Shun Shimohama

• Sapporo Medical University

Aim: Nicotinic acetylcholine receptors (nAChRs) expressed in midbrain dopaminergic (mDA) neurons modulate mDA neuronal activity. However, their expression patterns and functional roles during mDA neuronal development remain unknown. Here, we profiled the expression and function of nAChR subtypes during mDA neuron differentiation from human induced...

A 51-year-old Japanese man presenting with a several-month history of parasomnia, orthostatic hypotension and generalized myokymia was admitted to our hospital. He had a past medical history of unresectable recurrent thymoma, but chemotherapy for thymoma was discontinued according to the patient's decision four years before this hospitalization, an...

A 42-year-old woman presented at our hospital with acute paraphasia and word finding difficulty. She was not paralyzed or ataxic. Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) was diagnosed based on brain MRI finding of edematous lesions in bilateral temporal lobe cortexes that did not match the vascular...

Importance: The effectiveness of currently approved drugs for amyotrophic lateral sclerosis (ALS) is restricted; there is a need to develop further treatments. Initial studies have shown ultrahigh-dose methylcobalamin to be a promising agent. Objective: To validate the efficacy and safety of ultrahigh-dose methylcobalamin for patients with ALS e...

Amyloid-β (Aβ) accumulation and tauopathy are considered the pathological hallmarks of Alzheimer’s disease (AD), but attenuation in choline signaling, including decreased nicotinic acetylcholine receptors (nAChRs), is evident in the early phase of AD. Currently, there are no drugs that can suppress the progression of AD due to a limited understandi...

Microglia are tissue-resident macrophages located in brain parenchyma and play key roles not only in brain immunity but also interact with neurons to contribute to neurogenesis, axonal growth, and synaptic refinement. The origin of microglia has been shown to be primitive macrophages that arise in the yolk sac during embryonic hematopoiesis coloniz...

SIRT3 is an NAD+-dependent protein deacetylase localized in mitochondria. Several studies reported localization of SIRT3 in the cytoplasm or nucleus, but data of these studies were not consistent. We detected expression of mitochondrial (SIRT3mt) and cytoplasmic (SIRT3ct) Sirt3 mRNAs in the mouse brain, and we also found SIRT3 immunostaining of mit...

A 70-year-old woman presented with a 6-year history of cognitive dysfunction, neurogenic bladder, constipation and recurrent vomiting, and gradual worsening of symptoms. At the first admission to our department, she was also found to have hepatic encephalopathy due to intrahepatic portosystemic shunt. Head MRI revealed abnormal signal intensity at...

Sarcoidosis is a systemic inflammatory disease characterized by the formation of noncaseating epithelioid granulomas. Multiple organs, including the lung, eyes, and skin, are involved in this disorder, and cardiac involvement is a major cause of morbidity and mortality in patients with this disorder. We present the case history of a 22-year-old man...

Microglia are specialized macrophages that reside within the central nervous system and play key roles in brain immunity, development and homeostasis. Recent studies also revealed functions of microglia in neuroprotection and neuroinflammation, leading to the discovery that microglia are involved in several brain pathologies including Alzheimer’s d...

Introduction. Although Fisher syndrome and LEMS are classified into autoimmune neuromuscular diseases, we cannot find the coincidence of them in a single patient in the previous literature. Results. A 70-year-old female was admitted to our hospital because of bilateral hand numbness, double vision and unsteadiness which had developed 2 weeks. She h...

Introduction. The aim of this study is to elucidate the impairment of excitation-contraction (E-C) coupling in ICU-acquired weakness (ICUAW) using a unique electrophysiologic method in patients received the intensive care in ICU. Methods. We examined 13 patients with ICUAW and 11 normal controls. We performed successive recordings of electrophysiol...

Human induced pluripotent stem cells (hiPSCs) are powerful tools for modeling human brain development and treating neurodegenerative diseases. Here we established a robust protocol with high scalability for generating striatal medium spiny neurons (MSNs) from hiPSCs using small molecules under two- and three-dimensional culture conditions. Using th...

