Central sensitization (CS) is defined as an amplification of neural signaling within the central nervous system that elicits pain hypersensitivity and increased responsiveness of nociceptive neurons in the central nervous system to their normal or subthreshold afferent input. Evaluation of central sensitization is assessed by Quantitative Sensory Testing (QST), Brain imaging, and self–administered questionnaire. In the case of knee osteoarthritis, a pressure pain monitor (AlgoMed, Medoc) is used to compress the non–painful forearm at 1kg/s. The pressure felt by the subject as NRS 1 is measured three times at 30–second intervals, and the mean of three times is adopted. The Wind Up phenomenon is evaluated using a method called Temporal Summation (TS). The TS is assessed by differences in the initial and final pain intensity of multiple repeated stimuli, such as pressure and heat stimuli. Decreased descending pain control systems are assessed by the degree to which pain is reduced when noxious stimuli are added outside of pain sites. TS and CPM are used as indicators of central sensitization at the research level, but are rarely used clinically. The reasons for this include the high cost of equipment for evaluation and the time required for measurement. Central Sensitization Inventory (CSI) has been developed as an evaluation of CSS, and high validity and reliability have been reported.

CSI consists of Part A (CSI score), which questions the common health–related symptoms of CSS, and Part B, which questions the presence or absence of a history of disease characteristic of CSS.

Central sensitization (CS) is a unique phenomenon that indicates hypersensitivity of the central nervous system. It has been assumed that this phenomenon based on a dysregulation of sensory signaling and detected in the various pathological conditions, including neuropathic pain, fibromyalgia, migraine, irritable bowel syndrome, temporomandibular disorder, multiple chemical sensitivity and restless regs syndrome.

However, measuring subjective sensory experience is a task fraught with problems. Thus, objective biological markers are essential for precise diagnosis and understanding of pathophysiological mechanisms of CS.

In the symposium, we proposed several methods of objective assessment of CS using electrophysiological assessment such as auditory or somatosensory paired pulse inhibition. We also reported that the research results on the relationship between sensory hypersensitivity and social interaction.

I review the disease concept and recent developments in understanding multiple system atrophy (MSA). Recent studies have revealed that clinical diagnosis of MSA is not necessarily correct because of several different and varied clinical phenotypes as well as the presence of MSA mimics or look–alike syndromes. I discuss the limitations of revised consensus diagnostic criteria (Gilman et al : 2008), several atypical syndromes of MSA including mono–system atrophy, non–motor MSA, frontotemporal lobar degeneration (FTLD)–synuclein, and young–onset MSA, as well as clinical and imaging mimics. Because therapeutic interventions that target α–synuclein have started, further refinement of the diagnostic criteria is needed via biomarker researches with prospective study designs.

MRI and CT have been used to exclude other diseases with Parkinsonism in the diagnosis of Parkinson's disease (PD). Recently, susceptibility–weighted imaging and neuromelanin imaging at static magnetic field of 3 Tesla or above have reportedly enabled direct detection of pathological changes in PD. With respect to nuclear medicine, metaiodobenzylguanidine (MIBG) scintigraphy can document cardiac sympathetic denervation and dopamine transporter scintigraphy can demonstrate dysfunction of the nigrostriatal system in PD.

The combination of recent neuroimaging techniques, such as voxel–based morphometory (VBM), resting–state functional MRI (rs–MRI), diffusion tensor imaging and advanced network analysis methodology is expected to unveil the pathophysiology of various motor and non–motor symptoms observed in PD. For instance, VBM and rs–fMRI showed that impairment of the brain network consisted of several regions in the right parietal and temporal lobes are associated with frequent fall in PD (Otomune et al., 2019).

Knowing the features of each neuroimaging method and appropriately combining them, we can not only make early diagnosis of PD, but can also substantially interpret the underlying mechanism of various symptoms in PD.

