Neuromyelitis optica (NMO) is an inflammatory disease that resembles MS in the relapsing clinical course and occurrence of optic neuritis and myelitis. Two decades of studies have revealed that the antibody, reactive to a water channel protein AQP4, induces inflammatory pathology of NMO, which is mediated by proinflammatory cytokines, chemokines, and various inflammatory cells. The presumed disease mechanism constructed based on accumulating studies has led to the identification of possible targets of therapy, including interleukin–6 (IL–6) receptor signaling. Our group has discovered the role of IL–6R signaling in the pathomechanism of NMO, and showed the potential efficacy of anti–IL–6R antibody tocilizumab in NMO patients. Remarkably, recent randomized controlled clinical trials have shown the therapeutic efficacy of antibodies specific for IL–6 receptor satralizumab in the core patients of NMO, although there is no evidence for the efficacy in anti–AQP4 antibody–negative patients. The results imply that anti–AQP4 antibody is a biomarker predicting the efficacy of therapies, and indicate the future direction towards “precision medicine”. Given that the development of anti–IL–6R therapy was driven by academia and translational scientists in Japan, it is time to consider how to maintain and develop this construct for the future.

Neuromyelitis optica spectrum disorder (NMOSD) is an autoimmune disease caused by anti–aquaporin 4 antibody. One of the main cause of tissue injury is mediated by complement–dependent cytotoxicity against astrocytes. Now humoral immunity is the main target in NMOSD, there are 4 generally–approved antibiotics including eculizumab, satralizumab, inebilizumab, and rituximab. Anti–CD19 antibiotics, inebilizumab, is a well–tolerated treatment, which could start with two doses / months followed by injection every half a year. It is important to know the long–term safety of inebilizumab treatment in NMOSD, which was reported recently in 2022. In addition, it was reported that there is no impact on the efficacy of inebilizumab between cases with and without pre–use of rituximab. It is observed that the inebilizumab treatment could reduce the dose of prednisolone and other preventive medicine rapidly and improve some psychiatric and metabolic symptoms.

Rituximab was approved on 20^th June, 2022 based on the results of the RIN–1 study : a multicentre, randomised, double–blind, placebo–controlled trial for evaluating the safety and efficacy of rituximab in neuromyelitis optica spectrum disorders (NMOSD). We discussed the current states and issues of rituximab use in patients with NMOSD.

The Myasthenia Gravis (MG) Clinical Practice Guideline 2014 set a treatment goal of “MM-or-better-5mg” and indicated an “Early fast-acting treatment strategy.” In May of 2022, the MG/Lambert–Eaton Myasthenia Syndrome Clinical Practice Guideline 2022 was published and included the complement C5 inhibitor Eculizumab and newly clarifies the definition of refractory. In Japan, a new complement C5 inhibitor, Ravulizumab, has been approved and clinical trials of Zilcoplan are underway. In the future, it is expected to further improve the QOL of patients.

Improvement of the diagnosis and the expansion of the treatment has been boon to the patients with multiple sclerosis (MS), while also we evaluate the condition of a patient with MS appropriately, and it became more important to push forward treatment. The management of the MS which is a chronic disease is rarely concluded only with one medical institution, therefore, I introduce one model of MS regional collaboration from a point of view whether keeping good prognosis and supporting life. This might become the model of MS regional collaboration through making a role clear of the local medical care and welfare institution.

While immune modulation therapies have seen recent tremendous success in relapse remitting multiple sclerosis (MS), our limited knowledge of pathogenesis hampers the development of effective treatments for progressive MS (PMS). In this article, I review the results of completed clinical trials for disease–modifying drugs and their mode of action and discuss the future directions for the treatment of PMS. Those results indicate that, besides the immunoregulatory effects in the periphery, the transition into the central nervous system and the functional modification of resident immune cells such as microglia as well as lymphocytes are indispensable for the next–generation drugs.

Multiple sclerosis (MS) is an inflammatory disease of the central nervous system that produces multiple inflammatory demyelinating lesions, and its T– and B–cell mediated autoimmune pathogenesis has been extensively studied. Patients with MS experience the disease relapses and remissions over many years, and often suffer from gradual progression of neurodegeneration, forcing them to live in a wheelchair. Early intervention with disease–modifying therapies has led to good outcomes in some cases. Several disease–modifying therapies are available for patients with MS, whereas disease status and condition would be different in each patient, further emphasizing the need for personalized medicine.

