Encephalitis/Encephalopathy is a life–threatening disease with many causes. In the last 15 years the continual discovery of newly identified forms of autoimmune encephalitis (AE) associated with antibodies to cell–surface or synaptic proteins has changed the paradigms for diagnosing and treating disorders. AE is one of the most common causes of non–infectious encephalitis. It can be triggered by tumors, infections, or it may be cryptogenic. These disorders can occur in patients with or without cancer―often children or young adults who develop psychosis, catatonic or autistic features, memory problems, abnormal movements, or seizures that were previously considered idiopathic. We review here the process of discovery, the symptoms, and the target antigens of AE including our previous published research data. Anti–N–methyl–D–Aspartate receptor (NMDAR) encephalitis, several subtypes of limbic encephalitis, and other AEs that result in psychosis, seizures, or abnormal movements are described. We also discussed their recent diagnostic approach and treatment in AE.
This recent advances in AE research led to the identification of syndromes and biomarkers. Existing criteria for AE are too reliant on antibody testing. Since antibody test results are not available at onset, a practical, syndrome–based diagnostic approach is required. It is possible to proceed through a logical differential diagnosis of AE using criteria based on conventional clinical neurological assessment and standard diagnostic tests (MRI, EEG, and CSF studies). Through this approach, levels of evidence of probable and definite AE can be achieved early and therapies implemented quickly, with the possibility of fine–tuning the diagnosis and treatment when antibody results become available. Notably, most treatment recommendations in AE are based on the experience of experts in the field. However, there is a need for clinical trials to identify clinically meaningful cut–off values of autoantibody titres which provide a clear indication for immunotherapy and to compare the efficacy of different immunotherapeutic strategies more objectively. A task for the future is moving these strategies to the clinics.
A headache and sleep disorders are one of the most common disease that a front–line physician faces. Also, many people experience that a headache is improved by having taken the sleep well or a headache may occur adversely. Sleep and the headache have bi–directional association.
Interestingly, the disorders linked to migraine are quite varied, not only including insomnia, snoring and obstructive sleep apnea, restless legs, circadian rhythm disorders, narcolepsy but also almost all other diseases such as hypertension, depression, diabetes, obesity and dementia. Central sensitization of brain may be one cause for chronicity of them. Moreover, limbic system may contribute to pathophysiology of migraine and sleep.
If you master one thing, you can see others. Deep thoughts based on headache and sleep research will make new strategy for neurotherapeutics.
Oligonucleotide therapeutics are based on chemically synthesized oligonucleotides which are in almost all cases chemically modified. They are classified into some categories by their action mechanisms, such as antisense oligonucleotides (ASOs) and RNA interference (RNAi) drugs. These oligonucleotides can bind to their target molecules such as mRNAs by Watson–Click base pairing and/or other interaction also including multipoint hydrogen bonding. By their definitive action mechanisms and their molecular size which are between small molecules and antibody drug, oligonucleotide therapeutics can be highly–specific drugs that can target molecules in cells. In this review, we outline the classification and action mechanisms of oligonucleotide therapeutics. In addition, we also introduce nucleic acid chemistry, which can make biologically–unstable nucleic acid molecules into effective therapeutic reagents.
Recent progress in biotechnology has been accelerating the development of new modality drugs, including monoclonal antibodies, peptide drugs and cell–based therapeutics. Nucleic acid therapeutics, the subject of this manuscript, are negatively charged macromolecules consisting of tens or more nucleotides. This physicochemical property greatly determines their interaction with biological components, such as circulating cells in the blood and cells in organs, and serum proteins, which then determines their tissue distribution. To increase the binding affinity to target molecules, such as mRNA, as well as to increase the biological stability, most nucleic acid therapeutics consist of various types of nucleic acid derivatives or analogues. Then, they will exhibit unique tissue distribution profiles depending on their physicochemical properties. Drug delivery systems, which are intended to increase the potency of pharmaceuticals, have been developed also for nucleic acid therapeutics. They include : nanoparticles, galactose modification, and nanostructuration. Success in the control of the tissue distribution of nucleic acid therapeutics will further increase their therapeutic usefulness for various diseases, including neurological diseases.
