Lecanemab is a humanized IgG1 monoclonal antibody that preferentially targets soluble aggregated Aβ species (oligomers, protofibrils) and insoluble fibrils. In a phase II proof of concept study in early Alzheimer disease, lecanemab 10mg/kg bi–weekly treatment reduced amyloid PET SUVr and slowed clinical decline. In the CSF substudy, lecanemab showed reduction of CSF p–tau181, neurogranin, and slowed increase of Neurofilament light chain which are biomarkers of tau pathophysiology, synaptic dysfunction, and axon degeneration, respectively. An Open label extension (OLE) with 10mg/kg biweekly lecanemab dosing was implemented after analysis of the Core study, enrolling 180 subjects, with an intervening Gap period off–treatment of 9–59 months (mean 24 months). Amyloid PET SUVr level maintained over the gap period and further reduced with retreatment of lecanemab. Lecanemab showed amyloid reduction and slowing of clinical decline, reduced or slowed increase of CSF AD biomarkers indicating that lecanemab inhibits downstream AD pathophysiology by removing brain amyloid.

Dementia is one of the most important issues in the ageing world. Not only in Japan as a super aging society and whole developed nations with aging society, but also in the whole world. Disease–modifying therapies for Alzheimer disease (AD) have long been awaited for more than a quarter–century. One of the concerns for drug development is proper AD staging for clinical trials and difficulty for subject recruitment. As countermeasures for these obstacles, a concept of a preclinical stage Alzheimer disease and a trial–ready cohort have developed in several places. This article outlines a preclinical stage of AD and the Japanese trial–ready cohort (J–TRC).

To date, no anti–Parkinsonian drug has been proven to have disease–modifying effects, but Japanese guideline suggests that treatment should be initiated as early as possible after diagnosis unless there is a specific reason not to. Treatment should be initiated with L–dopa, dopamine agonists, or MAO–B inhibitors. The choice of initial treatment should be based on efficacy, short–term side effects, and avoidance of future motor complications. Currently, many types of dopamine agonists and MAO–B inhibitors are available, and it is possible that the choice of treatment may take into account their effects on non–motor symptoms. The author believes that the algorithm for early–stage Parkinson disease in the guideline is only an indication of what should be the mainstay of early treatment, and that combination treatment that utilizes the characteristics of each drug is important rather than relying on one drug.

In Parkinson disease, the dopamine replacement therapy has been established in 1960s and followed by dopamine agonists and monoamine oxidase B inhibitor. Motor complications are known as an ignition key of the advanced stage, which include motor fluctuation and dyskinesia. Variable pharmacological agents have been developed for advanced stage of Parkinson disease, which is based on the therapeutic strategic concept of continuous dopaminergic stimulation. Catechol–o–methyltransferase inhibitors, sustained–release oral agents and dopaminergic agonist patches, and L–dopa carbidopa intestinal gel are available in Japan. With the addition of opicapone to the therapeutic lineup in 2020, a wider choice of anti–parkinsonian drugs has been available. However, clinical picture of patients with advanced stage of Parkinson disease is changing due to the aging of Japanese society. Since clinical trials targeting only them are scarce, the development of anti–parkinsonian drugs targeting the older adults is an urgent issue.

Deep brain stimulation (DBS) and levodopa–carbidopa intestinal gel (LCIG) therapy for Parkinson disease (PD) have been covered by insurance in Japan since 2000 and 2016, respectively, and are both very useful for improving motor symptoms in advanced Parkinson disease. However, they have various problems in the perioperative, induction, and post–operative phases because they use surgery and devices. The indication for treatment is the occurrence of fluctuating motor symptoms, i.e., wear–off and dyskinesia, which cannot be adequately improved by drugs. In the perioperative and maintenance phases, there are complications due to the use of opportunity therapy, and the frequency of these complications should be considered. There is still insufficient evidence for post–operative treatment, and further findings are needed. In conclusion, the treatment of DBS and LCIG in PD should be considered strategic in itself.