Importance Repeat expansion of CGG in LRP12 has been identified as the causative variation of oculopharyngodistal myopathy (OPDM). However, to our knowledge, the clinicopathologic features of OPDM with CGG repeat expansion in LRP12 (hereafter referred to as OPDM_LRP12) remain unknown. Objective To identify and characterize the clinicopathologic fe...

Alzheimer’s disease (AD) is a common neurodegenerative disease that causes progressive cognitive decline. Deposition of amyloid-β (Aβ) peptides is the most important pathophysiological hallmark of AD. Oxidative stress induced by the generation of reactive oxygen species (ROS) is a prominent phenomenon in AD and is known to occur early in its course...

A 33-year-old man with an unremarkable family history has had limb muscle weakness, joint contracture and skeleton deformation from early childhood. He was diagnosed with spinal muscular atrophy (SMA) by a pediatrician. He needed assistance and used orthoses in his daily life. There was no subjective sensory disturbance. However, physical examinati...

Involvement of nicotinic acetylcholine receptors (nAChRs) in differentiation and maturation of microglia and/or dopaminergic (DA) has not been elucidated, and its clarification may greatly contribute to development of cell therapy against brain diseases, such as Alzheimer’s disease (AD) and Parkinson’s disease (PD). In this study, we analyzed the e...

SIRT1 is involved in the regulation of a variety of biological processes such as metabolism, stress response, autophagy and differentiation. Although progenitor cells of oligodendrocytes (OPCs) express high level of SIRT1, its function on differentiation is unknown. Because we have shown that SIRT1 plays a pivotal role in differentiation of neural...

Amyotrophic lateral sclerosis (ALS) due to a fused in sarcoma (FUS) P525L mutation is characterized by a rapidly progressive course. Multifocal motor neuropathy (MMN) may resemble ALS in early stage and is associated with anti-ganglioside antibodies. A 38-year-old woman was admitted to our hospital because of progressive muscle weakness in the righ...

Objectives Multiple system atrophy (MSA) is a refractory neurodegenerative disease, but novel treatments are anticipated. An accurate natural history of MSA is important for clinical trials, but is insufficient. This regional registry was launched to complement clinical information on MSA. Setting Patient recruitment started in November 2014 and i...

A 59-year-old woman presented with a 7-year history of facial numbness on the left side, and gradual worsening of symptoms. Over several years, facial muscle weakness, dysarthria, tongue atrophy and fasciculation had progressed. Then, she developed cerebellar ataxia affecting the left extremities, in addition to earlier symptoms. Brain MRI revealed...

HLA genotype-clinical phenotype correlations are not established for multiple sclerosis (MS) and neuromyelitis optica spectrum disorders (NMOSD). We studied HLA-DRB1/DPB1 genotype–phenotype correlations in 528 MS and 165 NMOSD cases using Japan MS/NMOSD Biobank materials. HLA-DRB1*04:05 , DRB1*15:01 and DPB1*03:01 correlated with MS susceptibility...

SIRT3 is a NAD+-dependent protein deacetylase localized in mitochondria. Although several previous studies reported cytoplasmic and/or nuclear localization of SIRT3, extra-mitochondrial SIRT3 was obscure. We found that mitochondrial (SIRT3mt) and cytoplasmic (SIRT3ct) Sirt3 mRNAs were expressed in the mouse brain and diffuse SIRT3 immunostaining in...

An 81-year-old man with a history of gingival bleeding presented with a fever, headache, and drowsiness. His mouth and full dentures were unsanitary. Laboratory tests revealed Streptococcus oralis meningitis caused by odontogenic bacteremia. We reviewed eight reported cases, including the present case, because S. oralis meningitis is rare. Our revi...

We herein report a patient with Wernicke-Korsakoff syndrome (WKS) who had neither a history of alcoholism or of history of gastric surgery. A 56-year-old female was transferred to our hospital because of the loss of consciousness and she was diagnosed to have Wernicke encephalopathy. She showed proton pump inhibitor-induced refractory hypergastrine...

We describe herein a case with left-side ptosis induced by pure midbrain infarction in a 49-year-old woman. She also presented with diplopia and right-side cerebellar ataxia. MRI demonstrated new ischemic stroke of the left ventral paramedian midbrain. In this case, ischemia of the left oculomotor fascicles caused the left-side ptosis and diplopia,...

