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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 with neurosarcoidosis complicated by abrupt onset of cardiac tamponade. Cardiac tamponade is a rare but potentially fatal manifestation of sarcoidosis, which is treatable with glucocorticoid therapy. Including the present case, previously reported cases of sarcoidosis with cardiac tamponade are reviewed to delineate its clinical characteristics.

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 right limbs. She had mild mental retardation and minor deformities. Initially, we suspected MMN given the asymmetric muscle weakness and detection of anti-ganglioside antibodies. However, physical and electrophysiological tests did not support MMN, instead suggesting ALS. We confirmed a heterozygous P525L mutation and finally diagnosed this case as ALS due to an FUS mutation.

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 review indicated that S. oralis meningitis needs to be considered when encountering cases of a fever, disturbance of consciousness, and headache with episodes of possible odontogenic bacteremia.

ObjectiveTo evaluate whether eculizumab helps patients with anti–acetylcholine receptor–positive (AChR+) refractory generalized myasthenia gravis (gMG) achieve the Myasthenia Gravis Foundation of America (MGFA) post-intervention status of minimal manifestations (MM), we assessed patients' status throughout REGAIN (Safety and Efficacy of Eculizumab in AChR+ Refractory Generalized Myasthenia Gravis) and its open-label extension.MethodsPatients who completed the REGAIN randomized controlled trial and continued into the open-label extension were included in this tertiary endpoint analysis. Patients were assessed for the MGFA post-intervention status of improved, unchanged, worse, MM, and pharmacologic remission at defined time points during REGAIN and through week 130 of the open-label study.ResultsA total of 117 patients completed REGAIN and continued into the open-label study (eculizumab/eculizumab: 56; placebo/eculizumab: 61). At week 26 of REGAIN, more eculizumab-treated patients than placebo-treated patients achieved a status of improved (60.7% vs 41.7%) or MM (25.0% vs 13.3%; common OR: 2.3; 95% CI: 1.1–4.5). After 130 weeks of eculizumab treatment, 88.0% of patients achieved improved status and 57.3% of patients achieved MM status. The safety profile of eculizumab was consistent with its known profile and no new safety signals were detected.ConclusionEculizumab led to rapid and sustained achievement of MM in patients with AChR+ refractory gMG. These findings support the use of eculizumab in this previously difficult-to-treat patient population.ClinicalTrials.gov IdentifierREGAIN, NCT01997229; REGAIN open-label extension, NCT02301624.Classification of EvidenceThis study provides Class II evidence that, after 26 weeks of eculizumab treatment, 25.0% of adults with AChR+ refractory gMG achieved MM, compared with 13.3% who received placebo.

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 woman 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 hypergastrinemia with the subsequent development of hyperemesis and a vitamin B1 deficiency.

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 the corticomedullary junction, the splenium of the corpus callosum, and bilateral middle cerebellar peduncles on DWI. She was diagnosed with intranuclear inclusion disease (NIID) based on skin biopsy and genetic testing of NOTCH2NLC. In a retrospective review of serial head MRI findings for ten years, abnormal signal intensity at the corticomedullary junction and the splenium of the corpus callosum on MRI existed prior to the onset of cognitive dysfunction, and expanded gradually. For early diagnosis of NIID, it is important to focus not only on the characteristic high signal intensity at the corticomedullary junction, but also on the signal at the splenium of the corpus callosum from the early stage.

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 examination showed slight sensory impairment, and nerve conduction study indicated sensory motor axonal neuropathy. This finding suggested Charcot-Marie-Tooth disease (CMT). Gene analysis detected MORC2 S87L mutation, leading to a diagnosis of CMT type 2Z. Patients with MORC2 S87L mutation are known to exhibit a severe phenotype, and may mimic SMA. It is important to demonstrate subclinical sensory neuropathy in patients with MORC2 S87L mutation mimicking SMA.

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 observed, and rheumatoid factor was prominently elevated. A peripheral nerve conduction test revealed mononeuritis multiplex in her limbs. We suspected that RV had developed rapidly despite RA having been stable for many years and started immunosuppression therapy with steroids combined with azathioprine. The treatment prevented worsening of muscle weakness and paresthesia.

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 cerebellar atrophy, and 99mTc-SPECT depicted cerebellar hypoperfusion. A repetitive nerve stimulation test (RNS) indicated abnormal decrement in the nasalis and trapezius muscles on the left side. Facial-onset sensory and motor neuronopathy (FOSMN) was diagnosed. Administration of intravenous immunoglobulin resulted in improvement of some symptoms. Although cerebellar ataxia is not a common symptom of FOSMN, a case showing TDP-43-positive glial cytoplasmic inclusions in cerebellar white matter has been reported. Therefore, it is possible that FOSMN may cause cerebellum impairment in some patients. Furthermore, RNS positive rate in the trapezius muscle is known to be high in amyotrophic lateral sclerosis (ALS) patients. It is speculated that RNS of the affected muscles in FOSMN may show abnormal decrement by the same mechanisms as ALS.

