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Introduction: National-level data on trends in the prognosis of age-stratified patients with intracerebral hemorrhage (ICH) are lacking. This study aimed to assess time trends in in-hospital mortality and functional outcomes of ICH patients by sex and age, and to explore factors associated with changes in in-hospital mortality trend., Patients and Methods: Using the largest nationwide, J-ASPECT stroke database in Japan, this serial cross-sectional study included ICH patients aged ⩾18 years who were hospitalized for non-traumatic ICH from April 2010 to March 2020. We examined trends in in-hospital mortality and functional outcomes using the modified Rankin Scale at discharge, as well as differences in in-hospital mortality change between age groups., Results: Among 262,399 ICH patients from 934 hospitals, crude in-hospital mortality showed a significant decreasing time trend (from 19.5% to 16.7%), and this trend was consistent across sex and age groups. In addition, differences in in-hospital mortality change over the 10-year study period were significant between male patients aged ⩾75 years and those aged ⩽64 years (-3.9% [95% confidence interval, -5.4 to -2.4] for 75-84 years; -4.1% [-6.3 to -1.9] for ⩾85 years). On the other hand, the proportion of dependent patients (mRS 3-5) at discharge increased from 52.0% to 54.9% over the 10-year study period., Conclusion: The in-hospital mortality of ICH patients improved, whereas the proportion of patients with dependent functional outcome at discharge increased, over the 10-year study period. Elucidating the mechanism underlying differences in in-hospital mortality reduction in men may provide insights into effective interventions in the future., Competing Interests: Declaration of conflicting interestThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: KI received grant support from Chugai Pharmaceutical Company Limited, Eisai Co., KM Biologics Company Limited, Nihon Medi-Physics, Nippon Zoki Pharmaceutical, Otsuka Pharmaceutical Company Limited, and Idorsia Pharmaceuticals Japan Limited. The other authors report no conflicts of interest.

Objectives: Intracerebral hemorrhage (ICH) and cerebral microbleeds (CMB) in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy are more common in East Asian populations than in people of white European ancestry. We hypothesized that the ethnic difference is explained by the East Asian-specific NOTCH3 p.R75P mutation., Methods: This retrospective observational study included 118 patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy in Japanese and Korean cohorts. We investigated whether the p.R75P mutation is associated with symptomatic ICH and multiple CMB (>5) using quasi-Poisson regression models. We predicted the NOTCH3 extracellular domain protein structures in silico and graded NOTCH3 extracellular domain immunostaining in skin vessels of some patients, with subsequent comparisons between p.R75P and other conventional mutations., Results: Among 63 Japanese patients (median age 55 years; 56% men), 15 had a p.R75P mutation, significantly associated with symptomatic ICH (adjusted relative risk 9.56, 95% CI 2.45-37.31), multiple CMB (3.00, 1.34-6.71), and absence of temporopolar lesions (4.91, 2.29-10.52) after adjustment for age, sex, hypertension, and antithrombotics. In the Korean cohort (n = 55; median age 55 years; 51% men), the p.R75P mutation (n = 13) was also associated with symptomatic ICH (8.11, 1.83-35.89), multiple CMB (1.90, 1.01-3.56), and absence of temporopolar lesions (2.32, 1.08-4.97). Structural analysis revealed solvent-exposed free cysteine thiols in conventional mutations, directly causing aggregation, whereas a stereochemically incompatible proline residue structure in p.R75P lowers correct disulfide bond formation probability, indirectly causing aggregation. Pathologically, the p.R75P mutation resulted in less vascular NOTCH3 extracellular domain accumulation than the other conventional mutations., Interpretation: NOTCH3 p.R75P mutation is associated with hemorrhagic presentations, milder temporopolar lesions, and distinct mutant protein structure properties. ANN NEUROL 2024;95:1040-1054., (© 2024 The Authors. Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Background: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), the most common form of hereditary cerebral small vessel disease (SVD), currently lacks disease-modifying treatments. Adrenomedullin (AM), a vasoactive peptide with angiogenic, vasodilatory, anti-inflammatory, and anti-oxidative properties, shows potential effects on the neuro-glial-vascular unit., Objective: The AdrenoMedullin for CADASIL (AMCAD) study aims to assess the efficacy and safety of AM in patients with CADASIL., Sample Size: Overall, 60 patients will be recruited., Methods: The AMCAD is a multicenter, investigator-initiated, single-arm phase II trial. Patients with a confirmed CADASIL diagnosis, based on NOTCH3 genetic testing, will receive an 8-h AM treatment (15 ng/kg/min) for 14 days following a baseline assessment (from day 1 to day 14). Follow-up evaluations will be performed on days 15, 28, 90, and 180., Study Outcomes: The primary endpoint is the cerebral blood flow change rate in the frontal cortex, evaluated using arterial spin labeling magnetic resonance imaging, from baseline to day 28. Summary statistics, 95% confidence intervals, and a one-sample t -test will be used for analysis., Conclusion: The AMCAD study aims to represent the therapeutic potential of AM in patients with CADASIL, addressing an unmet medical need in this challenging condition., Clinical Trial Registration: jRCT 2,051,210,117 (https://jrct.niph.go.jp/en-latest-detail/jRCT2051210117)., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: The authors declare that Kitamura K. own stock in Himuka AM Pharma Corporation, a company aiming to develop adrenomedullin and its derivatives as a novel drug., (© 2024 The Author(s).)

Objective: Postseizure functional decline is a concern in poststroke epilepsy (PSE). However, data on electroencephalogram (EEG) markers associated with functional decline are scarce. Thus, we investigated whether periodic discharges (PDs) and their specific characteristics are associated with functional decline in patients with PSE., Methods: In this observational study, patients admitted with seizures of PSE and who had scalp EEGs were included. The association between the presence or absence of PDs and postseizure short-term functional decline lasting 7 days after admission was investigated. In patients with PD, EEG markers were explored for risk stratification of short-term functional decline, according to the American Clinical Neurophysiology Society's Standardized Critical Care EEG Terminology. The association between EEG markers and imaging findings and long-term functional decline at discharge and 6 months after discharge, defined as an increase in the modified Rankin Scale score compared with the baseline, was evaluated., Results: In this study, 307 patients with PSE (median age = 75 years, range = 35-97 years, 64% males; hemorrhagic stroke, 47%) were enrolled. Compared with 247 patients without PDs, 60 patients with PDs were more likely to have short-term functional decline (12 [20%] vs. 8 [3.2%], p < .001), with an adjusted odds ratio (OR) of 4.26 (95% confidence interval [CI] = 1.44-12.6, p = .009). Patients with superimposed fast-activity PDs (PDs+F) had significantly more localized (rather than widespread) lesions (87% vs. 58%, p = .003), prolonged hyperperfusion (100% vs. 62%, p = .023), and a significantly higher risk of short-term functional decline than those with PDs without fast activity (adjusted OR = 22.0, 95% CI = 1.87-259.4, p = .014). Six months after discharge, PDs+F were significantly associated with long-term functional decline (adjusted OR = 4.21, 95% CI = 1.27-13.88, p = .018)., Significance: In PSE, PDs+F are associated with sustained neuronal excitation and hyperperfusion, which may be a predictor of postseizure short- and long-term functional decline., (© 2023 International League Against Epilepsy.)

