Diastolic Dysfunction as a Positive Predictor of Recurrent Vascular Events in Patients With Noncardioembolic Stroke.

BACKGROUND: This study aimed to assess the effects of left ventricular diastolic dysfunction (LVDD) on vascular outcomes among patients with stroke of noncardioembolic origins. METHODS: This prospective observational study enrolled 563 patients with noncardioembolic stroke (mean age, 67.9 years; 66.7% men and 33.3% women individuals) registered in the Tokyo Women's Medical University Stroke Registry between 2013 and 2020. Then, patients were divided into the LVDD and non-LVDD groups. The primary outcome was a composite of major adverse cardiovascular events, including nonfatal stroke, nonfatal acute coronary syndrome, and vascular death 1 year after stroke onset. The effect of LVDD on vascular events was assessed using multivariable Cox regression analyses. RESULTS: A total of 130 (23.1%) patients had any grade of LVDD, and patients with LVDD had a higher risk of major adverse cardiovascular event at 1 year than those without LVDD (annual rate, 20.9% versus 10.8%; log-rank P=0.001). The multivariable Cox proportional hazards regression model demonstrated that the presence of LVDD was independently associated with the major adverse cardiovascular event risk (hazard ratio, 1.79 [95% CI, 1.02-3.12]; P=0.019). Furthermore, the LVDD grade was proportional to the risk of major adverse cardiovascular events and recurrent stroke. CONCLUSIONS: LVDD may be associated with further vascular events after a noncardioembolic stroke, suggesting the importance of LVDD evaluations in risk stratification and secondary prevention in patients with noncardioembolic stroke. REGISTRATION: URL: https://upload.umin.ac.jp; Unique identifier: UMIN000031913.

Fluorescence guidance using near-infrared fluorescent clips in robotic rectal surgery: a case series.

PURPOSE: Tattoo markings are often used as preoperative markers for colorectal cancer. However, scattered ink markings adversely affect tumor site recognition intraoperatively; therefore, interventions for rectal cancer may lead to an inaccurate distal resection margin (DRM) and incomplete total mesorectal excision (TME). This is the first case series of fluorescence-guided robotic rectal surgery in which near-infrared fluorescence clips (NIRFCs) were used to localize rectal cancer lesions. METHODS: We enrolled 20 consecutive patients who underwent robotic surgery for rectal cancer between December 2022 and December 2023 in the current study. The primary endpoints were the rate of intraoperative clip detection and its usefulness for marking the tumor site. Secondary endpoints were oncological assessments, including DRM and the number of lymph nodes. RESULTS: Clip locations were confirmed in 17 of 20 (85%) patients. NIRFCs were not detected in 3 out of 7 patients who underwent preoperative chemoradiation therapy. No adverse events, including bleeding or perforation, were observed at the time of clipping, and no clips were lost. The median DRM was 55 mm (range, 22-86 mm) for rectosigmoid (Rs), 33 mm (range, 16-60 mm) for upper rectum (Ra), and 20 mm (range, 17-30 mm) for low rectum (Rb). The median number of lymph nodes was 13 (range, 10-21). CONCLUSION: The rate of intraoperative clip detection, oncological assessment, including DRM, and the number of lymph nodes indicate that the utility of fluorescence-guided methods with NIRFCs is feasible for rectal cancer.

Long-Term Outcome in Patients With Acute Ischemic Stroke and Heart Failure.

BACKGROUND: This study aimed to identify the association between long term functional outcomes and acute ischemic stroke (AIS) in patients with heart failure (HF) in Japan and whether 1-year event risks can be related to these patients.Methods and Results: This was a prospective observational study, and 651 patients registered in the Tokyo Women's Medical University Stroke Registry were classified into the HF and non-HF groups. Functional outcome at 1 year after stroke onset was defined as either good (modified Rankin Scale [mRS] score of 0-2) or poor (mRS score of 3-6). The primary outcome was a composite of major adverse cardiovascular events (MACE), including non-fatal stroke, non-fatal acute coronary syndrome, and vascular death. Patients with HF had a higher poor functional outcome rate at 1 year than those without HF (54.7% vs. 28.2%, P<0.001). Multivariate logistic regression analysis also demonstrated the prevalence of HF was an independent predictor of an mRS score of ≥3 at 1 year after stroke onset (odds ratio, 1.05; 95% confidence interval, 1.00-1.10; P=0.036). Furthermore, patients with HF tended to have a higher risk of MACE and all-cause mortality than those without HF. CONCLUSIONS: AIS patients with HF were associated with poor functional outcome at the 1-year follow up. Further multicenter studies involving a larger number of patients are warranted to verify these results.