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 and DRB1*01:01, DRB1*09:01, DRB1*13:02 and DPB1*04:01 were protective against MS. HLA-DRB1*15:01 was associated with increased optic neuritis and cerebellar involvement and worsened visual and pyramidal functional scale (FS) scores, resulting in higher progression index values. HLA-DRB1*04:05 was associated with younger onset age, high visual FS scores, and a high tendency to develop optic neuritis. HLA-DPB1*03:01 increased brainstem and cerebellar FS scores. By contrast, HLA-DRB1*01:01 decreased spinal cord involvement and sensory FS scores, HLA-DRB1*09:01 decreased annualized relapse rate, brainstem involvement and bowel and bladder FS scores, and HLA-DRB1*13:02 decreased spinal cord and brainstem involvement. In NMOSD, HLA-DRB1*08:02 and DPB1*05:01 were associated with susceptibility and DRB1*09:01 was protective. Multivariable analysis revealed old onset age, long disease duration, and many relapses as independent disability risks in both MS and NMOSD, and HLA-DRB1*15:01 as an independent risk only in MS. Therefore, both susceptibility and protective alleles can influence the clinical manifestations in MS, while such genotype–phenotype correlations are unclear in NMOSD.

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, and ischemia of the left decussation of the superior cerebellar peduncle caused the right-side cerebellar ataxia. These symptoms resulted from inner superior medial mesencephalic branch infraction. This case offers an educational example that can be explained by models proposed in the past and requires knowledge of neuroanatomy and cerebrovasculature.

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 memory disturbances and repeated transient ischemic attacks affecting the right limb. Diffusion-weighted magnetic resonance imaging revealed scattered areas of signal hyperintensity, and the patient was ultimately diagnosed with MMD based on angiography. Revascularization surgery was performed on the left side, where cerebral blood flow was impaired on 123I-N-isopropyl-p-iodoamphetamine single photon emission computed tomography. Postoperatively, the patient was discharged with a normal neurological examination. NHALE associated with LGI1 antibodies is an autoimmune disease. Although autoimmune disease is the most frequent finding other than atherosclerosis in quasi-MMD, this is the first report of NHALE associated with anti-LGI1 antibodies mimicking quasi-MMD. Inflammation and angiogenesis may contribute to the development of MMD, in addition to genetic background.

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 patients, fingolimod-treated MS patients had significantly higher serum concentrations of BAFF, which positively correlated with the proportions and the absolute numbers of transitional B cells in blood. Despite the elevated concentrations of BAFF in fingolimod-treated MS patients, serum levels of soluble transmembrane activator and calcium-modulating cyclophilin ligand interactor, and B cell maturation antigen were not elevated. Our results show that fingolimod induces BAFF in the circulation and expands transitional B cells, but does not activate memory B cells or plasma cells in MS, which is favorable for the treatment of this disease.

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 features of patients with OPDM_LRP12. Design, setting, and participants This case series included 208 patients with a clinical or clinicopathologic diagnosis of oculopharyngeal muscular dystrophy (OPDM) from January 1, 1978, to December 31, 2020. Patients with GCN repeat expansions in PABPN1 were excluded from the study. Repeat expansions of CGG in LRP12 were screened by repeat primed polymerase chain reaction and/or Southern blot. Main outcomes and measures Clinical information, muscle imaging data obtained by either computed tomography or magnetic resonance imaging, and muscle pathologic characteristics. Results Sixty-five Japanese patients with OPDM (40 men [62%]; mean [SD] age at onset, 41.0 [10.1] years) from 59 families with CGG repeat expansions in LRP12 were identified. This represents the most common OPDM subtype among all patients in Japan with genetically diagnosed OPDM. The expansions ranged from 85 to 289 repeats. A negative correlation was observed between the repeat size and the age at onset (r2 = 0.188, P = .001). The most common initial symptoms were ptosis and muscle weakness, present in 24 patients (37%). Limb muscle weakness was predominantly distal in 53 of 64 patients (83%), but 2 of 64 patients (3%) had predominantly proximal muscle weakness. Ptosis was observed in 62 of 64 patients (97%), and dysphagia or dysarthria was observed in 63 of 64 patients (98%). A total of 21 of 64 patients (33%) had asymmetric muscle weakness. Aspiration pneumonia was seen in 11 of 64 patients (17%), and 5 of 64 patients (8%) required mechanical ventilation. Seven of 64 patients (11%) developed cardiac abnormalities, and 5 of 64 patients (8%) developed neurologic abnormalities. Asymmetric muscle involvement was detected on computed tomography scans in 6 of 27 patients (22%) and on magnetic resonance imaging scans in 4 of 15 patients (27%), with the soleus and the medial head of the gastrocnemius being the worst affected. All 42 muscle biopsy samples showed rimmed vacuoles. Intranuclear tubulofilamentous inclusions were observed in only 1 of 5 patients. Conclusions and relevance This study suggests that OPDM_LRP12 is the most frequent OPDM subtype in Japan and is characterized by oculopharyngeal weakness, distal myopathy that especially affects the soleus and gastrocnemius muscles, and rimmed vacuoles in muscle biopsy.

