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Vertical "half-and-half" syndrome, characterized by contralateral upward and ipsilateral downward gaze palsy, is a rare variant of vertical eye movement disturbance. Similarly, pseudoabducens palsy, manifesting as abductive palsy despite no lesion to the pons, constitutes another rare type of eye movement disturbance. Both conditions have been associated with lesions in the thalamo-mesencephalic junction. We present a rare case report detailing a patient exhibiting vertical "half-and-half" syndrome with ipsilateral pseudoabducens palsy following a left lacunar infarction of the thalamo-mesencephalic junction. Additionally, we discuss the potential underlying mechanisms contributing to this rare combination of eye movement disorders., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Myasthenic crisis (MC) is a life-threatening complication of myasthenia gravis (MG), necessitating ventilation. Achieving a safe and timely diagnosis of myasthenic crisis with atypical, isolated presentation is a considerable challenge particularly in elderly patients, where myasthenia gravis can present with isolated dysarthria in rare instances, giving a clinical impression of lacunar stroke., Case Presentation: We present a compelling case of a 73-year-old Caucasian female presenting with abrupt onset of isolated dysarthria. Despite initial treatment for a presumed lacunar stroke, subsequent evaluations led to her diagnosis of a myasthenic crisis. Within 72 h of admission, the patient developed dysphagia and shortness of breath, requiring supplemental oxygen. The case highlights the sequential progression of events from the atypical presentation of isolated dysarthria and its course to the management of a myasthenic crisis., Conclusion: Our reported case focuses on the discussion of myasthenia that mimicked a lacunar stroke and was finally diagnosed at a critical time of medical crisis. This case highlights the imperative notion that isolated dysarthria in elderly individuals warrants vigilant monitoring for possible myasthenia gravis, given the low incidence of lacunar stroke presenting with only dysarthria., (© 2024. The Author(s).)

Background: The importance of thromboembolism in the pathogenesis of lacunar stroke (LS), resulting from cerebral small vessel disease (cSVD), is debated, and although antiplatelets are widely used in secondary prevention after LS, there is limited trial evidence from well-subtyped patients to support this approach. We sought to evaluate whether altered anticoagulation plays a causal role in LS and cSVD using 2-sample Mendelian randomization., Methods: From a recent genome-wide association study (n=81 190), we used 119 genetic variants associated with venous thrombosis at genome-wide significance ( P <5*10 -8 ) and with a linkage disequilibrium r 2 <0.001 as instrumental variables. We also used genetic associations with stroke from the GIGASTROKE consortium (62 100 ischemic stroke cases: 10 804 cardioembolic stroke, 6399 large-artery stroke, and 6811 LS). In view of the lower specificity for LS with the CT-based phenotyping mainly used in GIGASTROKE, we also used data from patients with magnetic resonance imaging-confirmed LS (n=3199). We also investigated associations with more chronic magnetic resonance imaging features of cSVD, namely, white matter hyperintensities (n=37 355) and diffusion tensor imaging metrics (n=36 533)., Results: Mendelian randomization analyses showed that genetic predisposition to venous thrombosis was associated with an increased odds of any ischemic stroke (odds ratio [OR], 1.19 [95% CI, 1.13-1.26]), cardioembolic stroke (OR, 1.32 [95% CI, 1.21-1.45]), and large-artery stroke (OR, 1.41 [95% CI, 1.26-1.57]) but not with LS (OR, 1.07 [95% CI, 0.99-1.17]) in GIGASTROKE. Similar results were found for magnetic resonance imaging-confirmed LS (OR, 0.94 [95% CI, 0.81-1.09]). Genetically predicted risk of venous thrombosis was not associated with imaging markers of cSVD., Conclusions: These findings suggest that altered thrombosis plays a role in the risk of cardioembolic and large-artery stroke but is not a causal risk factor for LS or imaging markers of cSVD. This raises the possibility that antithrombotic medication may be less effective in cSVD and underscores the necessity for further trials in well-subtyped cohorts with LS to evaluate the efficacy of different antithrombotic regimens in LS., Competing Interests: Disclosures None.