Loss–of–function mutations in SMN1 cause spinal muscular atrophy (SMA), a leading genetic cause of infant mortality. Humans have a closely related SMN2, but it only expresses low levels of SMN protein, due to alternative splicing of exon 7. Antisense oligonucleotides (ASOs) can be designed to regulate splicing of target pre–mRNAs. Based on an ASO–tiling method, we succeeded in identifying an optimized 2′–MOE phosphorothioate ASO that efficiently redirects SMN2 splicing. Its therapeutic efficacy, safety, and pharmacokinetics were proven in preclinical studies using mice and NHPs and further supported by clinical trials in SMA infants and children. Exploring of the in vivo spatial and temporal ASO effects yields insights into SMN roles in SMA pathogenesis, which in turn contributes to the successful development of targeted therapeutics.
We review the current status of treatment for hereditary spinocerebellar ataxia and multiple system atrophy and the methods used for evaluating ataxia symptoms. With the development of treatments for these disorders, the importance of genetic testing, including pre–symptomatic diagnosis, is expected to increase. Even in sporadic disease, multiple genes predisposing individuals to onset have been identified, and these results are expected to be applied to genomic medicine in the future. In order to perform appropriate medical care and targeted research, it is necessary to improve the clinician's and researcher's genetic literacy and cooperate smoothly with clinical genetics departments.
The amyloidoses are a large group of postsecretory protein misfolding and deposition diseases. There are 36 secreted human proteins misfolding and misassembly of which outside the cell are linked to amyloidosis. Transthyretin (TTR) and immunoglobulin light chain are representative amyloidogenic proteins in humans.
Transthyretin (ATTR) amyloidosis is a life–threatening, gain–of–toxic–function disease characterised by extracellular deposition of amyloid fibrils composed of TTR. TTR protein destabilised by TTR gene mutation is prone to dissociate from its native tetramer to monomer, then misfold and aggregate into amyloid fibrils, resulting in autosomal dominant hereditary ATTR amyloidosis (also called as familial amyloid polyneuropathy, FAP). Analogous misfolding of wild–type TTR results in senile systemic amyloidosis, now termed wild–type ATTR amyloidosis, characterised by acquired amyloid disease in the elderly. Liver transplantation used to be an only effective disease modifying therapy for hereditary ATTR amyloidois, which allows suppression of the main source of variant TTR. However, large numbers of patients are not suitable transplant candidates. Recently, the clinical effects of TTR tetramer stabilisers, diflunisal and tafamidis, were demonstrated in randomised clinical trials, and tafamidis has been approved for treatment of hereditary and wild–type ATTR amyloidosis in >40 countries. Moreover, clinical effects of small interfering RNAs and antisense oligonucleotides on hereditary ATTR amyloidosis were also demonstrated, and patisiran was approved for the treatment for hereditary ATTR amyloidosis in 2019.
Immunoglobulin light chain (AL) amyloidosis is an intractable disease in which abnormal plasma cell clone produces impaired monoclonal light chains in an unregulated manner, resulting in diffuse amyloid deposition and serious functional damage in multiple organs. The prognosis of patients with this disease was poor, with a median survival period of 1–2 years without effective therapeutic intervention. Recently, however, high–dose melphalan with stem–cell transplantation, melphalan–dexamethasone therapy, and bortezomib–dexamethasone therapy dramatically improve the patients' survival.
With the development of effective disease modifying therapies, early and precise diagnosis of amyloidosis is essential to improve patients' prognosis.
Neurodegenerative diseases are characterized by symptoms and signs due to a loss of neurons from a specific part of the brain. It is difficult to make a definite diagnosis of these diseases, because so far there is no highly specific biomarkers that are useful for differential diagnosis. To make a precise clinical diagnosis of the neurodegenerative diseases showing movement disturbance or dementia, various neuroimaging techniques are available in clinical field. Although a magnetic resonance imaging or a computed tomography visualizes the anatomical information of the patient's brain, such as atrophy or changes of parenchymal signal intensity/density, a single photon emission computed tomography (SPECT) or a positron emission tomography (PET) can visualize the functional alteration in the disease process. Since SPECT/PET findings can reflect early pathological changes occurred in the affected brains, these images will contribute to enable early therapeutic intervention.
Encephalitis is associated with high morbidity and mortality, and the neurologic manifestations of this condition include fever, headache, altered mental status, convulsions, and psychiatric symptoms. Early diagnosis of encephalitis is crucial to ensure that the right treatment is given on time. Herpes simplex virus was the most common infectious cause among acute encephalitis, followed by varicella zoster virus. Thus, more than a quarter of patients were potentially treatable with aciclovir. Recent repots have showed the increasing recognition of autoimmune encephalitis, and anti–NMDAR encephalitis was the most common autoimmune condition. In this article, the author describes the characteristic clinical findings, magnetic resonance imaging and spinal fluid analysis of herpes simplex encephalitis, varicella zoster encephalitis, and anti–NMDA receptor encephalitis. Early identification of these patients may allow timely initiation of aciclovir and/or immunomodulatory therapy, and help improve clinical outcomes.