Differential inhibition of platelet function by cilostazol in combination with clopidogrel.

PURPOSE: To assess the antiplatelet effect of cilostazol clinically, we compared the effects of cilostazol in combination with clopidogrel on various platelet function tests. METHODS: We recruited patients with ischemic stroke at high risk of recurrence who were treated with clopidogrel alone within 180 days after stroke onset. Subjects underwent baseline platelet function tests, and were then randomly assigned to receive dual antiplatelet therapy (DAPT) comprising clopidogrel and cilostazol or clopidogrel monotherapy (SAPT). After 6 months, platelet function was measured again and compared to that at baseline in each group, and the rate of change was compared between groups. RESULTS: Thirty-four patients were enrolled, but 4 patients were excluded for various reasons. In total, 30 subjects (13 in DAPT and 17 in SAPT group) were analyzed. Adenosine diphosphate- and collagen-induced aggregation, VerifyNow P2Y12 reaction units, vasodilator-stimulated phosphoprotein (platelet reactivity index: PRI) and plasma p-selectin concentration were significantly lower (P = 0.004, 0.042, 0.049, 0.003 and 0.006 respectively), while VerifyNow % inhibition was significantly higher at 6 months compared to baseline (P = 0.003) in the DAPT group only. Comparison of the rate of change in each parameter from baseline to 6 months showed that while PRI decreased at a greater rate (P = 0.012), VerifyNow % inhibition increased at a greater rate (P = 0.003) in the DAPT group than the SAPT group. CONCLUSIONS: The inhibitory effects of adjunctive cilostazol added to clopidogrel on platelet function differed by type of platelet function test. VerifyNow % inhibition and PRI were more inhibited than the other platelet function tests. TRIAL REGISTRATION: CSPS.com substudy in TWMU (UMIN000026672), registered on April 1, 2017. This study was performed as a substudy of CSPS.com (UMIN000012180, registered on October 31, 2013) and was retrospectively registered.

Atherogenic Dyslipidemia and Residual Vascular Risk After Stroke or Transient Ischemic Attack.

BACKGROUND AND PURPOSE: Notwithstanding the current guideline-based management, patients with stroke retain a substantial risk of further vascular events. We aimed to assess the contribution of atherogenic dyslipidemia (AD) to this residual risk. METHODS: This was a prospective observational study, in which 792 patients (mean age, 70.1 years; male, 60.2%) with acute ischemic stroke (n=710) or transient ischemic attack (n=82) within 1 week of onset were consecutively enrolled and followed for 1 year. AD was defined as having both elevated levels of triglycerides ≥150 mg/dL and low HDL-C (high-density lipoprotein cholesterol) <40 mg/dL in men or <50 mg/dL in women, under fasting conditions. The primary outcome was a composite of major adverse cardiovascular events, including nonfatal stroke, nonfatal acute coronary syndrome, and vascular death. RESULTS: The prevalence of AD was 12.2%. Patients with AD more often had intracranial artery stenosis than those without (42.3% versus 24.1%; P=0.004), whereas no differences were observed in the prevalence of extracranial artery stenosis (17.7% versus 12.9%; P=0.62) or aortic plaques (33.3% versus 27.0%; P=0.87). At 1 year, patients with AD were at a greater risk of major adverse cardiovascular events (annual rate, 24.5% versus 10.6%; hazard ratio [95% CI], 2.33 [1.44-3.80]) and ischemic stroke (annual rate, 16.8% versus 8.6%; hazard ratio [95% CI], 1.84 [1.04-3.26]) than those without AD. When patients were stratified according to baseline LDL-C (low-density lipoprotein cholesterol) level, AD was predictive of major adverse cardiovascular events among those with LDL-C ≥100 mg/dL (n=509; annual rate, 20.5% versus 9.6%; P=0.036) as well as those with LDL-C <100 mg/dL (n=283; annual rate, 38.6% versus 12.4%; P<0.001). CONCLUSIONS: AD is associated with intracranial artery atherosclerosis and a high residual vascular risk after a stroke or transient ischemic attack. AD should be a promising modifiable target for secondary stroke prevention. Registration: URL: https://upload.umin.ac.jp; Unique identifier: UMIN000031913.

Triglyceride-glucose index as a prognostic marker after ischemic stroke or transient ischemic attack: a prospective observational study.