A 70-year-old right-handed housewife suffered an acute loss of taste, an unpleasant change in the taste of foods and liquids, and a strong aversion to all kinds of food due to a small lacune in the right dorsomedial pontine tegmentum. Eating became so unpleasant that she lost 7 kg in three weeks. Olfaction and the sensibility of the tongue were spared. The right medial longitudinal fascicle, the central tegmental tract, or both, were injured by the tegmental lesion. A discrete right-sided lesion in the upper pontine tegmentum may cause a reversible syndrome consisting of bilateral hypogeusia which is more severe ipsilaterally.

Background: Recent studies, using diffusion tensor image analysis along the perivascular space (DTI-ALPS), suggest impaired perivascular space (PVS) function in cerebral small vessel disease, but they were cross-sectional, making inferences on causality difficult. We determined associations between impaired PVS, measured using DTI-ALPS and PVS volume, and cognition and incident dementia., Methods: In patients with lacunar stroke and confluent white matter hyperintensities, without dementia at baseline, recruited prospectively in a single center, magnetic resonance imaging was performed annually for 3 years, and cognitive assessments, including global, memory, executive function, and processing speed, were performed annually for 5 years. We determined associations between DTI-ALPS and PVS volume with cerebral small vessel disease imaging markers (white matter hyperintensity volume, lacunes, and microbleeds) at baseline and with changes in imaging markers. We determined whether DTI-ALPS and PVS volume at baseline and change over 3 years predicted incident dementia. Analyses were controlled for conventional diffusion tensor image metrics using 2 markers (median mean diffusivity [MD] and peak width of skeletonized MD) and adjusted for age, sex, and vascular risk factors., Results: A total of 120 patients, mean age 70.0 years and 65.0% male, were included. DTI-ALPS declined over 3 years, while no change in PVS volume was found. Neither DTI-ALPS nor PVS volume was associated with cerebral small vessel disease imaging marker progression. Baseline DTI-ALPS was associated with changes in global cognition (β=0.142, P =0.032), executive function (β=0.287, P =0.027), and long-term memory (β=0.228, P =0.027). Higher DTI-ALPS at baseline predicted a lower risk of dementia (hazard ratio, 0.328 [0.183-0.588]; P <0.001), and this remained significant after including median MD as a covariate (hazard ratio, 0.290 [0.139-0.602]; P <0.001). Change in DTI-ALPS predicted dementia conversion (hazard ratio, 0.630 [0.428-0.964]; P =0.048), but when peak width of skeletonized MD and median MD were entered as covariates, the association was not significant. There was no association between baseline PVS volume, or PVS change over 3 years, and conversion to dementia., Conclusions: DTI-ALPS predicts future dementia risk in patients with lacunar strokes and confluent white matter hyperintensities. However, the weakening of the association between change in DTI-ALPS and incident dementia after controlling for peak width of skeletonized MD and median MD suggests part of the signal may represent conventional diffusion tensor image metrics. PVS volume is not a predictor of future dementia risk., Competing Interests: Disclosures Dr Tozer was funded by the Medical Research Council. H.S. Markus discloses grant support from the British Heart Foundation. The other author reports no conflict.

Introduction: Posterior reversible encephalopathy syndrome (PRES) is a rare and complex disorder with variable clinical presentation and a typical magnetic resonance imaging (MRI) pattern of vasogenic edema with typical and atypical locations. It is often triggered by other diseases and drugs and the most prototypical association is with persistently elevated arterial pressure values. Among the potential cerebrovascular complications, intracranial bleeding has been described, but ischemic stroke is uncommonly reported., Methods: We are presenting a case of a male patient with prolonged and sustained arterial hypertension acutely presenting with lacunar ischemic stroke involving the right corona radiata and composite MRI findings with the association of chronic small vessel disease (SVD) markers, acute symptomatic lacunar stroke, and atypical, central variant, posterior fossa dominant PRES. In the MRI follow-up, the white matter hyperintensities in T2-fluid attenuated inversion recovery (FLAIR sequences) due to PRES., Discussion: The pathophysiology of PRES is not yet fully known, but the association with markedly increased values of arterial pressure is typical. In this context, ischemic stroke has not been considered in the clinical and neuroradiological manifestations of PRES and it has been only occasionally reported in the literature. In this case, the main hypothesis is that sustained hypertension may have triggered both manifestations, PRES, and ischemic stroke and the last one allowed to diagnose the first one., Conclusions: Atypical variants of PRES are not so rare and it may also occur in typical triggering situations. The association with ischemic stroke is even rarer and it may add some clues to the pathomechanisms of PRES., (© 2023. Fondazione Società Italiana di Neurologia.)