Tau protein is encoded by microtubule–associated protein tau (MAPT), which is located on chromosome 17 in humans, and contributes to microtubule stabilization. Tau protein is abundant in neurons of the central nervous system and is also expressed at very low levels in astrocytes and oligodendrocytes. Tau protein itself is highly soluble ; however, hyperphosphorylated tau protein becomes insoluble and highly aggregated tau fibrils, which accumulate inside and outside the cells and cause neurotoxicity. Such tau lesions are pathognomonic hallmarks observed in the brain of various neurodegenerative diseases collectively referred to as tauopathies, such as Alzheimer disease, progressive supranuclear palsy, corticobasal degeneration, and Pick disease, and are suspected of being related to neurological damage. Recently, the development of tau positron emission tomography (PET) imaging technology using PET and a PET ligand with binding affinity and selectivity for tau lesions has made it possible to visualize tau lesions in vivo, and research on brain pathology using this technology is progressing remarkably. This paper reviews the history of tau PET imaging technology development and the differences in the properties of each ligand, followed by a review of the latest findings of tau PET imaging research in Alzheimer disease and non–Alzheimer's tauopathies. Finally, future prospects for tau PET imaging research are discussed.

The magnetic field strength meant by ultra–high field magnetic resonance imaging (MRI) has been changing with the development of MRI, and in recent years, it is commonly used to refer to scanners with a magnet of 7 tesla (7T) or higher. The resolution of MRI depends on tissue relaxation time and contrast, as well as the signal–to–noise ratio (SNR). Increasing the magnetic field strength not only improves SNR, but also enhancing the tissue contrast. 7T MRI has significant advantages over conventional 3T MRI, including practical sub–millimeter order spatial resolution and improved sensitivity in functional MRI (fMRI). 7T MRI enhances intra–tissue (within gray and white matter) susceptibility contrast. In addition, high resolution of fMRI at 7T provides the opportunity for the separation of input and output information based on layer specific analysis in local brain regions. With the recent development of post–processing techniques, a paradigm shift from conventional macroscopic mapping (gyrus and sulcus) to analysis of function–structure relationships at the individual level is anticipated.

Now, the various images are necessary for the differential diagnosis of neurodegenerative diseases, and brain MRI and brain perfusion SPECT are widely used in daily medical practices. Furthermore, in the diagnosis of Parkinson related disorders, the images such as myocardial MIBG scintigraphy and dopamine transporter scintigraphy are useful, but not sufficient. Therefore, we assess that it is possible to obtain useful information for the differential diagnoses and elucidation of neurodegenerative diseases by introducing the new settings and the image analysis methods in common medical devices. 1) We developed Individual Voxel–based Morphometry Adjusting Covariates (iVAC), a new voxel–based morphometry for brain MRI. By evaluating the atrophy of the putamen, pons, and middle cerebellar peduncle, we could show the possibility of distinguishing between multiple system atrophy and Parkinson disease with high accuracy. 2) By evaluating the atrophy of the nucleus ruber and the subthalamic nucleus using quantitative susceptibility mapping, we are trying to distinguish Parkinson disease from progressive supranuclear palsy. 3) By analyzing the brain perfusion SPECT in many Parkinson disease cases, we are trying to show that the blood flow decrease of the occipital lobe is the remote effect. 4) We succeeded in developing the serotonin transporter imaging by utilizing the property that 123I–ioflupane, which is the nuclide of the dopamine transporter scintigraphy, also binds to serotonin transporter. We are trying to evaluate the abnormality of the serotonin transporter in multiple system atrophy, in which medullary serotonin nerve loss was reported.

Migraine is a neurological disease that is typically characterised by recurrent attacks of severe, unilateral, pulsating headaches associated with nausea, vomiting, photophobia, and phonophobia. Pharmacologic interventions for migraine include acute and preventive medications.

Several medications, including lomerizine, valproate acid, propranolol, amitriptyline, and verapamil, are used for migraine prophylaxis in Japan. However, substantial advances in migraine therapy mean that some individuals with migraine are refractory to guideline–based treatment.