Alzheimer's disease is a most common form of dementia and clinically characterized by progressive decline of cognitive function. The key hallmarks for the diagnosis of Alzheimer's disease are the accumulation of amyloid–β (Aβ) peptide into extracellular plaques and tau associated neurofibrillary tangles. There has been complicated mechanism in the development of Alzheimer's disease. Abnormal aggregates and accumulation of Aβ has been one of the most important mechanisms. Several clearance mechanisms in the brain have been assumed for Aβ excretion. There are two major type of clearance system through cerebrospinal fluid (CSF) and interstitial fluid (ISF), which are divided into perivascular drainage pathway and glymphatic pathway. CSF flows through the periarterial space and across the astroglial endfeet which express aquaporin 4 (AQP4) channels. Mixed CSF and ISF are driven into the perivenous space. Recently, the glymphatic pathway has been noted, and further implicated that the glymphatic function can be related pathologically to Alzheimer's disease. Amyloid β is deposited in the vascular smooth muscle cell layer in cerebral amyloid angiopathy (CAA), and CAA is closely associated with Alzheimer's disease. This close association might be attributable to the dysfunction of glymphatic system. Understanding the mechanism of glymphatic pathway might be pivotal to explore for the pathogenesis of Alzheimer's disease.

Alzheimer's disease (AD) is one of the most common neurodegenerative diseases responsible for progressive dementia. Accumulation of activated microglia in and around senile plaques has been demonstrated in autopsied brains from AD patients, and considered to modulate amyloid β (Aβ) clearance, inflammation and oxidative stress. Our research suggested that activated microglia in the advanced stage of AD model mice showed higher expression levels of CD14/TLR. CD14/TLR4 complex is known to play vital role in immune response, and we showed that the complex is needed for microglial Aβ clearance. We also demonstrated therapeutic effects of galantamine using AD model mice. Galantamine is one of the cholinesterase inhibitors already used in clinical application. Galantamine is also known as an allosterically potentiating ligand of nicotinic acetylcholine receptor (nAChR). Stimulation of microglial α7 nAChR results in anti–inflammation and Aβ clearance. We showed α7 nAChR was expressed in early stage of activated microglia and earlier treatment of galantamine enhanced Aβ clearance.

The development of drug delivery system across the blood–brain barrier (BBB) into the brain is still a challenging problem to introduce an effective molecular–targeted therapy for intractable neurological disorders. We have developed an efficient delivery system utilizing glucose transporter–1 (GLUT1), which is expressed at a remarkably high level in brain microvascular endothelial cells, by adopting a unique biological strategy.

We constructed a 30nm–sized self–assembled supramolecular micelle integrated with glucose on its surface. Intravenously administered glucosylated nanomicelle accumulated highly in the mouse brains (6% dose/g–brain) in response to a glycemic increase after a prior fasting condition. The accumulation of the micelle was considerably decreased by intravenous administration of a GLUT1 inhibitor. We directly observed the transport of the micelle from brain microvessels into brain by intravital real–time confocal laser scanning microscopy, and identified the delivery of the micelle into neurons by immunohistochemistry. In the course of crossing the BBB, the micelle was partially localized at recycling endosomes immunolabelled with anti–Rab11a antibody in the brain microvascular endothelial cells, suggesting GLUT1 intracellularly migrates from the luminal to the abluminal plasma membrane.

For targeting amyloid–β oligomer (AβO), the pathological hallmark of Alzheimer's disease (AD), we start to engineer an anti–AβO antibody, which has been used in a phase 1 clinical trial for AD patients in the United States, and combine the products with the above delivery system. A full–body anti–AβO antibody or its antibody fragments could be used to develop a nanomicelle decorated with GLUT1 ligands to penetrate the BBB. This nanomicelle containing some anti–AβO antibody is going to be used for the analysis of AβO pathophysiology, diagnosis of early AD, and treatment of AD.

