
    ジャーナル フリー

    Prion disease, previously known as transmissible spongiform encephalopathy, is a fatal neurodegenerative disease affecting humans and other mammals. The word “prion”, coined in 1982 by Stanley B. Prusiner, stands for “proteinaceous infectious particle”. In humans, prion diseases are extremely rare with an annual mortality rate of 1 per million. Sporadic Creutzfeldt–Jakob disease (CJD) is the most common human prion disease identified worldwide, accounting for over 85% of cases of prion disease in humans. Sporadic CJD usually has a rapid clinical course and patients reach the akinetic mutism state several months after disease onset. Among Caucasians, about 90% of patients with sporadic CJD die within 1 year of disease onset ; however, Japanese patients generally have longer survival because of the management procedures followed in Japan. The crucial factor resulting in longer survival is thought to be the introduction of tube feeding.

    The clinicopathologic manifestations of sporadic CJD are influenced by several factors, particularly prion protein (PrP) gene polymorphism and prion strain (type 1/type 2) in the patients. According to the genotype of the methionine (M)/valine (V) polymorphism at codon 129 of the PrP gene and the physicochemical properties of type 1 PrP/type 2 PrP, sporadic CJD has been classified into six subtypes : MM1, MM2, MV1, MV2, VV1, and VV2. MM2–type sporadic CJD is further divided into two types on the basis of clinicopathological phenotype : MM2–cortical–type and MM2–thalamic–type. Comprehensive analyses of the clinical and neuropathologic findings as well as analyses of PrP gene and PrP type should be applied to better understand these atypical cases. The neuropathology of CJD typically shows a spongiform change, gliosis (hypertrophic astrocytosis in particular), neuropil rarefaction, neuron loss, and PrP deposition. In sporadic CJD variants, the MM1–type shows the typical clinicopathological findings of CJD, wherein the fine vacuole–type spongiform change with diffuse granular synaptic–type PrP deposition. MM2–cortical–type is relatively frequent in Japan, and shows atypical findings, which include a large confluent vacuole–type spongiform change and perivacuolar–type PrP deposition.

症例から学ぶ
マラソンレクチャー
  • 荻野 美恵子
    2016 年 33 巻 3 号 p. 343
    発行日: 2016年
    公開日: 2016/11/10
    ジャーナル フリー
  • 小池 春樹
    2016 年 33 巻 3 号 p. 344-348
    発行日: 2016年
    公開日: 2016/11/10
    ジャーナル フリー

    Peripheral neuropathy is caused by a variety of diseases. Early diagnosis and initiation of treatment is important because irreversible damage may occur. Although careful assessment of the mode of progression, symptoms and signs, blood and cerebrospinal fluid examinations, and electrophysiological studies may lead to diagnosis, nerve biopsy is also useful to determine the underlying diseases in some of the patients with neuropathy. Sural nerve is usually taken for histopathological assessments, and it may reveal amyloid deposits, vasculitis, epithetioid granulomas, and invasion of lymphoma. In addition to these relatively disease–specific findings, nerve biopsy is also useful to demonstrate demyelination and axonal degeneration. Macrophage–mediated demyelination, widely spaced myelin, and uncompacted myelin lamellae are representative myelin abnormalities associated with chronic inflammatory demyelinating polyneuropathy (CIDP), anti–myelin–associated glycoprotein neuropathy, and POEMS syndrome, respectively. As for axonal neuropathies, large–fiber predominant loss is associated with Sjögren's syndrome, paraneoplastic syndrome, thiamine deficiency, and folate deficiency, while small–fiber predominant loss may be seen in patients with alcoholism, amyloidosis, Fabry disease, and diabetes. However, recent studies suggested that the modality of nerve fiber loss is more diverse even in a single etiology than previously appreciated. Physicians should carefully interprete the findings obtained by nerve biopsy.