Despite the definitions provided by the 3^rd edition of the International Classification of Headache Disorders, it does not include a definition of refractoriness in migraine. A growing need of a shared definition of refractoriness has already been claimed from a multidisciplinary expert group. Though some definitions of refractory migraine (RM) have been created, it is still being debated what should be the key parameter of a definition of refractoriness (e.g., unresponsiveness to treatment, high frequency, severe disability or all of these features). Therefore, there is not enough consensus on the definition of RM.

Calcitonin gene–related peptide (CGRP) is a neuropeptide that has an important role in migraine pathophysiology and is a target for migraine preventive therapies. Monoclonal antibodies targeting CGRP (galcanezumab, fremanezumab and eptinezumab) and its receptor (erenumab) showed consistent efficacy for migraine prophylaxis with excellent safety profiles. The effects on refractory cases have also been reported, and it is expected to bring the good news to many patients who have not been effective with existing treatments, and a paradigm shift in migraine treatment is expected.

Following the widespread use of monoclonal antibodies targeting CGRP and its receptor, European headache federation proposed the definition of two subsets of difficult–to–treat migraine, resistant and refractory migraine, and considers both frequency and disability from single and frequent attacks. The definition will be expected to solve the conflicts that have limited the use of definitions which have been put forward in the past.

Migraine is a common neurological disorder characterized by recurrent headache attacks of moderate to severe intensity. Accumulating evidence indicates that calcitonin gene–related peptide (CGRP) plays a pivotal role in migraine pathogenesis. CGRP–based pharmacological interventions are already in clinical use worldwide. CGRP–induced sensitization of the trigeminal system seems to be an important event for migraine headache generation. In the dura, CGRP expression is found in unmyelinated C–fibers, whereas the CGRP receptor components, CLR and RAMP1, are expressed in myelinated Aδ–fibers. Upon activation of the CGRP receptor, a cascade of intracellular events is provoked within the trigeminal ganglion neurons, including altered transcriptional activity, nitric oxide synthase activation and the post–translational modifications of receptors and ion channels. Moreover, CGRP–induced activation of satellite glial cells can drive inflammatory processes through the production of proinflammatory cytokines and nitric oxide. All these phenomena contribute to the development of trigeminal sensitization. CGRP–related antibodies are known to reach the dura and the trigeminal ganglia. CGRP and its receptors are also expressed in the central nervous system. Notably, CGRP expression is observed within the projections from the parabrachial nucleus to the central amygdala. This pathway is closely related to nocifensive reactions and provocation of unpleasant memories associated with past migraine attacks. It is obvious that CGRP exerts multifaceted actions in migraine disease mechanism.

Antibody drugs targeting the calcitonin gene–related peptide (CGRP) have recently started appearing in clinical guidelines in the U.S., Europe and Japan as new therapies for the prevention of migraine. In 2021, several CGRP–targeted antibody drugs were approved in Japan, adding to new prophylactic treatment options based on migraine pathophysiology. Erenumab is the first approved human anti–CGRP receptor monoclonal antibody that selectively binds to the CGRP receptor in the world. In 2018, erenumab was launched in the U.S. and Europe for the prevention of migraine. As of May 2021, erenumab had been approved in 71 countries and territories including all EU member states, the U.K., Canada and Australia. In June 2021, erenumab was approved in Japan for use in inhibiting the onset of migraine attacks. In this paper, we draw on the clinical trial data for erenumab in episodic migraine (EM) and chronic migraine (CM) patients to discuss the drug's efficacy and safety in treating migraine, and we describe how erenumab is expected to contribute to improved treatment outcomes in headache patients by targeting the underlying pathophysiology of migraine.