Importance: Recent evidence indicates the efficacy of β-amyloid immunotherapy for the treatment of Alzheimer disease, highlighting the need to promote β-amyloid removal from the brain. Cilostazol, a selective type 3 phosphodiesterase inhibitor, promotes such clearance by facilitating intramural periarterial drainage., Objective: To determine the safety and efficacy of cilostazol in mild cognitive impairment., Design, Setting, and Participants: The COMCID trial (A Trial of Cilostazol for Prevention of Conversion from Mild Cognitive Impairment to Dementia) was an investigator-initiated, double-blind, phase 2 randomized clinical trial. Adult participants were registered between May 25, 2015, and March 31, 2018, and received placebo or cilostazol for up to 96 weeks. Participants were treated in the National Cerebral and Cardiovascular Center and 14 other regional core hospitals in Japan. Patients with mild cognitive impairment with Mini-Mental State Examination (MMSE) scores of 22 to 28 points (on a scale of 0 to 30, with lower scores indicating greater cognitive impairment) and Clinical Dementia Rating scores of 0.5 points (on a scale of 0, 0.5, 1, 2, and 3, with higher scores indicating more severe dementia) were enrolled. The data were analyzed from May 1, 2020, to December 1, 2020., Interventions: The participants were treated with placebo, 1 tablet twice daily, or cilostazol, 50 mg twice daily, for up to 96 weeks., Main Outcomes and Measures: The primary end point was the change in the total MMSE score from baseline to the final observation. Safety analyses included all adverse events., Results: The full analysis set included 159 patients (66 [41.5%] male; mean [SD] age, 75.6 [5.2] years) who received placebo or cilostazol at least once. There was no statistically significant difference between the placebo and cilostazol groups for the primary outcome. The least-squares mean (SE) changes in the MMSE scores among patients receiving placebo were -0.1 (0.3) at the 24-week visit, -0.8 (0.3) at 48 weeks, -1.2 (0.4) at 72 weeks, and -1.3 (0.4) at 96 weeks. Among those receiving cilostazol, the least-squares mean (SE) changes in MMSE scores were -0.6 (0.3) at 24 weeks, -1.0 (0.3) at 48 weeks, -1.1 (0.4) at 72 weeks, and -1.8 (0.4) at 96 weeks. Two patients (2.5%) in the placebo group and 3 patients (3.8%) in the cilostazol group withdrew owing to adverse effects. There was 1 case of subdural hematoma in the cilostazol group, which may have been related to the cilostazol treatment; the patient was successfully treated surgically., Conclusions and Relevance: In this randomized clinical trial, cilostazol was well tolerated, although it did not prevent cognitive decline. The efficacy of cilostazol should be tested in future trials., Trial Registration: ClinicalTrials.gov Identifier: NCT02491268.

Background: Acute aortic dissection (AAD) often leads to out-of-hospital cardiac arrest (OHCA) and death before hospital arrival., Objectives: The purpose of this study was to investigate differences in AAD incidence by sex., Methods: A population-based study in a city with 121,180 residents was conducted using postmortem computed tomography data to identify patients with AAD who died before hospital arrival in 2008-2020. The incidence rate ratio and odds ratio were estimated using Poisson regression and univariable logistic regression, respectively., Results: A total of 266 patients with incident AAD were enrolled: 84 patients with OHCA, 137 women [n = 137], and 164 patients with type A AAD. The crude and age-adjusted incidence of AAD was 16.2 and 14.3/100,000 person-years, respectively. The incidence of AAD was comparable by sex (men, 16.7/100,000 person-years; women, 15.7/100,000 person-years; incidence rate ratio: 0.94; 95% CI: 0.74-1.20; P  = 0.64). Compared with men with AAD, women with AAD were older (77 ± 11 years vs 70 ± 14 years; P  < 0.001), and a higher proportion had type A AAD (76% vs 47%; P  < 0.001). Women with AAD had higher prehospital mortality than men with AAD (37% vs 21%; P  = 0.004; OR: 2.24; 95% CI: 1.30-3.87; P  = 0.004). Among 1,373 patients with OHCA, the proportion of women with AAD was significantly higher than the proportion of men with AAD (11% vs 3.9%; P  < 0.001; OR: 2.90; 95% CI: 1.86-4.53; P  < 0.001). AAD was most common in women aged 60 to 69 years (16.4%)., Conclusions: Women had a higher incidence of AAD presenting as prehospital death than men., Competing Interests: This work was supported in part by the 10.13039/100007449Takeda Science Foundation, the 10.13039/100015639Japan Cardiovascular Research Foundation, and 10.13039/501100001691JSPS KAKENHI Grant Number 22K16077. The authors have reported that they have no relationships relevant to the contents of this paper to disclose., (© 2023 The Authors.)

Background & Aims: This study aimed to investigate the associations of pre-existing sarcopenia with swallowing function, oral intake level, and aspiration pneumonia in patients with acute stroke., Methods: This observational study included patients (≥60 years of age) with acute ischemic stroke or intracerebral hemorrhage within 7 days of onset who were screened for sarcopenia, malnutrition, and swallowing difficulties in a stroke-care unit within 48 h of admission. Sarcopenia was defined by the Asian Working Group on Sarcopenia 2019 as having a low calf circumference, handgrip strength, and appendicular muscle mass index. The primary outcome was impaired oral intake (functional oral intake scale <5 points) at 3, 7, and 14 days after admission, and the secondary outcome was aspiration pneumonia during hospitalization., Results: We enrolled 350 patients (median age of 77 years; 63% males) who underwent the aforementioned screening. Sarcopenia was diagnosed in 34% of patients, and malnutrition was found in 66% of patients with sarcopenia. When compared with the comparison group (defined as patients with either or both normal calf circumference and handgrip strength), the sarcopenia group had significantly lower tongue pressure and a higher prevalence of dysphagia. Sarcopenia was associated with functional oral intake scale <5 at 7 days (adjusted odds ratio [OR], 4.72; 95% confidence interval [CI], 1.91-11.71); p = 0.002) and 14 days (adjusted OR, 3.93; 95% CI, 1.47-10.53; p = 0.006) and with aspiration pneumonia during hospitalization (adjusted OR, 6.12; 95% CI, 1.63-22.94; p = 0.007)., Conclusion: Acute stroke patients with sarcopenia may have weakness of the swallowing-related muscles which may lead to impaired oral intake and aspiration pneumonia., Competing Interests: Conflicts of interest The authors declare no conflict of interest., (Copyright © 2023. Published by Elsevier Ltd.)

