Kallikrein 6 secreted by oligodendrocytes regulates the progression of experimental autoimmune encephalomyelitis.

Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS), and experimental autoimmune encephalomyelitis (EAE) is a well-established animal model of the disease. Here, we examined the pathophysiological role of Kallikrein 6 (Klk6), a serine protease produced by oligodendrocytes (OLs), in EAE using Klk6 knockout (Klk6-/-) mice. Compared with Klk6+/+ (wild-type) mice, Klk6-/- mice showed milder EAE symptoms, including delayed onset and milder paralysis. Loss of Klk6 suppressed matrix metalloprotease-9 expression and diminished the infiltration of peripheral inflammatory cells into the CNS by decreasing blood-brain barrier (BBB) permeability and reducing expression levels of inflammatory cytokines, chemokines and their receptors. Scanning electron microscopic analysis revealed demyelination characterized by myelin detachment from the axons in the early phase of EAE progression (days 3-7) in Klk6+/+ mice but not in Klk6-/- mice. Interestingly, anti-MOG (myelin oligodendrocyte glycoprotein) autoantibody was also detected in the cerebrospinal fluid (CSF) and spinal cord on day 3 after MOG immunization. Furthermore, treatment of primary cultured OLs with anti-MOG autoantibody induced oligodendroglial morphological changes and increases in myelin basic protein and Klk6 expression. We also developed a novel enzyme-linked immunoabsorbent assay method for detecting activated KLK6 in human CSF. In human autopsy brain samples, expression of active KLK6 was detected in OLs using an antibody that specifically recognizes the protein's activated form. Taken together, our findings demonstrate that Klk6 secreted by OLs plays a critical role in the pathogenesis of EAE/MS and that it might serve as a potential therapeutic target for MS.

Recurrent ischemic stroke in a patient with the Trousseau syndrome treated with dabigatran.

A 70-year-old man with multiple ischemic strokes was diagnosed with cardiac embolism and treated with dabigatran. Three months later, he suddenly developed vertigo and vomiting. Magnetic resonance imaging, showed recurrent lesions and blood tests revealed hypercoagulability, hypoproteinemia, and elevated cytokeratin 19 fragments that serve as a tumor marker of lung cancer. Chest computed tomography showed there were small nodules in bilateral lungs and swollen mediastinal lymph nodes. A conclusive diagnosis was impossible because the patient declined invasive procedures. We suspected primary lung cancer and diagnosed concomitant arterial thrombosis. We initially administered low-molecular-weight heparin, which we later changed to vitamin K antagonist. Although stroke did not recur thereafter, liver metastasis resulted in death 6 months later. The effectiveness of novel oral anticoagulants for preventing the Trousseau syndrome remains unclear. Further study is needed to prevent venous and arterial thromboses arising from the Trousseau syndrome.

Atrial fibrillation, hypertension, and the cerebral vasodilatory reserve.

Schematic representation for the cascade model of atrial fibrillation, hypertension, the cerebral vasodilatory reserve, and cognitive decline.

Relationship between the Tortuosity of the Extracranial Internal Carotid and Vertebral Arteries on Magnetic Resonance Imaging/Angiography and Vascular Risk Factors in a Japanese Population.

Objective We aimed to investigate the relationship between tortuosity of the extracranial internal carotid artery (ICA) or vertebral artery (VA) and vascular risk factors among residents of Asahikawa, northeast Japan. Methods We retrospectively surveyed participants of "brain dock" medical brain checkups, which involved magnetic resonance imaging and angiography. We measured the tortuosity of the ICA and VA, and evaluated vascular risk factors based on medical interviews, questionnaires, and medical records. Results A total of 218 participants were enrolled in the study. ICA tortuosity (right and left) was significantly correlated with age [odds ratio (OR): 2.452, 95% confidence interval (CI): 1.695-3.548, p<0.001]. A more pronounced correlation was observed in females than in males (OR: 1.678, 95% CI: 1.004-2.807, p=0.048). VA tortuosity (right and left) was significantly correlated with age (OR: 1.786, 95% CI: 1.250-2.550, p=0.001) and smoking history (OR: 2.140, 95% CI: 1.235-3.707, p=0.007), and was more pronounced in females than in males (OR: 1.864, 95% CI: 1.107-3.137, p=0.019). Conclusion ICA tortuosity was correlated with age, while VA tortuosity was correlated with age and smoking history. ICA and VA tortuosity were more pronounced in females than in males.

A case of myopathy and markedly elevated creatine kinase levels with hypocalcemia, hypomagnesemia, and hyposelenemia due to short bowel syndrome after rectal cancer resection.