(Background)

Fremanezumab is a humanized IgGΔa/kappa monoclonal antibody developed for the prevention of migraine. It selectively binds to the calcitonin gene–related peptide (CGRP), which is considered to be intrinsically involved in the pathology of migraine, thereby inhibiting the binding of two isomers (α– and β–CGRP) to CGRP receptors and suppressing the activation of the trigeminal system. In Japan, marketing approval for fremanezumab was obtained for the indication of “inhibition of migraine attacks” in June 2021. Two dosing regimens, once every 12 weeks (quarterly) and once every 4 weeks (monthly), are available.

(Clinical studies)

In a global phase 3 study in patients with chronic migraine (CM) (the HALO CM study), least squares mean ± standard deviation changes from baseline in the monthly average number of headache days of at least moderate severity (average during the 12–week period after the first dose), the primary endpoint, were −4.3 ± 0.3 days in the fremanezumab 675mg quarterly group (Q group) and −4.6 ± 0.3 days in the fremanezumab 225mg monthly group (M group). These were significantly shorter than the −2.5 ± 0.3 days in the placebo group (P group), thus demonstrating the superiority of fremanezumab to placebo (p < 0.0001, Wilcoxon rank–sum test). Common adverse drug reactions in the fremanezumab groups were injection site pain, induration, and erythema, of which most were mild or moderate. In the Japan–Korea joint phase 2b/3 study in patients with CM in Japan and Korea conducted after the HALO CM study, changes from baseline in the monthly average number of headache days of at least moderate severity (average during the 12–week period after the first dose), the primary endpoint, were −4.1 ± 0.4 days in the Q group and −4.1 ± 0.4 days in the M group. These were significantly shorter than the −2.4 ± 0.4 days in the P group, again demonstrating the superiority of fremanezumab over placebo (p < 0.001, ANCOVA). Adverse drug reactions observed in the fremanezumab groups were injection site pruritus, pain, induration, and erythema, and many of these reactions were mild or moderate.

Conclusion

The results of these two studies in patients with CM were similar regardless of race or region. Quarterly and monthly subcutaneous administration of fremanezumab to such patients is expected to become a new treatment option.

Psychiatric disorders comorbid with patients with epilepsy are classified into antiseizure drug induced behavioural adverse reaction, ictal–related and interictal psychiatric disorders. Topiramate, levetiracetam and perampanel have been considered to be high risk antiseizure drugs for antiseizure drug induced behavioural adverse effect (BAE). Neither the diagnosis and treatment for the BAE remained to be clarified. Currently, switching of the causative antiseizure drug is recommended for treatment of BAE. Recently, the pathophysiology of BAE is exploring, and then several hypotheses suggested the similarities of pathomechanisms among ADHD, autism spectrum disorders and BAE.

Acute symptomatic seizures (ASS) and status epilepticus (SE) are common neurological emergencies. The definitions of ASS and SE and relationship between them should be understood to manage them appropriately. In this review, the definitions, epidemiology, relationship, and management strategy of ASS and SE are outlined. Importantly, seizures are classified into ASS and unprovoked seizures. ASS accounts for 55% of all seizures. While both ASS and unprovoked seizures can cause SE, ASS accounts for 50–87% of all SE. Therefore, we should differentiate ASS in most cases of seizures and SE. In patients with ASS, underlying etiologies must be treated, and further seizures be prevented according to the risk of seizure recurrence. The decision to start antiseizure medications, their choice, and treatment duration should be individualized with no clear guidelines available. In patients with SE, ongoing seizures must be stopped as soon as possible in parallel with the differentiation of ASS. SE should be treated in accordance with the treatment guidelines published in the US, Europe, and Japan : benzodiazepines as the first–line, intravenous antiepileptic drugs as the second–line, and anesthetics as the third–line drugs. When anesthetics are used, continuous electroencephalogram monitoring is recommended to monitor the level of sedation, assess the efficacy of treatment, and diagnose nonconvulsive seizures and nonconvulsive SE.