This article reviews MRI findings of the autoimmune inflammatory demyelinating disease of the central nervous system ; multiple sclerosis (MS), neuromyelitis optica spectrum disorders (NMOSD), and myelin–oligodendrocyte glycoprotein antibody–related disorders (MOGRD). MRI findings are useful for diagnosing these 3 diseases and excluding differential diseases. It is important to be familiar with their characteristic sites and morphology.
Neuropathological diagnosis has been still gold standard for neurodegenerative disorders. Clues of microscopic findings appear on macroscopic pictures. Characteristic macroscopic features are closely related to pathological lesions and distributions, clinical sings, and neuroimaging. Parkinsonism is one of the most frequent and complicated symptoms for clinical diagnosis. Abnormal pallor on substantia nigra is consequent of loss of pigmented neurons. Depigmentation of substantia nigra is essential feature of clinical presentation of Parkinsonism, such as Parkinson's disease, dementia with Lewy bodies, multiple system atrophy, progressive supranulear palsy, and corticobasal degeneration. Differential diagnosis is based on macroscopic appearances of brainstem. Depigmentation of substantia nigra and locus ceruleus without atrophy of pontine base or brainstem tegmentum suggests Lewy body pathology including Parkinson's disease and dementia with Lewy bodies. Multiple system atrophy is consisted of degeneration of olivopontocerebellar system, striatonigral system and autonomic nervous system in various degree. When atrophy of pontine base and cerebellum is distinctive, in addition to depigmentation of substantia nigra and locus ceruleus, differential diagnosis may include multiple system atrophy. While atrophy of midbrain tegmentum and relative preservation of locus ceruleus is clear, progressive supranulear palsy may be contained in differential diagnosis. Therefore, macroscopic findings of central nervous system are potential clues for practical clinical diagnosis.
In the diagnosis of muscle diseases, “muscle pathology” still plays a clinical important role in the present, although a large number of causative genes and myositis–specific autoantibodies have been discovered. Actually, many muscle diseases are defined based on muscle pathology. Muscle pathology provides many useful information for differentiation of inclusion body myositis in the diagnosis of idiopathic inflammatory myopathy. Muscle pathology is connected directly with a diagnosis name for congenital myopathy. Because some breakthrough therapies are developed in variable muscle diseases, the significance of diagnosis confirmation of muscle diseases increases more and more. However, muscle biopsy should not be performed in all cases. We should judge the indication of muscle biopsy exactly.
It is necessary that we take biopsy specimens from the appropriate site of the muscle in the appropriate facilities. In addition, proper handling and fixation of biopsy specimens are necessary to avoid artifacts. We should select muscles biopsy sites and perform an appreciate muscle biopsy procedure. Skeletal muscle MRI and electromyogram are useful for the decision of the biopsy site. We should appropriately freeze and fix the muscle specimens collected, because histochemistry and immunohistochemistry are required.
The most important stains are hematoxylin & eosin, modified Gomori–trichrome, and NADH–TR. With these three staining techniques, judgements about basic pathological findings can be made and lead to the definitive diagnosis in many muscle diseases. If necessary, other various kinds of histochemistry including myosin ATPase, cytochrome C oxidizing enzyme, succinic acid dehydrogenase, and PAS may be requested. In the present, immunohistochemistry stains against dystrophin, sarcoglycans, dysferlin, laminin–α2, α–dystroglycan, emerin, and collagen–6 are very significant for the definitive diagnosis of many muscular dystrophies. Similarly, immunohistochemical evaluations of MHC class I/II in muscle fibers and CD4/CD8 expression on infiltrating T cells are important for the definitive diagnosis of inflammatory myopathies.
Recently, neuromuscular ultrasound is recognized as a useful diagnostic tool for neuromuscular disorders. In the present review, useful evidence in clinical practice has been introduced for clinical laboratory technicians. Cross–sectional area for peripheral nerve disorders and muscle rightness and movement for muscular disorders are useful parameters. Tips for measuring these parameters have been introduced.