The terminal complement inhibitor eculizumab was shown to improve myasthenia gravis-related symptoms in the 26-week, phase 3, randomized, double-blind, placebo-controlled REGAIN study (NCT01997229). In this 52-week sub-analysis of the open-label extension of REGAIN (NCT02301624), eculizumab's efficacy and safety were assessed in 11 Japanese and 88 Caucasian patients with anti-acetylcholine receptor antibody-positive refractory generalized myasthenia gravis. For patients who had received placebo during REGAIN, treatment with open-label eculizumab resulted in generally similar outcomes in the Japanese and Caucasian populations. Rapid improvements were maintained for 52 weeks, assessed by change in score from open-label extension baseline to week 52 (mean [standard error]) using the following scales (in Japanese and Caucasian patients, respectively): Myasthenia Gravis Activities of Daily Living (-2.4 [1.34] and - 3.3 [0.65]); Quantitative Myasthenia Gravis (-2.9 [1.98] and - 4.3 [0.79]); Myasthenia Gravis Composite (-4.5 [2.63] and - 4.9 [1.19]); and Myasthenia Gravis Quality of Life 15-item questionnaire (-8.6 [5.68] and - 6.5 [1.93]). Overall, the safety of eculizumab was consistent with its known safety profile. In this interim sub-analysis, the efficacy and safety of eculizumab in Japanese and Caucasian patients were generally similar, and consistent with the overall REGAIN population. ispartof: JOURNAL OF THE NEUROLOGICAL SCIENCES vol:407 ispartof: location:Netherlands status: published

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-old Asian man who complained of emesis and diarrhea as primary symptoms. He rapidly progressed to coma and was eventually diagnosed with OPSI (pyogenic ventriculitis/spondylitis) caused by non-vaccine pneumococcal serotype 23A. Aggressive management, including empiric antibiotic therapy, a staircase approach for intracranial pressure-targeted therapy and laminectomy/laminoplasty, resulted in a good recovery. Our report highlights that non-vaccine pneumococcal serotypes can cause disease in vaccinated patients.

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 knockout mice (SIRT1-MKO) were generated. SIRT1-MKO mice showed muscular pathology similar to mild muscular dystrophies with increased numbers of centrally nucleated small myofibers and decreased numbers of middle-sized (2000-3001 μm2) myofibers compared to those of wild-type (WT) mice. Accordingly, SIRT1-MKO mice showed significantly decreased exercise capacity in treadmill and inverted hanging tests with higher levels of serum creatine kinase activities compared with those in WT mice. Evans blue dye uptake after exercise was greater in the muscles of SIRT1-MKO than those of WT mice, suggesting membrane fragility in SIRT1-MKO mice. Because SIRT1 was dominantly localized beneath the membranes of muscular cells, SIRT1 may have a new role in the membranes. We found that levels of fluorescent FM1-43 dye intake after laser-induced membrane disruption in C2C12 cells were significantly increased by SIRT1 inhibitors or Sirt1-siRNA compared with those of control cells. Inhibition of SIRT1 or SIRT1-knockdown severely disturbed the dynamic aggregation of membrane vesicles under the injured site but did not affect expression levels of membrane repair proteins. These data suggested that SIRT1 had a critical role in the resealing of membrane-ruptured muscle cells, which could affect phenotypes of SIRT1-MKO mice. To our knowledge, this report is the first to demonstrate that SIRT1 affected plasma-membrane repair mechanisms.

Fused - in - sarcoma ( FUS ) mutation is associated with a familial amyotrophic lateral sclerosis (fALS) characterized by early onset and rapid progression. Here, the authors describe a rare case of possible somatic mosaicism of a novel FUS variant for a fALS family with intrafamilial clinical variablity.

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 patients and healthy controls, fingolimod-treated MS patients had a significantly lower level of the bone resorption marker type I collagen cross-linked N-telopeptide in urine. This finding was prominent in female but was not seen in male subjects. Our results suggest that fingolimod may have a beneficial effect on bone mass loss in female MS patients.

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 the aggregation of polyQ-containing protein in a cellular model of spinocerebellar ataxia type 3 (SCA3), which is also known as Machado-Joseph disease. Overexpression of DNAJC8 in SH-SY5Y neuroblastoma cells significantly reduced the polyQ aggregation and apoptosis, and DNAJC8 was co-localized with the polyQ aggregation in the cell nucleus. Deletion mutants of DNAJC8 revealed that the C-terminal domain of DNAJC8 was essential for the suppression of polyQ aggregation, whereas the J-domain was dispensable. Furthermore, 22-mer oligopeptide derived from C-termilal domain could suppress the polyQ aggregation. These results indicate that DNAJC8 can suppress the polyQ aggregation via a distinct mechanism independent of HSP70-based chaperone machinery and have a unique protective role against the aggregation of expanded polyQ-containing proteins such as pathogenic ataxin-3 proteins.

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 callosum. DWI showed high intensity, but ADC map depicted iso-intensity in bilateral precentral gyri. Marchiafava-Bignami disease (MBD) was diagnosed. After intravenous drip of vitamin, his symptoms improved rapidly and the abnormal MRI findings in the splenium of the corpus callosum and bilateral precentral gyri disappeared gradually. MBD is pathologically characterized by demyelination and necrosis in the corpus callosum, which are generally caused by cytotoxic edema. Our case suggests that vasogenic edema may occur at the early stage of the MBD.

