REsveratrol for VAscular cognitive impairment investigating cerebral Metabolism and Perfusion (REVAMP trial): a study protocol for a randomized, double-blind, placebo-controlled trial.

Background: Carotid artery stenosis or occlusion (CASO) is a major cause of vascular cognitive impairment (VCI). There is currently no effective treatment for VCI induced by CASO. Resveratrol, a type of polyphenol, improves cognitive performance in rat CASO models via pleiotropic effects. Furthermore, we previously reported the longevity gene, SIRT1, which can be activated by resveratrol, improves cognitive and cerebral blood flow impairment in mouse CASO models by activating endothelial nitric oxide synthase. However, clinical evidence remains limited. Methods: The REsveratrol for VAscular cognitive impairment investigating cerebral Metabolism and Perfusion (REVAMP) trial is a randomized, double-blind, placebo-controlled trial involving patients with asymptomatic CASO. Each participant will receive either 150 mg/day of resveratrol or a placebo for 35 weeks. The primary objective is to determine whether resveratrol improves cognitive impairment, as assessed using the Alzheimer's disease Assessment Scale-cognitive subscale 13. One of our secondary objectives is to determine whether resveratrol improves cerebral hemodynamic impairment as assessed via 15O-gas positron emission tomography. We will recruit 100 patients (50 per group). Discussion: The REVAMP trial may provide valuable insights into new therapeutic options, as multitarget neuroprotection could potentially improve cognitive function along with enhancements in cerebral hemodynamic status in patients with asymptomatic CASO.Clinical trial registration: The REVAMP trial was prospectively registered in the Japan Registry of Clinical Trials (jRCTs051230013) on April 13, 2023.

Long-Term Resveratrol Intake for Cognitive and Cerebral Blood Flow Impairment in Carotid Artery Stenosis/Occlusion.

BACKGROUND AND PURPOSE: Carotid artery stenosis or occlusion (CASO) is a causative disease of vascular cognitive impairment (VCI) attributed to cerebral hypoperfusion, even without the development of symptomatic ischemic stroke. Preclinically, resveratrol has been demonstrated to play an important role in improving cognitive function in rodent CASO models. This study investigated the association between long-term resveratrol intake and improvements in cognitive and cerebral hemodynamic impairments in patients with CASO. METHODS: A retrospective cohort study was conducted on patients with asymptomatic carotid artery stenosis of ≥50% or occlusion who underwent 15O-gas positron emission tomography (15O-gas PET) and neuropsychological tests such as Montreal Cognitive Assessment (MoCA) and Alzheimer's Disease Assessment Scale-Cognitive Subscale 13 (ADAS-Cog) twice between July 2020 and March 2022 allowing >125-day interval. Patients were administered 30 mg/day resveratrol after the first 15O-gas PET and neuropsychological tests were compared with those who were not. RESULTS: A total of 79 patients were enrolled in this study; 36 received resveratrol and 43 did not. Over a mean follow-up of 221.2 and 244.8 days, long-term resveratrol treatment significantly improved visuospatial/executive function (P=0.020) in MoCA, and memory domain (P=0.007) and total score (P=0.019) in ADAS-Cog. Cerebral blood flow demonstrated improvement in the right frontal lobe (P=0.027), left lenticular nucleus (P=0.009), right thalamus (P=0.035), and left thalamus (P=0.010) on 15O-gas PET. No adverse events were reported. CONCLUSION: Long-term daily intake of oral resveratrol may prevent or treat VCI by improving the cerebral blood flow in asymptomatic patients with CASO.

High pillow and spontaneous vertebral artery dissection: A case-control study implicating "Shogun pillow syndrome".