Since 2006, many newer antiseizure medications (ASMs) have been launched in Japan. When using newer ASMs, it is recommended to consider their efficacy, side effects, and added values for providing personalized treatment. Recent studies on patients with focal epilepsy suggested that the efficacy of several newer ASMs is not inferior to that of carbamazepine, an established first–line drug. Newer ASMs have less drug–drug interaction and long–term adverse reactions such as osteoporosis and cardiovascular events than older ones. Among newer ASMs, zonisamide and lamotrigine exhibit a higher incidence of severe rash than others. Zonisamide and topiramate decrease cognitive functions. Psychiatric side effects are observed in zonisamide, topiramate, levetiracetam, and perampanel users. Added values include the anti–migraine effect of topiramate, anti–depression effect of lamotrigine, anti–anxiety effect of gabapentin, the long half–life of perampanel, and less drug–drug interaction of gabapentin, levetiracetam, and lacosamide. Various mechanisms of action of newer ASMs help more rational polytherapy. Comorbidities such as depression, migraine, dementia, and cardiovascular diseases are vital factors to optimize medication. Lamotrigine and levetiracetam are favorable for women of childbearing age because of their low teratogenicity. During pregnancy, the blood level of lamotrigine and levetiracetam should be monitored to keep optimal levels and avoid seizure worsening.

Neurological and muscular immune–related adverse events (irAE) associated with cancer treatment with immune checkpoint inhibitors (ICI) include diverse clinical subsets. The diseases affect the central nervous system, peripheral nerves, neuromuscular junction, and muscle. One of representative irAE is myasthenia gravis (MG). Recently, clinical features of MG occurred as irAE (irAE–MG) have been elucidated. Authors previously studied cancer patients who had received monotherapy with nivolumab between September 2014 and August 2016. As the control group, 105 patients with idiopathic MG were used. There were 12 MG cases (0.12%) among 9,869 cancer patients who had been treated with nivolumab. These 12 patients included six men and six women with a mean age of 73.5 ± 6.3 years. MG onset occurred in the early phase after nivolumab treatment and rapidly deteriorated. Nivolumab–related MG (nivoMG) included four patients with mild involvement and eight patients with severe involvement. Bulbar symptoms and myasthenic crisis were observed more frequently in nivoMG than idiopathic MG patients. Serum creatine kinase levels were markedly elevated to an average level of 4,799 IU/L. Among the 12 nivoMG patients, four had myositis and three had myocarditis, with one of these patients having both. Immunosuppressive therapy was effective. In addition, there is a tight association between irAE–MG and myositis, termed as “PD–1 myopathy”. There are guidelines for the diagnosis and treatment of irAE–MG. The prompt and correct recognition of MG following treatment with ICI in cancer patients is important.

In Japan, the Long–Term Care Insurance Law was revised in 2011, the Five–Year Plan for the Promotion of Dementia Policies (Orange Plan) was formulated in 2012, and the Comprehensive Strategy for the Promotion of Dementia Policies – Toward the Development of Regions Friendly to Elderly People with Dementia, etc. (New Orange Plan) was formulated in 2015. Based on the basic policy of “respecting the wishes of people with dementia,” efforts have been made to realize a society in which people with dementia can continue to live as they like in a good environment in their own neighborhoods as long as possible.

In December 2018, the Council of Ministers for the Promotion of Dementia Policies was established for the purpose of promoting comprehensive measures for various issues related to dementia through close collaboration among relevant government agencies, and on June 18, 2019, the Outline for the Promotion of Dementia Policies was compiled. The basic idea of the National Guideline for the Promotion of Measures to Cope with Dementia is to delay the onset of dementia and to create a society in which people can live their daily lives with hope even if they have dementia. Furthermore, while focusing on the viewpoints of people with dementia and their families, the government will promote measures based on the two wheels of “symbiosis” and “prevention”.

Currently, all municipalities are taking the initiative in promoting dementia measures based on this general framework for the promotion of dementia measures. Municipalities are required to formulate a plan for dementia measures every three years, and this year's plan has been formulated as the 8th Long–Term Care Insurance Business Plan. Based on the plan, municipalities must analyze the area in question, build a network to provide the necessary services at all stages of dementia, from the early stages of the disease, and systematically improve the system so that people with dementia can use the services as needed.