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 C3, and T2-weighted image showed abnormal hyperintensity within the left optic nerve. Cerebrospinal fluid (CSF) analysis revealed marked pleocytosis (1,719/μl) and hypoglycorrhachia (CSF glucose; 20 mg/dl). Intensive immunosuppressive therapy combined with antibiotics and antiviral agent were started immediately, resulting in relatively good visual outcome but no improvement of paraplegia and sensory disturbance. The patient's serum sample on admission was subsequently reported to be positive for anti-aquaporin-4 antibody. With no evidence of infectious diseases, neuromyelitis optica (NMO) was diagnosed. It should be borne in mind that marked hypogylcorrhachia may also be seen in NMO.

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 improve. However, he developed taste impairment on day 13 and right hemifacial weakness on day 16 after onset. A blink reflex test revealed right facial nerve impairment. On day 42 after onset, facial weakness and taste impairment remitted, and the blink reflex test result was normalized without additional treatment. Although it has been known that 10% of patients with Fisher syndrome complicated by delayed facial nerve palsy, the mechanism of the facial nerve palsy has not been elucidated. Therefore, this is a significant report to describe delayed facial nerve palsy combined with taste impairment and successive recordings of blink reflex and facial nerve conduction in a patient with Fisher syndrome.

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 ultrasonography respectively confirmed a patent foramen ovale and deep vein thrombosis in the bilateral femoral veins. Blood findings showed low protein S antigen, low protein S activity, and a missense mutation of the PROS 1 gene. The administration of apixaban 10 mg BID prevented ischemic stroke recurrence and decreased the deep vein thrombosis. These outcomes indicated that apixaban may be alternative to warfarin for the secondary prevention of ischemic stroke in a patient with a protein S deficiency.

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 early after IV t-PA in a 77-year-old woman. She presented with sudden neurological deterioration 86 min after IV t-PA. Magnetic resonance imaging demonstrated new ischemic stroke with right internal carotid artery occlusion. Endovascular thrombectomy improved her prognosis and we evaluated the left atrial appendage using transesophageal echocardiography. Conclusions Attention should be paid to ischemic stroke recurrence as a complication of IV t-PA, and preparation for mechanical thrombectomy is warranted. Further study of the left atrial appendage is needed to clarify the mechanisms of onset.

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 to treat ALS and new agents with larger effect sizes are warranted. Exploratory analyses in our previous study (study ID #E0302-J081-761) have suggested that high-dose methylcobalamin (E0302) prolonged the overall survival of ALS patients and suppressed ALS progression in patients with a disease duration of less than 12 months. Objective: This clinical trial aims to evaluate the efficacy and safety of E0302 for treatment of ALS patients within one year of onset. Methods: The Japanese early-stage trial of high-dose methylcobalamin for ALS (JETALS) is a prospective, multicenter, placebo-controlled, double-blind, randomized phase III study conducted at 24 tertiary neurology centers and is funded by the Japan Agency for Medical Research and Development. A total of 128 ALS patients within one year of onset were randomized at a 1:1 ratio to receive intramuscular injection with E0302 50 mg or placebo twice a week for 16 weeks. The primary endpoint is changes in the ALS Functional Rating Scale-Revised (ALSFRS-R) total score at 16 weeks. If patients wish to receive E0302 50 mg after the double-blind administration period, E0302 will be provided to them until March 2020 during the continuous administration period. Results: This study began in October 2017 and is being conducted at 24 participating institutions in Japan. The study is in progress and the patient enrollment period is scheduled to end in August 2019, with follow-up scheduled to end in March 2020. Conclusions: This study is being performed to revalidate the efficacy and safety of E0302 in patients with early-stage ALS in the first year of symptom onset. If positive results are obtained, the aim is to apply for E0302 approval as a new drug for the treatment of ALS. Trial Registration: ClinicalTrials.gov NCT03548311; https://clinicaltrials.gov/ct2/show/NCT03548311 (Archived by WebCite at http://www.webcitation.org/74Fw3rDzb) International Registered Report Identifier (IRRID): PRR1-10.2196/12046

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. Methods Age-matched healthy controls (age 75.3±6.8), patients with MCI (76.5±5.5), and AD (78.2±5.0) participated in this study. They carried out mental rotation tasks targeting geometric graphics or alphabetical characters with three rotating angles (0°, 90°, and 180°) and indicated the correct answer. Response accuracy and reaction time were recorded along with their eye movements using an eye tracker. To quantify their visual processing strategy, the run count ratio (RC ratio) was calculated by dividing the mean number of fixations in incorrect answers by that in correct answers. Results AD patients showed lower accuracy and longer reaction time than controls. They also showed a significantly greater number of fixation and smaller saccade amplitude than controls, while fixation duration did not differ significantly. The RC ratio was higher for AD, followed by MCI and control groups. By setting the cut-off value to 0.47 in the 180° rotating angle task, we could differentiate MCI patients from controls with a probability of 80.0%. Conclusions We established a new screening system for dementia patients by evaluating visuospatial function. The RC ratio during a mental rotation task is useful for discriminating MCI patients from controls.