Accumulation of amyloid-β (Aβ) in brain tissue contributes to the pathophysiology of Alzheimer’s disease (AD). We recently reported that intrahippocampal transplantation of mouse bone marrow-derived microglia-like (BMDML) cells suppresses brain amyloid pathology and cognitive impairment in a mouse model of AD. How these transplanted cells interact...

Rheumatoid vasculitis (RV) usually occurs in patients with refractory rheumatoid arthritis (RA). An 80-year-old woman was transferred to our hospital because of muscle weakness and paresthesia in all 4 limbs. She had been diagnosed with RA 30 years ago and achieved sustained clinical remission. At presentation, polyarthritis and drop foot were obse...

The spleen plays an important role in the body’s immune defense against invasive infections, particularly those caused by encapsulated bacteria. Encapsulated bacterial infection in asplenic patients is a medical emergency called overwhelming postsplenectomy infection (OPSI) and has a mortality rate of 50–70%. Here, we report the case of a 51-year-o...

A 57-year-old man with atherosclerosis obliterans was admitted with sudden-onset sensory aphasia and right hemiparesis. Brain MRI revealed acute cerebral infarctions in the left temporal lobe and magnetic resonance angiography showed occlusion of the posterior branch of the left middle cerebral artery. Transesophageal echocardiography and ultrasono...

Background Recurrent ischemic stroke early after administration of intravenous tissue plasminogen activator (IV t-PA) is a rare complication. Most previously reported cases have shown poor prognosis with only speculations regarding reasons for recurrence. Case description We report a case of recurrent cerebral infarction due to atrial fibrillation...

Mesenchymal stem cells (MSC) are increasingly being studied as a source of cell therapy for neurodegenerative diseases, and several groups have reported their beneficial effects on Alzheimer’s disease (AD). In this study using AD model mice (APdE9), we found that transplantation of MSC via the tail vein improved spatial memory in the Morris water m...

Alzheimer's disease (AD) is a common neurodegenerative disease that progressively impairs memory and cognition. Deposition of amyloid-β (Aβ) peptides is the most important pathophysiological hallmark of AD. Oxidative stress induced by generation of reactive oxygen species (ROS) is a prominent phenomenon in AD and known to occur early in the course...

Activation of SIRT1, an NAD⁺-dependent protein deacetylase, ameliorates muscular pathophysiology of δ-sarcoglycan-deficient TO-2 hamsters and dystrophin-deficient mdx mice. We found that SIRT1 was highly expressed beneath the cellular membranes of muscle cells. To elucidate functional roles of SIRT1 on muscles, skeletal muscle-specific SIRT1 knocko...

A 69-year-old Japanese woman presented with mild muscle weakness of the neck and symmetrical proximal parts of the upper and lower limbs. Laboratory tests, needle electromyography, and a muscle biopsy revealed inflammatory myopathy with an apparent clinical classification of polymyositis and positive findings for anti-PM/Scl-75 antibody. This antib...

Background: Data on the clinical and radiological characteristics of intracranial artery dissection (IAD) have remained limited. Our purpose was to reveal the clinical and radiological characteristics of IAD according to diagnostic criteria for IAD as recently reported by a group of international experts. Methods: Patients were retrospectively enro...

We previously demonstrated that microglia play an essential role in clearance of amyloid-β (Aβ) in Alzheimer’s disease (AD)-like pathology. Our prior work also showed that several receptors expressed on microglia participated in Aβ phagocytosis. However, clathrin-mediated endocytosis (CME), which is associated with production and release of Aβ in n...

Alzheimer’s disease (AD) is one of the most common neurodegenerative diseases responsible for progressive dementia. Deposition of amyloid-β (Aβ) in the brain is the most important pathophysiological hallmark of AD. In addition, recent evidence indicates that reactive oxygen species (ROS) derived from mitochondria contribute to progression of AD pat...

