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BackgroundThis study aimed to clarify the frequency and clinical features of monogenic cerebral small vessel disease (mgCSVD) among patients with adult-onset severe CSVD in Japan.MethodsThis study included patients with adult-onset severe CSVD with an age of onset ≤55 years (group 1) or >55 years and with a positive family history (group 2). After conducting conventional genetic tests forNOTCH3andHTRA1, whole-exome sequencing was performed on undiagnosed patients. Patients were divided into two groups according to the results of the genetic tests: monogenic and undetermined. The clinical and imaging features were compared between the two groups.ResultsGroup 1 and group 2 included 75 and 31 patients, respectively. In total, 30 patients hadNOTCH3mutations, 11 patients hadHTRA1mutations, 6 patients hadABCC6mutations, 1 patient had aTREX1mutation, 1 patient had aCOL4A1mutation and 1 patient had aCOL4A2mutation. The total frequency of mutations inNOTCH3,HTRA1andABCC6was 94.0% in patients with mgCSVD. In group 1, the frequency of a family history of first relatives, hypertension and multiple lacunar infarctions (LIs) differed significantly between the two groups (monogenic vs undetermined; family history of first relatives, 61.0% vs 25.0%, p=0.0015; hypertension, 34.1% vs 63.9%, p=0.0092; multiple LIs, 87.8% vs 63.9%, p=0.0134).ConclusionsMore than 90% of mgCSVDs were diagnosed by screening forNOTCH3,HTRA1andABCC6. The target sequences for these three genes may efficiently diagnose mgCSVD in Japanese patients.

This study aimed to clarify the frequency and clinical features of monogenic cerebral small vessel disease (mgCSVD) among patients with adult-onset severe CSVD in Japan.This study included patients with adult-onset severe CSVD with an age of onset ≤55 years (group 1) or55 years and with a positive family history (group 2). After conducting conventional genetic tests forGroup 1 and group 2 included 75 and 31 patients, respectively. In total, 30 patients hadMore than 90% of mgCSVDs were diagnosed by screening for

Cerebral small vessel disease (CSVD) causes dementia and gait disturbance due to arteriopathy. Cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL) is a hereditary form of CSVD caused by loss of high-temperature requirement A1 (HTRA1) serine protease activity. In CARASIL, arteriopathy causes intimal thickening, smooth muscle cell (SMC) degeneration, elastic lamina splitting, and vasodilation. The molecular mechanisms were proposed to involve the accumulation of matrisome proteins as substrates or abnormalities in transforming growth factor β (TGF-β) signaling. Here, we show that HTRA1(−/−) mice exhibited features of CARASIL-associated arteriopathy: intimal thickening, abnormal elastic lamina, and vasodilation. In addition, the mice exhibited reduced distensibility of the cerebral arteries and blood flow in the cerebral cortex. In the thickened intima, matrisome proteins, including the hub protein fibronectin (FN) and latent TGF-β binding protein 4 (LTBP-4), which are substrates of HTRA1, accumulated. Candesartan treatment alleviated matrisome protein accumulation and normalized the vascular distensibility and cerebral blood flow. Furthermore, candesartan reduced the mRNA expression of Fn1, Ltbp-4, and Adamtsl2, which are involved in forming the extracellular matrix network. Our results indicate that these accumulated matrisome proteins may be potential therapeutic targets for arteriopathy in CARASIL.

Progressive supranuclear palsy (PSP) is characterized by supranuclear gaze palsy, dystonic rigidity of the neck and upper trunk, frequent falls and mild cognitive impairment. Cerebellar ataxia is one of the exclusion criteria given by the National Institute of Neurological Disorders and Stroke and the Society for Progressive Supranuclear Palsy. As a result, pathologically proven PSP patients exhibiting cerebellar ataxia have often been misdiagnosed with spinocerebellar degeneration, specifically multiple system atrophy with predominant cerebellar ataxia (MSA-C). However, more recently, it has been recognized that patients with PSP can present with truncal and limb ataxia as their initial symptom and/or main manifestation. These patients can be classified as having PSP with predominant cerebellar ataxia (PSP-C), a new subtype of PSP. Since the development of this classification, patients with PSP-C have been identified primarily in Asian countries, and it has been noted that this condition is very rare in Western communities. Furthermore, the clinical features of PSP-C have been identified, enabling it to be distinguished from other subtypes of PSP and MSA-C. In this review, we describe the clinical and neuropathological features of PSP-C. The hypothesized pathophysiology of cerebellar ataxia in PSP-C is also discussed.