  • 城倉 健
    2016 年 33 巻 3 号 p. 349-351
    発行日: 2016年
    公開日: 2016/11/10
    ジャーナル フリー

    Vertigo/dizziness of the central origin is usually associated with other neurological signs or symptoms such as motor palsy, sensory deficit, dysarthria, ocular motor palsy, limb ataxia, and truncal ataxia. On the other hand, vertigo/dizziness of the peripheral origin is characterized by positional torsional nystagmus (posterior canal benign paroxysmal positional vertigo), direction–changing horizontal nystagmus (lateral canal benign paroxysmal positional vertigo), or unidirectional horizontal nystagmus (other acute peripheral vestibulopathies). Direction–changing horizontal nystagmus and unidirectional horizontal nystagmus can also be seen in the central vertigo/dizziness ; these nystagmus are caused by a disruption and/or cerebellar disinhibition of the vestibular nucleus.

    Most peripheral vertigo/dizziness can be diagnosed by characteristic nystagmus, whereas neuroimaging study is necessary to confirm the diagnosis of central vertigo/dizziness. In the acute phase of vertigo/dizziness, antihistamine may be used to reduce symptom. For benign paroxysmal positional vertigo, the most common cause of vertigo/dizziness, canalith–repositioning maneuver is effective.

  • 安藤 哲朗
    2016 年 33 巻 3 号 p. 352-356
    発行日: 2016年
    公開日: 2016/11/10
    ジャーナル フリー

    The first step in evaluating patients with spinal cord disease is to localize the lesion from the segmental sign. Cervical spondylosis, which can present as radiculopathy and myelopathy, is common in people over the age of 50. It is necessary to assess whether neurological symptoms result from cervical spondylosis or other neurological disorders. In order to avoid misdiagnosis, it is important to compare the levels of the lesions shown on imaging with the clinical findings. Differential diagnosis between amyotrophic lateral sclerosis and cervical spondylosis is an issue of major clinical importance. The cervical spinal cord MR images of spinal cord sarcoidosis sometimes mimics that of cervical spondylotic myelopathy.

    Spinal dural arteriovenous fistula is a treatable spinal cord disease, however it is still underdiagnosed.

  • 平田 幸一
    2016 年 33 巻 3 号 p. 357-361
    発行日: 2016年
    公開日: 2016/11/10
    ジャーナル フリー

    Making the center of the refractory migraine is chronic migraine (CM) and medication overuse headache.

    CM is a disabling neurological condition affecting 0.5–2% of the population.

    In the current third edition of the International Classification of Headache Disorders, medication overuse is no longer an exclusion criterion and CM is diagnosed in patients suffering from at least 15 headache days per month of which at least eight are related to migraine.

    CM is difficult to treat, and preventive treatment options are limited.

  • 辰巳 寛, 山本 正彦
    2016 年 33 巻 3 号 p. 362-367
    発行日: 2016年
    公開日: 2016/11/10
    ジャーナル フリー

    Aphasia greatly influences a patient's quality of life (QOL). Recovery from aphasia requires a long time, and improvements in anterior language function can be difficult to achieve. Aphasia is a major obstacle for returning to work and thus can have serious economic consequences.

    The diagnosis of aphasia requires a qualitative assessment (classification of type of aphasia) and a quantitative judgment (severity assessment). Importantly, the various symptoms that constitute the pathology of aphasia must be understood when making a qualitative assessment. Quantitative assessments must also be evaluable using a systematic objective test.

    The mainstream of aphasia treatment is the classical stimulus–facilitation method. Recently, a cognitive neuropsychological approach, a pragmatic approach, and Melodic Intonation Therapy have also attracted attention as possible therapies. Furthermore, studies on pharmacotherapy and noninvasive therapy for aphasia are proceeding.

    The psychosocial study of aphasic persons and their families has become a very important theme. Lately, a depression rating scale and a QOL rating scale for people with aphasia, a family's communication burden scale, and a communication self–efficacy scale have been developed. Clinically, it is important to provide hospitable support to both people with aphasia and their families.