The accumulation of amyloid-β peptides (Aβ) is a critical trigger of Alzheimer's disease (AD) pathogenesis. Aβ is derived from sequential proteolysis of amyloid precursor protein by β- and γ-secretases. Nicotinic acetylcholine receptors (nAChRs) are ligand-gated ion channels. Microglia and bone marrow-derived microglia-like (BMDML) cells have Aβ ph...

The patient in Case 1 was a 25-year-old female nurse. While she was working at a day-care, she fell down shortly after using a barcode reader. This was followed by a tonic-clonic seizure. The seizure spontaneously stopped after approximately 5 minutes. However, consciousness impairment continued for about 30 minutes. The patient in Case 2 was a 30-...

BACKGROUND Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that affects the upper and lower motor neurons. Currently, only riluzole and edaravone are approved as drugs for ALS in the world, and new agents with larger effect size are warranted. Our previous study (E0302-J081-761) has suggested that high-dose methylcobalamin (E0302...

Background: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that affects the upper and lower motor neurons. Currently, only riluzole and edaravone are approved as drugs for ALS in the world, and new agents with larger effect size are warranted. Our previous study (E0302-J081-761) has suggested that high-dose methylcobalamin (E030...

A 70-year-old man, a urinary retention of unknown origin from 10 years ago, decreased cognitive function from 4 years ago, vision impairment advanced a year ago. Brain MRI with DWI showed high intensity erea in the cortico-medullary junction. We diagnosed as intranuclear inclusion body disease (NIID) because of p62-positive intranuclear inclusion b...

Peripheral neuropathy often occurs in hereditary spinocerebellar ataxia (hSCA), but the features of nerve involvement have not been fully investigated. We evaluated the prevalence of peripheral neuropathy in hSCAs and classified the underlying pathologies into length-dependent axonopathy and neuronopathy based on sural/radial amplitude ratio (SRAR)...

We report a case of moyamoya disease (MMD), which developed after non-herpetic acute limbic encephalitis (NHALE) associated with anti-leucine-rich glioma-inactivated 1 (LGI1) antibody. The patient's mother had a history of MMD. No vascular lesions were identified at the time of the NHALE. Nine years later, the patient visited our hospital due to me...

Both of the two most common neurodegenerative disorders, namely Alzheimer's disease (AD) and Parkinson's disease (PD), have multiple lines of evidence, from molecular and cellular to epidemiological, that nicotinic transmission is implicated in those pathogenesis. This review presents evidences of nicotinic acetylcholine receptor (nAChR)-mediated p...

This open access book presents the roles and mechanisms of signal transduction triggered by nicotinic acetylcholine receptors (nAChRs) stimulation in neuroprotection against toxic effects of risk factors of neurodegenerative diseases. Accumulating evidence suggests that nAChRs in the CNS play important roles not only in excitatory neurotransmission...

Background The mental rotation task is well-known for the assessment of visuospatial function; however, it has not been used for screening of dementia patients. Objective The aim of this study was to create a simple screening test for patients with mild cognitive impairment (MCI) and Alzheimer’s disease (AD) by focusing on non-amnestic symptoms....

Background and purpose: A group of international experts on intracranial artery dissection (IAD) recently reported a consensus statement and criteria about the diagnosis of IAD (Debette S, et al: Lancet Neurol 2015). But there are little data showing clinical features of IAD based on the new criteria. We aimed to elucidate clinical and radiological...

The neuropathological hallmarks of Alzheimer's disease (AD) are the presence of senile plaques and neurofibrillary tangles along with extensive neuronal loss. Senile plaques and neurofibrillary tangles consist mainly of amyloid-β (Aβ) peptides and intracellularly accumulated hyperphosphorylated tau proteins, respectively. The Aβ is derived from seq...

We previously demonstrated that stimulation of nicotinic acetylcholine receptors (nAChRs) increases amyloid-β (Aβ) phagocytosis in rat microglia and is closely associated with the decrease of brain Aβ and amelioration of memory dysfunction in a transgenic mouse model of Alzheimer's disease (AD). Here, we examined the subtypes of nAChRs involved in...

Patients with multiple sclerosis (MS) who are treated with fingolimod have an increased proportion of transitional B cells in the circulation, but the underlying mechanism is not known. We hypothesized that B cell-activating factor of the tumor necrosis factor family (BAFF) is involved in the process. Compared with healthy controls and untreated MS...