Lipohyalinosis is an important concept in the independence of lacunar stroke; however, its role has been overemphasized and has led to much confusion in the understanding of lacunar stroke. Classical lipohyalinosis has declined following the widespread availability of antihypertensive therapy, and lacunar stroke secondary to age-related hyaline atherosclerosis is more commonly observed in clinical practice. Clinically diagnosed lacunar stroke is associated with several etiopathogenetic contributors. Excluding cardiogenic embolism, lacunar stroke can be categorized based on the detection of an atheroma. Atheroma imaging is possible in recent years, and strokes that are not associated with an atheroma are shown to present with deep white matter hyperintensity on MRI. Additionally, risk gene analysis has confirmed a group of risk genes associated with the extracellular matrix in lacunar stroke with white matter hyperintensity on MRI. These findings suggest the role of a variety of etiopathogenetic mechanisms underlying lacunar stroke and that lacunar stroke with deep white matter hyperintensity on MRI may be attributable to unique pathogenetic contributors. This group is known to be strongly associated with genetic contributors. Hopefully, lacunar stroke will be diagnosed from this perspective with the development of interventional strategies tailored to the pathogenesis of this condition.

A 52-year-old man was admitted to our hospital because of two episodes of bacterial meningitis within a 6-month period. CSF examination showed neutrophilic pleocytosis with marked elevation of protein and hypoglycorrhachia, but the inflammatory reaction was mild and blood and CSF cultures were negative. At the time of the second admission, intermittent watery nasal discharge caused by CSF rhinorrhea was evident. CT and MR imaging revealed a tiny clival bone defect, and transnasal endoscopic repair was performed successfully. The pathological diagnosis was chordoma based on immunohistochemical staining for brachyury. Although chordoma presenting as recurrent bacterial meningitis occurs extremely rare, asking patients detailed questions about the CSF rhinorrhea must be essential for disclosing unclear infection sources.

A 42-year-old woman with bronchial asthma was admitted to our hospital due to sensory dominant mononeuritis multiplex lasting for more than 6 months. At that time, her eosinophil count was 761/μl and her sural nerve biopsy showed no findings suggestive of vasculitis. Four months later, she experienced sudden convulsions and right hemiparesis due to left lobular parietal subcortical hemorrhage, when her eosinophil count was elevated to 3,257/μl. Numerous microbleeds and small infarctions were also detected in the intracerebral areas of different regions with MRI. Eosinophilic granulomatosis with polyangiitis (EGPA) is a systemic necrotizing vasculitis of the small vessels, commonly affecting the peripheral nerves. Subarachnoid hemorrhage in patients with EGPA is extremely rare. Steep elevation of the eosinophil count may release certain cytokines, causing cerebral hemorrhage.

The crystal structure and electrode properties of delithiated Li1-xMn1/3Ni1/3Co1/3O2 as a Mg rechargeable battery cathode material were investigated. Electrochemically delithiated Li0.3Mn1/3Ni1/3Co1/3O2 and Li0.4Mn1/3Ni1/3Co1/3O2 in a Mg cell exhibited capacities of approximately 50 and 80 mAh g−1, respectively. On the other hand, chemically delithiated Li0.1Mn1/3Ni1/3Co1/3O2 and Li0.4Mn1/3Ni1/3Co1/3O2 exhibited capacities of approximately 40 and 130 mAh g−1, respectively. Synchrotron X-ray diffraction was performed to refine the crystal structure of these two chemically delithiated samples and their crystal structures were analyzed in detail. Although Li0.4Mn1/3Ni1/3Co1/3O2 was identified as a monophase of a hexagonal crystal system (R 3 ¯ m), Li0.1Mn1/3Ni1/3Co1/3O2 was identified as two phases of the hexagonal O3-type (R 3 ¯ m) and the trigonal O1-type (P 3 ¯ m1). Therefore, the Li deficient O3 structure is considered to be more suitable than O1 structure in the electrochemical intercalation and deintercalation of Mg ions.