BACKGROUND: Triglyceride-glucose (TyG) index has been proposed as a simple and credible surrogate for insulin resistance and an independent predictor of cardiovascular outcomes. Due to lack of data on TyG index in stroke, we aimed to evaluate the predictive value of the index for recurrent vascular event risk among stroke patients. METHODS: This was a prospective observational study, in which 866 patients (mean age, 70.1 years; male, 60.9%) with ischemic stroke (n = 781) or transient ischemic attack (n = 85) within 1 week of onset were consecutively enrolled and followed up for 1 year. The TyG index was calculated as ln (fasting triglycerides [mg/dL] × fasting glucose [mg/dL]/2). Patients were divided into 3 groups according to the tertile of TyG index levels: tertile 1, < 8.48; tertile 2, 8.48-9.01; and tertile 3, > 9.01. The primary outcome was a composite of major adverse cardiovascular events (MACE), including nonfatal stroke, nonfatal acute coronary syndrome, and vascular death. RESULTS: The median TyG index was 8.74 (interquartile range, 8.34-9.16). Higher levels of TyG index were significantly associated with increased prevalence of ipsilateral extracranial carotid (P = 0.032) and intracranial (P = 0.003) atherosclerotic stenosis. There were significant differences in the MACE risk between the three groups (annual rate, 8.6%, 11.6%, and 17.3% in the tertile 1, tertile 2, tertile 3 groups, respectively; log-rank P = 0.005). After multivariable adjustments, the TyG index remains to be a significant predictor of MACE, with an adjusted hazard ratio for tertile 3 versus tertile 1 groups (95% confidence interval) of 2.01 (1.16-3.47). Similar results were also found for the risk of recurrent stroke. CONCLUSIONS: TyG index is associated with cervicocerebral atherosclerosis and the MACE risk after a stroke, suggesting the potential value of TyG index to optimize the risk stratification of stroke patients. Trial registration URL:  https://upload.umin.ac.jp . Unique identifier: UMIN000031913.

Neuropsychological Profile of Early Cognitive Impairment in Cerebral Small Vessel Disease.

INTRODUCTION: The neuropsychological feature of vascular mild cognitive impairment is a deficit of the frontal-subcortical circuit; however, the features in the early stage are not consistent. In the present study, we aimed to investigate the neuropsychological features of the very early stage of cognitive impairment with cerebral small vessel disease (CSVD) and to elucidate the cognitive differences among CSVD subtypes. METHODS: A comprehensive neuropsychological test battery was applied to nondemented subjects scoring below the cutoff point 26 of the Japanese version of the Montreal Cognitive Assessment. After factor analysis was conducted to identify covert cognitive factors in the battery, correlation analyses were performed between the factors and CSVD subtypes: white matter hyperintensity (WMH), lacunar infarcts (LIs), cerebral microbleeds (CMBs), perivascular spaces, and cortical atrophy. RESULTS: Among the 465 recruited patients, 139 underwent a full neuropsychological test battery. Through factor analysis, the following three factors were extracted: executive function, memory, and attention. Of the CSVD features, total WMH was correlated with executive function and memory, whereas deep WMH was correlated with memory alone. Of the CSVD subtypes, LIs and CMBs were correlated only with executive function. Frontal and posterior atrophy were correlated with memory and attention, whereas medial temporal atrophy was correlated with memory alone. CONCLUSIONS: Executive dysfunction accompanied by subtle impairment of memory and processing speed was the main feature of neuropsychological profiles in the subjects with CSVD, even in the very early stage. Furthermore, each CSVD feature and focal cerebral atrophy are associated with cognitive impairment.

Prolonged central motor conduction time and pyramidal tract degeneration in amyotrophic lateral sclerosis.

Electrophysiological methods to detect the degeneration of the upper motor neuron system have not been fully established in patients with amyotrophic lateral sclerosis (ALS). This may be partly because the parallel demonstration of electrophysiology and a corresponding pathological abnormality is insufficient, and because a substantial number of patients with ALS do not exhibit upper motor neuron degeneration. Recently, we encountered 2 patients with ALS who had been examined for abnormal central motor conduction time (CMCT) using transcranial magnetic stimulation within a 20-day period prior to their death. Autopsy revealed that 1 patient had marked pyramidal degeneration with prolonged CMCT; in contrast, the other patient had no obvious pyramidal degeneration and showed normal CMCT. Both the patients with contrasting clinicopathological differences contributed to the identification that the prolongation of CMCT was possibly linked to the degeneration of the corticospinal tract. This report indicates that CMCT is useful for predicting the severity of upper motor neuron degeneration in patients with ALS.

IgG4-related brain pseudotumor mimicking CNS lymphoma. A case report.