A 66-year-old Japanese man was referred to our hospital with myalgia and muscle weakness. He had a history of rectal cancer, which invaded into the urinary bladder and ileum and was treated with chemotherapy, radiotherapy, resection of the rectum, colostomy, and ileal conduit construction. He showed recurrent markedly elevated serum creatine kinase levels and concurrent hypocalcemia. Muscle magnetic resonance imaging demonstrated abnormal signals in the proximal limb muscles, and needle electromyography showed myopathic changes. Further examination revealed hypomagnesemia and hyposelenemia with underlying short bowel syndrome. Calcium, magnesium and selenium supplementation improved his symptoms and laboratory findings.

Possible Chronic Graft-versus-host Disease in the Central Nervous System Manifesting as Cerebellar Ataxia after Allogeneic Hematopoietic Stem Cell Transplantation for Acute Myeloid Leukemia.

A 44-year-old woman was admitted to our hospital with a fever, dizziness, and gait disturbance after undergoing allogeneic hematopoietic stem cell transplantation for acute myeloid leukemia followed by graft-versus-host disease. She presented with cerebellar ataxia, nystagmus, and numbness of the lower extremities. Brain magnetic resonance imaging and perfusion scintigraphy showed progressive cerebellar involvement. Cerebrospinal fluid tests showed mildly elevated protein and IgG levels without pleocytosis. Anti-ganglioside antibodies were detected, but their levels did not follow the patient's clinical course. The patient did not respond sufficiently to steroids or other immunotherapies. We herein report the clinical characteristics of this case and a literature review.

NOTCH2NLC mutation-positive neuronal intranuclear inclusion disease with retinal dystrophy: A case report and literature review.

INTRODUCTION: Neuronal intranuclear inclusion disease (NIID) is a neurodegenerative disorder that produces a broad spectrum of clinical conditions such as dementia, upper motor neuron involvement, extrapyramidal symptoms, and neuropathy. Some studies have reported ophthalmological conditions associated with the disease; however, the details of these conditions remain unclear. PATIENT CONCERNS: We report a 63-year-old Japanese female with cognitive decline, blurred vision, photophobia, and color blindness at 52 years of age who was diagnosed with cone dystrophy. She also had anxiety, insomnia, depression, delusions, hallucinations, a wide-based gait with short steps, and urinary incontinence. DIAGNOSES, INTERVENTIONS, AND OUTCOMES: Magnetic resonance imaging revealed diffuse cerebral white matter changes and subcortical hyperintensity on diffusion-weighted imaging. Skin biopsy showed p62-positive intranuclear inclusions in sweat glands. NOTCH2NLC gene analysis revealed abnormal GGC expansion; therefore, NIID was diagnosed. CONCLUSION: NOTCH2NLC mutation-positive NIID may be associated with retinal dystrophy. Brain magnetic resonance imaging and skin biopsy are helpful diagnostic clues, and gene analysis is crucial for accurate diagnosis and appropriate management.

Meta-analysis of cerebrospinal fluid neuron-specific enolase levels in Alzheimer's disease, Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy.

BACKGROUND: This study examined the usefulness of cerebrospinal fluid (CSF) neuron-specific enolase (NSE) levels as a candidate biomarker of neurodegeneration in Alzheimer's disease (AD), Parkinson's disease (PD), PD with dementia (PDD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA). METHODS: We performed a systematic search of PubMed, the Cochrane Library, Scopus, and Google Scholar to find studies that measured CSF NSE levels in AD, PD, DLB, and/or MSA. For each disease, we pooled all available data and performed a meta-analysis, and meta-regression analyses of age and sex were conducted if the main analysis found a significant association. RESULTS: Twenty studies were included (13 for AD, 8 for PD/PDD/DLB, and 4 for MSA). Significantly elevated CSF NSE levels were detected in AD (Hedges' g = 0.822, 95% confidence interval [95% CI] 0.332 to 1.311, p = 0.0010), but the data exhibited high heterogeneity (I2 = 88.43%, p < 0.001). The meta-regression analysis of AD showed that age (p < 0.001), but not sex, had a significant effect on CSF NSE levels. A meta-analysis of the pooled data for PD/PDD/DLB did not show any significant changes in the CSF NSE level, but a sub-group analysis of PDD/DLB revealed significantly elevated CSF NSE levels (Hedges' g = 0.507, 95% CI 0.020 to 0.993, p = 0.0412). No significant changes in CSF NSE levels were detected in MSA. CONCLUSIONS: The CSF NSE level may be a useful biomarker of neurodegeneration in AD and PDD/DLB. Age was found to affect the CSF NSE levels of AD patients.

TDP-43 pathology in sporadic ALS occurs in motor neurons lacking the RNA editing enzyme ADAR2.