  • 朝比奈 正人
    2016 年 33 巻 3 号 p. 368-372
    発行日: 2016年
    公開日: 2016/11/10
    ジャーナル フリー

    Clinically it is very important to diagnose and treat autonomic symptoms such as syncope, urinary problems and sweat abnormalities. Vasovagal syncope, the most common syncopal disorder, usually develops under 40 years old. As the sensitivity of head–up tilt test is low, history taking is more important for the diagnosis. Carotid sinus syncope usually develops over 60 years old and its diagnosis is confirmed based on the evidence of bradycardia and hypotension induced by stimulation to the carotid sinus. Orthostatic hypotension is defined as a sustained reduction of systolic blood pressure of at least 20mmHg or diastolic blood pressure of 10mmHg within 3 minutes of standing or during head–up tilt test. Non–pharmacological management is important : salt supplementation, fluid intake and avoiding precipitating factors such as high carbohydrate meals, hot environments, alcohol and vasodilator drugs. Vasopressor drugs, which are used for treatment of orthostatic hypotension, can cause or aggravate recumbent hypertension. Urinary dysfunction is classified into storage and voiding symptoms. Anticholinergic drugs, which are used for treatment of storage symptoms, may exacerbate cognitive impairment. In regard to impaired voiding, clean intermittent selfcatheterization is preferred in patients having over 100ml of residual urine. Sudomotor abnormalities include hyperhidrosis and hypo/anhidrosis. For focal hyperhidrosis such as palmoplantar hyperhidrosis treatment like aluminium chloride application, tap water iontophoresis and thoracic sympathectomy may be performed. For acquired idiopathic generalized anhidrosis corticosteroid therapy is often effective.

  • 吉田 眞理
    2016 年 33 巻 3 号 p. 373-377
    発行日: 2016年
    公開日: 2016/11/10
    ジャーナル フリー

    Diagnostic neuropathology of central nervous system leading to treatment is divided into two domains. One is brain biopsy and the other is autopsy proven pathological diagnosis. Brain biopsy is useful in difficult cases, in which less invasive measures have been unable to yield a definitive diagnosis, especially associated with space occupying lesions of white matter on imaging studies. These lesions include primary central nervous system lymphoma (PCNSL), tumefactive demyelinating lesions (TDL), progressive multifocal leukoencephalopathy (PML), and amyloid β–related angiitis (ABRA). Brain biopsies lead to early pathological diagnosis and suitable treatment. As brain biopsies often consist of small pieces of tissue, sampling error might occur. Preoperative discussion among neurologists, neurosurgeons, neuroradiologists, and pathologists is very important about differential diagnosis and biopsy regions. Furthermore, preoperative steroid or immunosuppressive therapy often obscure or obliterate pathological findings from naive inflammatory reaction. Therefore, it is recommended to plan a brain biopsy before steroid or immunosuppressive therapy.

    In neurodegenerative disorders or dementias, correct pathological diagnosis is obtained in autopsy. The worldwide decrease of autopsy rate has been reported, which make correct pathological diagnosis difficult. The characteristic pathological findings of neurodegenerative disorders consist of disease specific inclusions in neurons and glia composed of abnormally aggregated disease specific proteins. Alzheimer's disease has neurofibrillary tangle with tau aggregation and senile plaques with amyloid β fibrils. Parkinson disease and dementia with Lewy bodies shows α–synuclein positive Lewy bodies and Lewy neurites. In multiple system atrophy α–synuclein positive glial cytoplasmic inclusions in oligodendroglia are pathological hallmark. Major tauopathies consist of Pick disease with Pick bodies composed of 3 repeat tau, progressive supranuclear palsy and corticobasal degeneration with glioneuronal inclusions composed of 4 repeat tau. Amyotrophic lateral sclerosis and frontotemporal lobar degeneration present TDP–43 proteinopathies. In elderly overlapping of several neurodegenerative diseases is not uncommon. Pathological confirmations contribute the verification and understanding of clinical and neuroradiological findings, and treatment.