Nerve conduction studies (NCSs) are essential for diagnosis of peripheral neuropathy. NCSs should be performed for the purpose of complementing the findings obtained by detailed neurological examinations. If weakness or numbness is consistent with the territory innervated by a peripheral nerve or spinal nerve, it is more likely to be a peripheral lesion than a central lesion. A fibular NCS is useful for the diagnosis of foot drop. The compound muscle action potential (CMAP) of the fibular nerve is usually recorded on the extensor digitorum brevis, but the CMAP is susceptible to potential damage and may not be suitable for the evaluation of foot drop. In that case, it is recommended to record the CMAP on the tibialis anterior. Sensory conduction studies can distinguish lesions before and after the dorsal root ganglion (L5 radiculopathy vs. fibular neuropathy). It should be noted that conduction block and temporal dispersion are not always demyelinating findings.
Although needle electromyography (needle EMG) is only performed by medical doctors, clinical laboratory technicians should be especially familiar with needle EMG, as well as other paramedical staff.
Because the needle is thinner than the blood collection needle, the pain during the needle electromyography insertion is lighter than the blood sampling. However, if the subject complains of pain, it should be dealt with immediately, such as by changing the position of the needle tip. In order to reduce pain, it is important to keep the muscle length isometric, including during contraction. Hemorrhage is not frequent in needle EMG, but attention should be paid to the bleeding diathesis and antithrombotic medication.
In needle EMG, spontaneous discharges at rest and discharges at voluntary contraction are observed. It is possible to evaluate the localized diagnosis of the extent, the quality and extent, and the distribution of the disorder, as well as the diagnosis of finding–specific diseases.
It is not enough to perform the needle EMG simply as requested by the doctor who ordered it. It is recommended that the examiner perform “neuromuscular electrodiagnosis” by conducting a detailed questioning and neurological examination before the test to prepare the test plan and by changing the test content flexibly according to the test results.
The necessity of the nurses who have expert knowledge and skills for the care for Parkinson's disease patients (i.e. Parkinson's disease nurse) is recently increasing. The rapid increase of the prevalence of Parkinson's disease, the comprehensive assessment of the various motor and nonmotor symptoms and the complicated therapeutic strategy including the development of the device aided therapy and the non–oral dopaminergic therapies heighten the necessity of Parkinson's disease nurses. Together with the physicians, Parkinson's disease nurses are expected to play an important role in the multidisciplinary team for the care of Parkinson's disease patients. In several foreign countries, particularly in United Kingdom, the educational and training systems for developing Parkinson's disease nurses are well established and several guidelines for Parkinson's disease nurses are available for clinical practice. The educational courses for developing Parkinson's disease nurses are recently held also in Japan, however the training system remains to be well organized. In this article, the necessity, the current situation in the foreign countries and a variety of role of Parkinson's disease nurses are discussed.
In Japan, support for intractable diseases has entered a new era after legislation of the Act on Medical Care for Patients with Intractable Diseases in 2015 following the formulation of the Guidelines for Measures against Intractable Diseases. The challenges faced in treatment of intractable neurological diseases lie in the great diversity, complexity and individuality of symptoms, as no two people are alike. Furthermore, there are practical challenges associated with utilizing social resources, improving the support system. It is no exaggeration to say that the patient's quality of life (QOL) is determined by whether various social resources can be utilized or not. Therefore, when considering treatment support, it is critical to have a perspective of the illness course and to grasp the whole picture rather than being informed of only a certain treatment stage. The illness course begins with the “onset phase”, which is the period spanning the development of symptoms to the diagnosis of the disease. This is followed by the “progressive phase”, during which mild health problems and difficulties in daily activities become severe, followed by the “transitory phase”, which is when the patient makes various decisions about where they will receive care, which medical procedures they will undergo, and makes “links” based on these decisions ; this is then followed by the “sustenance and stable phase”. Since the disease is progressive, the patient repeatedly undergoes these four phases. However, even in the “sustenance and stable phase”, the patient experiences the “changing phase”, wherein the patient suffers from the development of novel and hither to unknown symptoms (complications or associated symptoms), but moves in time to the “terminal phase”. One characteristic of intractable neurological diseases is that this “terminal phase” cannot be clearly demarcated from other phases. This article provids phase–by–phase points to improve support for intractable diseases and serves an overview of experts' efforts and the challenges they face in working towards the development of support for such diseases.