Background: The RNF213 p.R4810K variant is associated with moyamoya disease in East Asian individuals and increases the risk of developing intracranial major artery stenosis/occlusion (ICASO) that affects anterior circulation. Meanwhile, 0.5% to 2.5% of asymptomatic East Asian individuals also carry this variant. As such, additional factors are likely required to develop ICASO in variant carriers. Familial hypercholesterolemia (FH) is a common genetic disorder in Japan that has a significant associated risk of developing premature coronary atherosclerosis; however, the relationship between ICASO and FH remains unknown., Objectives: This study aimed to determine if FH facilitates RNF213 p.R4810K carriers to develop ICASO., Methods: We enrolled patients with FH who had undergone brain magnetic resonance angiography at our hospital from May 2005 to March 2020. The RNF213 p.R4810K variant, and LDLR and PCSK9 mutations were genotyped. ICASO lesions in the brain magnetic resonance angiogram were analyzed., Results: Six RNF213 p.R4810K variant carriers were identified among 167 patients with FH ( LDLR , n = 104; PCSK9 , n = 22). Five of the carriers (83.3%) exhibited ICASO in the anterior circulation; a significant difference in ICASO frequency was observed between the variant carriers and noncarriers ( P  = 0.025). The median number of stenotic or occluded arteries in the anterior circulation was also significantly larger in the variant carriers (3 vs 1, P  = 0.01); however, did not differ between patients with FH with LDLR and PCSK9 mutations., Conclusions: Patients with FH exhibit increased prevalence and severity of ICASO associated with RNF213 p.R4810K. Gene mutations for FH may confer an increased risk of ICASO in RNF213 p.R4810K carriers., Competing Interests: This study was supported by the Japan Agency for Medical Research and Development (Grant Nos. JP21ek0210120 and JP21ek0210126) (Dr Ihara) and the Takeda Medical Research Foundation, Suzuken Memorial Foundation, and Koyanagi Foundation (Dr Hattori). Dr Yoshimoto is supported by lecture fees from Takeda Pharmaceutical and Nippon Boehringer Ingelheim. Dr Ihara has received lecture fees from Daiichi Sankyo and Eisai; and grants from Panasonic, Bristol Myers Squibb, and Shimadzu Corporation, outside the submitted work. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (© 2023 The Authors.)

Importance: Chronic hemodynamically significant aortic regurgitation (AR) is associated with excess risk of death, yet data for Asian patients are lacking, and whether Asian patients can abide by Western guidelines as to when aortic valve surgery should be performed is unknown., Objective: To assess AR presentation and cutoffs of left ventricular ejection fraction (LVEF), LV end-systolic dimension index (LVESDi), and LV end-systolic volume index (LVESVi) that are associated with risk of death in Asian patients with AR., Design, Setting, and Participants: This retrospective cohort study included consecutive patients with chronic, moderately severe to severe AR from 3 tertiary referral centers (2 in Japan and 1 in Taiwan) from June 11, 2008, through November 19, 2020, with follow-up through November 11, 2021., Exposures: Aortic regurgitation severity, graded by a comprehensive integrated approach., Main Outcomes and Measures: The primary outcome was the association between volume-derived LVEF, LVESDi, and LVESVi and all-cause death (ACD). The secondary outcome was the association of these LV indexes with cardiovascular death (CVD). Clinical and echocardiographic data were analyzed retrospectively. A de novo disk-summation method was used to derive LV volumes and volume-derived LVEF., Results: Of 1259 patients (mean [SD] age, 64 [17] years; 934 [74%] male), 515 (41%) were Japanese and 744 (59%) were Taiwanese. The median follow-up was 4.1 years (IQR, 1.56-7.24 years). The mean (SD) body surface area was 1.67 (0.21) m2; LVEF, 55% (11%); LVESDi, 24.7 (5.7) mm/m2; LVESVi, 50.1 (28.0) mL/m2; and indexed mid-ascending aorta size, 24.7 (5.5) mm/m2. Aortic valve surgery occurred in 483 patients (38%); 240 patients (19%) died during follow-up. Overall mean (SD) 8-year survival was 74% (2%). Separate multivariate models adjusted for covariates demonstrated independent associations of LVEF, LVESDi, and LVESVi with ACD (LVEF: hazard ratio [HR] per 10%, 0.80; 95% CI, 0.70-0.92; P = .002; LVESDi: HR, 1.04; 95% CI, 1.01-1.06; P = .002; LVESVi: HR per 10 mL/m2, 1.11; 95% CI, 1.05-1.17; P < .001) and CVD (LVEF: HR per 10%, 0.69; 95% CI, 0.56-0.85; P < .001; LVESDi: HR, 1.05; 95% CI, 1.01-1.09; P = .01; LVESVi per 10 mL/m2: HR, 1.15; 95% CI, 1.06-1.24; P < .001). In the total cohort, spline curves showed that mortality started to increase for an LVEF of 53% or less, LVESDi of 22 mm/m2 or greater, and LVESVi of 46 mL/m2 or greater for both ACD and CVD. Early surgery was beneficial in 3 strata of LVESDi (<20, 20 to <25, and ≥25 mm/m2) and 2 strata of LVESVi (<46 and ≥46 mL/m2)., Conclusions and Relevance: This multicenter cohort study of Asian patients with hemodynamically significant AR found cutoff values of LVEF, LVESDi, and LVESVi that were associated with increased risk of death. These findings suggest that Western guidelines seem applicable in Asian patients and, most importantly, that indexed LV parameters with a lower cutoff could be used in discriminating patients with excess mortality risk.