In advancing personalized medicine for patients with MS, a multifaceted assessment of disease status is important. In addition to neurological symptoms and clinical imaging findings, the cognitive assessment batteries and patient–reported outcomes may be useful in evaluating whether current treatment is optimal. Although the Expanded Disability Status Scale (EDSS) score has been used to assess neurological disability, a combined measure has been reported to better reflect the patient quality of life. In addition to MRI imaging, neuro–ophthalmologic testing or serum neurofilament light chain levels have been highlighted as objective hallmarks reflecting disease severity. While research into autoimmune pathogenesis has brought several therapies for patients with MS, there are surprisingly few immunological indices that reflect the pathophysiology of the disease and are useful for therapeutic strategies. This review provides an overview of the current status and outlines future perspectives for the development of personalized medicine in MS.

Molecular targeted therapies for the neurodegenerative diseases are currently being developed, including Alzheimer disease, Parkinson disease, amyotrophic lateral sclerosis, and spinocerebellar ataxias, some of which are now clinically tested in patients with these diseases. To evaluate the clinical efficacy of these drug candidates, it is necessary to develop pathological biomarkers that enable evaluation of drug efficacy during a short–term period of clinical trials. Compared to functional brain imaging biomarkers, biochemical biomarkers using body fluids, such as blood, cerebrospinal fluid, and urine, are highly versatile and advantageous, because they are relatively easy to collect and do not require special equipment for measurement. Current candidates for biochemical biomarkers for the neurodegenerative diseases include pathogenic proteins, such as amyloid–β, tau, α–synuclein, and ataxin–3, and neurofilament light chain (NF–L), which is thought to reflect neuronal damage. In addition, exosomes and other extracellular vesicles, which are secreted from cells and abundantly present in body fluids, have attracted much attention as a potential source of biomarkers, because they contain a variety of cellular proteins and RNAs and may change in response to the intracellular environment and pathological events. In this review, we will summarize the status of clinical development of therapies and biomarkers for spinocerebellar ataxias, and discuss the current issues on clinical samples for future biomarker development.

In recent years, the disease concept of autoimmune cerebellar ataxia has expanded with the identification of anti–neural antibodies. Autoimmune cerebellar ataxia (ACA) is a group of diseases for which pathophysiological elucidation and therapeutic strategies are expected to be established in the future. Although proposed diagnostic criteria for ACA was published from Europe in 2022, the number of patients with ACA and its pathophysiology are still unknown in Japan. That is why early diagnosis and classification of ACA is difficult, which often leads to difficulties in treatment. It is important to establish diagnostic criteria of ACA in Japan.

Multiple system atrophy (MSA) is a neurodegenerative disease that is associated with various degrees of cerebellar ataxia or parkinsonism, pyramidal disturbances, and sleep disturbances, in addition to autonomic neuropathy. The median life expectancy from disease onset is reported to be 9 years, with a relatively poor prognosis. Symptomatic treatment of autonomic and parkinsonian symptoms may be useful in the short term, but there is a lack of disease–modifying therapies for MSA. In recent years, various therapeutic approaches for MSA are under development, including α–synuclein–targeted therapy (Epigallocatechin gallate and Rifampicin to inhibit pathological aggregation of α–synuclein, Lithium to promote α–synuclein removal, α–synuclein immunotherapy, and nucleic acid drugs to inhibit α–synuclein expression), neuroinflammation–targeted therapy (Minocycline, Fluoxetine, and Verdiperstat), neuroprotection (Rasagiline and Exenatide), and cell therapy (Mesenchymal stem cell therapy). We are developing a novel approach to slow the disease progression of MSA by high–dose ubiquinol supplementation, based on the elucidation of the genetic factors of MSA. Although many disease–modifying therapies for MSA have been developed and each has a number of genetic and cellular biological rationales, no reliable therapeutic approaches have yet been established. Clinical trials are currently underway and are expected to establish effective treatments targeting multiple mechanisms in future.

There is accumulating evidence that intensive neurorehabilitation improves ataxia and activities of daily living in patients with spinocerebellar ataxia. Most rehabilitation programs comprise optimal combination of coordination, balance, and gait exercise according to the principles of motor learning such as repetition of task–oriented practice and increasing balance challenge. There are considerable varieties in the extent and degrees of degeneration in the cerebellar system depending on the type of diseases. For instance, SCA 6 and SCA31 have main lesions in the Purkinje cells that are essential to internal model formation, while SCA 3 has degeneration in the afferent and efferent systems of the cerebellum. These suggest that optimal rehabilitation program need be considered for each type of spinocerebellar ataxia to maximize effect of rehabilitative intervention. Furthermore neuromodulation combined with rehabilitation may facilitate functional gains. There are several clinical trials including non–invasive cerebellar stimulation and neurofeedback for activating the motor related areas.