Objective: Genome-wide association studies have identified 1q22 as a susceptibility locus for cerebral small vessel diseases, including non-lobar intracerebral hemorrhage (ICH) and lacunar stroke. In the present study, we performed targeted high-depth sequencing of 1q22 in ICH cases and controls to further characterize this locus and prioritize potential causal mechanisms, which remain unknown., Methods: A total of 95,000 base pairs spanning 1q22, including SEMA4A, SLC25A44, and PMF1/PMF1-BGLAP were sequenced in 1,055 spontaneous ICH cases (534 lobar and 521 non-lobar) and 1,078 controls. Firth regression and Rare Variant Influential Filtering Tool analysis were used to analyze common and rare variants, respectively. Chromatin interaction analyses were performed using Hi-C, chromatin immunoprecipitation followed by sequencing, and chromatin interaction analysis with paired-end tag databases. Multivariable Mendelian randomization assessed whether alterations in gene-specific expression relative to regionally co-expressed genes at 1q22 could be causally related to ICH risk., Results: Common and rare variant analyses prioritized variants in SEMA4A 5'-UTR and PMF1 intronic regions, overlapping with active promoter and enhancer regions based on ENCODE annotation. Hi-C data analysis determined that 1q22 is spatially organized in a single chromatin loop, and that the genes therein belong to the same topologically associating domain. Chromatin immunoprecipitation followed by sequencing and chromatin interaction analysis with paired-end tag data analysis highlighted the presence of long-range interactions between the SEMA4A-promoter and PMF1-enhancer regions prioritized by association testing. Multivariable Mendelian randomization analyses demonstrated that PMF1 overexpression could be causally related to non-lobar ICH risk., Interpretation: Altered promoter-enhancer interactions leading to PMF1 overexpression, potentially dysregulating polyamine catabolism, could explain demonstrated associations with non-lobar ICH risk at 1q22, offering a potential new target for prevention of ICH and cerebral small vessel disease. ANN NEUROL 2024;95:325-337., (© 2023 American Neurological Association.)

Background: Previous observational studies reported that a lower serum 25-hydroxyvitamin D [25(OH)D] concentration is associated with a higher burden of cerebral small vessel disease (cSVD). The causality of this association is uncertain, but it would be clinically important, given that 25(OH)D can be a target for intervention. We tried to examine the causal effect of 25(OH)D concentration on cSVD-related phenotypes using a Mendelian randomization approach., Methods: Genetic instruments for each serum 25(OH)D concentration and cSVD-related phenotypes (lacunar stroke, white matter hyperintensity, cerebral microbleeds, and perivascular spaces) were derived from large-scale genome-wide association studies. We performed 2-sample Mendelian randomization analyses with multiple post hoc sensitivity analyses. A bidirectional Mendelian randomization approach was also used to explore the possibility of reverse causation., Results: We failed to find any significant causal effect of 25(OH)D concentration on cSVD-related phenotypes (odds ratio [95% CI], 1.00 [0.87-1.16], 1.01 [0.96-1.07], 1.06 [0.85-1.33], 1.00 [0.97-1.03], 1.02 [0.99-1.04], 1.01 [0.99-1.04] for lacunar stroke, white matter hyperintensity, cerebral microbleeds, and white matter, basal ganglia, hippocampal perivascular spaces, respectively). These results were reproduced in the sensitivity analyses accounting for genetic pleiotropy. Conversely, when we examined the effects of cSVD phenotypes on 25(OH)D concentration, cerebral microbleeds were negatively associated with 25(OH)D concentration (0.94 [0.92-0.96])., Conclusions: Given the adequate statistical power (>0.8) of the analyses, our findings suggest that the previously reported association between 25(OH)D concentration and cSVD phenotypes might not be causal and partly attributed to reverse causation., Competing Interests: Disclosures None.