INTRODUCTION: The underlying causes of spontaneous vertebral artery dissection (sVAD) remain insufficiently understood. This study aimed to determine whether high-pillow usage is associated with an increased risk of sVAD and evaluate the frequency of sVAD attributable to high-pillow usage. PATIENTS AND METHODS: This case-control study identified patients with sVAD and age- and sex-matched non-sVAD controls (case-to-control ratio: 1:1) treated at a certified comprehensive stroke center in Japan between 2018 and 2023. The pillow height used at the onset of the index disease was measured and classified into three categories between 12 and 15 cm boundaries. Univariable logistic regression was performed to assess the odds ratio (OR) with a 95% confidence interval (CI) of high-pillow usage for sVAD development. A subgroup of sVAD attributable to high-pillow usage was defined with the following three conditions: high-pillow usage (⩾12 or ⩾15 cm); no minor preceding trauma; and wake-up onset. RESULTS: Fifty-three patients with sVAD and 53 non-sVAD controls (42% women, median age: 49 years) were identified. High-pillow usage (⩾12 and ⩾15 cm) was more common in the sVAD group than in the non-sVAD group (34 vs 15%; OR = 2.89; 95%CI = 1.13-7.43 and 17 vs 1.9%; OR = 10.6; 95%CI = 1.30-87.3, respectively). The subgroup of sVAD attributed to high-pillow usage (⩾12 and ⩾15 cm) was found in 11.3% (95%CI = 2.7%-19.8%) and 9.4% (95%CI = 1.5%-17.3%), respectively. CONCLUSION: High-pillow usage was associated with an increased risk of sVAD and accounted for approximately 10% of all sVAD cases. This tentative subgroup of sVAD may represent a distinct spectrum of disease-Shogun pillow syndrome.

Neuroprotective effects of oral metformin before stroke on cerebral small-vessel disease.

BACKGROUND: Metformin (MET) treatment prior to stroke might have neuroprotective effects other than hypoglycemic effects. This study evaluated whether MET treatment prior to stroke is associated with neurological severity and functional outcome in patients with stroke who were not indicated for endovascular treatment and whether the effects of MET differ for each ischemic stroke subtype. METHODS: We investigated 160 type 2 diabetes mellitus patients with ischemic stroke without endovascular treatment who were taking some oral antidiabetic agents prior to stroke in two tertiary hospitals. Lower neurological severity was defined as a National Institutes of Health Stroke Scale score of 3 or lower on admission, and favorable functional outcome was defined as a modified Rankin Scale score = 0-2 at discharge. We analyzed the effects of MET on the neurological severity and functional outcome in each ischemic stroke subtype on logistic regression analysis with adjustments for multiple confounding factors. RESULTS: MET treatment prior to stroke was associated with lower stroke severity and favorable functional outcome. In the stroke subtypes, MET use affected both neurological severity (P = 0.037) and functional outcome (P = 0.041) in only patients with small-vessel disease (SVD). CONCLUSIONS: MET may be useful to improve the outcome of patients with SVD.

Efficacy and Safety of Cilostazol in Mild Cognitive Impairment: A Randomized Clinical Trial.

Importance: Recent evidence indicates the efficacy of ß-amyloid immunotherapy for the treatment of Alzheimer disease, highlighting the need to promote ß-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.

Border-associated macrophages promote cerebral amyloid angiopathy and cognitive impairment through vascular oxidative stress.

BACKGROUND: Cerebral amyloid angiopathy (CAA) is a devastating condition common in patients with Alzheimer's disease but also observed in the general population. Vascular oxidative stress and neurovascular dysfunction have been implicated in CAA but the cellular source of reactive oxygen species (ROS) and related signaling mechanisms remain unclear. We tested the hypothesis that brain border-associated macrophages (BAM), yolk sac-derived myeloid cells closely apposed to parenchymal and leptomeningeal blood vessels, are the source of radicals through the Aß-binding innate immunity receptor CD36, leading to neurovascular dysfunction, CAA, and cognitive impairment. METHODS: Tg2576 mice and WT littermates were transplanted with CD36-/- or CD36+/+ bone marrow at 12-month of age and tested at 15 months. This approach enables the repopulation of perivascular and leptomeningeal compartments with CD36-/- BAM. Neurovascular function was tested in anesthetized mice equipped with a cranial window in which cerebral blood flow was monitored by laser-Doppler flowmetry. Amyloid pathology and cognitive function were also examined. RESULTS: The increase in blood flow evoked by whisker stimulation (functional hyperemia) or by endothelial and smooth muscle vasoactivity was markedly attenuated in WT → Tg2576 chimeras but was fully restored in CD36-/- → Tg2576 chimeras, in which BAM ROS production was suppressed. CAA-associated Aß1-40, but not Aß1-42, was reduced in CD36-/- → Tg2576 chimeras. Similarly, CAA, but not parenchymal plaques, was reduced in CD36-/- → Tg2576 chimeras. These beneficial vascular effects were associated with cognitive improvement. Finally, CD36-/- mice were able to more efficiently clear exogenous Aß1-40 injected into the neocortex or the striatum. CONCLUSIONS: CD36 deletion in BAM suppresses ROS production and rescues the neurovascular dysfunction and damage induced by Aß. CD36 deletion in BAM also reduced brain Aß1-40 and ameliorated CAA without affecting parenchyma plaques. Lack of CD36 enhanced the vascular clearance of exogenous Aß. Restoration of neurovascular function and attenuation of CAA resulted in a near complete rescue of cognitive function. Collectively, these data implicate brain BAM in the pathogenesis of CAA and raise the possibility that targeting BAM CD36 is beneficial in CAA and other conditions associated with vascular Aß deposition and damage.