Both the appearance of cytoplasmic inclusions containing phosphorylated TAR DNA-binding protein (TDP-43) and inefficient RNA editing at the GluR2 Q/R site are molecular abnormalities observed specifically in motor neurons of patients with sporadic amyotrophic lateral sclerosis (ALS). The purpose of this study is to determine whether a link exists between these two specific molecular changes in ALS spinal motor neurons. We immunohistochemically examined the expression of adenosine deaminase acting on RNA 2 (ADAR2), the enzyme that specifically catalyzes GluR2 Q/R site-editing, and the expression of phosphorylated and non-phosphorylated TDP-43 in the spinal motor neurons of patients with sporadic ALS. We found that all motor neurons were ADAR2-positive in the control cases, whereas more than half of them were ADAR2-negative in the ALS cases. All ADAR2-negative neurons had cytoplasmic inclusions that were immunoreactive to phosphorylated TDP-43, but lacked non-phosphorylated TDP-43 in the nucleus. Our results suggest a molecular link between reduced ADAR2 activity and TDP-43 pathology.

Cerebrospinal Fluid Biomarkers in Parkinson's Disease: A Critical Overview of the Literature and Meta-Analyses.

Parkinson's disease (PD) is a common neurodegenerative disorder; however, well-established biochemical markers have not yet been identified. This review article covers several candidate cerebrospinal fluid (CSF) biomarkers for PD based on the recent literature and meta-analysis data. The decrease of α-synuclein in PD is supported by meta-analyses with modest reproducibility, and a decrease of amyloid ß42 is seen as a prognostic marker for cognitive decline. Tau, phosphorylated tau (p-tau), and neurofilament light chains have been used to discriminate PD from other neurodegenerative disorders. This article also describes more hopeful biochemical markers, such as neurotransmitters, oxidative stress markers, and other candidate biomarkers.

Myotonic dystrophy type 2 in Japan: ancestral origin distinct from Caucasian families.

Myotonic dystrophy type 2 (DM2) is caused by expansion of a tetranucleotide CCTG repeat in intron 1 of the ZNF9 gene on chromosome 3q21. All studied DM2 mutations have been reported in Caucasians and share an identical haplotype, suggesting a common founder. We identified a Japanese patient with DM2 and showed that the affected haplotype is distinct from the previously identified DM2 haplotype shared among Caucasians. These data strongly suggest that DM2 expansion mutations originate from separate founders in Europe and Japan and are more widely distributed than previously recognized.

A Sporadic Case of Fabry Disease Involving Repeated Fever, Psychiatric Symptoms, Headache, and Ischemic Stroke in an Adult Japanese Woman.

Fabry disease can cause various neurological manifestations. We describe the case of a Japanese woman with Fabry disease who presented with ischemic stroke, aseptic meningitis, and psychiatric symptoms. The patient had a mutation in intron 4 of her α-galactosidase A gene, which was not detected in her family. This case suggests that Fabry disease should be considered in young patients who exhibit central nervous system symptoms such as ischemic stroke, even if there is no family history of the condition. The episodes of aseptic meningitis and stroke experienced by our patient suggest that persistent inflammation might be the mechanism underlying Fabry disease.

Prevalence of multiple sclerosis in Asahikawa, a city in northern Japan.

Twenty-two years after the first survey, a follow-up study was performed on the prevalence of multiple sclerosis (MS) in Asahikawa, a city in northern Japan. The crude prevalence of MS rose from 2.5/100,000 (in 1975) to 10.2/100,000 (in 2002). The clinical diagnosis was established using the Poser diagnostic criteria, and the degree of physical disability was determined using the Expanded Disability Status Scale (EDSS). The distribution of patients according to the clinical form of MS was 65% with relapsing-remitting MS, 19% with secondary chronic progressive MS and 16% with the primary chronic progressive forms of MS. Symptoms at onset in the present study less often affected optic nerves (3%) than previously reported in Japan and was more like that seen in western MS series. Although prevalence of MS increase four-fold in Japan over the last two decades, it remains uncertain whether this apparent increase is real or reflects better ascertainment.

[A patient of sensorimotor neuropathy with small cell lung carcinoma and anti-GM1 antibody].

We reported a 62-year-old woman had sensorimotor neuropathy with small cell lung carcinoma (SCLC) and anti-GM1 antibody. She was admitted with several months history of progressive numbness, walking disturbance and anorexia. Neurologic examination revealed severe numbness and deep sensory disturbance of extremities and body, and mild weakness of distal extremities. Deep tendon reflexes were absent. Her limbs were ataxic. Nerve conduction studies showed no sensory evoked responses. CSF protein was elevated. Sural nerve biopsy revealed severe loss of myelinated fibers and perivascular mononuclear cells surrounding the perineurial vessel. Vasculitic neuropathy was diagnosed, and prednisolone was started, with no benefit. In the clinical course, she developed cough attacks and was found the lymphnode swelling in the mediastinum and supraclavicular fossa, which was diagnosed SCLC. Although anti-Hu antibody were not detected, anti-GM1 antibody was positive. She was treated with intravenous immunoglobulin, with transient improvement. The rare case of the paraneoplastic peripheral neuropathy with SCLC and anti-GM1 antibody was reported.