Here, we report a case of IgG4-related brain pseudotumor (IgG4-BP) in a 39-year-old woman, mimicking central nervous system (CNS) lymphoma. She presented with headache, fever, and fatigue. Her medical history was notable for appearance of a tumefactive brain lesion seven years before. Brain biopsy performed at the age of 32 revealed nonspecific inflammatory changes, and her condition improved with oral low-dose steroid therapy. Magnetic resonance imaging performed at the age of 39 identified a hyperintensity lesion with edema located at the medial temporal lobe region adjacent to the inferior horn of the left lateral ventricle on fluid-attenuated inversion recovery images, which showed gadolinium-contrast enhancement on T1-weighted images and a slightly hyperintensity signal on diffusion-weighted images. Methionine-positron emission tomography (PET) depicted a high methionine uptake in the lesion. Additionally, soluble levels of interleukin (IL)-2 receptor (sIL-2R) and IL-10 were increased in cerebrospinal fluid (CSF). Based on these findings, we suspected CNS lymphoma and performed partial resection of the brain lesion. Pathological examination revealed prominent lymphocytic infiltration associated with plasma cell infiltration. Most of the plasma cells were immunoreactive for IgG4. Storiform fibrosis and partially obliterative phlebitis were concomitantly observed. Thus, the patient was diagnosed as having IgG4-BP. To the best of our knowledge, this is the first case report of IgG4-BP with detailed findings obtained by CSF testing, methionine-PET, and pathological examination. Because IgG4-related diseases can present as a pseudotumor that mimics CNS lymphoma, it is essential to carefully differentiate IgG4-BP from CNS lymphoma.

Blood Pressure Level and Variability During Long-Term Prasugrel or Clopidogrel Medication After Stroke: PRASTRO-I.

BACKGROUND AND PURPOSE: High blood pressure increases bleeding risk during treatment with antithrombotic medication. The association between blood pressure levels and the risk of recurrent stroke during long-term secondary stroke prevention with thienopyridines (particularly prasugrel) has not been well studied. METHODS: This was a post hoc analysis of the randomized, double-blind, multicenter PRASTRO-I trial (Comparison of Prasugrel and Clopidogrel in Japanese Patients With Ischemic Stroke-I). Patients with noncardioembolic stroke were randomly assigned (1:1) to receive prasugrel 3.75 mg/day or clopidogrel 75 mg/day for 96 to 104 weeks. Risks of any ischemic or hemorrhagic stroke, combined ischemic events, and combined bleeding events were determined based on the mean level and visit-to-visit variability, including successive variation, of systolic blood pressure (SBP) throughout the observational period. These risks were also compared between quartiles of mean SBP level and successive variation of SBP. RESULTS: A total of 3747 patients (age 62.1±8.5 years, 797 women), with a median average SBP level during the observational period of 132.5 mm Hg, were studied. All the risks of any stroke (146 events; hazard ratio, 1.318 [95% CI, 1.094-1.583] per 10-mm Hg increase), ischemic stroke (133 events, 1.219 [1.010-1.466]), hemorrhagic stroke (13 events, 3.247 [1.660-6.296]), ischemic events (142 events, 1.219 [1.020-1.466]), and bleeding events (47 events, 1.629 [1.172-2.261]) correlated with increasing mean SBP overall. Similarly, an increased risk of these events correlated with increasing successive variation of SBP (hazard ratio, 3.078 [95% CI, 2.220-4.225] per 10-mm Hg increase; 3.051 [2.179-4.262]; 3.276 [1.172-9.092]; 2.865 [2.042-4.011]; 2.764 [1.524-5.016], respectively). Event rates did not differ between the clopidogrel and prasugrel groups within each quartile of SBP or successive variation of SBP. CONCLUSIONS: Both high mean SBP level and high visit-to-visit variability in SBP were significantly associated with the risk of recurrent stroke during long-term medication with either prasugrel or clopidogrel after stroke. Control of hypertension would be important regardless of the type of antiplatelet drugs. Registration: URL: https://www.clinicaltrials.jp; Unique identifier: JapicCTI-111582.

New Scoring System for Predicting the Risk of Surgical Site Infections Following Stoma Reversal.