Objective: To assess whether post-stroke epilepsy (PSE) is associated with neuroimaging findings of hemosiderin in a case-control study, and whether the addition of hemosiderin markers improves the risk stratification models of PSE., Methods: We performed a post-hoc analysis of the PROgnosis of POST-Stroke Epilepsy study enrolling PSE patients at National Cerebral and Cardiovascular Center, Osaka, Japan, from November 2014 to September 2019. PSE was diagnosed when one unprovoked seizure was experienced >7 days after the index stroke, as proposed by the International League Against Epilepsy. As controls, consecutive acute stroke patients with no history or absence of any late seizure or continuing antiseizure medications at least 3 months after stroke were retrospectively enrolled during the same study period. We examined cortical microbleeds and cortical superficial siderosis (cSS) using gradient-echo T2*-weighted images. A logistic regression model with ridge penalties was tuned using 10-fold cross-validation. We added the item of cSS to the existing models (SeLECT and CAVE) for predicting PSE and evaluated performance of new models., Results: The study included 180 patients with PSE (67 women; median age 74 years) and 1,183 controls (440 women; median age 74 years). The cSS frequency was higher in PSE than control groups (48.9% vs 5.7%, p < 0.0001). Compared with the existing models, the new models with cSS (SeLECT-S and CAVE-S) demonstrated significantly better predictive performance of PSE (net reclassification improvement 0.63 [p = 0.004] for SeLECT-S and 0.88 [p = 0.001] for CAVE-S at the testing data)., Interpretation: Cortical superficial siderosis was associated with PSE, stratifying stroke survivors at high risk of PSE. ANN NEUROL 2023;93:357-370., (© 2022 The Authors. Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Aims: We aimed to determine the association between acute platelet reactivity and clinical outcome in acute ischemic stroke (AIS) or transient ischemic attack (TIA) with large-artery atherosclerosis (LAA)., Methods: In this prospective, 16-multicenter study, we enrolled AIS/TIA patients with LAA receiving clopidogrel. We assessed the association of P2Y12 reaction units (PRU) 24 hours after initiation of antiplatelets with the CYP2C19 genotype and recurrent ischemic stroke within 90 days, and the difference between acute (≤ 7 days) and subacute (8-90 days) phases., Results: Among the 230 AIS/TIA patients enrolled, 225 with complete outcome data and 194 with genetic results were analyzed. A higher PRU was significantly associated with recurrent ischemic stroke within 90 days (frequency, 16%), and within 7 days (10%). Twenty-nine patients (15%) belonged to a CYP2C19 poor metabolizer group (CYP2C19 ＊ 2/ ＊ 2, ＊ 2/ ＊ 3, or ＊ 3/ ＊ 3). Multivariable receiver-operating characteristic analysis showed a greater area-under-the-curve (AUC) in predicting recurrence within 7 days, compared to 8-90 days (AUC, 0.79 versus 0.64; p=0.07), with a cut-off PRU of 254. Multivariable analysis showed high PRU (≥ 254), which had a comparable predictive performance for recurrent ischemic stroke within 7 days (odds ratio, 6.82; 95% CI, 2.23-20.9; p＜0.001) to the CYP2C19 poor metabolizer genotype. The net reclassification improvement, calculated by adding high PRU (≥ 254) to a model including the CYP2C19 poor metabolizer genotype in the prediction of recurrence within 7 days, was 0.83 (p＜0.001)., Conclusions: Acute PRU evaluation possesses predictive value for recurrent ischemic stroke, especially within 7 days in AIS/TIA with LAA.

Background: The development of numerous disease-modifying drugs for age-related dementia has been attempted based on the amyloid-β (Aβ) hypothesis without much success. Taxifolin (TAX), a natural bioactive flavonoid, shows pleiotropic neuroprotective effects with inhibition of Aβ aggregation, production, and glycation, antiinflammatory effects, and amelioration of the waste clearance system. We hypothesized that TAX intake is associated with the suppression of cognitive deterioration., Objective: To investigate associations between TAX intake and cognitive changes., Methods: We retrospectively identified patients who orally took TAX 300 mg/day and regularly underwent Alzheimer's Disease Assessment Scale-Cognitive Subscale 13 (ADAS-Cog) and Montreal Cognitive Assessment (MoCA) and compared the temporal changes in ADAS-Cog and MoCA between the non-treatment (pre-TAX) period (180±100 days) and following treatment (on-TAX) period (180±100 days) from June 2020 to November 2021. Since some additional patients underwent the Mini-Mental State Examination (MMSE) instead of the MoCA at the beginning of the pre-TAX period, the same comparison was performed using the MoCA total score converted from MMSE as a sensitivity analysis., Results: Sixteen patients were identified. TAX intake was associated with significantly higher interval changes in the MoCA subscale scores of visuospatial/executive function (p = 0.016), verbal fluency (p = 0.02), and the total score (p = 0.034), but not with ADAS-Cog (total score, p = 0.27). In the sensitivity analysis, 29 patients were included. TAX intake was associated with a significantly higher interval change in the total MoCA score (p = 0.004) but not with ADAS-Cog (p = 0.41)., Conclusion: Our findings provide a basis for TAX as a novel strategy for maintaining brain health during aging. A prospective cohort study is required to confirm these findings.

Introduction: The insufficient quantity and quality of clinical epidemiological evidence in the field of rare diseases have posed methodological challenges to develop clinical practice guidelines (CPGs). Guideline development groups struggle to provide patients and their families with beneficial guidance, such as that for medical care and in complex circumstances. Motivated by the challenges, we focused on information on resources for supporting the daily and social life to improve the CPGs for users. We aimed to assess the methodological quality of CPGs for rare diseases in Japan and to evaluate information on resources to support the daily and social life in the CPGs., Methods: We conducted a systematic search using PubMed, three electronic Japanese databases, and two hand-searched sources in Japan. The Appraisal of Guidelines for Research and Evaluation (AGREE) II instrument with six domains was used to assess the methodological quality of the CPGs. A content analysis of the CPG text was conducted using five keywords as information on non-medical resources, e.g., "Intractable Disease Consultation Support Center," "Japan Intractable Disease Information Center," and "Patient Association.", Results: A total of 55 CPGs met the inclusion criteria. Among four domains of AGREE II with low scores (Stakeholder Involvement, Rigor of Development, Applicability, and Editorial Independence), Rigor of Development had the lowest median score. As for information on non-medical resources, 41 CPGs included at least 1 of the 5 keywords, while 14 CPGs included none., Conclusions: At the Rigor of Development domain, methodological challenges may have resulted in an insufficient description of items regarding the translation evidence to recommendations. As the sufficiency of five keywords as information on non-medical resources could be improved, the information will be advocative as clues to provide pragmatic guidance, particularly for rare diseases with limited medical evidence., Competing Interests: Dr. Nakayama reports personal fees from Pfizer Japan Inc., MSD K.K., Otsuka Pharmaceutical Co., Chugai Pharmaceutical Co., Dentsu Co., Takeda Pharmaceutical Co., Janssen Pharmaceutical K.K., Boehringer Ingelheim International GmbH, Eli Lilly Japan K.K., Baxter, Alexion, Mitsubishi Tanabe Pharma Corporation, Novartis Pharma K.K., Allergan Japan K.K., Maruho Co., Ltd., research grants from HANSHIN Dispensing Holding Co., Ltd., Nakagawa Pharmacy Co., Ltd., and Konica Minolta, Inc. All of them were outside the submitted work., (Copyright © Japan Medical Association.)