In this symposium, I explained how the involvement of professionals in the “business plans” promoted by local governments can advance community development, using the example of the project to promote intensive initial support for dementia as an example from my experience as both a physician and an administrative physician.

Dementia has an extremely long course of disease, more than 10 years, from the time of initial awareness to mild, moderate, and severe conditions, during which changes in symptoms such as cognitive dysfunction and Behavioral and Psychological Symptoms of Dementia occur. Therefore, living with dementia is not an easy matter for people with dementia, family caregivers, or medical and care professionals. Given these circumstances surrounding dementia, the concept of community–based integrated care is becoming more and more important in order to value life in the community and to effectively utilize local resources for care. However, there was a question as to whether dementia care could be successfully encompassed within the principle of community–based integrated care. We thought that dementia cafés could be an important breakthrough for it, and we actually operated a dementia café. We also verified the factors necessary for effective café operation, methods to ensure the skills required for dementia café staff, and the significance of participation and involvement of medical professionals in dementia cafes. Based on these findings, we hope that the continuation of dementia cafés will help establish community–based integrated care for people with dementia and for all people living in this aging society.

On June 18, 2019, the Ministerial Council on the Promotion of Policies for Dementia Care was held. At the meeting, a discussion was held on the draft Framework for Promoting Dementia Care. In this framework, relevant measures have firmly been implemented, focusing on inclusion and prevention, much like two wheels of a cart, while putting emphasis on the perspectives of the patients and their families. Specifically, advances of measures to make all aspects of everyday life more accessible have been emphasized, aiming at materializing inclusion so that dementia patients can maintain their own lifestyle in their communities with which they are familiar. On the other hand, we will promote prevention through the development of a place where the elderly can easily find and attend various exercises which are effective for prevention, and the promotion of research and development on preventive cares methods. Team Orange is a new challenge which can provide the provision of early life support for people with dementia and their families by a neighboring team of dementia supporters. People with dementia are expected to join the team as members. This paper reports on the dementia café carried out in our university by SWOT analysis. In the Framework for Promoting Dementia Care, dementia café administered by Team Orange is positioned as one of community activities to maintain the lifestyle of persons with dementia and their families. Also, it is well known that the activities of dementia café increase the recognition and awareness of dementia in the community, which will make easier for persons with dementia to live in the community. Launching Team Orange is a first step which is necessary to create a comfortable place with persons with dementia including local residents.

The prevalence of dementia is constantly increasing because of the aging population, and it emerges not only as a medical but also a social problem in the world. Shortening the time from onset to diagnosis of dementia and providing appropriate medical and nursing care information from an early stage, can lead to the start of nursing care insurance services, and may affect the prognosis of patients and their families. Since 2014, we have implemented the “Project for Establishing a Medical and Nursing Care Coordination System for Dementia Care” as a joint project with the Mie Prefectural Medical Association and established the early detection and intervention system for dementia through outreach–type dementia care. Dementia IT Screening (DITS) is conducted for patients suspected of having dementia. When the family physician suspected the patient as dementia, the physician can order DITS. Cognitive function is assessed by Mini Mental State Examination (MMSE) and Brain Function Battery (BFB). Daily life is assessed with the Action Observation Sheet (AOS) and Dementia Assessment Sheet for Community–based Integrated Care System–21 items (DASC). The dementia specialist makes a comprehensive judgment for the necessity of visiting a specialized medical doctor. From April 2015 to March 2021, 708 examinees were tested. Of these, 415 (58.6%) were recommended to see a specialist medical doctor, 276 (66.5%) were referred to a specialist medical doctor, and 192 (69.5%) were diagnosed with dementia as a result of differential diagnosis. This system can provide the post–diagnosis support to the patients with dementia and their families by enabling early diagnosis through the corroboration between family physician and specialized medical doctor. Moreover, we also can promote medical and welfare cooperation between regional comprehensive support centers, early intensive support teams for dementia, and medical institutions.