Historically, the diagnosis of myositis with skin rash fell under the classification of dermatomyositis, while myositis without skin rash were classified as polymyositis. However, with advances in pathology, autoimmune myositis is now classified into four categories : inclusion body myositis (IBM), immune–mediated necrotizing myopathy (IMNM), dermatomyositis (DM), and anti–synthetase syndrome (ASS). All four exhibit their own characteristic muscle pathology findings. The pathological features of IBM are non–necrotic fibers surrounded and invaded by CD8+ T cells and the expression of both major histocompatibility complex (MHC) class I and MHC class II. In addition to the inflammatory infiltrates, fibers with rimmed vacuoles are seen. Immunohistochemical staining reflects the pathological aggregate of TDP–43 and p62. In IMNM, muscle pathology shows many necrotic and regenerating fibers. On the other hand, lymphocytic infiltration is very mild. In chronic cases, endomysial fibrosis is increased, making the distinction between IMNM and muscular dystrophy difficult. The expression of MHC class I is relatively weak but class II is usually not observed. The circumferential deposit of membrane attack complex (MAC) on the sarcolemma is also observed, which suggests that the complement activation pathway is related to the mechanism of the disease. In addition, p62 immunohistochemical staining shows a diffuse expression on the sarcoplasm, reflecting chaperone–assisted selective autophagy. The muscle pathology of dermatomyositis is characterized by the presence of punched–out vacuoles and perifascicular atrophy. Atrophic muscle fibers show dark staining of NADH–TR and decreased cytochrome c oxidase activity. Microinfarction within the fascicles is sometimes seen. The intensity of MHC class I expression is sometimes increased on the edge of the fascicles. The presence of MAC deposits on the endomysial capillaries is a specific feature. MxA expression is a highly sensitive and specific marker for dermatomyositis and is thought to be related to interferon type I. In ASS, necrotic and regenerating fibers are mainly seen at the edge of the fascicles (perifascicular necrosis). Fragmentation of the perimysial connective tissue and alkaline phosphatase enzymatic activity in the perimysium are also seen. An increase in both MHC class I and II expression have been observed, especially on the fibers located at the edge of the fascicles. Understanding the classification of myositis is important because of its impact in the selection of the treatment options that are appropriate for each condition.

Idiopathic inflammatory myopathy (IIM) is a heterogenous autoimmune disorder and its subclassification is important in management of the patients. To date, a variety of myositis–specific autoantibodies (MSAs) have been identified and their clinical significance has been elucidated. MSAs can help us not only to diagnose and classify IIMs but also to predict clinical course and prognosis. Among MSAs, anti–aminoacyl–tRNA synthetase (ARS) antibody and anti–melanoma differentiation–associated gene 5 (MDA5) antibody have the strongest association with interstitial lung disease (ILD). ILD with anti–ARS tends to show chronic disease course and respond well to initial glucocorticoid (GC) therapy but often recur. On the other hand, anti–MDA5–positive patients often show acute/ subacute ILD which is resistant to treatment, showing rapidly progressive respiratory distress. For these patients, combined immunosuppressive therapy including high–dose GC, calcineurin inhibitor and intravenous cyclophosphamide pulse in early stage of the disease has been widely used in Japan with increasing evidences for its effectiveness. Anti– transcriptional intermediary factor 1–γ (TIF1–γ), anti–Mi–2, anti–nuclear matrix protein 2 (NXP2) and anti– SUMO–1 activating enzyme (SAE) are associated with dermatomyositis. Moreover, anti–TIF1–γ and anti–NXP2 are associated with malignancy in adult IIM, the latter of which is associated with subcutaneous calcinosis especially in pediatric patients. Anti–signal recognition particle (SRP) and anti–3–hydroxy–3–methylglutaryl–coenzyme A reductase (HMGCR) are associated with immune mediated necrotizing myopathy. Anti–SRP–positive patients tend to show severe muscle weakness, dysphasia and high creatine kinase (CK) level, and anti–HMGCR–positive patients often have episode of statin exposure.

Thus, MSAs can be useful in prediction of clinical course and early determination of treatment strategy for IIM patients.