Background: Lipid-rich plaque is an important substrate that causes future coronary events. However, the clinical implications of underlying plaque characteristics in coronary lesions after newer-generation drug-eluting stent (DES) implantation remain unknown., Methods: The current study analyzed 445 target lesions after newer-generation DES implantation in 416 patients with coronary artery disease (CAD) (chronic coronary syndrome/acute coronary syndrome = 264/181) from the REASSURE-NIRS multicentre registry. Near-infrared spectroscopy (NIRS) imaging was used to evaluate maximum lipid core burden index after stent implantation in target lesions (residual maxLCBI 4mm ). The primary and secondary outcomes were 3-year lesion-oriented clinical outcomes (LOCO): cardiac death, nonfatal target-lesion-related myocardial infarction (MI), or ischemia-driven target-lesion revascularization (ID-TLR) and patient-oriented clinical outcomes (POCO): all-cause death, nonfatal MI, or ID unplanned revascularization. Outcomes were compared by residual maxLCBI 4mm tertile., Results: Median residual maxLCBI 4mm was 183; 16% of lesions had residual maxLCBI 4mm > 400. Higher residual maxLCBI 4mm was not associated with a greater likelihood of LOCO or POCO during the observational period (LOCO, log-rank P = 0.76; POCO, log-rank P = 0.84). Mixed-effects logistic regression demonstrated that residual maxLCBI 4mm does not predict LOCO (odds ratio [OR], 1.000; 95% confidence interval [CI], 0.997-1.003; P = 0.95). There was no significant relationship between residual maxLCBI 4mm and POCO (OR, 1.001; 95% CI, 0.999-1.002; P = 0.30)., Conclusions: Residual maxLCBI 4mm is not associated with LOCO or POCO in patients with CAD after newer-generation DES implantation. Our findings suggest that NIRS-derived underlying lipid-rich plaque is not associated with the risk of stent-related events and patient-based outcomes in patients with CAD who have received newer-generation DESs., (Copyright © 2022 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.)

Objective: Motivated by the challenges raised by diagnosing poststroke epilepsy (PSE), especially in nonmotor onset seizure (non-MOS), we aimed to investigate the features of non-MOS, including seizure sequences, patient characteristics, and electrophysiological and imaging findings in PSE., Methods: This observational cohort study enrolled patients with PSE whose seizure onset was witnessed. According to the International League Against Epilepsy (ILAE) 2017 seizure classification, we classified seizure-onset symptoms into the non-MOS and MOS groups. We compared the different clinical characteristics between the two groups., Results: Between 2011 and 2018, we enrolled 225 patients with PSE (median age, 75 years), consisting of 97 (43%) with non-MOS and 128 (57%) with MOS. Overall, 65 (67%) of the patients without MOS had no subsequent convulsions. Multivariable logistic regression analysis showed significant associations of non-MOS with absence of poststroke hemiparesis (adjusted odds ratio [OR], 1.88; 95% confidence interval [CI], 1.03-3.42), frontal stroke lobe lesions (OR, 2.11; 95% CI, 1.14-3.91), and putaminal stroke lesions (OR, 2.51; 95% CI, 1.22-5.18) as negative indicators. Postictal single-photon emission computed tomography (SPECT) detected prolonged hyperperfusion in the temporal lobe more frequently in the non-MOS than in the MOS group (48% vs 31%; p = .02). The detection rate was higher than spikes/sharp waves in scalp electroencephalography, both in the non-MOS group (72% vs 33%; p < .001) and the MOS group (68% vs 29%; p < .001)., Significance: This study provides the clinical features of non-MOS in patients with PSE. Compared with the patients with MOS, patients with non-MOS showed less likely subsequent convulsive seizures, highlighting the clinical challenges. Postictal perfusion imaging and negative indicators of the non-MOS type may help diagnose and stratify PSE., (© 2022 International League Against Epilepsy.)

Objectives: Wandering behavior is one of the most troublesome behavioral disturbances in dementia. Inconsistent associations between physical function and wandering behavior were reported, and the effect of cognitive decline may be different according to walking ability. The purposes of this study are to investigate whether high walking ability is a risk factor for wandering behavior and to investigate the interaction of walking ability and cognitive function with wandering behavior in older adults with dementia., Methods: This retrospective cohort study included 3979 elderly adults with dementia. The association of cognitive function and walking ability with incidence of wandering behavior during a 5-year follow-up period were examined using a generalized linear model, and relative excess risk due to interaction (RERI) was calculated., Results: Severe cognitive decline and high walking ability were associated with a higher risk for wandering behavior. Additionally, some joint effects of cognitive decline and walking ability decline were higher than the sum of its individual effects (RERI [95% confidence interval], severe cognitive decline × 'walk with help': 1.58 [0.35, 2.81]; severe cognitive decline × 'independent': 3.09 [1.05, 5.14])., Conclusions: Effects of cognitive decline and walking ability on incidence of wandering behavior were observed, and the effects varied depending on their combination., (© 2022 John Wiley & Sons Ltd.)

Background: The International Atherosclerosis Society (IAS) has proposed "severe familial hypercholesterolemia" (FH) as a phenotype with the highest cardiovascular risk. However, whether this criteria could appropriately stratify a high-risk Japanese patient with FH remains unknown., Objectives: This study sought to characterize atherosclerotic cardiovascular diseases in IAS-defined Japanese subjects with severe FH., Methods: This study analyzed 380 clinically diagnosed subjects with heterozygous FH without any history of atherosclerotic cardiovascular diseases. Severe FH was defined as untreated low-density lipoprotein cholesterol >400 mg/dL, >310 mg/dL plus 1 high-risk feature, or >190 mg/dL plus 2 high-risk features according to IAS-proposed statement. The occurrence of first and subsequent composite outcomes (cardiac [cardiac death + coronary artery disease + coronary revascularization] and noncardiac events [stroke + peripheral artery disease] was compared between subjects with severe (n = 135) and non-severe (n = 227) FH., Results: Severe FH was identified in 40.3% of study population. They had higher low-density lipoprotein cholesterol ( P < 0.001) and lipoprotein(a) ( P = 0.03) levels. Moreover, they more frequently received high-intensity statin ( P < 0.001), PCSK9 inhibitor ( P < 0.001), and lipoprotein apheresis ( P = 0.01) than nonsevere FH subjects did, which resulted in a lower on-treatment low-density lipoprotein cholesterol level of subjects with severe FH (113 ± 47.2 vs 130 ± 53.9 mg/dL; P = 0.007). However, during the 7.4-year observational period, subjects with severe FH exhibited a 9.3-, 15.4-, and 5.9-fold greater risk for first composite ( P < 0.001), cardiac ( P < 0.001), and noncardiac outcomes (P = 0.02), respectively. Multivariate Cox proportional hazard model consistently revealed the 7.8- and 7.9-fold elevated risks of first ( P < 0.001) and of subsequent ( P < 0.001) composite outcomes in subjects with severe FH., Conclusions: Japanese subjects with severe FH present profound risks of both first and subsequent atherosclerotic cardiovascular diseases in the primary prevention settings. These findings support the clinical applicability of IAS-defined severe FH in Japanese patients, which identifies those who require further stringent antiatherosclerotic management., Competing Interests: Dr Kataoka has received research support from Nipro and Abbott; and honoraria from Nipro, Abbott, Kowa, Amgen, Sanofi, Astellas, Takeda, and Daiichi-Sankyo. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (© 2021 The Authors.)