Factors that contribute to falls are divided into three major categories : physical, behavioral, and environmental factors. Physical variables in patients with neurological illnesses include paralysis, postural instability, and sensory disturbance. Geriatric syndrome, such as sarcopenia/frailty, osteoporosis, poor nutrition, and cognitive impairment, as well as comorbidities, enhance the risk of falls in the elderly. To prevent falls in elderly patients with neurological diseases, these issues must be addressed. A suitable environment should be created by keeping the characteristics of each neurological condition in mind, which includes using the toilet before the urge to urinate and proper placement of things to ensure that they do not fall. It is essential to establish fall prevention strategies with the involvement of patients and their families and to actively communicate these strategies to patients. We should intervene in a multidisciplinary and multifaceted manner, and make the intervention enjoyable for both patients and medical staff. It is also vital to consider the causes and mechanisms of falls, and to avoid falls that can be prevented as much as possible.

Older adults with dementia (OAwD) present serious fall risks, potentially affecting other risks, that dramatically increase the chances of falling. The severity of these risks may vary across time depending upon a variety of factors. The individual fall risk seen in dementia involves executive function disorders, including excretion behaviour related with visual space recognition, functional disorder, and attention–deficit disorder.

Upon hospitalization, OAwD are often in a confused, unconscious, or agitated state that may lead to an increased chance of falling during their stay. Although healthcare professionals are trained to address the medically significant physiological risks presented by OAwD, their high risk of falling is often neglected. Furthermore, the side effects of psychotropic medication and the experience of delirium can cause OAwD to fall while walking due to a disturbance of consciousness.

Via the implementation of person–centred care in geriatric institutions, healthcare staff practiced appropriate palliative care targeting the behavioural and psychological symptoms of dementia and tailoring to the individual needs of OAwD, and they were able to effectively reduce the occurrence of falls.

The following results, including the assessment of fall risk related to the executive functional disorder of dementia and person–centred care for fall prevention, have been proven to be effective methods to reduce the occurrence of falls in OAwD.

Patients with neurological diseases such as cerebrovascular disease and Parkinson disease are required appropriate nutritional assessment and intervention because of high frequency of falls. We focus on the following three key points of nutrition to prevent falls : (1) malnutrition, (2) sarcopenia, and (3) osteoporosis. In older adults, malnutrition is one of the risk factors of falls. Nutritional screening tools such as MNA^®–SF and SGA takes account of weight loss, body mass index, and changes in dietary intake, but the GLIM criteria for the diagnosis of malnutrition published in 2018 allows assessment that also considers inflammation associated with the diseases. In order to prevent malnutrition, it is essential to ensure that the diet provides sufficient energy. Many patients with neurological diseases have dysphagia and may not be able to intake their energy requirements with texture–modified diets. We recommend that avoiding skipping meals, using nutritional supplements appropriate for their swallowing ability. Additionally, adequate intake of protein is also important for older patients, as they have less skeletal muscle and are more susceptible to sarcopenia. Branched–chain amino acids (BCAAs) have been reported to promote synthesis and inhibit catabolism of muscle proteins. In older adults with low blood vitamin D levels, vitamin D supplementation may be useful in preventing falls. Because some patients who fall suffer from fractures, it is important to prevent of osteoporosis. The osteoporosis guidelines recommend to intake not only calcium, the main component of bone tissue, but also vitamin D and vitamin K. Our hospital provides nutritional counseling consecutively at the time of discharge and during outpatient visits to prevent falls at home.

Botulinum toxin injection improves abnormal posture and limited range of motion associated with spasticity. Botulinum toxin therapy has been approved for post–stroke spasticity. It can also be used to treat limb spasticity in cerebral palsy, multiple sclerosis, hereditary spastic paraplegia, lower limb spasticity in HTLV–1–associated myelopathy (HAM), and upper limb spasticity in corticobasal syndrome (CBS). In order to inject the muscles safely and accurately, it is recommended to use ultrasound, electromyography, or electrical stimulation. Because the effects of botulinum toxin diminish 3 to 4 months after infection, it is often repeated to increase the therapeutic efficacy. Adverse events of the treatment include pain, bleeding, and weakness due to overdosage, but serious side effects are rare and can be safely repeated. Rehabilitation after botulinum toxin injection is extremely important to achieve efficacy, and collaboration with physical and occupational therapists is essential.

