Study Profile of the Tsuruoka Metabolomics Cohort Study (TMCS).

The Tsuruoka Metabolomics Cohort Study (TMCS) is an ongoing population-based cohort study being conducted in the rural area of Yamagata Prefecture, Japan. This study aimed to enhance the precision prevention of multi-factorial, complex diseases, including non-communicable and aging-associated diseases, by improving risk stratification and prediction measures. At baseline, 11,002 participants aged 35-74 years were recruited in Tsuruoka City, Yamagata Prefecture, Japan, between 2012 and 2015, with an ongoing follow-up survey. Participants underwent various measurements, examinations, tests, and questionnaires on their health, lifestyle, and social factors. This study used an integrative approach with deep molecular profiling to identify potential biomarkers linked to phenotypes that underpin disease pathophysiology and provide better mechanistic insights into social health determinants. The TMCS incorporates multi-omics data, including genetic and metabolomic analyses of 10,933 participants and comprehensive data collection ranging from physical, psychological, behavioral, and social to biological data. The metabolome is used as a phenotypic probe because it is sensitive to changes in physiological and external conditions. The TMCS focuses on collecting outcomes for cardiovascular disease, cancer incidence and mortality, disability, functional decline due to aging and disease sequelae, and the variation in health status within the body represented by omics analysis that lies between exposure and disease. It contains several sub-studies on aging, heated tobacco products, and women's health. This study is notable for its robust design, high participation rate (89%), and long-term repeated surveys. Moreover, it contributes to precision prevention in Japan and East Asia as a well-established multi-omics platform.

"Missing-piece" sign with dural arteriovenous fistula at craniocervical junction: A case report.

OBJECTIVES: Spinal dural arteriovenous fistula (sDAVF) is a rare and often underdiagnosed spinal disease. Early diagnosis is required because the deficits are reversible and delays in treatment cause permanent morbidity. Although the abnormal vascular flow void is a critical radiographic feature of sDAVF, they are not always present. A characteristic enhancement pattern of sDAVF has been recently reported as the "missing-piece" sign which can lead to the early and correct diagnosis. METHODS: We presented imaging findings, treatment decisions, and the outcome of a rare case of sDAVF, in which the "missing-piece" sign appeared atypical. RESULTS: A 60-year-old woman developed numbness and weakness in her extremities. Spinal MRI revealed longitudinal hyperintensity in the T2-weighted image, extending from the thoracic level to medulla oblongata. At first, myelopathy with inflammation or tumor was suspected because of the lack of flow voids and vascular abnormalities in CT-angiography and MR-DSA. However, we administered intravenous methylprednisolone and her symptom got worse with the appearance of the "missing-piece" sign. Then, we successfully diagnosed sDAVF by angiography. The "missing-piece" sign was considered to derive from inconsistency of the intrinsic venous system of spinal cord, with the abrupt segments without enhancement. The same etiology was considered in our case. CONCLUSIONS: Detecting the "missing-piece" sign can lead to the correct diagnosis of sDAVF, even if the sign appeared atypical.

Anti-N-methyl-D-aspartate receptor encephalitis with concurrent human herpes virus-6A deoxyribonucleic acid detection: An autopsy case.

We report an autopsy case of anti-N-methyl-D-aspartate (NMDA) receptor (NMDAR) encephalitis with concurrent human herpes virus-6 (HHV-6) A deoxyribonucleic acid (DNA) detection in cerebrospinal fluid (CSF). A 38-year-old previously healthy Japanese man presented with a generalized seizure. Brain magnetic resonance imaging (MRI) findings were unremarkable, but CSF revealed pleocytosis. On Day 11, HHV-6 DNA was detected in CSF, and IgG antibodies against the NR1 subunit of the NMDAR (GluN1) were subsequently detected. Since HHV-6 encephalitis was initially suspected, the patient was treated with foscarnet and ganciclovir, but the HHV-6A copy number increased from 200 (Day 22) to 2000 copies/mL (Day 47), and the therapy was ineffective. As typical symptoms of anti-NMDAR encephalitis developed, we changed the patient's treatment to combat anti-NMDAR encephalitis. He was repeatedly treated with first-line immunotherapy, and GluN1 antibody titer decreased. He was not treated with second-line immunotherapy because of recurrent infections; he died on Day 310. Postmortem examinations did not show systemic tumors. Microscopic examination of the brain revealed only severe neuronal rarefaction in the hippocampal cornu ammonis (CA) 3-4 areas with gliosis. Early initiation of aggressive immunotherapy may be required in a refractory case of anti-NMDAR encephalitis, even with HHV-6A DNA detection, because the significance of this concurrent detection in autoimmune encephalitis remains unclear.

Characteristics of cortical spreading depression and c-Fos expression in transgenic mice having a mutation associated with familial hemiplegic migraine 2.