[An adult case of tuberculous meningitis].

A 36-year-old man was referred to our hospital with complaints of high fever and headache. A diagnosis of miliary tuberculosis with tuberculous meningitis was made. He was treated with isoniazid (400 mg/day), rifampicin (300 mg/day), ethambutol (750 mg/day), pyrazinamide (1.0 g/day) and prednisolone (60 mg/day). However, he lost consciousness because of hydrocephalus on the second day of hospitalization. Emergency cerebrospinal fluid drainage improved his neurological symptoms. After two months, he again complained of headache with nausea and double vision. Numerous tuberculomas were found not only in the cerebrum but also in the liver, the spleen and the retina. Recurrent hydrocephalus was treated with a V-P shunt, and combination therapy with four antituberculous agents was maintained for 18 months. He was discharged in a healthy condition, although a mild left facial palsy remained. In addition, we examined the inflammatory cytokine levels in both the CSF and the serum over the period of the patient's hospitalization. We concluded that the cytokine levels in the CSF may be associated with the progress and the prognosis of tuberculous meningitis.

Effectiveness of oral iron chelator treatment with deferasirox in an aceruloplasminemia patient with a novel ceruloplasmin gene mutation.

A 59-year-old man presented with refractory anemia, choreoathetosis in the left upper extremity, an unsteady gait and cognitive dysfunction. The laboratory findings showed a marked decrease in ceruloplasmin. Magnetic resonance images revealed iron deposition in the brain and visceral organs. Iron accumulation was also observed in hepatocytes. Genetic analyses of the ceruloplasmin gene revealed a novel homozygous mutation of c.2185 delC in exon 12. The oral chelator deferasirox was effective in treating the left-side choreoathetosis and unsteady gait. Providing early treatment using deferasirox may be useful for preventing the progression of symptomatic neurological dysfunction.

Treatment of Japanese restless legs syndrome patients with cabergoline: an open clinical preliminary trial.

OBJECTIVE: To determine the effective dose of cabergoline in Japanese patients with restless legs syndrome (RLS). METHODS: Six cases of idiopathic RLS and three of RLS with Parkinson disease (PD) participated in an open clinical preliminary trial. All cases were diagnosed based on the clinical criteria of the International RLS Study Group. Three RLS cases (1.3%) were detected out of 229 consecutive cases with PD. RLS severity was evaluated with International RLS Study Group (IRLSSG) Rating Scale Version 2.2 before and one year after the treatment with cabergoline. RESULTS: For 6 idiopathic RLS patients, the IRLSSG questionnaire scores improved from 25.5+/-3.7 to 10.7+/-8.9 (p=0.028, Wilcoxon test) with 1 mg of daily cabergoline at the endpoint. For 3 RLS cases with PD, the score was 21.7+/-3.7 before the treatment, and RLS symptoms completely disappeared with 1 mg of cabergoline. One of RLS cases with PD required additional cabergoline later because of parkinsonism. No adverse event with cabergoline was reported in this study. CONCLUSION: One mg of daily cabergoline is effective in some Japanese patients of RLS.

Edaravone diminishes free radicals from circulating neutrophils in patients with ischemic brain attack.

OBJECTIVE: Treatment with a free radical scavenger could be a new option for ischemic brain attack, however, little is known about the alteration of oxidative stress markers induced by edaravone, a novel free radical scavenger, in human ischemic brain attack. METHODS: We investigated the effects of edaravone on the oxidative stress markers in patients with ischemic brain attack. Twenty-one patients with ischemic brain attack and 19 controls were enrolled in this study. Blood samples were obtained just before and soon after the first administration of edaravone (30 mg) or ozagrel (40 mg). Intracellular reactive oxygen species of neutrophils were measured using 6-carboxy-2', 7'-dichlorodihydrofluorescin diacetate and a fluorescence-activated cell sorter. Superoxide from neutrophils, induced by phorbol myristate acetate (PMA), was determined by luminol-amplified chemiluminescence assay. RESULTS: Treatment with 30 mg of edaravone significantly decreased the intracellular reactive oxygen species (ROS) of neutrophils (Wilcoxon test, p=0.0001) and PMA-induced superoxide produced by neutrophils (Wilcoxon test, p=0.001). Ozagrel did not alter the intracellular ROS or superoxide production of neutrophils. CONCLUSION: Reduction of intracellular ROS and suppression of superoxide production in neutrophils provide a potential explanation for the clinical efficacy of edaravone in patients with ischemic brain attack.