Objective: The ice-pack test is a convenient diagnostic testing procedure for myasthenia gravis (MG). We investigated the underlying mechanism of the ice-pack test performed on bilateral masseters. Methods: We performed trigeminal repetitive nerve stimulation (RNS), excitation-contraction (E-C) coupling assessment (Imai's method) and bite force...

Objective: A case in which intracranial arterial stenosis was exacerbated 5 months after percutaneous intracranial stent retriever thrombectomy is reported. Case Presentation: In a 62-year-old male, percutaneous intracranial thrombectomy using a stent retriever was performed for acute occlusion of the basilar artery. After complete recanalization,...

We report the case of a 67-year-old woman with non-convulsive status epilepticus (NCSE) due to hyponatremia. She had a history of psychogenic polydipsia but not epilepsy. She was admitted to our hospital with dysbulia. On admission, she was confused and disoriented (Glasgow Coma Scale: 6, E1V1M4). Magnetic resonance imaging of the brain showed no a...

A 79 year-old female was admitted to our hospital because of high serum creatine kinase level together with proximal muscle weakness and pain on grasping. MRI revealed inflammatory changes in femoral muscles on both sides. Muscle biopsy showed size irregularity of muscle cells, and necrosis and regeneration of fibers. Study of antibodies was also c...

In response to changes of the central nervous system environment, microglia are capable of acquiring diverse phenotypes for cytotoxic or immune regulation and resolution of injury. Alzheimer’s disease (AD) pathology also induces several microglial activations, resulting in production of pro-inflammatory cytokines and reactive oxygen species or clea...

A 55-year-old man was admitted to our hospital because of acute onset of diplopia and gait disturbance. On admission, ophthalmoplegia, ataxia and areflexia were observed. He was diagnosed with Fisher syndrome and given intravenous immunoglobulin therapy from day 6 to day 10 after disease onset. After treatment, ophthalmoplegia and ataxia began to i...

Previously, DJ-1 modulator UCP0054278/comp-B was identified by virtual screening, where comp-B interacts with DJ-1 to produce antioxidant and neuroprotective responses in Parkinson’s disease models. However, the effect of comp-B in an in vivo Alzheimer’s disease (AD) model is yet undetermined. Thus, we examined the effect of comp-B on spatial learn...

Background Higher latitude and human leukocyte antigen (HLA)-DRB1*04:05 increase susceptibility to multiple sclerosis (MS) in the Japanese population, but their effects on disease severity are unknown. We aimed to clarify the effects of latitude and the HLA-DRB1 and HLA-DPB1 genes on disease severity in Japanese patients with MS. Methods We enrolle...

A 57-year-old man initially developed chest discomfort, nausea, vomiting, headache and low-grade fever, followed by paraplegia, sensory disturbance below level Th5 and bilateral visual loss. He was admitted to our hospital on the 15th day of illness. MRI short T1 inversion recovery image showed multiple longitudinal lesions in the spinal cord below...

Parkinson’s disease (PD) is a progressive, age-related, neurodegenerative disorder, and oxidative stress is an important mediator in its pathogenesis. DJ-1, the product of the causative gene of a familial form of PD, plays a significant role in anti-oxidative defence to protect cells from oxidative stress. DJ-1 undergoes preferential oxidation at t...

Background Malnutrition induced by swallowing difficulties (SD) impairs the quality of life and gives rise to SD-related costs in Parkinson’s disease (PD) patients. With results of a swallowing difficulty questionnaire and data of resources specifically obtained such as SD-related costs, caregivers, and dietary therapies, this study is to suggest s...

Fingolimod is a sphingosine-1-phosphate receptor agonist used to inhibit the inflammatory activity of multiple sclerosis (MS), and has been shown to suppress osteoporosis in mouse models. In this study, levels of bone turnover markers were quantified in serum and urine samples from MS patients treated with fingolimod. Compared with untreated MS pat...

We investigated the effect of load against self-paced movement on cortical involvement for motor execution. Ten right-handed healthy volunteers were requested to perform brisk extension of the right index finger at self-paced intervals exceeding 10 s for three load conditions: 0 g, 50 g and 100 g. Movement-related magnetic fields were recorded usin...