Association of thyroid peroxidase antibody with the RNF213 p.R4810K variant in ischemic stroke/transient ischemic attack.

BACKGROUND AND AIMS: RNF213 is a susceptibility gene for moyamoya disease and vasospastic angina, with a second hit considered necessary for their development. Elevated thyroid peroxidase antibody (TPO-Ab) levels have been observed in both diseases, suggesting a possible role of TPO-Ab as a second hit for developing RNF213-related vasculopathy. We investigated the association of TPO-Ab levels with RNF213-related ischemic stroke (IS)/transient ischemic attack (TIA), other than moyamoya disease. METHODS: From the National Cerebral and Cardiovascular Center Genome Registry, a multicenter, prospective, observational study, we enrolled patients with IS/TIA who were admitted within 1 week of onset. Patients with IS/TIA due to definite moyamoya disease or hemorrhagic stroke were excluded. Participants underwent genotyping for RNF213 p. R4810K, and baseline characteristics and TPO-Ab levels were compared between RNF213 p. R4810K variant carriers and non-carriers. RESULTS: In total, 2090 IS/TIA patients were analyzed [733 women (35.1%); median age 74 (interquartile range, 63-81) years, baseline NIHSS score 3 (2-6)], and 85 (4.1%) of them carried the variant. Median TPO-Ab levels were significantly higher in variant carriers (8.5 IU/mL vs. 2.1 IU/mL, p < 0.01), who also showed a higher frequency of elevated TPO-Ab levels (>16 IU/mL) (27.1% vs. 4.4%). In the multivariate analysis, presence of the RNF213 p. R4810K variant (adjusted odds ratio, 12.42; 95% confidential interval, 6.23-24.75) was significantly associated with elevated TPO-Ab levels. CONCLUSIONS: Elevated TPO-Ab levels may be significantly associated with presence of the RNF213 p. R4810K variant in IS/TIA patients. Thus, TPO-Ab may inherently modify IS/TIA development in RNF213 p. R4810K variant carriers.

Amplified Risk of Intracranial Artery Stenosis/Occlusion Associated With RNF213 p.R4810K in Familial Hypercholesterolemia.

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.

Cell autonomous role of border associated macrophages in ApoE4 neurovascular dysfunction and susceptibility to white matter injury.

Apolipoprotein-E4 (ApoE4), the strongest genetic risk factor for sporadic Alzheimer's disease, is also a risk factor for microvascular pathologies leading to cognitive impairment, particularly subcortical white matter injury. These effects have been attributed to alterations in the regulation of the brain blood supply, but the cellular source of ApoE4 and the underlying mechanisms remain unclear. In mice expressing human ApoE3 or ApoE4 we report that border associated macrophages (BAM), myeloid cells closely apposed to neocortical microvessels, are both the source and the target of the ApoE4 mediating the neurovascular dysfunction through reactive oxygen species. ApoE4 in BAM is solely responsible for the increased susceptibility to oligemic white matter damage in ApoE4 mice and is sufficient to enhance damage in ApoE3 mice. The data unveil a new aspect of BAM pathobiology and highlight a previously unrecognized cell autonomous role of BAM in the neurovascular dysfunction of ApoE4 with potential therapeutic implications.

Case Report: Postmortem brain and heart pathology unveiling the pathogenesis of coexisting acute ischemic stroke and electrocardiographic abnormality.