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 characteristics based on the criteria. Methods: Patients with suspected IAD were retrospectively enrolled using a prospective single-center stroke registry between 2011 and 2016. Baseline characteristics and radiological findings including conventional MRI sequences, MRA, 3D-T1 weighted TSE blood black (3DT1BB) sequence and digital subtraction angiography (DSA) were reviewed. Results: Of 147 patients with suspected IAD, 63 patients (15 women; mean age, 51±12 years) finally met the criteria of definite (n=47), probable (n=14) or possible (n=2) idiopathic IAD. Thirty-five (56 %) had a history of hypertension, 21 (33 %) had dyslipidemia, and 39 (62 %) had smoking habit. Ischemic stroke alone was found in 50 %, subarachnoid hemorrhage plus ischemic stroke in 6 %, TIA in 3 %, and head or neck pain alone in 41 % on admission. Vertebral artery was affected in 66 %, basilar artery in 2 %, posterior inferior cerebral artery in 5 %, anterior cerebral artery in 11 %, middle cerebral artery in 6 %, intracranial internal carotid artery in 2 % and multi-vessels in 8 %. Intimal flap, double lumen and aneurysmal dilatation were similarly observed between 3DT1BB and MRI/MRA/DSA. Intramural hematoma was more frequently detected in 3DT1BB sequence than conventional MRI/MRA (initial image, 53 % vs. 14 %, P < 0.001; follow-up image, 59 % vs. 22 %, P < 0.001). Follow-up image was essential to fulfill the criteria in 12 patients; rapid morphological change of aneurysmal dilation in 3, a newly detection of intramural hematoma in 3, double lumen in 2, pearl and string sign in 2, and aneurysmal dilation without change in morphology in 2 on follow-up images. Modified Rankin Scale score of ≤ 1 at 90 days was observed in 54 patients (86 %). Conclusions: Intracranial vertebral artery was most frequently affected. 3DT1BB sequence was apparently useful in detecting intraluminal hematoma in the recently proposed diagnostic criteria of idiopathic IAD.

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 protection against neurotoxicity induced by β amyloid (Aβ), glutamate, rotenone, and 6-hydroxydopamine (6-OHDA) and the signal transduction involved in this mechanism. Our studies clarified that survival signal transduction, α7 nAChR-Src family-PI3K-AKT pathway and subsequent upregulation of Bcl-2 and Bcl-x, would lead to neuroprotection. Recently analyzing the properties of galantamine, we clarified the neuroprotective pathway, which is mediated by enhancement of microglial α7 nAChR resulting in upregulation of Aβ phagocytosis. Galantamine sensitizes microglial α7 nAChRs to choline and induce Ca2+ influx into microglia. The Ca2+-induced intracellular signaling cascades may then stimulate Aβ phagocytosis through the actin reorganization. This discovery would facilitate further investigation of possible nAChRs enhancing drugs targeting not only neuronal but also microglial nAChRs.

Alzheimer 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 is prominent in AD, and several reports suggest the relationship between a change in redox status and AD pathology containing progressive Aβ deposition, the activation of glial cells, and mitochondrial dysfunction. Therefore, we performed immunohistochemical analysis using a transgenic mouse model of AD (APdE9) and evaluated the activity of superoxide dismutase in brain tissue homogenates of APdE9 mice in vitro. Together with those analyses, in vivo changes in redox status with age in both wild-type (WT) and APdE9 mouse brains were measured noninvasively by three-dimensional electron paramagnetic resonance (EPR) imaging using nitroxide (3-methoxycarbonyl-2,2,5,5-tetramethylpyrrolidine-1-yloxy) as a redox-sensitive probe. Both methods found similar changes in redox status with age, and in particular a significant change in redox status in the hippocampus was observed noninvasively by EPR imaging between APdE9 mice and age-matched WT mice from 9 to 18 months of age. EPR imaging clearly visualized the accelerated change in redox status of APdE9 mouse brain compared with WT. The evaluation of the redox status in the brain of AD model rodents by EPR imaging should be useful for diagnostic study of AD.

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, which resulted in little improvement. Approximately ten months after the first admission, left ptosis appeared and she was re-admitted to our hospital. One day after admission, external ophthalmoplegia and conjunctival injection on the left side appeared. MRI revealed abnormal flow void in the right cavernous sinus. Based on cerebral angiographic findings, dural arteriovenous fistula of the right cavernous sinus was diagnosed. Symptoms on the left side were considered to result from increased perfusion pressure due to venous drainage via the intercavernous sinus to the contralateral cavernous sinus. After transvenous embolization, symptoms and signs improved gradually. In a case of external ophthalmoplegia with unknown etiology, detailed neuroradiologyical examinations such as cerebral angiogram are advisable.

To explore a novel therapy against Parkinson's disease (PD), we evaluated the therapeutic effects of human bone marrow-derived mesenchymal stem cells (hBM-MSCs), pluripotent stromal cells with secretory potential of various neurotrophic and anti-inflammatory factors, in a hemi-parkinsonian rat model. The unilateral intrastriatal 6-hydroxydopamine (6-OHDA)-lesioned rats were injected hBM-MSCs (1.0 × 107 cells) or PBS intravenously 16 days after lesioning. Administration of hBM-MSCs inhibited methamphetamine-stimulated rotational behavior at 7, 14, 21 and 28 days after transplantation. Immunohistochemical analysis also showed that number of TH-positive neurons in the substantia nigra pars compacta was significantly preserved in hBM-MSCs-transplanted rats compared to sham-operated rats, whereas the immunoreactivity of ionized calcium binding adaptor molecule 1 was markedly inhibited. In this study, we demonstrated the therapeutic effects of intravenous hBM-MSCs administration in parkinsonian model rats presenting distinct parkinsonian phenotype at 16 days after 6-OHDA lesioning. The favorable findings raise the possibility that hBM-MSCs could be a novel therapeutic option to promote survival of dopaminergic neurons in PD.