BACKGROUND: Surgical site infections (SSI) are one of the most frequent complications following stoma reversal (SR-SSI) and lead to multiple problems such as decreased mobility of the patients or increased hospital costs. Several risk factors for SR-SSI have been reported, but there are no risk scoring systems for predicting SR-SSI. The current study aimed to analyze the risk factors for SR-SSI and develop a scoring system. MATERIALS AND METHODS: Multivariate analysis of risk factors for SR-SSI was performed in patients who underwent elective SR and were followed-up during the first month after surgery. A logistic regression model was used to identify risk factors and construct a predictive score. RESULTS: Of the 182 patients, 53 (29.1%) developed SSI. In multivariate analysis, three variables as preoperative risk factors were associated with increased SR-SSI incidence: subcutaneous fat thickness (≥ 20 mm) (odds ratio [OR]: 8.46 [95% confidence interval (CI): 3.45-20.7], P <0.001), period from stoma creation (≤ 20 weeks) (OR: 2.88 [95% CI: 1.14-7.28], P = 0.025), and SSI after the primary operation (OR: 3.06 [95% CI: 1.19-7.90], P = 0.021). Each of these variables contributed 2,1, and 1 points to the risk score, respectively. The SR-SSI rate was 2.9%, 20.3%, 34.2%, 54.5%, and 81.8% for the scores of 0,1,2,3, and 4 points, respectively. The area under the receiver operating characteristic curve was 0.773 (95% CI: 0.703-0.844). CONCLUSIONS: A simple clinical scoring system based on three preoperative variables may be useful in predicting the risk of SR-SSI.

Association between Excessive Daytime Sleepiness and the Cholinergic Ascending Reticular System in Parkinson's Disease.

BACKGROUND: Excessive daytime sleepiness (EDS) in Parkinson's disease (PD) may occur because of dysfunction on the brain areas in controlling wakefulness; however, the pathophysiology of EDS in PD has not been completely clarified. The Pb component of a middle-latency auditory evoked response (MLR) is generated from the cholinergic ascending reticular activating system (ARAS) projecting to the auditory cortex via the thalamus. We examined the association between EDS and the Pb component in patients with PD. METHODS: Participants were 38 patients with nondemented PD and 18 age-matched controls. EDS was evaluated using the Japanese version of the Epworth Sleepiness Scale (JESS). PD patients were classified into the high sleepiness (HS) group and the low sleepiness (LS) group by the score of JESS. MLRs were recorded from the scalp with each earlobe as a reference under presentation of 1-Hz and 65- to 90-dB click sounds. RESULTS: There was no difference in age, duration, and motor function between the HS PD and the LS PD groups. Peak latencies of Pb were not different between PD group and controls; however, Pb amplitudes were significantly increased in the HS PD group compared with the LS PD group and controls. CONCLUSION: One of the mechanisms of EDS in PD was suggested to be dysregulation of cholinergic neurons from the ARAS projecting to cortical cholinergic neurons.

Prevalence of Microembolic Signals in Embolic Stroke of Undetermined Source and Other Subtypes of Ischemic Stroke.

Background and Purpose- Embolic stroke of undetermined source (ESUS) has been proposed to cause thromboembolic infarction from unknown but potential embolic sources. However, an embolus remains undetected in ESUS. The goal of this study was to characterize the prevalence and risk factors of microembolic signals (MESs) in ESUS. Methods- We examined 108 patients with acute ischemic stroke in the internal carotid artery territory or transient ischemic attack within 14 days of symptom onset and who were admitted to our hospital between April 2017 and March 2019. MESs were monitored in the middle cerebral artery on transcranial Doppler for 60 minutes. We examined the prevalence and number of MES in ESUS and other stroke subtypes, such as cardioembolism, large artery atherosclerosis, cerebral small vessel disease, and transient ischemic attack. The present study was registered in University Hospital Medical Information Network Clinical Trials Registry (UMIN000031913). Results- MESs were detected in 33 (31%) of 108 patients. ESUS showed the highest proportion (12/24 [50%]), followed by large artery atherosclerosis (8/20 [40%]), cardioembolism (6/18 [33%]), transient ischemic attack (4/24 [17%]), and cerebral small vessel disease (3/21 [14%]). Univariate analysis showed that higher systolic blood pressure, body mass index, hemoglobin A1c, and ESUS were significantly associated with MES. In multiple logistic regression analysis, ESUS remained significantly associated with MES after adjustment for described covariates from univariate analysis (odds ratio, 2.86 [95% CI, 1.01-8.08]). Conclusions- This study demonstrated significant association of ESUS with MES, supporting the embolic nature of this stroke subtype. Registration- URL: https://upload.umin.ac.jp. Unique identifier: UMIN000031913.

Safety and Efficacy of Prasugrel in Elderly/Low Body Weight Japanese Patients with Ischemic Stroke: Randomized PRASTRO-II.