Objective: To identify risk factors for early neurological deterioration (END) in acute lacunar stroke patients and its influence on functional outcome., Methods: Consecutive acute lacunar stroke patients defined by magnetic resonance imaging (MRI) between January 2018 and June 2020 were included in the study. END was defined as any persisting increase in National Institutes of Health Stroke Scale (NIHSS) score of ⩾ 2 points post admission, and favorable outcome was defined as a modified Rankin Scale (mRS) of 0-2 at discharge. Univariable and multivariable logistic regression were performed to identify risk factors related to END, as well as the influence of END on functional outcome., Results: Among a total of 638 lacunar stroke patients (420 males (65.8%), median age 66 years (interquartile range (IQR): 56-74)), 108 (16.9%) developed END, and 94.4% (102/108) of the END occurred within 72 h post admission. Admission NIHSS score (adjusted odds ratio (aOR) 1.132, 95% confidence interval (CI) 1.046-1.225, p  = 0.002), female (aOR 2.752, 95% CI 1.277-5.933, p  = 0.010), admission systolic blood pressure (SBP) (160-179 mm Hg) (aOR 9.395, 95% CI 4.310-20.479, p  < 0.001) and admission SBP (⩾180 mm Hg) (aOR 16.030, 95% CI 5.991-42.891, p < 0.001) were significantly associated with END. Delay time from onset to admission (aOR 0.995, 95% CI 0.990-1.000, p  = 0.031), SBP dropping (⩾20 mm Hg) within 3 days or when END occurred (aOR 0.037, 95% CI 0.016-0.086, p  < 0.001) and thalamic lacunar infarction (aOR 0.098, 95% CI 0.012-0.827, p  = 0.033) were inversely associated with END. END (aOR 12.374, 95% CI 6.881-22.254, p  < 0.001) and higher admission NIHSS score (aOR 1.488, 95% CI 1.359-1.629, p  < 0.001) predicted unfavorable outcome at discharge., Conclusion: END in lacunar stroke patients is common and is associated with unfavorable outcome. Admission high SBP is a potentially modifiable risk factor for prevention of END, but this needs further investigation.

Background: Coronary heart disease (CHD) and lacunar infarction (LI) are the most common cardio- cerebrovascular complications of type 2 diabetes mellitus (T2DM) and a recognized risk factor for renal injury. Although a unidirectional association of CHD or LI with T2DM or the kidney has been demonstrated, however, it remains unknown whether there is an interactive effect of the coexistence of CHD and LI on renal function in T2DM patients. The aim of our study was to investigate the interaction between CHD and LI on renal function in gender-specific patients with T2DM and the association between cardio-cerebrovascular disease-related conventional serum markers and the estimated glomerular filtration rate (eGFR)., Methods: We conducted a cross-sectional study in Beijing and Tianjin from April 2019 to August 2021. Participants with T2DM aged ≥18 years were asked to complete a one-to-one questionnaire and physical examination., Results: In this study, 389 eligible patients with T2DM were included, with a mean age of 63.04 ± 9.41 years, of whom 200 (51.41 %) were male. The proportions of patients with CHD, LI, and both CHD and LI were 28.53 %, 24.42 %, and 11.05 %, respectively. Compared to T2DM patients without either CHD or LI, those with both CHD and LI were found to have a significantly greater risk of reduced eGFR (OR: 12.82, 95 % CI 5.06-32.52, P < 0.001) than those with CHD alone (OR: 2.42, 95 % CI 1.37-3.00, P = 0.004) or LI alone (OR: 1.15, 95 % CI 0.61-2.18, P = 0.664). The combined presence of CHD and LI is associated with a significantly greater risk of decreased eGFR in female T2DM patients compared to their male counterparts. We found both multiplicative and additive effects in all T2DM patients; however, when stratified by sex, only multiplicative effects were observed. After controlling for interference from CHD, LI, and age, we found that total cholesterol (TC) was negatively correlated with eGFR in females (r = -0.156, P = 0.034), and low-density lipoprotein cholesterol (LDL-C) was negatively correlated with eGFR in males (r = -0.229, P = 0.001)., Conclusion: This study provides novel evidence that the synergistic effect of CHD and LI on renal injury in patients with T2DM is significantly greater than their individual effects. Women with T2DM who have both CHD and LI are at a 4.85-fold higher risk of decreased eGFR than men. Therefore, increased clinical attention should be given to preventing and treating vascular complications in T2DM patients, as well as aggressively reducing lipid levels, particularly TC and LDL-C, to delay or prevent renal dysfunction in T2DM patients., Competing Interests: Conflict of interest All authors have no conflict of interest of any kind., (Copyright © 2023. Published by Elsevier Inc.)

