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Introduction: Alzheimer's disease (AD) is one of the most common causes of dementia. Pathogenic variants in the presenilin 1 (PSEN1) gene are the most frequent cause of early-onset AD. Medications for patients with AD bearing PSEN1 mutation (PSEN1-AD) are limited to symptomatic therapies and no established radical treatments are available. Induced pluripotent stem cell (iPSC)-based drug repurposing identified bromocriptine as a therapeutic candidate for PSEN1-AD. In this study, we used an enrichment strategy with iPSCs to select the study population, and we will investigate the safety and efficacy of an orally administered dose of bromocriptine in patients with PSEN1-AD., Methods and Analysis: This is a multicentre, randomised, placebo-controlled trial. AD patients with PSEN1 mutations and a Mini Mental State Examination-Japanese score of ≤25 will be randomly assigned, at a 2:1 ratio, to the trial drug or placebo group (≥4 patients in TW-012R and ≥2 patients in placebo). This clinical trial consists of a screening period, double-blind phase (9 months) and extension phase (3 months). The double-blind phase for evaluating the efficacy and safety is composed of the low-dose maintenance period (10 mg/day), high-dose maintenance period (22.5 mg/day) and tapering period of the trial drug. Additionally, there is an open-labelled active drug extension period for evaluating long-term safety. Primary outcomes are safety and efficacy in cognitive and psychological function. Also, exploratory investigations for the efficacy of bromocriptine by neurological scores and biomarkers will be conducted., Ethics and Dissemination: The proposed trial is conducted according to the Declaration of Helsinki, and was approved by the Institutional Review Board (K070). The study results are expected to be disseminated at international or national conferences and published in international journals following the peer-review process., Trial Registration Number: jRCT2041200008, NCT04413344., Competing Interests: Competing interests: TK has a patent, agent for preventing and/or treating Alzheimer’s disease, licensed to HIn and TK; HB reports funding for this clinical trial from Time Therapeutics, trial drugs from Towa Pharmaceutical Co., during the conduct of the study; personal fees from Sumitomo Dainippon Pharma Co., outside the submitted work; RU reports personal fees from Eisai, Sawai Pharmaceutical Co. and CAC Croit, outside the submitted work; SM reports personal fees from AstraZeneca KK, Bristol-Myers Squibb Company, Chugai Pharmaceutical Co. Eli Lilly Japan KK, MSD KK, Nippon Boehringer Ingelheim Co., Ono Pharmaceutical Co., Pfizer Japan and Taiho Pharmaceutical Co.; YT reports personal fees from Sumitomo Dainippon Pharma Co., Otsuka Pharmaceutical Co., AbbVie GK, Kyowa Kirin Co., Takeda Pharmaceutical Company, Tsumura & Co., Eisai Co., Sanofi KK, Mylan EPD GK and Ono Pharmaceutical Co., outside the submitted work; TM reports personal fees from Bayer Yakuhin and Otsuka Pharmaceutical Co., outside the submitted work; MI reports grants and personal fees from Eisai Co., Sumitomo Dainippon Pharma Co., Otsuka Pharmaceutical Co., MSD KK, Daiichi Sankyo Co. and Takeda Pharmaceutical Company, grants from Mitsubishi Tanabe Pharma Corporation, personal fees from Janssen Pharmaceutical KK, Nihon Medi-Physics Co., Fujifilm, Novartis Japan, Meiji Seika Pharma Co., Nippon Chemiphar Co., Eli Lily Japan KK and Chugai Pharmaceutical Co., outside the submitted work; KF reports grants from Novartis, outside the submitted work; YI reports grants from Sumitomo Dainippon Pharma Co., Eisai Co., Japan Blood Products Organisation, Otsuka Pharmaceutical Co., Kyowa Kirin Co., Teijin Pharma, Nihon Pharmaceutical Co. and FP Pharmaceutical Corporation, outside the submitted work; KI reports grants, personal fees and other from GE Healthcare, during the conduct of the study; grants and personal fees from Nihon Medi-Physics Co., and Eli Lilly Japan KK, personal fees and other from Eisai Co. and Chugai Pharmaceutical Co., other from Biogen, personal fees from Novartis, outside the submitted work; YK reports personal fees from Tsumura & Co., Novartis Japan, UCB Japan Co. and Janssen Pharmaceutical KK, outside the submitted work; YS reports grants from Nippon Shinyaku Co. and The Nakatomi Foundation, personal fees from FP Pharmaceutical Corporation, Sumitomo Dainippon Pharma Co., and Novartis Japan, outside the submitted work; SK reports grants and personal fees from Eisai Co., personal fees from Janssen Pharmaceutical KK, Novartis Japan, Daiichi-Sankyo, Sumitomo Dainippon Pharma Co., Fujifilm Toyama Chemical Co., Nippon Chemiphar, Nihon Medi-Physics Co., Tsumura & Co. and Eli Lily Japan KK, outside the submitted work; SS is an employee of Time Therapeutics; TW is an employee of Time Therapeutics, during the conduct of the study; TW reports personal fees from KanonCure, Tsubota Laboratory, Dompé Farmaceutici S.p.A., and Novaliq GmbH, outside the submitted work; OU is an employee of Towa Pharmaceutical Co.; RT reports grants and personal fees from Takeda Pharmaceutical Co., Nippon Boehringer Ingelheim Co., Sumitomo Dainippon Pharma Co., Eisai Co., Kyowa Kirin Co., Otsuka Pharmaceutical Co. and Sanofi KK, grants from Astellas Pharma, Novartis Japan, and Nihon Medi-Physics Co., personal fees from AbbVie GK, Mitsubishi Tanabe Pharma Corporation, Mylan NV, Japan Blood Products Organization, Sanwa Kagaku Kenkyusho Co., FP Pharmaceutical Corporation, Tsumura & Co., KAN Research Institute, Kissei Pharmaceutical Co., Chugai Pharmaceutical Co., and Biogen, outside the submitted work; HTo reports personal fees from Daiichi Sankyo Co., outside the submitted work; HIn reports grants and personal fees from Takeda Pharmaceutical Co., Eisai Co., Suntory Wellness, Institute for Health Care Science, and Mitsubishi Tanabe Pharma Corporation, grants from Taisho Pharmaceutical Co., Toray Industries, KAN Research Institute, Shimadzu Corporation, MicroBiopharm Japan Co., Kaneka Corporation, Panasonic Corporation, Biogen and Stem Cell & Device Laboratory (SCAD), personal fees from Nomura Securities Co., FP Pharmaceutical Corporation, Nippon Chemiphar Co., Kansai Pharmaceutical Industries Association, Otsuka Pharmaceutical Co., Kyowa Kirin Co., outside the submitted work. HIn possesses unlisted stocks of Time Therapeutics. In addition, Kyoto University grants an exclusive license to Time Therapeutics through iPS Academia Japan regarding the invention of the trial drug (intellectual property) which was discovered through drug screening by the principal investigator (HIn). Thereby, Kyoto University and the principal investigator obtain a patent income from Time Therapeutics. HIn does not engage in data management, monitoring and statistical analyses. The coordinating investigators (HTo and HB) and Time Therapeutics will conduct the trial under the investigator-initiated clinical trial agreement. Prior to the trial, the principal investigator and the coordinating investigators underwent a review and received approval by the Conflict of Interest Review Committee based on the conflict of interest management policy at each site. All remaining authors have declared no conflicts of interest., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Mu opioid receptor (MOR) is involved in various brain functions, such as pain modulation, reward processing, and addictive behaviors, and mediates the main pharmacologic effects of morphine and other opioid compounds. To gain genetic access to MOR-expressing cells, and to study physiological and pathological roles of MOR signaling, we generated a MOR-CreER knock-in mouse line, in which the stop codon of the Oprm1 gene was replaced by a DNA fragment encoding a T2A peptide and tamoxifen (Tm)-inducible Cre recombinase. We show that the MOR-CreER allele undergoes Tm-dependent recombination in a discrete subtype of neurons that express MOR in the adult nervous system, including the olfactory bulb, cerebral cortex, striosome compartments in the striatum, hippocampus, amygdala, thalamus, hypothalamus, interpeduncular nucleus, superior and inferior colliculi, periaqueductal gray, parabrachial nuclei, cochlear nucleus, raphe nuclei, pontine and medullary reticular formation, ambiguus nucleus, solitary nucleus, spinal cord, and dorsal root ganglia. The MOR-CreER mouse line combined with a Cre-dependent adeno-associated virus vector enables robust gene manipulation in the MOR-enriched striosomes. Furthermore, Tm treatment during prenatal development effectively induces Cre-mediated recombination. Thus, the MOR-CreER mouse is a powerful tool to study MOR-expressing cells with conditional gene manipulation in developing and mature neural tissues., (© 2019 Wiley Periodicals, Inc.)

A 67-year-old woman developed dropped head. Her neck was severely flexed, with prominent cervical paraspinal muscles, although no parkinsonism was observed. Brain MRI showed no significant findings. We considered dystonia as the cause of the dropped head and administered trihexyphenidyl, an anticholinergic. After 10 years of follow-up, remarkable psychotic symptoms, including hallucinations regarding insects, appeared. Following the discontinuation of trihexyphenidyl, the psychotic symptoms decreased but still remained. (123)I-N-isopropyl-p-iodoamphetamine single-photon emission computed tomography ((123)I-IMP SPECT) revealed hypoperfusion in the bilateral occipital lobes. We diagnosed the patient with dementia with Lewy bodies (DLB). This case suggests that dropped head syndrome may precede the onset of DLB.

We report a case of lymphocytic primary angiitis of the central nervous system (PACNS) with a characteristic gadolinium-enhancement pattern on magnetic resonance imaging (MRI). A 48-year-old, right-handed man presented with a 3-month history of tremor and progressing dementia. Neurologic examination revealed cognitive decline with anterograde amnesia and postural tremor of the fingers. Except for the positive result of serum antinuclear antibody, intense investigations for infectious, rheumatic and neoplastic diseases were negative. Analysis of cerebrospinal fluid showed mild pleocytosis (14 cells/μl). Brain MRI revealed diffuse hyperintense areas in the deep cerebral white matter on T2-weighted images. Gadolinium-enhanced T1-weighted images demonstrated fan-shaped multiple linear enhancements converging to the body of the lateral ventricles. Brain biopsy showed intense infiltration of small lymphocytes without atypia or granuloma mainly within the vessel walls and perivascular spaces. The diagnosis of lymphocytic PACNS was made. Administration of corticosteroid markedly improved the tremor and cognitive dysfunction. MRI after the treatment showed resolution of the abnormal fan-shaped linear enhancement. He returned to his previous occupation. PACNS should be included in the differential diagnosis for fan-shaped linear enhancement converging to the lateral ventricles on MRI in patients with unexplained progressing dementia.