INTRODUCTION: The safety of prasugrel in elderly and/or low body weight Japanese patients with ischemic stroke who have a relatively high bleeding risk with antiplatelet therapy remains unknown. OBJECTIVE: We aimed to investigate the safety and efficacy of long-term prasugrel monotherapy for stroke prevention compared with clopidogrel in elderly and/or low body weight Japanese patients with non-cardioembolic ischemic stroke. METHODS: In this randomized, double-blind, comparative, phase III study, elderly (age ≥75 years) and/or low body weight (≤50 kg) Japanese patients with a previous history of non-cardioembolic ischemic stroke were assigned to a prasugrel 3.75 mg (PRA3.75) group, a prasugrel 2.5 mg (PRA2.5) group, or a clopidogrel 50 mg (CLO50) group and followed up for 48 weeks. The primary safety endpoint was the combined incidence of primary safety events, defined as life-threatening, major, and other clinically relevant bleeding. The efficacy endpoint was a composite of ischemic stroke, myocardial infarction, and death from other vascular causes. RESULTS: A total of 654 patients (age 76.4 ± 7.3 years, body weight 55.6 ± 9.3 kg, women 43.9%) from 74 medical institutions within Japan were enrolled. The combined incidence (95% CI) of primary safety events was 4.2% (1.9-7.8%), 1.9% (0.5-4.7%), and 3.6% (1.6-6.9%) in the PRA3.75 group (n = 216), PRA2.5 group (n = 215), and CLO50 group (n = 223), respectively (hazard ratios [HR] PRA3.75/CLO50, 1.13 [0.44-2.93]; PRA2.5/CLO50, 0.51 [0.15-1.69]). The incidences of bleeding leading to treatment discontinuation (95% CI) were 2.3% (0.8-5.3%), 0.9% (0.1-3.3%), and 2.2% (0.7-5.2%) in the PRA3.75, PRA2.5, and CLO50 groups, respectively (HRs PRA3.75/CLO50, 1.01 [0.29-3.48]; PRA2.5/CLO50, 0.41 [0.08-2.12]). There was no significant difference in all bleeding events between groups. The incidence of ischemic stroke, myocardial infarction, and death from other vascular causes was lower, but not significantly so, in patients treated with prasugrel than in patients treated with clopidogrel: PRA3.75, 0.0% (0/216); PRA2.5, 3.3% (7/215); and CLO50, 3.6% (8/223; HRs PRA3.75/CLO50, 0.00 [0.00-0.00]; PRA2.5/CLO50, 0.90 [0.32-2.47]). CONCLUSIONS: Elderly and/or low body weight -Japanese patients with previous non-cardioembolic ischemic stroke who received PRA3.75 showed similar results in terms of primary safety endpoint, and a numerically lower incidence of ischemic stroke, myocardial infarction, and death from other vascular causes, compared with those who received CLO50.

Phenotypic variability and its pathological basis in amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is characterized by its inherent clinicopathological variability. The concurrence of upper and lower motor neuron signs is a common feature in the majority of patients with ALS. However, some patients manifest an atypical clinical course, with only upper or lower motor neuron signs, or various extra-motor symptoms including cognitive dysfunction, parkinsonism, autonomic dysfunction, or ophthalmoparesis. This variability indicates different manifestations of ALS and is reflected by ALS pathology spreading into the central nervous system. The presence of cytoplasmic inclusions positive for transactivation response DNA-binding protein 43 kDa (TDP-43) is a key feature in ALS. Loss of TDP-43 from the nucleus and its subsequent aggregation in the cytoplasm may occur in susceptible regions and may be associated with neuronal loss. However, in some regions, there is no apparent neuronal loss while TDP-43 accumulation is evident; in contrast, in other regions, neuronal loss is apparent without any evidence of TDP-43 accumulation. Therefore, in addition to TDP-43 dysfunction, underlying region-specific cellular vulnerability may exist in the upper and lower motor neurons and frontotemporal system in patients with ALS. The microscopic discrepancy and selective vulnerability may be linked to the macroscopic propensities of the sites of onset, and may also determine the direction and rate of progression of the lesions. Thus, there may be multicentric sites of onset, region-oriented disease development, and different speeds of disease progression across patients with ALS. ALS lesions occur in motor-related areas but may spread to neighboring areas. However, since lesions may spread in a discontinuous manner, and the dynamics of disease propagation have not been able to be identified, it remains controversial whether the stepwise appearance of TDP-43-positive inclusions is based on direct cell-to-cell protein propagation. Further understanding of the phenotypic variability of ALS and its pathological basis may serve as a guide for investigating the underlying pathogenesis of ALS.