Idiopathic inflammatory myopathies have traditionally been classified as dermatomyositis, polymyositis, as well as inclusion body myositis and overlapping myositis. Recently new disease eintities have also been proposed due to advances in research on disease–specific autoantibodies. Dermatomyositis has been defined by the presence of myositis and characteristic skin lesions. The skin lesions of dermatomyositis include pathognomonic rash included in the classification criteria, characteristic rash, and other skin lesions that are not disease–specific but are useful for diagnosis. Treatment of dermatomyositis skin lesions includes topical and systemic therapies, and novel therapies are emerging.

Proximal muscle dominant weakness has long been emphasized in inflammatory myopathy patients except inclusion body myositis (PM/DM). This is of course true, but it is necessary to recognize that most frequently and intractably involved muscles in PM/DM are neck flexor and trunk muscles. In addition to muscles in four extremities, routine evaluation of MMT in neck flexor and pectoralis major muscles is mandatory in general practice of PM/DM patients. Although glucocorticoids, immunosuppressants, and intravenous immunoglobulin are mainstay in PM/DM treatment at present, an individual treatment regimen will develop based on the recent classification of PM/DM. A lot of novel drugs including alpha–interferon antibody, C5 antibody and JAK inhibitors are waiting.

Since Prof. David Marsden pointed out the challenges (i.e. motor complications) associated with long–term L–dopa therapy in 1977, various efforts and innovations have been made to overcome motor complications. This article focuses on the role of novel anti–parkinsonian drugs in advanced Parkinson Disease (PD), including those approved and under development overseas. It is important to achieve continuous dopaminergic stimulation (CDS) in order to improve motor complications. Treatment strategies to achieve CDS with novel drugs include optimization of L–dopa delivery, optimization of L–dopa pharmacokinetics, parenteral administration of short–acting dopamine agonists, and oral administration of long–acting dopamine agonists. Amantadine extended release has been developed for levodopa–induced dyskinesia. L–dopa inhalation powder and apomorphine sublingual film are approved and marketed overseas as rescue drug for off–period.

Since dopamine deficiency was first implicated in the pathophysiology of Parkinson disease (PD) in 1960, oral therapy using levodopa and other drugs is the mainstay of treatment for PD. However, device–aided therapy is increasingly being used in recent years for the management of advanced PD refractory to medical therapy. Currently, deep brain stimulation (DBS) therapy is widely used globally for advanced PD after nearly 30 years since 1990. In addition to conventional stimulation, adaptive deep brain stimulation (aDBS) is a novel method available in Japan since 2020. The aDBS technique is feedback–based, on–demand real–time stimulation. The signal inputs are referred to as local nerve action potentials with need–based adjustment of stimulation in contrast to cDBS. Advances in aDBS will provide personalized therapy and enable stimulation under a more physiological environment and expand the application of DBS for the management of many diseases in addition to movement disorders.

Nearly 200 years after James Parkinson wrote ‘An essay on the shaking palsy’, advances in understanding of the pathogenesis of Parkinson disease have led to the development of various therapies. In the early stages of Parkinson disease, pharmacotherapy such as L–dopa, dopamine agonists, and MAO–B inhibitors play a central role in the treatment of motor symptoms. In the advanced stages, when movement complications such as wearing–off and dyskinesia appear, adjunct therapeutics such as COMT inhibitors, zonisamide, and adenosine A2A receptor antagonist are used. When motor complications do not improve adequately with medical therapy alone, device–assisted therapy (DAT) such as deep brain stimulation therapy or Levodopa–Carbidopa Intestinal Gel (LCIG) infusion therapy may be indicated. In this article, I introduced the recent advances in LCIG therapy.

Device Aided Therapy (DAT) is a strong and well–established treatment option to manage the advanced stages of Parkinson Disease. DAT includes deep brain stimulation (DBS) and pump therapies including levodopa–carbidopa intestinal gel therapy (LCIG), continuous subcutaneous injection of foslevodopa and foscarbidopa, and continuous subcutaneous injection of apomorphine. DAT and Other surgical procedures such as thermal coagulation and MR guided focused ultrasound (MRgFUS) are sometimes classified as invasive therapies. DAT is now the standard treatment option for treatment–resistant involuntary movements and motor complications in patients with advanced Parkinson disease. The strengths and weaknesses of each therapy must be evaluated, and long–term strategies after the introduction of each therapy must also be considered. Indications for each treatment do not appear rapidly at a certain point in the disease progression and disappear suddenly at a certain point, but the degree of recommendation and expected therapeutic benefit vary continuously. In addition, the time when drug therapy can be used and the optimal time for invasive therapies such as DAT sometimes overlap. In addition to recommendations based on symptoms and condition, it is important to make a comprehensive judgment of the patient's environment, the presence of caregivers, and the medical situation in the community, and to propose treatment options.