Electrocardiography abnormalities have been occasionally reported at the onset of stroke. Simultaneous electrocardiographic abnormalities and stroke require a rapid differentiated diagnosis among several diseases. However, direct causal relationships remain unclear. A 92-year-old woman presented to our emergency department in a sudden-onset coma. The patient suffered from huge acute ischemic stroke with bilateral internal carotid artery occlusion assessed by brain magnetic resonance imaging, and her electrocardiography showed ST-segment elevation at II, III, aVF and V4-6, and atrial fibrillation (AF). However, the etiology of the medical condition was clinically unknown. Eventually, the patient died on day 4 of hospitalization before the diagnosis could be completed. Therefore, an autopsy was performed to investigate pathological findings after obtaining informed consent from the family. A postmortem pathological evaluation demonstrated that fibrin mural thrombi in the left atrial appendage (LAA), and the cerebral and coronary arteries possessed CD31-positive endothelial cells, and CD68-positive and CD168-positive macrophages in a similar fashion, suggesting the fibrin thrombi observed in the three sites implicated to be identical. We concluded that nearly concurrent cerebral and coronary artery embolism because of the fibrin thrombi in LAA developed by AF. Simultaneous cerebral infarction and myocardial infarction are referred to as cardiocerebral infarction (CCI), a rare disorder for which clear pathomechanisms remain unknown, although several mechanisms of CCI have been proposed. We first revealed the clear pathology of CCI using the autopsy. Additional pathological studies are warranted to establish clear pathomechanisms and preventive strategies of CCI.

Border-associated macrophages promote cerebral amyloid angiopathy and cognitive impairment through vascular oxidative stress.

Background: Cerebral amyloid angiopathy (CAA) is a devastating condition common in patients with Alzheimer's disease but also observed in the general population. Vascular oxidative stress and neurovascular dysfunction have been implicated in CAA but the cellular source of reactive oxygen species (ROS) and related signaling mechanisms remain unclear. We tested the hypothesis that brain border-associated macrophages (BAM), yolk sac-derived myeloid cells closely apposed to parenchymal and leptomeningeal blood vessels, are the source of radicals through the Aß-binding innate immunity receptor CD36, leading to neurovascular dysfunction, CAA, and cognitive impairment. Methods: Tg2576 mice and WT littermates were transplanted with CD36 -/- or CD36 +/+ bone marrow at 12-month of age and tested at 15 months. This approach enables the repopulation of perivascular and leptomeningeal compartments with CD36 -/- BAM. Neurovascular function was tested in anesthetized mice equipped with a cranial window in which cerebral blood flow was monitored by laser-Doppler flowmetry. Amyloid pathology and cognitive function were also examined. Results: The increase in blood flow evoked by whisker stimulation (functional hyperemia) or by endothelial and smooth muscle vasoactivity was markedly attenuated in WT®Tg2576 chimeras but was fully restored in CD36 -/- ®Tg2576 chimeras, in which BAM ROS production was suppressed. CAA-associated Aß 1-40 , but not Aß 1-42 , was reduced in CD36 -/- ®Tg2576 chimeras. Similarly, CAA, but not parenchymal plaques, was reduced in CD36 -/- ®Tg2576 chimeras. These beneficial vascular effects were associated with cognitive improvement. Finally, CD36 -/- mice were able to more efficiently clear exogenous Aß 1-40 injected into the neocortex or the striatum. Conclusions: CD36 deletion in BAM suppresses ROS production and rescues the neurovascular dysfunction and damage induced by Aß. CD36 deletion in BAM also reduced brain Aß 1-40 and ameliorated CAA without affecting parenchyma plaques. Lack of CD36 enhanced the vascular clearance of exogenous Aß. Restoration of neurovascular function and attenuation of CAA resulted in a near complete rescue of cognitive function. Collectively, these data implicate CNS BAM in the pathogenesis of CAA and raise the possibility that targeting BAM CD36 is beneficial in CAA and other conditions associated with vascular Aß deposition and damage.

Taxifolin for Cognitive Preservation in Patients with Mild Cognitive Impairment or Mild Dementia.