Duplex ultrasonography is useful to evaluate arterial lesions of carotid artery and vertebral artery. Duplex ultrasonography is a simple and convienient technique to detect carotid and intracranial artery lesions, which is useful information for endvascular treatment. Transcranial Doppler and Transcranial color flow image are useful to detect occlusion or stenosis of intracranial artery. Embolic stroke of undetermined source (ESUS) is a novel entity for cryptogenic stroke. In ESUS patients, Transesophyageal echocardiography frequently yielded additional findings that are mainly related to paroxysmal arterial fibrillation, paradoxical embolism, or aortogenic embolism. Venous limited compression ultrasonography of lower extremity is recommended in case of suspicion of paradoxical embolism to detect deep venous thrombosis.
Ultrasonography is useful for diagnosis and secondary prevention of acute ischemic stroke.
Spinal cord injury (SCI) is caused by high energy trauma such as traffic accidents, falls, and contact sports. Breakage of spinal stability results in permanent neurologic dysfunction. Spinal fixation surgery and subsequent rehabilitation are the only procedures for the treatment of SCI, but they cannot cure the irreversible changes of the spinal cord. To overcome this situation, we have conducted basic research to establish cell transplantation therapy using human iPS cell–derived neural precursor cells (NPCs). We reported efficacy of NPCs after transplantation. At the same time, however, some iPSC–NPCs showed tumor–life proliferation in the spinal cord, and provision for this unfavorable phenomenon is urgently necessary. We have developed several methods to inhibit tumor formation, and will introduce them in this review. So far, we have worked towards the clinical application of human iPSC–NPCs for SCI. This exciting clinical research will start soon around the corner.
The function of the central nervous system, once damaged by cerebrovascular disease, brain injury, or spinal cord injury, does not recover and there is currently no effective therapy. We hitherto identified factors that regulate regeneration of a damaged neural network and has unveiled its molecular mechanism. As a consequence, we set out to develop a drug that would promote restoration of the central nervous system, examined the possibility of antibody therapy for RGM, and developed an anti–RGM humanized monoclonal antibody, which takes the molecular form, for human administration. This anti–RGM antibody inhibited activation of RGM. Furthermore, when the antibody was administered to rats with spinal cord injury, they showed marked improvement in motor functions and regeneration of damaged axons. The said antibody also improved motor functions, especially skilled motor activities, in a rhesus macaque spinal cord injury model. We also showed improvement of neurological function of animal models of multiple sclerosis and neuromyelitis optica after administration of anti–RGM antibody. We unveiled the molecular mechanism of the RGM's action on neurons and laid the scientific foundation for its medicinal effect. In 2019, we started conducting international clinical trials of this drug on spinal cord injury patients.
Tauopathy is characterized by the fibrillar tau accumulation in central nervous system. Neurofibrillary lesions strongly correlated with cognitive deficits in neurodegenerative diseases. However, causal mechanisms of tau–induced neuronal dysfunction are still unresolved. Recent advance of in vivo imaging techniques has opened a window to capture a real time event during brain aging. Especially, researchers are going to establish positron emission tomography (PET) imaging of tau lesions using several tau PET tracers. [11C]PBB3 and [18F]PM–PBB3 are promising PET tracers to diagnose not only Alzheimer's disease (AD) also non–AD tauopathies (e.g., Progressive supranuclear palsy, Corticobasal degeneration, and Chronic traumatic encephalopathy). In addition to clinical research, these PET tracers are feasible to visualize tau pathologies in mouse models of tauopathy. Therefore, tau PET imaging is a translatable research tool between human and mouse tauopathies. Furthermore, PBB3 and PM–PBB3 can be used for fluorescence imaging to detect filamentous tau inclusions in living animals using two–photon microscopy. Pathological tau–induced neurotoxicity can be examined at cellular levels in a mouse model of tauopathy. Since progression of tau pathology is closely associated with neuronal cell death, volumetric analysis by magnetic resonance imaging (MRI) is another bench mark of tau–induced neurodegeneration. At present, these multimodal imaging techniques allow verification of the pathogenesis of tauopathies. In this review, we will discuss current progress of the development of tau PET tracers and a imaging–based diagnostic platform of tauopathy.