BACKGROUND: Cortical spreading depression is thought to be the underlying mechanism of migraine aura. In 2006, three relatives having the point mutation E700K in ATP1A2 exon 15 were diagnosed with familial hemiplegic migraine 2 characterized by complicated forms of aura. Here, we generated a transgenic mouse model having the human E700K mutation in the Atp1a2 orthologous gene. OBJECTIVE: To investigate the characteristics of cortical spreading depression in a mouse model with E700K mutation in the Atp1a2. METHODS: Cortical spreading depression was induced by applying stepwise increases of KCl concentration or electrical stimulation intensity to C57BL/6J-Tg(Atp1a2*E700K)9151Kwk mice (Tg, both sexes) and corresponding wild-type animals. Under urethane anesthesia, the responsiveness and threshold to cortical spreading depression were examined and the distribution of c-Fos expression, a neuronal activity marker, was immunohistochemically determined. RESULTS: Overall, Tg mice showed significantly faster propagation velocity (p < 0.01) and longer full-width-at-half-maximum (p < 0.01) than wild-type animals, representing a slower recovery from direct current potential deflection. The cortical spreading depression threshold tended to be lower in Tg, especially in females. c-Fos-positive cells were significantly enhanced in the ipsilateral somatosensory cortex, piriform cortex, amygdala and striatum (each p < 0.05 vs. contralateral side). Numbers of c-Fos positive cells were significantly higher in the ipsilateral amygdala of Tg, as compared with wild-type animals (p < 0.01). CONCLUSION: The effect of cortical spreading depression may be greater in E700K transgenic mice than that in wild-type animals, while the threshold for cortical spreading depression shows little change. Higher c-Fos expression in the amygdala may indicate alterations of the limbic system in Tg, suggesting an enhanced linkage between cortical spreading depression and amygdala connectivity in familial hemiplegic migraine 2 patients.

Trends of Antiplatelet Therapy for the Management of Moyamoya Disease in Japan: Results of a Nationwide Survey.

BACKGROUND: The efficacy and safety of antiplatelet drugs in the treatment of moyamoya disease remain unclear. This study reports results of a nationwide survey conducted in 2016 on the trends of antiplatelet therapy for moyamoya disease in Japan. METHODS: Data were obtained through questionnaires related to treatment policies regarding antiplatelet drugs from each specialized stroke management department of 765 hospitals in Japan. Data were also compared between experienced facilities (defined as facilities managing more than 10 cases per year) and those less experienced (not more than 10 cases per year) to determine experts' opinion. RESULTS: Of the 389 departments in 375 hospitals that responded, 330 departments provided medical care for moyamoya disease. Regarding ischemic stroke, numerous departments considered the use of antiplatelet drugs "in principle" (218 departments). After surgery for ischemic moyamoya disease, the use of antiplatelet drugs for a certain period of time was the most popular opinion (74 departments). Regarding asymptomatic moyamoya disease, majority departments reported no use of APDs "in principle" (256 departments). The experienced facilities reported "no use of antiplatelet drugs" more frequently than those less experienced for treating asymptomatic moyamoya disease. In moyamoya disease, aspirin was the most commonly used antiplatelet drugs followed by cilostazol and clopidogrel. CONCLUSIONS: This survey revealed details of treatment policies, and the selection of antiplatelet drugs widely varied across facilities. Further prospective studies are necessary to improve the current unclear situation regarding the use of antiplatelet drugs for the management of moyamoya disease.

Differential diagnosis between intracranial dissemination of spinal cord astrocytoma and paraneoplastic limbic encephalitis.

We describe the clinical features of limbic encephalitis that developed after palliative spinal cordotomy in 2 patients with malignant thoracic astrocytoma. Both patients showed short-term memory loss, hallucinations of smells and psychiatric symptoms. Brain MRI on T2-weighted and fluid-attenuated inversion recovery sequences revealed high intensity lesions in bilateral temporal lobe areas. We considered that both patients had paraneoplastic limbic encephalitis associated with astrocytoma because of various clinical and radiological features. But the possibility of intracranial dissemination of astrocytoma could not be fully excluded. The differential diagnosis between intracranial dissemination of spinal cord astrocytoma and paraneoplastic limbic encephalitis may be sometimes difficult.

Astroglial pentose phosphate pathway rates in response to high-glucose environments.

ROS (reactive oxygen species) play an essential role in the pathophysiology of diabetes, stroke and neurodegenerative disorders. Hyperglycaemia associated with diabetes enhances ROS production and causes oxidative stress in vascular endothelial cells, but adverse effects of either acute or chronic high-glucose environments on brain parenchymal cells remain unclear. The PPP (pentose phosphate pathway) and GSH participate in a major defence mechanism against ROS in brain, and we explored the role and regulation of the astroglial PPP in response to acute and chronic high-glucose environments. PPP activity was measured in cultured neurons and astroglia by determining the difference in rate of (14)CO(2) production from [1-(14)C]glucose and [6-(14)C]glucose. ROS production, mainly H(2)O(2), and GSH were also assessed. Acutely elevated glucose concentrations in the culture media increased PPP activity and GSH level in astroglia, decreasing ROS production. Chronically elevated glucose environments also induced PPP activation. Immunohistochemical analyses revealed that chronic high-glucose environments induced ER (endoplasmic reticulum) stress (presumably through increased hexosamine biosynthetic pathway flux). Nuclear translocation of Nrf2 (nuclear factor-erythroid 2 p45 subunit-related factor 2), which regulates G6PDH (glyceraldehyde-6-phosphate dehydrogenase) by enhancing transcription, was also observed in association with BiP (immunoglobulin heavy-chain-binding protein) expression. Acute and chronic high-glucose environments activated the PPP in astroglia, preventing ROS elevation. Therefore a rapid decrease in glucose level seems to enhance ROS toxicity, perhaps contributing to neural damage when insulin levels given to diabetic patients are not properly calibrated and plasma glucose levels are not adequately maintained. These findings may also explain the lack of evidence for clinical benefits from strict glycaemic control during the acute phase of stroke.