In-home monitoring systems have been used to detect cognitive decline in older adults by allowing continuous monitoring of routine activities. In this study, we investigated whether unobtrusive in-house power monitoring technologies could be used to predict cognitive impairment. A total of 94 older adults aged ≥65 years were enrolled in this study. Generalized linear mixed models with subject-specific random intercepts were used to evaluate differences in the usage time of home appliances between people with and without cognitive impairment. Three independent power monitoring parameters representing activity behavior were found to be associated with cognitive impairment. Representative values of mean differences between those with cognitive impairment relative to those without were -13.5 min for induction heating in the spring, -1.80 min for microwave oven in the winter, and -0.82 h for air conditioner in the winter. We developed two prediction models for cognitive impairment, one with power monitoring data and the other without, and found that the former had better predictive ability (accuracy, 0.82; sensitivity, 0.48; specificity, 0.96) compared to the latter (accuracy, 0.76; sensitivity, 0.30; specificity, 0.95). In summary, in-house power monitoring technologies can be used to detect cognitive impairment.

This study aims to develop and validate prediction models for the number of all heatstroke cases, and heatstrokes of hospital admission and death cases per city per 12 h, using multiple weather information and a population-based database for heatstroke patients in 16 Japanese cities (corresponding to around a 10,000,000 population size). In the testing dataset, mean absolute percentage error of generalized linear models with wet bulb globe temperature as the only predictor and the optimal models, respectively, are 43.0% and 14.8% for spikes in the number of all heatstroke cases, and 37.7% and 10.6% for spikes in the number of heatstrokes of hospital admission and death cases. The optimal models predict the spikes in the number of heatstrokes well by machine learning methods including non-linear multivariable predictors and/or under-sampling and bagging. Here, we develop prediction models whose predictive performances are high enough to be implemented in public health settings., (© 2021. The Author(s).)

The impact of glucose fluctuation on intracranial artery stenosis remains to be elucidated. This study aimed to investigate the association between glucose fluctuation and intracranial artery stenosis. This was a cross-sectional study of type 2 diabetes mellitus (T2DM) patients equipped with the FreeStyle Libre Pro continuous glucose monitoring system (Abbott Laboratories) between February 2019 and June 2020. Glucose fluctuation was evaluated according to the standard deviation (SD) of blood glucose, coefficient of variation (%CV), and mean amplitude of glycemic excursions (MAGE). Magnetic resonance angiography was used to evaluate the degree of intracranial artery stenosis. Of the 103 patients, 8 patients developed severe internal carotid artery (ICA) siphon stenosis (≥70%). SD, %CV, and MAGE were significantly higher in the severe stenosis group than in the non-severe stenosis group (<70%), whereas there was no significant intergroup difference in the mean blood glucose and HbA1c. Multivariable logistic regression analysis adjusted for sex showed that SD, %CV, and MAGE were independent factors associated with severe ICA siphon stenosis. In conclusion, glucose fluctuation is significantly associated with severe ICA siphon stenosis in T2DM patients. Thus, glucose fluctuation can be a target of preventive therapies for intracranial artery stenosis and ischemic stroke.

Background: Dementia-related missing and subsequent deaths are becoming serious problems with increases in people with dementia. However, there are no sufficient studies investigating the incidence rate, the mortality rate, and their risk factors., Methods: An ecological study aggregated at the Japanese prefectural level was conducted. Dementia-related missing persons cases and deaths in 2018 were extracted from the statistics of the National Police Agency in Japan. We extracted variables about older adults' characteristics, care, and safety as candidate variables considered to be relevant to dementia-related missing persons cases and deaths. Associations of the candidate variables with the incidence and mortality rates were analyzed using the generalized linear model (family: quasi-poisson, link: log) adjusted for confounding factors (proportion of older adults and gross prefectural product)., Results: The incidence rate and mortality rate per 100,000 person-year was 21.72 and 0.652 in Japan, respectively. One facility increase in the number of nursing care facilities for older adults per 100,000 persons aged 65-years-old or more was associated with a 7.9% (95% confidence interval [CI], 3.3-12.4%) decrease in the incidence rate. One increase in the number of public health nurses per 100,000 persons was associated with a 3.2% (95% CI, 1.6-4.9%) decrease in the incidence rate. A ten percent increase in the proportion of people who live in an urban area was associated with a 20.3% (95% CI, 8.7-33.2%) increase in the incidence rate and a 12.9% (95% CI, 5.6-19.8%) decrease in the mortality rate., Conclusions: Identified associated factors may be useful for managing or predicting dementia-related missing persons cases and associated deaths.