It is well known that the brain is one of the organs particularly affected by aging in terms of function, relative to the gastrointestinal tract and liver, which exhibit less functional decline. There is also a wide range of age–related neurological disorders such as stroke, Alzheimer's disease (AD), and Parkinson's disease. Therefore, it is very important to understand the relationship between functional age–related change and neurological dysfunction. Neuroimaging techniques including magnetic resonance imaging and positron emission tomography (PET) have been significantly improved over recent years. Many physicians and researchers have investigated various mechanisms of age–related cerebral change and associated neurological disorders using neuroimaging and biochemical techniques. In this session, we would like to focus on neuroimaging and biomarkers, which are a range of tools used to visualize structure, functions, and pathogenic molecules in the nervous system. Concerning the neuroimaging in neurological disorders especially AD, “amyloid β (Aβ)” and “tau” are believed to be key molecules in its pathomechanism. With this background, molecular imaging techniques using PET to visualize Aβ and tau in the living humans are now drastically advancing. We are discussing here about several new findings concerning neuroimaging modalities and fluid biomarkers of neurological diseases causing dementia.
Glycan structures of glycoproteins are often cell–type specific, suggesting that glycan isoforms could be cell type–specific biomarkers. Two glycan isoforms of transferrin (Tf) were found in cerebrospinal fluid (CSF), i.e., brain–type Tf and serum–type Tf. Serum–type Tf appears to be derived from blood due to its glycan similarity. Histochemical staining with anti–Tf antibody and a lectin, specific probe for brain–type glycan, reveals that brain–type Tf is secreted from choroid plexus, CSF–producing tissue. Idiopathic normal pressure hydrocephalus (iNPH) is an elderly dementia caused by abnormal metabolism of CSF. Brain–type Tf levels decreased in in iNPH but rapidly returned to normal levels within 1–3 months after shunt surgery. This change was positively correlated with recovery from dementia at 11.8±7.7 months post–operation, suggesting that brain–type Tf is a prognostic marker for recovery from dementia after shunt surgery for iNPH.
Accurate and sensitive molecular biomarkers are needed urgently to make an objective diagnosis of Alzheimer's disease (AD). There is still a substantial unmet need for less invasive and lower–cost blood–based biomarkers to detect brain AD pathology. In this context, we have developed a novel ultrasensitive immunoassay using an ultrasensitive digital array technology (Simoa system, Quanterix) to quantify plasma tau phosphorylated at threonine 181 (p–tau181) in 2017.
In the first cohort composed of 20 AD patients and 15 age–matched controls, the plasma levels of p–tau181 were significantly higher in the AD patients than those in the controls. In the second cohort composed of 20 patients with Down syndrome (DS) and 22 age–matched controls, the plasma concentrations of p–tau181 were significantly higher in the DS group. All of the DS individuals showing an extremely high concentration of plasma p–tau181 (>1.0pg/ml) were older than the age of 40. In the third cohort composed of 11 patients including those with AD and disease controls, the levels of plasma p–tau181 significantly correlated with those of CSF p–tau181.
We have reported for the first time quantitative data on the plasma levels of p–tau181 in controls and patients with AD and DS, and these data suggest that the plasma p–tau181 is a promising blood biomarker for brain AD pathology. Large–scale and well–controlled studies to validate the usefulness of plasma p–tau as a blood biomarker for AD are urgently needed to realize blood–based biomarkers for the diagnosis and evaluation of disease severity of AD in clinical practice.
As many as 50 million people across the world have dementia, an umbrella term for a series of neurodegenerative conditions that cause memory loss. These conditions can become severe enough to impair a person's ability to continue their normal daily activities. Some of risk factors of dementia are lifestyle–related and, as such, modifiable. The World Health Organization published a new set of guidelines that seek to advise governments, policymakers, and healthcare providers on how best to tackle dementia prevention. These possible factors are : low levels of physical activity, smoking, a poor diet, alcohol misuse, insufficient or impaired cognitive reserve, lack of social activity, unhealthy weight gain, hypertension, diabetes, dyslipidemia, depression, and hearing loss. The existence of potentially modifiable risk factors means that prevention of dementia is possible through a public health approach, including the implementation of key interventions that delay or slow cognitive decline or dementia.
Molecular hydrogen (H2) functions as an antioxidant and anti–inflammatory agent. The routes of H2 administration are roughly classified into three types, inhalation of H2 gas, drinking H2–dissolved water, and injection of H2–dissolved saline. This review discusses some of remarkable progress that has been made in the research of H2 use for neurological disorders in animal models and clinical studies. Many studies suggest that administration of H2 is efficacious in the treatments of cerebrovascular diseases including ischemia–reperfusion injury and subarachnoid hemorrhage. Inhalation of H2 gas has a neuroprotective effect comparable to therapeutic hypothermia for brain injury after cardiac arrest. Drinking H2–dissolved water is potentially useful for alleviating neurodegenerative diseases including Parkinson's disease and Alzheimer's disease and improving the quality of life in senior people. Several of the potential effectors of H2 will also be discussed, including cell signaling molecules that are responsible for preventing oxidative stress and inflammation. Nevertheless, further investigation will be required to determine the direct target molecule of H2.