  • 中原 一郎
    2016 年 33 巻 3 号 p. 378
    発行日: 2016年
    公開日: 2016/11/10
    ジャーナル フリー
  • 武田 篤
    2016 年 33 巻 3 号 p. 379
    発行日: 2016年
    公開日: 2016/11/10
    ジャーナル フリー
  • 尾崎 紀夫
    2016 年 33 巻 3 号 p. 380
    発行日: 2016年
    公開日: 2016/11/10
    ジャーナル フリー
シンポジウム5:脳卒中治療の最前線
シンポジウム6:神経疾患への工学からのアプローチ
  • 葛原 茂樹, 梶 龍兒
    2016 年 33 巻 3 号 p. 395
    発行日: 2016年
    公開日: 2016/11/10
    ジャーナル フリー
  • 中島 孝
    2016 年 33 巻 3 号 p. 396-398
    発行日: 2016年
    公開日: 2016/11/10
    ジャーナル フリー

    The neuromuscular diseases affect commonly motor–unit that constitutes spinal motor neuron and/or muscle fiber. They develop incurable progressive amyotrophy and have patients bedridden. We aimed to assess the efficacy and safety of intermittent walk program using Cybernic exoskeleton robot, Hybrid Assistive Limb (HAL) for improvement of ambulatory dysfunction of them in an open–labelled multicenter randomized controlled crossover trial. This clinical trial suggested that Cybernic walk program using HAL had the same safety as the ordinary walk program with hoist. This trial also suggested that only 9 times of Cybernic walk program proved clinical efficacy for the neuromuscular disease. Our general hypothesis is that intention based errorless motor learning using HAL may improve walking dysfunction due to a variety of neurological disorders. We name it Cybernic neurorehabilitaion because this method can be regarded as one of neurorehabilitation programs based on both Hebbian theory and Edelman's neural group selection theory. We are thinking that Cybernic walk program which is combined with another etiological treatment using compounds, oligonucleotides, antibodies and stem cells may be important for the therapy of incurable progressive diseases in the future because neurorehabilitation process may be essential for functional recovery. The clinical study report of this trial and summary technical document have been successfully reviewed by Japanese authority, Pharmaceutical and Medical Devices Agency. HAL–HN01 (ML05) has been approved as a new medical device by Ministry of Health Labor and Welfare on the 25th of November 2015.

  • 平田 雅之
    2016 年 33 巻 3 号 p. 399-404
    発行日: 2016年
    公開日: 2016/11/10
    ジャーナル フリー

    Research and development of brain-machine interfaces (BMIs) are now ongoing to support severely disabled people due to intractable neurological disease, spinal cord injury and stroke etc. Implantable brain-machine interfaces using intracranial electrodes require surgical intervention. However, it may achieve higher performance. Here I describe the trends of domestic and international BMI research for clinical application.

    In USA, clinical research of BMIs using micro–needle electrode array are ongoing in University of Pittsburgh and in Brown University. They reported that three dimensional real time control of a robotic arm and writing using a mouse cursor were successfully performed by severely disabled people. We demonstrated that, real time control of a robotic arm was successfully performed by patients with intractable epilepsy or intractable pain whom intracranial electrodes were temporarily implanted. And most recently we demonstrated that a severely disabled patient with ALS successfully controlled a robotic arm and writing.

    A fully implantable device is another key to clinical application for implantable BMIs. Development of 40 to 100 channel implantable devices are ongoing in USA, France and Germany. However clinical application of these implantable devices has not been reported yet. We developed a 128–ch electrocorticographic fully implantable device using a contour fitting 3D cortical electrodes and completed chronic implantation in monkey for 6 months. Translational research with companies is indispensable for clinical application. We have to establish a business model and perform strategic pharmaceutical affairs based on it.