Background: Vulnerable plaque features including lipidic plaque have been shown to affect fractional flow reserve (FFR). Given that formation and propagation of lipid plaque is accompanied by endothelial dysfunction which impairs vascular tone, the degree of lipidic burden may affect vasoreactivity during hyperemia, potentially leading to reduced FFR. Our aim is to elucidate the relationship of the extent of lipidic plaque burden with coronary physiological vasoreactivity measure., Methods: We analyzed 89 subjects requeuing PCI due to angiographically intermediate coronary stenosis with FFR ≤0.80. Near-infrared spectroscopy (NIRS) and intravascular ultrasound were used to evaluate lipid-core burden index (LCBI) and atheroma volume at both target lesion (maxLCBI 4mm ; maximum value of LCBI within any 4 mm segments) and entire target vessel (LCBI vessel : LCBI within entire vessel). In addition to FFR, delta-FFR was measured by difference of distal coronary artery pressure/aortic pressure (Pd/Pa) between baseline and hyperemic state., Results: The averaged FFR and delta-FFR was 0.74 (0.69-0.77), and 0.17±0.05, respectively. On target lesion-based analysis, maxLCBI 4mm was negatively correlated to FFR (ρ=-0.213, P=0.040), and it was positively correlated to delta-FFR (ρ=0.313, P=0.002). Furthermore, target vessel-based analysis demonstrated similar relationship of LCBI vessel with FFR (ρ=-0.302, P=0.003) and delta-FFR (ρ=0.369, P<0.001). Even after adjusting clinical characteristics and lesion/vessel features, delta-FFR (by 0.10 increase) was independently associated with maxLCBI 4mm (β=57.2, P=0.027) and LCBI vessel (β=24.8, P=0.007) by mixed linear model analyses., Conclusions: A greater amount of lipidic plaque burden at not only "target lesion" alone but "entire target vessel" was associated with a greater delta-FFR. The accumulation of lipidic plaque materials at both local site and entire vessel may impair hyperemia-induced vasoreactivity, which causes a reduced FFR., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at: http://dx.doi.org/10.21037/cdt-20-1024). Kota Murai has received honoraria from Abbot, ZEON MEDICAL. Yu Kataoka serves as an unpaid editorial board member of Cardiovascular Diagnosis and Therapy from Jul 2019 to Jun 2021, and has received research support from Nipro and Abbott, and honoraria from Nipro, Abbott, Kowa, Amgen, Sanofi, Astellas, Takeda and Daiichi-Sankyo. The other author has no conflicts of interest to declare., (2021 Cardiovascular Diagnosis and Therapy. All rights reserved.)

Aims: To evaluate the prognostic impact of fragmented QRS (fQRS) on idiopathic dilated cardiomyopathy (DCM)., Methods and Results: We conducted a prospective observational study of 290 consecutive patients with DCM (left ventricular ejection fraction ≤ 40%) and narrow QRS who underwent cardiac magnetic resonance. We defined fQRS as the presence of various RSR' patterns in ≥2 contiguous leads representing the anterior (V1-V5), inferior (II, III, and aVF), or lateral (I, aVL, and V6) myocardial segments. Multiple fQRS was defined as the presence of fQRS in ≥2 myocardial segments. Patients were divided into three groups: no fQRS, single fQRS, or multiple fQRS. The primary endpoint was a composite of hard cardiac events consisting of heart failure death, sudden cardiac death (SCD), or aborted SCD. The secondary endpoints were all-cause death and arrhythmic event. During a median follow-up of 3.8 years (interquartile range, 1.8-6.2), 31 (11%) patients experienced hard cardiac events. Kaplan-Meier analysis showed that the rates of hard cardiac events and all-cause death were similar in the single-fQRS and no-fQRS groups and higher in the multiple-fQRS group (P = 0.004 and P = 0.017, respectively). Multivariable Cox regression identified that multiple fQRS is a significant predictor of hard cardiac events (hazard ratio, 2.23; 95% confidence interval, 1.07-4.62; P = 0.032). The multiple-fQRS group had the highest prevalence of a diffuse late gadolinium enhancement pattern (no fQRS, 21%; single fQRS, 22%; multiple fQRS, 39%; P < 0.001)., Conclusion: Multiple fQRS, but not single fQRS, is associated with future hard cardiac events in patients with DCM., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2020. For permissions, please email: journals.permissions@oup.com.)

Background and Aims: Calcified nodule (CN) is an eruptive calcified mass causing acute coronary syndrome (ACS). Since coronary calcification is associated with an elevated cardiac event's risk, ACS attributable to CN may exhibit worse clinical outcome following percutaneous coronary intervention (PCI)., Methods: We retrospectively analyzed 657 ACS patients receiving PCI with newer-generation drug-eluting stent (DES) implantation under intravascular ultrasound (IVUS) guidance. CN was defined as (1) protruding calcification with its irregular surface and (2) the presence of calcification at adjacent proximal and distal segments. The primary endpoint was a composite of major adverse cardiac event [MACE = cardiac death + ACS recurrence + target lesion revascularization (TLR)]., Results: CN was identified in 5.3% (=35/657) of the study subjects. CN patients were more likely to have coronary risk factors including hypertension (p = 0.005), chronic kidney disease (p < 0.001), maintenance hemodialysis (p < 0.001) and a history of PCI (p < 0.001). During the observational period (median = 1304 days), CN was associated with an increased risk of MACE (HR = 7.68, 95%CI = 4.61-12.80, p < 0.001), ACS recurrence (HR = 12.32, 95%CI = 6.05-25.11, p < 0.001) and TLR (HR = 10.48, 95%CI = 5.80-18.94, p < 0.001). These cardiac risks related to CN were consistently observed by Cox proportional hazards model (MACE: p < 0.001, ACS recurrence: p < 0.001, TLR: p < 0.001) and a propensity score-matched cohort analysis (MACE: p = 0.002, ACS recurrence: p = 0.01, TLR: p = 0.005). Of note, over 80% of TLR at the CN lesion was driven by its re-appearance within the implanted DES., Conclusions: ACS patients attributable to CN have an increased risk of ACS recurrence and TLR, mainly driven by the continuous growth and protrusion of the calcified mass., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Preventing dementia in elderly individuals is an important public health challenge. While early identification and modification of predictors are crucial, predictors of dementia based on routinely collected healthcare data are not fully understood. We aimed to examine potential predictors of dementia diagnosis using routinely collected claims data. In this retrospective cohort study, claims data from fiscal years 2012 (baseline) and 2016 (follow-up), recorded in an administrative claims database of the medical care system for the elderly (75 years or older) in Niigata prefecture, Japan, were used. Data on baseline characteristics including age, sex, diagnosis, and prescriptions were collected, and the relationship between subsequent new diagnoses of dementia and potential predictors was examined using multivariable logistic regression models. A total of 226,738 people without a diagnosis of dementia at baseline were followed. Of these, 26,092 incident dementia cases were detected during the study period. After adjusting for confounding factors, cerebrovascular disease (odds ratio, 1.15; 95% confidence interval, 1.11-1.18), depression (1.38; 1.31-1.44), antipsychotic use (1.40; 1.31-1.49), and hypnotic use (1.17; 1.11-1.24) were significantly associated with subsequent diagnosis of dementia. Analyses of routinely collected claims data revealed neuropsychiatric symptoms including depression, antipsychotic use, hypnotic use, and cerebrovascular disease to be predictors of new dementia diagnoses.