Myasthenia gravis (MG) is an autoimmune disorder induced by antibodies against molecules on the postsynaptic membrane. The primary targets are the acetylcholine receptor (AChR) and muscle–specific tyrosine kinase (MuSK). The reason why patients produce such autoantibodies remains unknown. The therapy for MG improved its efficacy and safety in recent years. We admit non–specific immunosuppressive therapy and thymectomy are adequate for treatments of MG. According to the National Epidemiological Surveillance in Japan, the prevalence of MG almost doubled in 2018 compared to that of 2005. Lerner (2016) reported that autoimmune diseases are increasing over countries. As a regional specificity, the northwest area has a high prevalence than the southeast region. Generally, the factors that influence the disease are genetics, living environment, working environment, food, exercise habit, lifestyle, and mental health. There might be some risks in the westernized lifestyle for the onset of autoimmune diseases that we do not realize yet. Westerberg (2018) studied the lifestyle of MG patients in Sweden. They reported patients with MG tended to be obesity, eat less fish, smoke frequently, have a problem in mental health, and less physical activities. Iwasa (2018) reported that titers of anti–AChR antibody in MG patients related to the incidence of Mycoplasma pneumonia and influenza virus infections. These two reports are precious to connect the etiology of MG and environmental factors. In a further study of the prevention of MG, we should go straight forward to integrated research of epidemiology, genomics, transcriptomics, proteomics, metabolomics, and microbiomics. As well, we need to cooperate with researchers in the field of other autoimmune diseases.
Most important factor to prevent stroke for the first time is hypertension. However, there are relatively few people who get normal blood pressure, although they aware their own hypertension. Recently that tendency was called “hypertension Paradox”. In Japan many people receive medical checkup which named “Ningen Dock” or “Brain Dock”. At those medical checkup, the measured blood pressures are often dissociated from the blood pressure of the usual daily life. Especially, people with 50 years old or higher have been spending tough and stressful days. The percentage of those stressful time part per day sometimes become very high. We should distinguish the difference of their life pattern to evaluate their blood pressure data at “Ningen dock”, or “Brain Dock”.
Migraine is a common, disabling, and recurrent neurological disorder. The guideline published by Japanese Headache Society, based on evidence–based medicine data, is a useful source of guidance, especially for acute and preventive therapies of migraine (Japanese Guideline for Chronic Headache 2013). In acute treatment, we give migraineurs NSAIDs or triptans. In preventive therapy, we usually use calcium blockers, anti–epileptic drugs, anti–depressants, and β–blockers. Among them, lomerizine, verapamil, valproic acid, amitriptyrine, and propranolol have insurance adaptations in Japan. When we prescribe those drugs, we should choose an appropriate preventive drug with an individual patient. However, we cannot get the enough effects from those preventive drugs of migraine. Because those are not specific medicine for migraine. Recently, monoclonal antibody formulations against calcitonin gene–related peptide (CGRP) or its receptor which is one of causative molecules on migraine pathophysiolohy has been developed. Those formulations are more effective in migraine prophylaxis with minimal adverse events compared to existing preventive medicine. In this article, recent advance in CGRP–based migraine therapy and its perspective are discussed.
Spinal and bulbar muscular atrophy (SBMA) is a lower motor neuron disease caused by an expanded trinucleotide CAG repeat, which encodes the polyglutamine tract, in the androgen receptor (AR) gene. The main symptoms are slowly progressive muscle weakness and atrophy of bulbar, facial and limb muscles. The cardinal histopathological findings of SBMA are an extensive loss of lower motor neurons and intranuclear accumulations of mutant AR protein in the residual motor neurons. SBMA exclusively occurs in adult males, whereas both heterozygous and homozygous females are usually asymptomatic. To elucidate the pathogenic mechanism and develop the therapeutics, we generated a model mouse with AR–97Q in androgen receptor gene. Androgen deprivation through castration or leuprorelin acetate administration improved the symptoms, histopathological findings, and nuclear accumulation of the pathogenic AR in the male AR–97Q mice. Androgen deprivation rescues neuronal dysfunction in animal models of SBMA associated with disappearance of nuclear pathogenic AR accumulation, suggesting that the molecular basis for motor neuron degeneration in this disorder is androgen–dependent nuclear accumulation of the mutant AR. We then performed an investigator–initiated clinical trial of leuprorelin for SBMA. Suppression of disease progression of the swallowing function, serum CK level and incidence of pneumonia by leuprorelin acetate has been demonstrated and leuprorelin was approved PMDA in Japan. Based on these clinical trials, we also demonstrated that disease–modifying therapy like the leuprorelin on SBMA takes a along term treatment up to 7 to 8 years long to assess the efficacy on the true endpoint like death or permanent respirator support.