BACKGROUND: The development of numerous disease-modifying drugs for age-related dementia has been attempted based on the amyloid-ß (Aß) hypothesis without much success. Taxifolin (TAX), a natural bioactive flavonoid, shows pleiotropic neuroprotective effects with inhibition of Aß 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.

Harboring Cnm-expressing Streptococcus mutans in the oral cavity relates to both deep and lobar cerebral microbleeds.

BACKGROUND: Cerebral microbleeds (CMBs) influence long-term prognoses of stroke patients. Streptococcus mutans expressing the collagen-binding protein Cnm induces cerebrovascular inflammation, impairing blood brain barrier integrity and causing cerebral bleeding. Here, we examine the association of Cnm-positive S. mutans with CMBs. METHODS: Acute stroke patients were selected from a single-center registry database. Oral carriage of Cnm-positive or Cnm-negative S. mutans was determined using polymerase chain reaction assays. The associations of Cnm-positive S. mutans with CMB number and specifically the presence of >10 CMBs were examined using quasi-Poisson and logistic regression models, respectively. RESULTS: This study included 3154 stroke patients, of which 428 patients (median [interquartile range] age, 73.0 [63.0-81.0] years; 269 men [62.9%]) underwent oral bacterial examinations. In total, 326 patients harbored S. mutans. After excluding four patients without imaging data, we compared patients with Cnm-positive (n = 72) and Cnm-negative (n = 250) S. mutans. Harboring Cnm-positive S. mutans was independently associated with the presence of >10 CMBs (adjusted odds ratio 2.20 [1.18-4.10]) and higher numbers of deep and lobar CMBs (adjusted risk ratio 1.61 [1.14-2.27] for deep; 5.14 [2.78-9.51] for lobar), but not infratentorial CMBs, after adjusting for age, sex, hypertension, stroke type, National Institutes of Health Stroke Scale score, and cerebral amyloid angiopathy. CONCLUSIONS: Harboring Cnm-positive S. mutans was independently associated with a higher number of CMBs in deep and lobar locations. Reducing Cnm-positive S. mutans in the oral cavity may serve as a novel therapeutic approach for stroke.

A Case of Multiple Intracranial Major Artery Stenoses With Coexisting PCSK9 p.E32K and RNF213 p.R4810K Variants.

Objectives: Familial hypercholesterolemia (FH), caused by PCSK9 p.E32K, is characterized by early-onset coronary artery disease. However, the relationship between PCSK9 p.E32K and cerebrovascular disease is unclear. One of our patients with the PCSK9 p.E32K had several intracranial artery stenoses (ICAS). The objective of this case series was to identify factors that may be associated with ICAS in the variant carriers. Methods: A 75-year-old Japanese woman with FH carrying PCSK9 p.E32K was found to have 5 asymptomatic ICAS when brain magnetic resonance angiography (MRA) was performed. We retrospectively investigated additional patients with FH who underwent brain MRA at our institution to explore the unknown factors accelerating ICAS. Results: We investigated an additional 5 patients with FH who underwent brain MRA. Of them, only one had mild ICAS. The RNF213 p.R4810K that is an established genetic risk for ICAS, particularly in East Asians, was identified only in the patient with 5 ICAS. Discussion: PCSK9 and RNF213 play an important role in lipid metabolism and endothelial integrity. Therefore, together, these variants could be involved in the development of multiple ICAS. Our case series indicated that PCSK9 p.E32K carriers should undergo early brain screening to obtain appropriate stroke prevention measures in the asymptomatic stage.

Impact of blood flow volume in determining the destination of intracardiac thrombi using computational fluid dynamics.

Atrial fibrillation (AF) induces cardioembolic stroke due to intracardiac fibrin thrombus formation. Although it is well established that a cardioembolic stroke affects the anterior circulation more frequently than it affects the posterior circulation, the destination where the thrombi migrate when cardioembolic stroke occurs in each patient remains unclear. We present a critical case wherein a bilateral internal carotid artery (ICA) territory infarction was diagnosed in a patient with AF who apparently developed nearly simultaneous occlusion in the ICAs bilaterally. A 92-year-old woman with AF who appeared to have developed bilateral occluded common carotid artery (CCA)-ICAs almost simultaneously presented after the sudden onset of coma and quadriplegia and was diagnosed with bilateral ICA territory infarction. The patient died at 4 days after the onset due to the huge infarction. The blood flow in the aorta and the major branches of the aortic arch were examined using computational fluid dynamics (CFD) based on contrast-enhanced computed tomography angiography, which revealed that the right and left CCAs covered larger flow volumes than the other aortic arch branches, suggesting that the intracardiac thrombi migrated into the bilateral CCA-ICAs in the patient. The study findings imply that the fluid dynamic factors of major branches from the aortic arch can be one of the decisive factors for intracardiac thrombus distribution. CFD could simulate patient-specific hemodynamics and may be useful to investigate the susceptibility of the aortic arch branches to occlusion by AF-induced intracardiac emboli.