Objectives: We conducted a cross-sectional study to evaluate the socioeconomic systems supporting outpatients with Parkinson's disease (PD) in Japan. Methods: The study was performed in 2013 at two private hospitals and one clinic in Hokkaido Prefecture, Japan. A survey was conducted with 248 consecutive PD patients, and the data from 237 PD out...

Polyglutamine (polyQ) diseases comprise neurodegenerative disorders caused by expression of expanded polyQ-containing proteins. The cytotoxicity of the expanded polyQ-containing proteins is closely associated with aggregate formation. In this study, we report that a novel J-protein, DNAJ (HSP40) Homolog, Subfamily C, Member 8 (DNAJC8), suppresses t...

Background and purpose: Single photon emission computed tomography (SPECT) is recommended for assessing cerebral ischemia in patients with symptomatic stenosis or occlusion of the middle cerebral artery (MCA) and internal carotid artery (ICA). The purpose of this study was to investigate the relationship between MCA signal density on magnetic reson...

Galantamine, an acetylcholine esterase (AChE) inhibitor used to treat dementia symptoms, also acts as an allosteric potentiating ligand (APL) at nicotinic acetylcholine receptors (nAChRs). This study was designed to evaluate the allosteric effect of galantamine on nAChR regulation of nigrostrial dopaminergic neuronal function in the hemiparkinsonia...

A 61-year-old alcoholic man was admitted to our hospital because of disturbance of consciousness. He also exhibited external ophthalmoplegia, diplopia and mild rigidity, but tendon reflex was normal. On brain MRI, diffusion weighted images (DWI) and apparent diffusion coefficient (ADC) map depicted high intensity in the splenium of the corpus callo...

Mutations of the lamin A/C gene have been associated with several diseases such as Emery-Dreifuss muscular dystrophy, dilated cardiomyopathy and Charcot-Marie-Tooth disease, referred to as laminopathies. Only one report of spinal muscular atrophy and cardiomyopathy phenotype with lamin A/C gene mutations has been published. The concept that lamin A...

Background: Alzheimer's disease (AD) is characterized by senile plaques, extracellular deposits composed primarily of amyloid-beta (Aβ), and neurofibrillary tangles, which are abnormal intracellular inclusions containing hyperphosphorylated tau. The amyloid cascade hypothesis posits that the deposition of Aβ in the brain parenchyma initiates a seq...

Objective: The aim of this study was to evaluate post-tetanic potentiation of muscle twitch in myasthenia gravis (MG). Methods: Post-tetanic potentiation was evaluated by recording the compound muscle action potential (CMAP) of abductor pollicis brevis and movement-related potential (MRP) of the thumb using an accelerometer after tetanic stimula...

Case 1: A 63-year-old man developed right vertebral arterial dissection with an aneurysm of 6 mm and headache after neck rotation. After commencement of antihypertensive treatment, the symptom of headache improved and disappeared on the 17th disease day. And he was discharged on the 26th disease day. Case 2: A 39-year-old man developed headache sud...

Obesity and type 2 diabetes are risk factors of Alzheimer's disease (AD). We reported that a high fat diet (HFD) promotes amyloid precursor protein (APP) cleavage by β-site APP cleaving enzyme 1 (BACE1) without increasing BACE1 levels in APP transgenic mice. However, the detailed mechanism had remained unclear. Here we demonstrate that HFD promotes...

An 85-year-old woman was first admitted to our hospital because of right ptosis and diplopia. Examinations showed right oculomotor paralysis and reduced vision in the right eye. Serological and neuroradiological examinations failed to reveal the etiology. Oral prednisolone was started for a presumptive diagnosis of idiopathic oculomotor nerve palsy...

Alzheimer's disease (AD) is a neurodegenerative disease clinically characterized by progressive cognitive dysfunction. Deposition of amyloid-β (Aβ) peptides is the most important pathophysiological hallmark of AD. Oxidative stress induced by reactive oxygen species (ROS) is prominent in AD, and several reports suggest the relationship between the c...