Neurorehabilitation encompasses the process of improving motor and cognitive functions by modifying the functions and network of the brain, based on neuroscience. The synaptic transmission efficiency varies in the brain and exhibits dynamic changes because of synaptic activity levels and interactions with other synaptic inputs. Synaptic plasticity refers to the physiological basis of motor learning by modifying synaptic connections in an activity–dependent manner. Transcranial direct current stimulation (tDCS) and repetitive transcranial magnetic stimulation (rTMS) are types of non–invasive brain stimulation. They synergistically increase synaptic plasticity upon combination with rehabilitation treatment. The duration of depolarization by electrical stimulation to the motor field began expansion from the 1960s. Subsequently, researchers developed stimulation methods using high–voltage current and magnetic fields that did not decay even in skulls with high electrical resistance in the 1980s. tDCS and circular coil rTMS have a wide range of stimulation ; nonetheless, the figure–eight rTMS coil developed in Japan enables local stimulation and is being clinically applied. The effect of rTMS on neural activity depends on the frequency of stimulation. High frequency ≥5Hz enhances neural activity, whereas low frequency ≤1Hz suppresses it. It is necessary to increase the neural activity of the site that compensates for the impaired function in patients with cerebrovascular accidents. Thus, researchers have proposed the following two approaches : (i) applying high frequency rTMS to the ipsilesional primary motor cortex (M1) and (ii) applying inhibitory low frequency rTMS to the contralateral M1. The application of inhibitory low frequency attenuates the interhemispheric inhibition from the stimulated cerebral hemisphere to the functional compensation site. In addition, it indirectly activates the functional compensation site by releasing it from the interhemispheric inhibition. The aforementioned patients are divided into groups effective for the high frequency on the diseased side and for the low frequency on the healthy side. Neurorehabilitation promotes functional improvement when used in combination with contemporary rehabilitation treatment.

Studies reporting rehabilitation therapy using robots began in the 1980s and have increased since 2000s. In Japan, against the background of an aging society, the use of imported robots for research purposes began, followed by the development of domestic products and their clinical application.

Robots used by therapists for training are called training assist robots. In order to understand the wide variety of robots, it is helpful to divide them into the “structure”, the “motion”, and the “movement”.

The “structure” of the upper limb is the end effector type in which the joints are moved with the peripheral side fixed, the “motion” is the single joint functional training of dexterity movements such as reaching movements, and the “movement” is the three–dimensional movement of the shoulder and elbow forearm joints and one–dimensional movement of the single joint.

The “structure” of the lower limb is the exoskeletal type in which joint axes are made with an exoskeleton to move the joints, “motion” is gait, and “movement” is mostly 2–dimensional movements of the hip, knee, and ankle joints.

Training assist robots are usually used in combination with conventional therapy. Evidence of their effectiveness has been steadily accumulating, and they might be effective in improving upper limb function, dexterity, and ADL. It is expected to improve the level of walking independence for those who are unable to walk within 3 months of onset of illness.

Training assist robots are characterized by their ability to safely perform the uniform repetitive movements required in rehabilitation therapy, with a low burden on the therapist, a sufficient amount of training, and the ability to provide evaluation and feedback. However, they play only an auxiliary role in rehabilitation therapy, and their weaknesses are that they take time to set up and prepare, and that they have no applications other than setting up.

Recently, hand training assist robots have been developed, which can perform gripping and pinching movements with a glove attached. The direction of future evolution is likely to be divided into two directions : one is to provide large, unitized, safe treatment that can accommodate severe disabilities with fine–tuning by taking advantage of its multiple functions, and the other is to provide compact, lightweight, fixed treatment in various settings, including at home, by taking advantage of its portability.