Advances in basic and clinical researches on SBMA are providing the way for clinical application of molecular targeting therapeutics.
Clinical trials targeting neurodegenerative diseases have particular difficulties in planning and operation due to the complexity of clinical evaluation and the small numbers of patients. Information from clinical trials of pharmaceuticals approved for neurological diseases in Japan is useful. The information of clinical trials can be obtained from package inserts, review reports, and summary of application documents. One of important point of views is whether the test drug is a symptomatic drug or a disease modifying drug. As an example of symptomatic drugs developed in Japan, the review report of zonisamide for Parkinsonism of dementia with lewy body describes association between mechanism of action and endpoints. As an example of disease–modifying drugs developed in Japan, the review report of edaravone for amyotrophic lateral sclerosis describes the selection of endpoints and clinical trial design including treatment period. In addition, guidelines and guidance on clinical trials are useful information for understanding information on clinical trials for drugs approved for neurological diseases. In order to succeed in clinical trials for neurodegenerative diseases and create new evidence, it is important to plan and conduct clinical trials based on the characteristics of the target neurodegenerative diseases.
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that affects the upper and lower motor neurons. Only riluzole and edaravone are approved as drugs for ALS in the world, and new agents with larger effect size are warranted. Recently, investigator–initiated clinical trial of ALS with Hepatocyte Growth Factor, Perampanel, high dose of methylcobalamin, Ropinirole, and Bosutinib were conducted in Japan.
The Japan Early–stage Trial of high dose methylcobalamin for ALS (JETALS) is a prospective, multicenter, placebo–controlled, double–blind, randomized phase III study conducted at 25 neurology centers and is funded by the Japan Agency for Medical Research and Development. At JETALS, we will evaluate the efficacy and safety of high dose methylcobalamin, evaluate that the updated Awaji criteria are useful for early diagnosis of ALS, and verify that high dose methylcobalamin can be appropriately administered by self–administration.
JETLAS was started in November 2017. The patient enrollment period is scheduled to end on October 2019 and the follow–up is scheduled to end on March 2022.
Cerebral small vessel diseases cause lacunar infarcts, cerebral microbleeds, or diffuse white matter diseases. Approximately 5% of them are considered hereditary, including COL4A1/COL4A2–related disorders. COL4A1/COL4A2 encode type IV collagen α1/α2. Heterozygous pathogenic variations in COL4A1/COL4A2, usually missense variants substituting Gly residue at G–X–Y repeat of COL4A1/COL4A2 procollagen peptides, are associated with wide variety of multi–organ phenotypes. As for brain features, they can cause porencephaly, schizencephaly, hydranencephaly, or intraventricular/subependymal hemorrhage as the most severe phenotypes, to adult–onset intracerebral hemorrhage, lacunar stroke, microbleeds, leukoencephalopathy, migraine, or cerebral aneurysm as milder or asymptomatic forms. Other organs possibly affected include eye, kidney, muscle, cardiovascular system, as well as blood (hemolytic anemia). Hereditary angiopathy with nephropathy, aneurysm, and muscle cramp (HANAC syndrome), pontine autosomal dominant microangiopathy and leukoencephalopathy (PADMAL), and hereditary multi–infarct dementia of the Swedish type (hMID) are the specific forms of COL4A1–related disorders with respective pathogenic–variant hotspots. The diagnostic yield of COL4A1/COL4A2 in patients with clinically suspected COL4A1/COL4A2–related disorders are around 20%, implying that there might be other genetic cause to explain this disease. Under this hypothesis, we identified COLGALT1 as a novel aberrant gene associated with autosomal recessive cerebral small vessel disease which shares common molecular pathogenesis with COL4A1/COL4A2–related disorders.