Astrocytes release glutamate via cystine/glutamate antiporter upregulated in response to increased oxidative stress related to sporadic amyotrophic lateral sclerosis.

A vast body of evidence implicates increased oxidative stress and extracellular glutamate accumulation in the pathomechanism of sporadic amyotrophic lateral sclerosis (ALS). Cystine/glutamate antiporter (xCT) carries extracellular cystine uptake and intracellular glutamate release (cystine/glutamate exchange) in the presence of oxidative stress. The aim of the present study was to determine the involvement of xCT in ALS. Immunohistochemical observations in the spinal cord sections demonstrated that xCT was mainly expressed in astrocytes, with staining more intense in 12 sporadic ALS patients as compared to 12 age-matched control individuals. Western blot and densitometric analyses of the spinal cord samples revealed that the relative value of xCT/ß-actin optical density ratio was significantly higher in the ALS group as compared to the control group. Next, we conducted cell culture experiments using a human astrocytoma-derived cell line (1321N1) and a mouse motor neuron/neuroblastoma hybrid cell line (NSC34). In 1321N1 cells, the normalized xCT expression levels in cell lysates were significantly increased by H2 O2 treatment. Glutamate concentrations in 1321 N1 cell culture-conditioned media were significantly elevated by H2 O2 treatment, and the H2 O2 -driven elevations were completely canceled by the xCT inhibitor erastin pretreatment. In motor neuron-differentiated NSC34 cells (NSC34d cells), both the normalized xCT expression levels in the cell lysates and glutamate concentrations in the cell-conditioned media were constant with or without H2 O2 treatment. The present results provide in vivo and in vitro evidence that astrocytes upregulate xCT expression to release glutamate in response to increased oxidative stress associated with ALS, contributing to extracellular glutamate accumulation.

Soluble iron accumulation induces microglial glutamate release in the spinal cord of sporadic amyotrophic lateral sclerosis.

Previous studies on sporadic amyotrophic lateral sclerosis (SALS) demonstrated iron accumulation in the spinal cord and increased glutamate concentration in the cerebrospinal fluid. To clarify the relationship between the two phenomena, we first performed quantitative and morphological analyses of substances related to iron and glutamate metabolism using spinal cords obtained at autopsy from 12 SALS patients and 12 age-matched control subjects. Soluble iron content determined by the Ferrozine method as well as ferritin (Ft) and glutaminase C (GLS-C) expression levels on Western blots were significantly higher in the SALS group than in the control group, while ferroportin (FPN) levels on Western blots were significantly reduced in the SALS group as compared to the control group. There was no significant difference in aconitase 1 (ACO1) and tumor necrosis factor-alpha (TNFα)-converting enzyme (TACE) levels on Western blots between the two groups. Immunohistochemically, Ft, ACO1, TACE, TNFα, and GLS-C were proven to be selectively expressed in microglia. Immunoreactivities for FPN and hepcidin were localized in neuronal and glial cells. Based on these observations, it is predicted that soluble iron may stimulate microglial glutamate release. To address this issue, cell culture experiments were carried out on a microglial cell line (BV-2). Treatment of BV-2 cells with ferric ammonium citrate (FAC) brought about significant increases in intracellular soluble iron and Ft expression levels and conditioned medium glutamate and TNFα concentrations. Glutamate concentration was also significantly increased in conditioned media of TNFα-treated BV-2 cells. While the FAC-driven increases in glutamate and TNFα release were completely canceled by pretreatment with ACO1 and TACE inhibitors, respectively, the TNFα-driven increase in glutamate release was completely canceled by GLS-C inhibitor pretreatment. Moreover, treatment of BV-2 cells with hepcidin resulted in a significant reduction in FPN expression levels on Western blots of the intracellular total protein extracts. The present results provide in vivo and in vitro evidence that microglial glutamate release in SALS spinal cords is enhanced by intracellular soluble iron accumulation-induced activation of ACO1 and TACE and by increased extracellular TNFα-stimulated GLS-C upregulation, and suggest a positive feedback mechanism to maintain increased intracellular soluble iron levels, involving TNFα, hepcidin, and FPN.

Impaired Endothelial Function in Embolic Stroke of Undetermined Source.