Hypertension is the most important risk factor for cerebral small vessel disease (SVD). In this cross-sectional study, we tested the independent association of cerebral SVD burden with global cognitive function and each cognitive domain in patients with vascular risk factors. The Tokyo Women's Medical University Cerebral Vessel Disease (TWMU CVD) registry is an ongoing prospective, observational registry in which patients with any evidence of CVD in magnetic resonance imaging (MRI) and at least one vascular risk factor were consecutively enrolled. For SVD-related findings, we evaluated white matter hyperintensity, lacunar infarction, cerebral microbleeds, enlarged perivascular space, and medial temporal atrophy. We used the total SVD score as the SVD burden. They underwent the Mini-mental State Examination (MMSE) and Japanese version of the Montreal Cognitive Assessment (MoCA-J) global cognitive tests, and each cognitive domain was evaluated. After excluding patients without MRI T2* images and those with MMSE score <24, we analyzed 648 patients. The total SVD score was significantly associated with MMSE and MoCA-J scores. After adjustment for age, sex, education, risk factors, and medial temporal atrophy, the association between the total SVD score and MoCA-J score remained significant. The total SVD score was independently associated with attention. In conclusion, the total SVD score, cerebral SVD burden, was independently association with global cognitive function and attention. A strategy to reduce SVD burden will have the potential to prevent cognitive decline. A total of 648 patients with any evidence of cerebral small vessel disease (SVD) in MRI and at least one vascular risk factor underwent Mini-mental State Examination (MMSE) and Japanese version of the Montreal Cognitive Assessment (MoCA-J) global cognitive tests. The total SVD scores count the presence of each SVD-related findings (white matter hyperintensity, Lacunar infarction, cerebral microbleeds and enlarged perivascular space), ranging from 0 to 4, as the SVD burden. Total SVD scores were significantly associated with MoCA-J scores (r = -0.203, P < 0.001). After adjustment for age, sex, education, risk factors, and medial temporal atrophy, the association between the total SVD score and global cognitive scores remained significant., (© 2023. The Author(s), under exclusive licence to The Japanese Society of Hypertension.)