    From technological point of view, implantable BMIs will be clinically applied in the next 5 to 10 years. Now it's time to think well about its application.

  • 里宇 明元
    2016 年 33 巻 3 号 p. 405
    発行日: 2016年
    公開日: 2016/11/10
    ジャーナル フリー
シンポジウム7:精神科とのクロストーク
シンポジウム8:認知症研究の新展開
  • 東海林 幹夫, 山田 正仁
    2016 年 33 巻 3 号 p. 414
    発行日: 2016年
    公開日: 2016/11/10
    ジャーナル フリー
  • 田平 武
    2016 年 33 巻 3 号 p. 415-419
    発行日: 2016年
    公開日: 2016/11/10
    ジャーナル フリー

    Alzheimer's disease is characterized by deposition of aggregated amyloid β protein and tau protein. Since active and passive immunization of Alzheimer model mice with aggregated Aβ or antibody to Aβ showed clearance of aggregated amyloid β deposits and improved memory and learning, immunotherapy targeting Aβ is being developed. Although a human trial of active immunization with Aβ and adjuvant QS21 was halted because of autoimmune encephalitis, the trial revealed that it is possible to clear Aβ deposits in humans. On this proof of concept, several clinical trials using monoclonal antibodies are on–going. Although solanezumab which recognizes Aβ monomer turned out ineffective in the primary endpoint, it showed significant beneficial effect in mild AD cases in the secondary outcome. Therefore, solanezumab is now on a large scale phase III trial in mild AD cases in the world. If it turns out to be effective, it will be the first disease modifying drug for AD in a few years. However, since monoclonal antibodies are extremely expensive, less expensive and long acting active immunization with Aβ peptide (a vaccine) will be widely accepted, if it is safe. If peptide vaccines are successful, more effective and sophisticated vaccines such as safe DNA and recombinant viral vector vaccines will be utilized in future.

  • 富田 泰輔
    2016 年 33 巻 3 号 p. 420-424
    発行日: 2016年
    公開日: 2016/11/10
    ジャーナル フリー

    β–Site amyloid precursor protein cleaving enzyme 1 (BACE1) and γ–secretase are proteolytic enzymes required for the production of the amyloid–β peptide (Aβ), which is associated with Alzheimer disease (AD). These enzymes have emerged as a prime molecular target for reducing the brain Aβ levels. Recently, several BACE1 inhibitors have been developed in clinical trials to test the efficacy in AD patients and individuals with prodromal AD. This review summarizes the current status of the development of secretase inhibitors/modulators and the evaluation of their therapeutic potential against AD.

  • 岩田 修永
    2016 年 33 巻 3 号 p. 425-427
    発行日: 2016年
    公開日: 2016/11/10
    ジャーナル フリー

    Accumulation of amyloid–β peptide (Aβ) in the brain is a triggering event of the long–term pathological cascade of Alzheimer's disease (AD), and is closely associated with the metabolic balance of Aβ. Almost all familial AD mutations of causal genes, such as PSEN1, PSEN2 and APP, cause an increase in the anabolism (production) of a particular form of Aβ, Aβ1–42, leading to Aβ deposition and accelerating progression of AD pathological cascade. As well, a chronic reduction in the Aβ–catabolic (degrading) activity would also promote Aβ deposition. Neprilysin is a rate–limiting peptidase involved in brain Aβ catabolism. Mounting evidence that expression levels of neprilysin are decreased selectively in the hippocampus and cerebral cortex of AD patients from the early stages of disease development and also with aging in humans, suggests a close association of reduced levels of neprilysin with the etiology and pathogenesis of AD. Thus, a subtle but long–term decline in neprilysin activity appears to be at least partly responsible for the memory–related symptoms of AD, and up–regulation of neprilysin would be a promising strategy for disease–modifying therapy of AD.