Autoimmune encephalitis (AE) is now defined as a form of encephalitis that occurs as a result of a brain–specific immune response with or without a cancer association, and it usually associates with antibodies against a neuronal, or glial, cell surface antigen (Dalmau and Graus definition 2022).

A variety of neuronal surface (NS) antibodies (NS–Abs) have been identified since 2007. It has been shown that NS–Abs play an important role in the pathophysiology of various neurological and neuropsychiatric disorders, including non–infectious/post–infectious encephalitis, first episode psychosis, epileptic/non–epileptic seizures, demyelinating syndrome, progressive dementia, involuntary movements (orofacial–limb dyskinesias, faciobrachial dystonic seizures, catatonia, rigidity, stiffness, tremors, myoclonus, chorea, stereotypies, oculomotor abnormalities), and non–REM/REM sleep disorder.

In 2016, a practical diagnostic approach to AE was proposed to achieve prompt immunotherapy at 3 levels of evidence for AE (possible, probable, and definite) along with newly proposed diagnostic criteria for possible AE, probable AE, probable and definite anti–NMDAR encephalitis, autoimmune limbic encephalitis, ADEM, and Hashimoto encephalopathy. In patients with new–onset refractory status epilepticus (NORSE), AE with antibodies against NMDAR, LGI1, GABAbR or GABAaR is often considered in the differential diagnosis of secondary NORSE ; however, cryptogenic NORSE is not an AE, rather a heterogeneous group of disorders that presents with NORSE as a condition, in which neuroinflammation or innate immunity–mediated mechanisms have been implicated. C–NORSE score based on the initial clinical assessments is useful for discriminating C–NORSE from secondary one. Neuronal IgM or IgA class antibodies have been described but should not be used as diagnostic markers ; only IgG neural antibodies are considered to have diagnostic significance. Identification of NS–Abs is crucial in making the diagnosis of AE or paraneoplastic syndrome ; however, the testing results using commercial assays (line blots, fixed cell–based assay, or rodent brain immunohistochemistry) should be interpreted with caution when measured with commercial assay alone.

In this lecture, I focus on pitfalls in clinical diagnosis and antibody testing in patients with AE, including recent update.

Autoimmune glial fibrillary acidic protein (GFAP) astrocytopathy (GFAP–A) was first reported as an autoimmune inflammatory central nervous system disorder associated with immunoglobulin G (IgG) antibodies that recognize GFAP, which is the main intermediate filament protein in mature astrocytes. In recent years, the clinical features of GFAP–A have become better understood. Approximately 10∼15% of patients complicate with neoplasm including ovarian teratoma. The common phenotype of this disorder includes meningoencephalitis with or without myelitis. The pathogenesis of GFAP–A is poorly understood. Pathologically, there is a marked lymphocytic infiltration of the meningeal and brain parenchyma, with many CD8+ and CD4+ T cells, especially in the perivascular area. GFAP–specific cytotoxic T cells are also likely effectors of this disorder. During the clinical course, patients present with consciousness disturbances, meningeal irritation, ataxia, involuntary movements such as tremor and myoclonus, urinary dysfunction, cognitive dysfunction, optic disc edema, area postrema syndrome, and respiratory failure. The cerebrospinal fluid (CSF) can be probed for lymphocyte–predominant pleocytosis and elevated protein levels. The positivity rate of oligoclonal bands was about 70%. The detection of CSF GFAP–IgG by tissue– and cell–based testing is essential for a diagnosis of GFAP–A. Brain magnetic resonance imaging (MRI) can show abnormal hyperintensity lesions on T2–weighted and fluid–attenuated inversion recovery images. Brain linear perivascular radial gadolinium–enhancement patterns, an imaging hallmark of GFAP–A, are observed in about half of all patients. Spinal cord MRI can show longitudinal extensive spinal cord lesions. While the response to corticosteroid therapy is typically good, some patients had poor prognosis. Patients with high mRS scores at peak and the elderly may have a poor prognosis. The relapse rate was about 10%. The main sequelae were cognitive and urinary dysfunctions.