Very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency is characterized by impaired mitochondrial β-oxidation of fatty acids. The fatty acid oxidation plays a significant role in energy production especially in skeletal muscle. VLCAD is one of four acyl-CoA dehydrogenases with different-chain length specificity and catalyzes the initial step in mitochondrial β-oxidation of fatty acids. While the clinical phenotypes in neonates and infants are described as severe, adolescent-onset or adult-onset VLCAD deficiency has a more benign course with only skeletal muscle involvement. These myopathic phenotypes are characterized by episodic muscle weakness and rhabdomyolysis triggered by fasting and strenuous exercise. We report a male teenager who manifested repeated episodes of rhabdomyolysis immediately after exertional exercise. Rhabdomyolysis was diagnosed based on the marked elevation of serum creatine kinase and myoglobinuria. Acylcarnitine analysis by tandem mass spectrometry (MS/MS) revealed elevation of serum tetradecenoylcarnitine (C14:1-AC), which represents an abnormal acylcarnitine profile associated with the mitochondrial β-oxidation defect. High performance liquid chromatographic analysis showed decreased production of 2-hexadecenoyl-CoA (C16:1) from palmitoyl-CoA (C16:0), indicating the defect of VLCAD activity. Direct sequencing of the acyl-CoA dehydrogenase, very long-chain gene (ACADVL) that codes VLCAD revealed a heterozygous mutation (c.1242G>C) in exon 12 (E414D), which is a novel mutation in myopathic-type VLCAD deficiency. Because VLCAD functions as a homodimer, we assume that this heterozygous mutation may exhibit dominant-negative effect. This patient remains asymptomatic thereafter by avoiding exertional exercise. The findings of reduction of enzyme activity and clinical features associated with this novel missense mutation of VLCAD are discussed.

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 measurement before and after cooling of the masseters in MG patients and normal controls. After placing the ice-pack on the masseters for 3 min, serial recordings of the three tests were performed at various time intervals during 10 min after cooling. Results The bite force increased significantly after cooling in ice-pack-positive MG patients. The acceleration and acceleration ratio (acceleration at a given time to baseline acceleration) of jaw movement increased significantly after cooling of the masseters in ice-pack-positive MG patients compared to ice-pack-negative patients and normal controls. The prolonged effect of cooling continued until the end of recording even though decremental response to RNS had returned to baseline value. Conclusions Cooling of myasthenic muscle may induce two effects. One is relatively short effect on electrical synaptic transmission at the endplate, and another is prolonged effect on E-C coupling in the muscle. Significance The ice-pack test induces a prolonged effect of ameliorating impaired E-C coupling in MG.

A 30-year-old woman was admitted to our hospital because of intractable orbital pain and ptosis on the left side. On admission, she had left oculomotor, ophthalmic and maxillary nerves palsy. MRI revealed a contrast enhanced lesion of the left oculomotor and trigeminal nerves through the covernous sinus and orbita. We diagnosed her condition as Tolosa-Hunt syndrome. The orbital pain was resolved within 48-hours by the pulse therapy with intra-venous methylpredonisolone. The cranial nerve palsy was gradually improved, but never reached complete remission. The left oculomotor and trigeminal nerves also remained enhanced on MRI until 200 days from the onset. Although there have been few reports to demonstrate the contrast enhancement of cranial nerves in Tolosa-Hunt syndrome, these MRI findings may be a specific indicator of the pathological process.

Involvement of cranial nerves caused by cranial base lesions manifests diverse symptoms according to the localization of lesions. These localization-related symptoms are classified into syndromes such as orbital apex syndrome, cavernous sinus syndrome, and jugular foramen syndrome. Since the lesions may have various etiologies including infection, inflammation and tumor, etiological diagnosis should be performed simultaneously if possible. However, previous reports have described poor and/or fatal outcome following inappropriate treatment mainly due to difficulties in making a definitive pathological diagnosis. Nineteen patients with multiple cranial nerve involvement caused by skull base lesions were enrolled over the past 12 years. The patients were divided into an "infectious" group (n=11) and a "noninfectious" group (n=8) based on the final diagnosis. Chi-square analysis was conducted to examine the sensitivity and specificity of various factors including patient characteristics, clinical course and treatment response in infectious and noninfectious groups. Consequently, we identified some patients with good outcome irrespective of infectious or noninfectious etiology, even though a pathological diagnosis was not reached before the initial treatment. These patients with good outcome consistently received antifungal therapy in the early stage if infectious etiologies were suspected. We recommend conducting diagnostic therapy with antifungal drugs in patients with skull base lesions of unknown origin although infection cannot be excluded, when a pathological diagnosis is difficult due to various patient conditions.

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 consistent with the diagnostic criteria of anti-signal recognition particle (anti-SRP) antibody-positive myopathy. On admission, the patient required pericardiocentesis for the management of exudative pericarditis. Accompanying the aggravation of myositis, negative T wave in precordial leads on ECG, ventricular extrasystoles and non-sustained ventricular tachycardia were observed. These abnormalities were resolved with the improvement of myositis by immunosuppressive treatment. These observations suggest that the myopericarditis was associated with anti-SRP antibody-positive myopathy.