BACKGROUND: Impairment of endothelial function is associated with atherosclerosis and atrial fibrillation, and could underlie several types of ischemic stroke. Embolic stroke of undetermined source (ESUS) recently attracted much attention as the major cause of cryptogenic stroke. This study aimed to clarify the endothelial function of patients with ESUS. METHODS AND RESULTS: Between 2015 September and July 2017 July, we used flow-mediated vasodilation (FMD) test to evaluate vascular endothelial function in 182 patients with any vascular risk factors or a history of cerebrovascular events. The subject group was classified into the No Stroke group and 5 stroke subtype groups, large artery atherosclerosis (LAA), cardiogenic embolism (CE), small vessel disease (SVD), ESUS, and others (Other). Endothelial function was expressed as percentage increase in brachial vessel diameter (%FMD) after the interruption of blood flow with mechanical compression for 5 minutes. Mean FMD in the No stroke, LAA, CE, SVD, ESUS and Other groups were 7.03 ± 2.14%, 5.02 ± 2.75%, 4.97 ± 1.62%, 5.19 ± 2.67%, 3.55 ± 1.42%, and 6.55 ± 3.50%, respectively. After the adjustment for confounding factors, FMD was significantly lower in the ESUS group than in the No stroke, SVD, and Other groups. FMD tended to be lower in the ESUS group than in the LAA and CE groups, but the difference was not significant. CONCLUSIONS: Endothelial function was impaired in patients with ESUS and may underlie its pathophysiology.

Association of IgG4-Related Arteritis With Recurrent Stroke.

Immunoglobulin G4-related disease (IgG4)-related disease is a newly recognized form of immune-mediated disease, which is characterized by IgG4+ lymphoplasmacytic infiltration and fibrosis in the systemic organs. Although aortitis/periaortitis is a phenotype of IgG4-related disease, the relationship between cerebrovascular disease and IgG4-related disease remains unclear. Herein, we report the case of a 49-year-old man with recurrent stroke induced by IgG4-related arteritis. Case reports or studies examining the association between IgG4-related arteritis and stroke are limited. Although a definitive link between IgG4-related arteritis and stroke has not been established, IgG4-related arteritis should be considered as an etiology in patients with recurrent idiopathic stroke.

High-Dose Versus Low-Dose Pitavastatin in Japanese Patients With Stable Coronary Artery Disease (REAL-CAD): A Randomized Superiority Trial.

BACKGROUND: Current guidelines call for high-intensity statin therapy in patients with cardiovascular disease on the basis of several previous "more versus less statins" trials. However, no clear evidence for more versus less statins has been established in an Asian population. METHODS: In this prospective, multicenter, randomized, open-label, blinded end point study, 13 054 Japanese patients with stable coronary artery disease who achieved low-density lipoprotein cholesterol (LDL-C) <120 mg/dL during a run-in period (pitavastatin 1 mg/d) were randomized in a 1-to-1 fashion to high-dose (pitavastatin 4 mg/d; n=6526) or low-dose (pitavastatin 1 mg/d; n=6528) statin therapy. The primary end point was a composite of cardiovascular death, nonfatal myocardial infarction, nonfatal ischemic stroke, or unstable angina requiring emergency hospitalization. The secondary composite end point was a composite of the primary end point and clinically indicated coronary revascularization excluding target-lesion revascularization at sites of prior percutaneous coronary intervention. RESULTS: The mean age of the study population was 68 years, and 83% were male. The mean LDL-C level before enrollment was 93 mg/dL with 91% of patients taking statins. The baseline LDL-C level after the run-in period on pitavastatin 1 mg/d was 87.7 and 88.1 mg/dL in the high-dose and low-dose groups, respectively. During the entire course of follow-up, LDL-C in the high-dose group was lower by 14.7 mg/dL than in the low-dose group (P<0.001). With a median follow-up of 3.9 years, high-dose as compared with low-dose pitavastatin significantly reduced the risk of the primary end point (266 patients [4.3%] and 334 patients [5.4%]; hazard ratio, 0.81; 95% confidence interval, 0.69-0.95; P=0.01) and the risk of the secondary composite end point (489 patients [7.9%] and 600 patients [9.7%]; hazard ratio, 0.83; 95% confidence interval, 0.73-0.93; P=0.002). High-dose pitavastatin also significantly reduced the risks of several other secondary end points such as all-cause death, myocardial infarction, and clinically indicated coronary revascularization. The results for the primary and the secondary composite end points were consistent across several prespecified subgroups, including the low (<95 mg/dL) baseline LDL-C subgroup. Serious adverse event rates were low in both groups. CONCLUSIONS: High-dose (4 mg/d) compared with low-dose (1 mg/d) pitavastatin therapy significantly reduced cardiovascular events in Japanese patients with stable coronary artery disease. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01042730.