Objective: Improved outcomes in patients with subarachnoid hemorrhage (SAH) treated at high-volume centers have been reported. The authors sought to examine whether hospital case volume and comprehensive stroke center (CSC) capabilities affect outcomes in patients treated with clipping or coiling for SAH., Methods: The authors conducted a nationwide retrospective cohort study in 27,490 SAH patients who underwent clipping or coiling in 621 institutions between 2010 and 2015 and whose data were collected from the Japanese nationwide J-ASPECT Diagnosis Procedure Combination database. The CSC capabilities of each hospital were assessed by use of a validated scoring system based on answers to a previously reported 25-item questionnaire (CSC score 1-25 points). Hospitals were classified into quartiles based on CSC scores and case volumes of clipping or coiling for SAH., Results: Overall, the absolute risk reductions associated with high versus low case volumes and high versus low CSC scores were relatively small. Nevertheless, in patients who underwent clipping, a high case volume (> 14 cases/yr) was significantly associated with reduced in-hospital mortality (Q1 as control, Q4 OR 0.71, 95% CI 0.55-0.90) but not with short-term poor outcome. In patients who underwent coiling, a high case volume (> 9 cases/yr) was associated with reduced in-hospital mortality (Q4 OR 0.69, 95% CI 0.53-0.90) and short-term poor outcomes (Q3 [> 5 cases/yr] OR 0.75, 95% CI 0.59-0.96 vs Q4 OR 0.65, 95% CI 0.51-0.82). A high CSC score (> 19 points) was significantly associated with reduced in-hospital mortality for clipping (OR 0.68, 95% CI 0.54-0.86) but not coiling treatment. There was no association between CSC capabilities and short-term poor outcomes., Conclusions: The effects of case volume and CSC capabilities on in-hospital mortality and short-term functional outcomes in SAH patients differed between patients undergoing clipping and those undergoing coiling. In the modern endovascular era, better outcomes of clipping may be achieved in facilities with high CSC capabilities.

Vascular risk factors, such as type 2 diabetes mellitus (T2DM), are associated with the increased risk of Alzheimer's disease. One of the common T2DM medications, dipeptidyl peptidase (DPP)-4 inhibitors, have a minimum risk for hypoglycemia and have recently been suggested to ameliorate β-amyloid pathology. However, conflicting results have been reported regarding the effects of DPP-4 inhibition on cognitive function and tau pathology. Thus, we investigated whether inhibiting DPP-4 affects tau pathology and cognition in a mouse model of tauopathy with hyperglycemia. Male mice overexpressing the P301S mutant human microtubule-associated protein tau gene (PS19) were fed either a low or high-fat diet. PS19 mice were then administered either linagliptin, a DPP-4 inhibitor, or vehicle, from 6 weeks to 8 months of age. Linagliptin-treated mice exhibited higher levels of glucagon-like peptide-1 and decreased fasting blood glucose, compared with the vehicle-treated mice at 8 months. Linagliptin treatment significantly restored spatial reference memory and increased cerebral blood flow without affecting phosphorylation levels of tau or endothelial nitric oxide synthase (eNOS) in the brain. Linagliptin may ameliorate HFD-induced cognitive worsening in tauopathy, at least partially, by increasing cerebral perfusion via the eNOS-independent pathway.

Objective: Valid and reliable measures are needed to assess post-stroke cognitive impairment. The Montreal Cognitive Assessment (MoCA) has been considered a superior screening test to the Mini-Mental State Examination (MMSE) for patients with post-stroke cognitive impairment, particularly in executive function, which may be related to reduction in regional cerebral blood flow (rCBF). In this study, we determined whether MoCA and MMSE scores correlate with rCBF assessed with SPECT in the subacute phase after ischemic stroke., Patients and Methods: We retrospectively enrolled 28 patients who were admitted to the Red Cross Otsu Hospital with acute cerebral infarction, which was confirmed by magnetic resonance imaging (MRI), if they underwent cognitive assessment (MoCA/MMSE) and 123 I-IMP SPECT imaging within 3 weeks post-stroke during a study period of 5 months. Correlation analyses between rCBF and MoCA or MMSE scores were performed by statistical parametric mapping (SPM) and volume-of-interest (VOI) analyses., Results: Total MoCA score correlated with the rCBF in the prefrontal cortex, cingulate cortex, caudate nucleus and thalamus by SPM analysis (uncorrected p < 0.001; cluster-level corrected p < 0.05). Among the subtest scores of MoCA, visuoexecutive function, attention, language and delayed recall scores were positively correlated with rCBF in the prefrontal cortex by VOI analysis (p < 0.05). However, total MMSE score did not correlate significantly with any of the rCBF measures., Conclusions: Post-stroke cognitive performance assessed with MoCA positively correlated with rCBF in brain regions mainly comprising the prefrontal-subcortical circuits. The findings of this hypothesis-generating study support the notion that MoCA is useful for assessing post-stroke cognitive status., (Copyright © 2018 Elsevier B.V. All rights reserved.)

A 39 year-old man was admitted to this hospital because of severe headache and vomiting. He had been suffering from lumbago about one month previously, and diplopia ten days previously. The neurological examination revealed disturbance of right eye abduction, no nuchal rigidity. The cerebrospinal fluid (CSF) at the time of admission included erythrocytes (1,490/μl), white blood cell (62/μl) and increased level of protein (531 mg/dl), but no malignant cells were detected. He was treated as meningitis. Cranial magnetic resonance imaging (MRI) demonstrated heterogeneous intensity lesion in the left maxillary sinus and gadolinium enhancement of diffuse meninges and cranial nerves. Spine MRI showed gadolinium enhancement of lumbar spinal meninges and the cauda equina. Biopsy of the lesion in the left maxillary sinus was performed. The pathological findings demonstrated malignant melanoma. Because malignant cells were also observed in CSF, we diagnosed this case as leptomeningeal melanomatosis. Leptomeningeal carcinomatosis should be suspected when headache accompanied with pleomorphic clinical manifestations.

We report a 59-year-old right-handed woman with smoldering leucine-rich glioma-inactivated 1 (LGI1) antibody-associated limbic encephalitis (LE) following faciobrachial dystonic seizures. During 8 months before her admission, she developed partial seizures manifesting very brief and very frequent dystonia in her right hand sometimes with oral automatism and loss of awareness. In addition, she showed psychiatric disturbances such as emotionally labile condition and personality changes. On admission, neuropsychological examination revealed short-term memory impairment. During electroencephalography (EEG) monitoring, ictal EEG showed rhythmic delta waves and interictal EEG showed intermittent irregular slow waves at the bilateral frontotemporal area. Brain MRI demonstrated high T2/FLAIR signal changes in the left amygdala expanding into the left hippocampus. FDG-PET showed hypermetabolism in the left amygdala, hippocampus and the bilateral basal ganglia. Cerebrospinal fluid analysis was unremarkable. There were no signs of malignant tumor detected on systemic examination. LGI1 antibody was positive in the serum and the cerebrospinal fluid and the clinical diagnosis of LGI1 antibody-associated LE was confirmed. Her symptoms and the abnormalities in the brain MRI/FDG-PET showed immediate improvement after anti-epileptic and steroid therapy.