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 learning, memory, and amyloid-β (Aβ) clearance in a transgenic mouse model of AD. We found that comp-B resolved the cognitive deficits, reduced insoluble Aβ42 levels, and prevented the degeneration of synaptic functions, thereby suggesting that comp-B may become a major compound for AD treatment.

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 enrolled 247 MS patients and 159 healthy controls (HCs) from the northernmost main island of Japan, Hokkaido Island (42–45° north), and 187 MS patients and 235 HCs from the southern half (33–35° north) of the Japanese archipelago (33–45° north). We genotyped HLA-DRB1 and HLA-DPB1 alleles, compared demographic features, and analyzed factors contributing to differences in clinical and laboratory findings between MS patients from southern and northern Japan. The Multiple Sclerosis Severity Score (MSSS), which adjusts the Kurtzke’s Expanded Disability Status Scale score according to disease duration, was used to estimate disease severity. Results The HLA-DRB1*04:05 and DRB1*15:01 alleles conferred susceptibility to MS in our Japanese population (pcorr = 0.0004 and pcorr = 0.0019, respectively). Southern patients had higher MSSS scores than northern patients (p = 0.003). Northern patients had higher frequencies of brain lesions meeting the Barkhof criteria (Barkhof brain lesions) and cerebrospinal fluid (CSF) IgG abnormalities than southern patients (p = 0.0012 and p

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 statistically supported ideas for improvements in arrangements for how participants cope with SD and maintain general well-being. Methods We interviewed 237 PD patients. The SD-related costs involved those incurred by the provision of dietary modifications, care oriented foods, alternatives, and supplements. Dietary therapies included rice porridge and commercially available care foods. The relationships between BMI (body mass index) and the severity of SD assumed in this paper as indicators for general well-being and as resources for coping with SD for PD patients were statistically analyzed. Results A lower BMI was found in participants eating porridge consistency rice (p = 0.003) and eating porridge rice is significantly related to the severity of SD (p

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 the cysteine residue at position 106 (Cys-106) under oxidative stress. Here, using specific antibodies against Cys-106-oxidized DJ-1 (oxDJ-1), it was found that the levels of oxDJ-1 in the erythrocytes of unmedicated PD patients (n = 88) were higher than in those of medicated PD patients (n = 62) and healthy control subjects (n = 33). Elevated oxDJ-1 levels were also observed in a non-human primate PD model. Biochemical analysis of oxDJ-1 in erythrocyte lysates showed that oxDJ-1 formed dimer and polymer forms and that the latter interacts with 20S proteasome. These results clearly indicate a biochemical alteration in the blood of PD patients, which could be utilized as an early diagnosis marker for PD.

Objectives Tacrolimus (FK506) is a macrolide T-cell immunomodulator used to treat myasthenia gravis (MG). Besides immunosuppression, tacrolimus has been reported to have the potential to increase muscle strength by enhancing ryanodine receptor (RyR) function. However, few attempts have been made to demonstrate the early effect of tacrolimus as an RyR enhancer in clinical investigation. Methods In 20 MG patients, masseteric compound muscle action potential (CMAP) and mandibular movement-related potentials (MRPs) were recorded simultaneously after stimulating the trigeminal motor nerve with a needle electrode. The excitation–contraction (E–C) coupling time (ECCT) was calculated by the latency difference between CMAP and MRP. Bite force was measured using a pressure-sensitive sheet. Serial assessments of % decrement in masseteric repetitive nerve stimulation (RNS), ECCT and bite force were performed before and within 4weeks of tacrolimus (3mgday −1 ) treatment. The median (mean, range) interval of assessment was 2 (2.4, 1–4) weeks. We also measured serum antibodies against RyR, acetylcholine receptor and muscle-specific receptor tyrosine kinase. Results Bite force increased after tacrolimus treatment accompanying clinical improvement assessed by Myasthenia Gravis Foundation of America classification, but the bite force difference did not reach statistical significance. Wilcoxon matched-pairs signed-ranks test detected a significant ECCT shortening in 12 patients assessed after 1–2weeks of tacrolimus treatment as well as in eight patients assessed after 3–4weeks. In contrast, masseteric CMAP and % decrement showed no significant changes after short-term tacrolimus treatment. Conclusions Tacrolimus induces ECCT shortening accompanying clinical improvement despite no improvement in % decrement within 2weeks. Significance This early effect of tacrolimus may imply a pharmacological enhancement of RyR function to improve E–C coupling in MG.

Parkinson's disease (PD) is characterized by relatively selective degeneration of dopaminergic neurons in the substantia nigra and loss of dopamine in the striatum. More than 50 epidemiological studies confirmed the low incidence of PD in smokers. Examining the distribution of subtypes of nicotinic acetylcholine receptors (nAChRs) in dopaminergic neurons of nigrostriatal system and its change in PD patients is quite important to elucidate possible neuroprotective cascade triggered by nicotine. Evidences of nAChR-mediated protection against neurotoxicity induced by rotenone, 6- hydroxydopamine (6-OHDA), and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) are briefly reviewed. In rotenone- and 6-OHDA-induced PD models, nAChR-mediated neuroprotection was blocked not only by α4β2 but also by α7 nAChR antagonists. The survival signal transduction, α7 nAChR-Src family-PI3K-Akt/PKB cascade and subsequent upregulation of Bcl-2, would lead to neuroprotection. These findings suggest that nAChR-mediated neuroprotection is achieved through subtypes of nAChRs and common signal cascades. An early diagnosis and protective therapy with specific nAChR modulations could be effective in delaying the progression of PD.