Purpose: Sarcopenia is associated with poor outcomes, and evidence suggests an inverse relationship between skeletal muscle mass and cardiovascular risk. Sarcopenia has been studied after stroke, but its value as a risk factor for stroke has not been examined. This prospective cohort study measured sarcopenia in stroke/TIA patients at baseline to explore its role in predicting recurrent events., Method: The Arterial Stiffness In lacunar Stroke and TIA (ASIST) study included 96 patients with TIA/lacunar stroke, of which 82 patients (mean age 71.2±10.8 years) had bioimpedance analysis to assess body composition. Skeletal Mass Index (SMI) was calculated and parameters of sarcopenia assessed using Davison (1) and Janssen (2) criteria. Recurrent cerebrovascular events were monitored over 5 years., Results: Eighteen patients had recurrent events. On independent samples t test there were significantly more participants with sarcopenia in the recurrent events group (89% vs 56%, p<0.001) using Davison (1) criteria, as well as lower mean SMI, significantly more participants with diabetes and higher arterial stiffness. On binary logistic regression, the only significant predictors of recurrent events were SMI (p=0.036, hazard ratio=0.414, 95% confidence interval 0.195-0.948) and diabetes (p=0.004, hazard ratio=9.06, 95% confidence interval 2.009-40.860) when corrected for age, sex and cardiovascular risk factors. Using Janssen (2) criteria in the regression, severe sarcopenia was a significant predictor of recurrent events (p=0.028). There was a significant association between sarcopenia and recurrent events on Chi square based on Davison (p=0.02) and Janssen (p=0.034) definitions., Conclusions: The presence of baseline sarcopenia in stroke and TIA patients is an independent predictor of recurrent events., Competing Interests: Declarations of Competing Interest None We certify that this work is A) novel. We believe this is the first study to investigate the relationship of baseline to sarcopenia to recurrent events in stroke and TIA patients., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background and Purpose: Intracranial carotid artery calcifications (ICACs) are a common finding on noncontrast computed tomography (NCCT) and have been associated with an increased risk of ischemic stroke. However, no data are available about the association between ICAC patterns and stroke etiology. We investigated the association between ICAC patterns and etiological subtypes of ischemic stroke., Methods: We retrospectively analyzed a single center cohort of patients admitted for ischemic stroke with known etiology. Each carotid artery was evaluated separately on NCCT scans to define the ICAC pattern (intimal, medial, mixed). The association between ICAC patterns and stroke etiology was investigated using logistic regression models adjusting for relevant confounders., Results: A total of 485 patients were included (median age = 78 [interquartile range (IQR) = 70-85] years, 243 [50%] female, median National Institutes of Health Stroke Scale = 6 [IQR = 3-12]). Frequencies of ICAC patterns were: intimal, n = 96 (20%); medial, n = 273 (56%); mixed, n = 51 (11%), indistinct/absent, n = 65 (13%) patients. Intimal pattern was more frequent in lacunar compared with nonlacunar (33% vs. 16%, p < 0.001) stroke etiology, whereas medial pattern was less frequent in lacunar compared with nonlacunar stroke (36% vs. 62%, p < 0.001). After adjustment for confounders, intimal ICAC predominant pattern remained associated with lacunar stroke etiology in two multivariate models (Model 1: adjusted odds ratio [aOR] = 2.08, 95% confidence interval [CI] = 1.20-3.56; Model 2: aOR = 2.01, 95% CI = 1.16-3.46)., Conclusions: Our study suggests that intimal ICAC pattern is associated with lacunar stroke and may serve as a marker for lacunar stroke etiology, possibly strengthening the relation between endothelial dysfunction and lacunar stroke., (© 2023 European Academy of Neurology.)

Background: Cerebral small vessel disease (CSVD) is a systemic disease, affecting not only the brain, but also eyes and other organs. The total CSVD score is a tool for comprehensive evaluation of brain lesions in patients with CSVD. The ophthalmic artery (OA) is a direct response to ocular blood flow. However, little is known about the correlation between CSVD and characteristics of OA. We investigated the OA morphologies and hemodynamics in patients with CSVD and the correlation between these changes and the total CSVD score., Methods: This cross-sectional observational study included 34 eyes from 22 patients with CSVD and 10 eyes from 5 healthy controls. The total CSVD score was rated according to the CSVD signs on magnetic resonance imaging. OA morphological characteristics were measured on the basis of 3D OA model reconstruction. OA hemodynamic information was calculated using computational fluid dynamics simulations., Results: The total CSVD score negatively correlated with the OA diameter, blood flow velocity, and mass flow ratio (all P < 0.05). After adjusting for potential confounding factors, the total CSVD score was still independently correlated with the OA blood velocity (β = - 0.202, P = 0.005). The total CSVD score was not correlated with OA angle (P > 0.05). The presence of cerebral microbleeds and enlarged perivascular spaces was correlated with the OA diameter (both P < 0.01), while the lacunar infarcts and white matter hyperintensities were correlated with the OA blood velocity (both P < 0.001)., Conclusions: The decrease of the blood velocity in the OA was associated with the increase in the total CSVD score. The changes of the OA diameter and velocity were associated with the presence of various CSVD signs. The findings suggest that more studies are needed in the future to evaluate CSVD by observing the morphologies and hemodynamics of OA., (© 2023. The Author(s).)