Case report: Near-complete cortical hearing loss caused by sequential development of bilateral putaminal hemorrhage.

Intracerebral hemorrhage with sudden hearing loss as the initial symptom is rare. A right-handed man with a history of right putaminal hemorrhage developed near-complete hearing loss and right hemiplegia and was taken to our hospital by ambulance. Non-contrast computed tomography demonstrated acute intracerebral hemorrhage in the left putamen. A region of old right putaminal hemorrhage involving the right temporal stem was also shown on fluid-attenuated inversion recovery. Standard pure-tone audiometry showed right-dominant bilateral sensorineural hearing loss. More than 2 months after onset, the bilateral sensorineural hearing loss gradually improved without interfering with daily life. Detailed history-taking indicated that the old hemorrhage in the right putamen 12 years previously had caused sudden left-dominant bilateral hearing impairment due to asymmetric but bilateral innervation from the auditory nerve. The bilateral damage to the temporal stem involving acoustic radiation resulted in temporary near-complete hearing loss after the recurrence, but the amelioration of edema in the left temporal stem may have resulted in partial recovery of the hearing loss. This patient's clinical progression suggests that the auditory tract ascends mainly on the side opposite the ear and may explain the left dominance in the level of acoustic radiation.

Risk Assessment of Cnm-Positive Streptococcus mutans in Stroke Survivors (RAMESSES): Protocol for a Multicenter Prospective Cohort Study.

Introduction: The role of commensal microbiota in systemic diseases, including brain diseases, has attracted increasing attention. Oral infectious diseases, such as dental caries and periodontitis, are also involved in cerebrovascular diseases and cognitive impairment. Cerebral microbleeds (CMBs) and intracerebral hemorrhage due to small vessel disease (SVD), are presumably associated with a high risk of vascular cognitive impairment and stroke. We previously reported that Streptococcus mutans (S. mutans, the main pathogen of dental caries), harboring the cnm gene that encodes the collagen-binding protein Cnm, is associated with the development of hypertensive intracerebral hemorrhage and aggravation of CMBs. We also proposed a mechanism by which the circulating Cnm-expressing S. mutans causes intracerebral hemorrhage or CMBs; it binds to denuded basement membranes mainly composed of collagen IV through damaged tight junctions or it directly invades endothelial cells, resulting in blood-brain barrier injury. In November 2018, we initiated a multicenter, prospective cohort study (RAMESSES: Risk Assessment of Cnm-positive S. mutans in Stroke Survivors; UMIN Clinical Trials Registry: UMIN000045559) to explore the longitudinal association between Cnm-positive S. mutans and CMBs with comprehensive dental findings, which should determine the effect of Cnm-positive S. mutans in the oral cavity on the risk of CMB development and cognitive decline. Methods: Fifteen domestic institutes will be enlisted to enroll 230 patients who have at least one CMB in the deep brain area and develop a stroke within the past year. The prevalence of Cnm-positive S. mutans based on oral specimens and dental hygiene will be examined. The primary outcome is the number of newly developed deep CMBs. The secondary outcomes include the new development of lobar, subtentorial, or any type of CMBs; symptomatic intracerebral hemorrhage or ischemic stroke; changes in cognitive function or frailty; major bleeding; all-cause mortality; and antibody titers against periodontal pathogens. The observation period will be 2 years. Discussion: The 2-year longitudinal prospective cohort study is expected to establish the role of Cnm-positive S. mutans in SVD including CMBs and intracerebral hemorrhage from the perspective of the "brain-oral axis" and provide guidance for novel prophylactic strategies against Cnm-positive S. mutans-induced SVD.