MHLW launched a committee called “the Evaluation Committee on unapproved or Off–labeled Drugs with High Medical Needs” in 2009 in order to address the issue that many unapproved drugs or off–label uses of drugs are approved in the other developed counties but not in Japan. The MHLW's initiative worked well to let academia and industry collaborate to resolve the situation and showed certain progress, although there has been some issue remained. For example, difference in dosage approved among countries still exist in many cases and generally high dose which is approved in other countries is not approved in Japan. Much effort is needed to get approval of off–label use drug and fill the gap between the indication and clinical practice in pediatric setting. Also burden to development unapproved drug need to be appropriately taken care off. As is often the case with the discussion with regulatory bodies, Ministry of Health, Labor and Welfare (MHLW) has tendency to mandate clinical trial for the drug, which seems unnecessary from academia and industry's perspective.

In this article, our experience to get approval of off–label indication of methylprednisolone for the indication of acute exacerbation of Multiple Sclerosis (MS) was introduced. The safety and efficacy of intravenous methylprednisolone pulse therapy for the patients with MS has been well established and it's used as a standard treatment world widely including Japan with the guideline recommendation. However MHLW judged that there is not enough evidence in Japanese patients and requested to conduct a surveillance of drug utilization to assess actual usage of intravenous methylprednisolone pulse therapy for the Japanese patients with MS. The surveillance was led by Japanese Society of Neurology and twenty–eight neurology department of major hospital all over the Japan participated. Based on the result, “Kochi” application was accepted and the result was published by international journal. Eventually it became good example to use real world evidence for regulatory approval, which have been hot topics these days. In the future it would be desirable to establish more efficient way to collect real world data and across hospital disease registry would be one of the options.

The number of pharmaceuticals approved based on investigator–initiated clinical trials is increasing, and investigator–initiated clinical trials currently function as a means for new drug application.

In multicenter trials, a coordinating investigator assumes the responsibilities that would be borne by a sponsor under sponsor–initiated clinical trials. It is impossible, however, for coordinating investigator alone to fulfill all tasks. Therefore, he/she needs to create an implementation structure by requesting the cooperation of hospital staffs and outsourcing some operations to contract research organization (CRO). As in sponsor–initiated trials, the main services provided by CRO in investigator–initiated clinical trials include study monitoring, auditing, registration center function, data management, statistical analysis, and clinical study report preparation. CRO is sometimes also involved in the study from its planning phase as a supporter for coordinating investigator to examine the protocol, establish an implementation structure, and even provide support for consultation meeting with PMDA. Further, it may assist for compliance review after the application for approval.

To finalize the clinical trial protocol or implementation structure (including medical institution and CRO), it is critical to consider the period and budget specified when a grant is awarded. It means that you have to think about the approaches to planning, conducting, and completing the trial under a restricted condition. CRO needs to place the most importance on such comprehensive approaches when it supports for coordinating investigator.

During the trial, CRO engages in various roles such as supporting the coordinating investigator and monitoring the trial. Basically, each task is performed under the instruction by coordinating investigator and the service provided by CRO should be same as in sponsor–initiated clinical trials. However, especially for investigator–initiated clinical trials, CRO needs to work on the task actively, not passively, as the coordinating investigator has less experience in clinical trials compared with pharmaceutical companies.

症例は，67歳男性である．2014年1月，四肢末梢のしびれ感を自覚し当科を受診した．免疫グロブリン静注療法（intravenous immunoglobulin：IVIg）で症状は改善するも，同年4月，再度しびれ感が出現したが，IVIgで症状は再び改善した．慢性炎症性脱髄性多発ニューロパチーと診断した．その後しびれ感が増悪するたび2か月毎にIVIgをくりかえし施行し，しびれ感は改善した．神経伝導検査でも改善傾向を認めた．四肢末梢の軽度の痛覚鈍麻が残存するが，握力と四肢筋力は保たれている．本例ではしびれ感の増悪を契機に定期的にIVIgがなされ，症状改善を自覚できていることが4年間以上にわたる治療継続の動機付けになっている．しびれ感の増悪を契機として2か月毎にIVIgをくりかえし施行する治療が維持療法として有効であることを確認した．