INTRODUCTION Currently, the secondary battery having a high energy density as a high performance secondary battery has been developed. Although polyvalent cations secondary batteries such as Mg and Ca batteries are a promising candidate, polyvalent cations secondary battery as alternative to lithium ion batteries has not been reported. In the lithium-ion battery, LiNi0.5Mn1.5O4 was well known to show two-electron reaction from Ni2 + to Ni4+ and high potential of 4.7 V. Interestingly, the electrochemical characteristic of LiNi0.5Mn1.5O4 was due to firing temperature changes. Therefore, the oxides consisted of Mg and Ni can be expected to be high potential and capacity from a viewpoint of the combination with divalent cations and two-electron reaction. However, synthesis of the oxides consisting of Mg and Ni has been only reported in the limited chemical composition, MgNiO2 and Mg0.67Ni1.33O2, and not reported the synthesis of other Mg / Ni ratio1,2). The present study was aimed at examination of difference in the electrochemical properties due to the difference in the firing temperature, controlling the rock-salt type MgxNi1-xO2 to Mg/Ni ratio, and evaluation as a magnesium ion battery cathode material. EXPERIMENTAL MgxNi1-xO2 was synthesized by a reverse coprecipitation synthesis1). MgxNi1-xO2 synthesized by nitrate aqueous solution of Mg and Ni were mixed to Na2CO3 solution while heating to 80° C, and the precursor dried (100 ° C, Air, 24h), and firing (550 - 950° C, Air, 24h). It was examined that the change in Mg/Ni ratio by changing the concentration of Na2CO3 solution. The samples were characterized by powder X-ray diffraction and ICP measurements. We also examined the valence of Ni by XAFS analysis (BL14B2, SPring-8). Before Charge-discharge test, active material and conductive agent in a weight ratio of 10:3 carbon coating (300rpm, 2h) by a planetary ball-mill. The positive electrodes were mixed active material and a conductive carbon and a binder (PTFE) at 5: 5: 1 weight ratio. Negative electrode used Mg metal or AZ31, electrolyte used 0.5 mol/L-Mg(N(CF3SO2)2)2/Acetonitrile (AN) or 1.0 mol/L-Mg(N(CF3SO2)2)2/Triglyme (G3). We attempted the Rietveld analysis (RIETAN-FP) and MEM analysis (Dysnamia) using the measured synchrotron X-ray diffraction data(BL19B2, SPring-8) RESULTS AND DISCUSSION The synthesized samples were identified as Rock-salt structure with space group Fd-3m by powder X-ray diffraction. To refine the crystal structure of the samples, we performed the Rietveld analysis using the synchrotron X-ray diffraction (e.g. R wp=5.60%, R e=2.35%). In addition, the results of ICP analyses for the compounds revealed that Mg/Ni ratio of the samples were ranged from 0.28 to 0.48 by changing Na2CO3 aq. concentration. The XAFS analysis, the valence state of Ni was determined to be divalent (Fig.1). The intensity ratio of d 111/d 200increased with the increasing the Mg/Ni ratio in the X-ray diffraction. We performed a charge-discharge test. Results of the charge-discharge test using AN showed 217mAh/g for the sample fired at 950 °C . The sample being higher Mg/Ni ratio tended to show higher capacity. However, the capacity might increase by a side reaction because of the electrochemical reaction occurred at extremely low voltage. To solve this reaction, electrolyte was changed from AN to G3 and the current collector was changed from Pt to Ni. As a result for such condition, it showed high reversibility and suppressed the side reactions. We examined the elimination of Mg by an oxidizing agent of NO2BF4. Since the lattice constants did not change before and after treatment, it was suggested elimination of Mg by chemical treatment was difficult. Therefore, we partly replaced Mg with Ca for the improvement of electrochemical property.We confirmed that (Mg,Ca)xNi1-xO2 was synthesized from the increase of the lattice parameter. As a result of the charge-discharge test for (Mg,Ca)xNi1-xO2, discharge potential was increased from 0.5V to 0.8V. Therefore, it may be possible to significantly improve the properties of Mg secondary battery of rock-salt type by Ca substitution. It was performed by help of ALCA-SPRING and shows thanks to the members concerned. References 1)S. Yagi et al., Jpn. J. Appl. Phys., 52,025501 (2013). 2)T. Ichitsubo, T. Adachi, S. Yagi, T. Doi, J.Mater.Chem., 21, 11764(2011). Figure 1