    We screened a compound modulating brain neprilysin activity and/or gene expression using a Nagasaki University natural product library, and found that some polyphenols, such as (–)–epigallocatechin gallate (EGCg) were capable of up–regulating neprilysin. However, the polyphenols are less hydrophobic, and their bioavailabilities and blood–brain barrier permeabilities are not always so good. We developed aliphatic catechin derivatives by introducing an aliphatic moiety into the A–ring of EGCg to increase Log P values. Some of the aliphatic catechin derivatives more strongly up–regulated neprilysin, and another compounds did both neprilysin and α–secretase, which acts to preclude Aβ production, than EGCg did. The aliphatic catechins are expected as promising drug candidates for therapy and prevention of AD.

  • 富山 貴美
    2016 年 33 巻 3 号 p. 428-432
    発行日: 2016年
    公開日: 2016/11/10
    ジャーナル フリー

    Active and passive tau immunization has been shown to attenuate phenotypes in tauopathy model mice. So far, two tau vaccines and three anti–tau monoclonal antibodies have been subjected to clinical trials for patients with Alzheimer's disease or progressive supranuclear palsy. In the present study, we developed new monoclonal antibodies to hyperphosphorylated tau for future clinical use. Selected antibodies to pSer413–tau (Ta1505) and to pSer396–tau (Ta4 and Ta9) were injected intraperitoneally into aged mouse models of tauopathy once a week at 0.1 or 1mg/shot 5 times. Ta1505 antibody significantly improved memory in a dose–dependent manner, while Ta4 and Ta9 antibodies showed less effect. The cognitive improvement paralleled a reduction in the levels of tau hyperphosphorylation, tau oligomer accumulation, synapse loss, neurofibrillary tangle formation, and neuronal loss. Furthermore, Ta1505 antibody displayed suppressive effects against not only tau hyperphosphorylation but also Aβ oligomer accumulation in a different, aged mouse model of Alzheimer's disease. These results indicate that pSer413 is a promising target in the treatment of Alzheimer's disease and other tauopathies.

MSシンポジウム4:チームで取り組む認知症対応
  • 吉井 文均, 鷲見 幸彦
    2016 年 33 巻 3 号 p. 433-434
    発行日: 2016年
    公開日: 2016/11/10
    ジャーナル フリー
  • 鷲見 幸彦
    2016 年 33 巻 3 号 p. 435-438
    発行日: 2016年
    公開日: 2016/11/10
    ジャーナル フリー

    Many issues need to be solved for acute hospitals to provide appropriate treatment and care for inpatients with dementia who have admitted to the hospital due to physical complications. The problems are aggravated by lack of knowledge and skills of staff, and further more lack of experienced advisors to the staff. Facing these issues, we launched the “Dementia & Delirium Support Team : D2ST” in August 2011 with the purpose to improve skills and knowledge to provide optimal care for inpatients with dementia. The mission of the team was to provide support and advice to the staff in charge of the inpatients with dementia and delirium to increase treatment effects. The D2ST has been well established in our hospital, and the team accepted around 140 consultation every year. The interventions based on support and advice by the team have worked well in reducing root troubles and symptoms of screaming and agitation, whereas the issues remained for amelioration of eating disorders including anorexia.

    Following the achievement of our hospital, we have supported the launch of the teams modeled after D2ST in the 3 acute hospitals with more than 500 beds in Aich Prefecture in 2014. In the 3 hospitals under the leadership of the hospital executives, the support teams were launched and they prepared the operational manuals, and in the 2 hospitals among them, the teams have commenced the rounds in some wards of the hospitals. These 3 cases have revealed that D2ST in our hospital is an effective model to ameliorate treatment and care for the inpatients with dementia and delirium, and the model can be well implemented in other hospitals.

  • 猿渡 進平
    2016 年 33 巻 3 号 p. 439
    発行日: 2016年
    公開日: 2016/11/10
    ジャーナル フリー
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