Paraneoplastic neurologic syndromes (PNS) are a group of neurological disorders possibly caused by immunological mechanisms triggered by the underlying tumor that involve every part of the nervous system. Most antibodies associated with PNS (onconeural antibodies) are excellent diagnostic markers for the neurological syndromes and underlying tumors which were categorized as high–risk antibodies for cancer detection. These antibodies bind to intracellular proteins without functional roles for neuronal loss, instead, the direct effector for neuronal damage is thought to be cytotoxic T cells. While antibodies against cell surface antigens are less likely linked to cancer and those having these antibodies are usually responsive to immune–therapies. Frequently associated symptoms are limbic encephalitis, cerebellar ataxia and sensory neuronopathy. Associated tumors are mainly small cell lung cancer, breast/ovary/uterus cancers and thymoma. Timely diagnosis, prompt immunotherapy, and treatment of the underlying tumor are essential components of management of these cases. However, we need to be cautious for high frequency of false–positive/negative results of antibody–detection using commercial antibody–tests which alerts the importance of careful evaluation of clinical features. Recently, PNS emerged after immune check point inhibitor administration became a subject of attention to explore the pathogenesis of PNS. Other basic research for understanding immunological background of PNS has been progressing.

We retrospectively reviewed 60 patients with muscular dystrophy who tested positive for coronavirus disease 2019 (COVID–19) and visited our hospital from January 2020 to October 2022. The number of infected patients increased from 2 patients in 2020 to 55 in 2022. Since COVID–19 is largely considered a community–acquired infection, prevention is challenging. Worsening of COVID–19 was only observed in a steroid– and immunosuppressant–treated patient, and muscular dystrophy in itself was unlikely to be an aggravating factor of COVID–19. However, since aggressive respiratory physiotherapy is contraindicated in active COVID–19 patients to prevent aerosol diffusion, many patients showed difficulty in airway clearance and intercurrent bacterial pneumonia. In addition, cardiac function deteriorated in several patients even in cases where COVID–19 symptoms were mild. When treating patients with muscular dystrophy for COVID–19 infection, cardiac function should be carefully monitored.

Objective : Several biological drugs have been introduced as relapse prevention therapy for neuromyelitis optica spectrum disorders (NMOSD) in recent years, and cases introduced have been increasing owing to their high efficacy. In this report, we present the transition of relapse prevention treatment before and after the introduction of biologics.

Methods : Patients with NMOSD who visited our hospital were categorized into before– (2018–2019) and after–biologics (2020–2021) groups based on the launch of biologics. We retrospectively analyzed patients' data from their medical records.

Results : Before the market release of biologics, we encountered 18 patients with NMOSD (14 women, 4 men), mean age 58.3 years, mean disease duration 7.7 years, mean Expanded Disability Status Scale (EDSS) 4.8, and mean number of recurrences per year 0.4. Prednisolone (PSL) was administered to 13 patients (72.2%, mean dose 10.7 mg/day) and immunosuppressive drugs to 11 patients (61.1%) as recurrence preventive treatment. Following the market release of biologics, we encountered 27 patients with NMOSD (21 women, 6 men), mean age 54.9 years, mean disease duration 6.8 years, mean EDSS 4.2, and mean number of relapses per year 0.3. PSL was administered as recurrence preventive treatment to 23 patients (85.2%, mean dose 9.1 mg/day), immunosuppressive drugs to 12 patients (44.4%), and biologic agents to 7 patients (25.9%).

Conclusion : The introduction of biologics decreased the use of PSL and immunosuppressive agents, which decreased the EDSS and annual recurrence rates. Careful evaluation of the risks and benefits and appropriate patient selection are important for introduction of biologics.

Previous basic studies on Alzheimer's disease (AD) models have reported that rosmarinic acid (RA) can inhibit the aggregation including oligomerization of amyloid β–protein (Aβ) resulting in the decrease of cyto– and synaptic toxicities. We conducted the randomized placebo–controlled double–blind trials aimed to assess i) pharmacokinetics, ii) safety and tolerability, and iii) efficacy of lemon balm (Melissa officinalis : M. officinalis) extract containing RA on cognition in older adults without dementia. We conducted three randomized placebo–controlled double–blind trials ; the first one was performed in healthy individuals (n = 11) to assess the tolerability and safety of M. officinalis extract capsule, the second one aimed to show the safety, tolerability, and efficacy in patients with mild AD dementia (n = 20), and the third one investigated the effects on cognition in older adults (n = 323) without dementia. The results indicate that M. officinalis extract is tolerable and safe in healthy individuals and patients with mild AD dementia. Additionally, M. officinalis may prevent cognitive decline in older adults without hypertension.