J. Neurochem. (2012) 121, 964–973. Abstract We have recently reported that Presenilin 1 (PS1), a causative gene of familial Alzheimer disease (AD), down-regulates the expression level of insulin receptor (IR) as well as its signaling through a γ-secretase-independent pathway. PS1 is phosphorylated by glycogen synthase kinase 3 β at the serine 353 and 357 residues. The main purpose of the present study was to clarify the effect of PS1 phosphorylation on IR/insulin signaling. Here, we demonstrate that the pseudo-phosphorylation mutant of PS1 inhibited IR transcription and reduced IR expression compared with wild-type PS1. Importantly, there was a decrease in expression of IR in AD brains, and the phosphorylation ratio of PS1 was negatively correlated with IR level in human brain samples. In the data from mouse models of AD, IR reduction was not observed at the pre-Aβ deposition stage but became apparent in that of post-Aβ deposition. Together with our previous reports, these results suggest that phosphorylated PS1 can promote the down-regulation of insulin signaling, which may be a positive feed-forward mechanism inhibiting insulin signaling. As insulin resistance is reported to be a risk factor for sporadic AD, this PS1-mediated regulatory mechanism of brain insulin signaling may be causally associated with AD pathology.

We assessed the clinicopathological features of nine patients with pure autonomic neuropathy, that is, neuropathy without sensory or motor deficits. The duration from symptom onset to diagnosis ranged from 1 month to 13 years. Of eight patients in whom serum antiganglionic acetylcholine receptor antibody was determined, four were positive. All patients who tested positive for this antibody manifested widespread autonomic dysfunction, with the exception of one patient who only experienced orthostatic hypotension. However, patients who were negative for the antiganglionic acetylcholine receptor antibody presented with partial autonomic failure. One of these patients had diffuse parasympathetic failure and generalized hypohidrosis but no orthostatic hypotension, which is clinically compatible with postganglionic cholinergic dysautonomia. Electron microscopic examination revealed a variable degree of reduction in unmyelinated fibers. Compared with normal controls, the patients had a significantly increased density of collagen pockets (p < 0.05). Additionally, the percentage of Schwann cell subunits with axons (out of the total number of Schwann cell subunits associated with unmyelinated fibers) was significantly decreased (p < 0.01). The density of unmyelinated fibers tended to decrease with increasing time between the onset of autonomic symptoms and biopsy (p < 0.05). In conclusion, the clinical and pathological features of pure autonomic neuropathy vary in terms of progression, autonomic involvement, presence of the antiganglionic acetylcholine receptor antibody, and loss of unmyelinated fibers.

Parkinson's disease (PD) is a progressive extrapyramidal motor disorder. Pathologically, this disease is characterized by the selective dopaminergic (DAergic) neuronal degeneration in the substantia nigra. Correcting the DA deficiency in PD with levodopa (L-dopa) significantly attenuates the motor symptoms; however, its effectiveness often declines, and L-dopa-related adverse effects emerge after long-term treatment. Nowadays, DA receptor agonists are useful medication even regarded as first choice to delay the starting of L-dopa therapy. In advanced stage of PD, they are also used as adjunct therapy together with L-dopa. DA receptor agonists act by stimulation of presynaptic and postsynaptic DA receptors. Despite the usefulness, they could be causative drugs for valvulopathy and nonmotor complication such as DA dysregulation syndrome (DDS). In this paper, physiological characteristics of DA receptor familyare discussed. We also discuss the validity, benefits, and specific adverse effects of pharmaceutical DA receptor agonist.

Synaptic loss, which strongly correlates with the decline of cognitive function, is one of the pathological hallmarks of Alzheimer disease. N-cadherin is a cell adhesion molecule essential for synaptic contact and is involved in the intracellular signaling pathway at the synapse. Here we report that the functional disruption of N-cadherin-mediated cell contact activated p38 MAPK in murine primary neurons, followed by neuronal death. We further observed that treatment with Aβ42 decreased cellular N-cadherin expression through NMDA receptors accompanied by increased phosphorylation of both p38 MAPK and Tau in murine primary neurons. Moreover, expression levels of phosphorylated p38 MAPK were negatively correlated with that of N-cadherin in human brains. Proteomic analysis of human brains identified a novel interaction between N-cadherin and JNK-associated leucine zipper protein (JLP), a scaffolding protein involved in the p38 MAPK signaling pathway. We demonstrated that N-cadherin expression had an inhibitory effect on JLP-mediated p38 MAPK signal activation by decreasing the interaction between JLP and p38 MAPK in COS7 cells. Also, this study demonstrated a novel physical and functional association between N-cadherin and p38 MAPK and suggested neuroprotective roles of cadherin-based synaptic contact. The dissociation of N-cadherin-mediated synaptic contact by Aβ may underlie the pathological basis of neurodegeneration such as neuronal death, synaptic loss, and Tau phosphorylation in Alzheimer disease brain.