Background: Small vessel disease (SVD) is associated with vascular cognitive impairment (VCI) but why VCI occurs in some, but not other patients, is uncertain. We determined the prevalence of, and risk factors for, VCI in a large cohort of patients with lacunar stroke., Methods: Participants with magnetic resonance imaging (MRI)-confirmed lacunar stroke were recruited in the multicenter DNA Lacunar 2 study and compared with healthy controls. A logistic regression model was used to determine which vascular risk factors and MRI parameters were independent predictors of VCI, assessed using the Brief Memory and Executive Test (BMET)., Results: A total of 912 lacunar stroke patients and 425 controls were included, with mean ( SD ) age of 64.6 (12.26) and 64.7 (12.29) years, respectively. VCI was detected in 38.8% lacunar patients and 13.4% controls. In a logistic regression model, diabetes mellitus (odds ratio (OR) = 1.98 (95% confidence interval (CI) = 1.40-2.80), p  < 0.001) and higher body mass index (BMI) (OR = 1.03 (95% CI = 1.00-1.05), p  = 0.029) were independently associated with increased risk of VCI, and years of full-time education with lower risk (OR = 0.92 (95% CI = 0.86-0.99), p  = 0.018). When entering both lacune count and white matter hyperintensity (WMH) in the same logistic regression model, only WMH grade was significantly associated with VCI (OR = 1.46 (95% CI = 1.24-1.72), p  < 0.001)., Conclusion: VCI is common in lacunar stroke patients, affecting almost 40%. This prevalence suggests that it should be routinely screened for in clinical practice. Risk factors for VCI in patients with lacunar stroke include diabetes mellitus, depressive symptoms, higher BMI, and WMH severity, while education is protective.

Introduction: Transient ischaemic attack (TIA) has classically been defined as an episode of self-limited focal neurological deficit lasting up to 24 hours, with no neuroimaging evidence of established acute ischaemic injury. However, the definition of this entity is changing, and is adapting to new times and new diagnostic techniques, including magnetic resonance imaging (MRI) with diffusion sequences. An early and comprehensive approach to TIA, including MRI, is important to rule out clinically recovered established ischaemic strokes, in order to optimise the diagnostic and therapeutic management of patients., Patients and Methods: Patients admitted to our stroke unit over a six-month period with suspected TIA were identified, and the definitive diagnosis and approach was studied based on the tests performed., Results: A sample of 106 suspected cases of TIA were studied, in which early MRI was performed. Of these, 42 (39.62%) were clinically recovered ischaemic strokes (CRIS); 32 (30.18%), other pathologies (six epileptic seizures, five migraine auras, nine functional disorders, two amyloid spells and nine other causes, totalling 31); 26 (24.52%), TIAs; and six (5.66%), haemorrhagic stroke. Of 43 CRIS, eight (18.6%) were cardioembolic; eight (18.6%), atherothrombotic; eight (18.6%), embolic stroke of unknown origin; six (13.95%), lacunar stroke; five (11.62%) of infrequent cause; and four (9.3%), totalling 39, of undetermined cause. CRIS patients received significantly more individualised therapeutic management than TIA patients., Conclusions: The early use of MRI in the clinical suspicion of TIA makes it possible to gather evidence of CRIS and optimises the diagnostic and therapeutic approach for patients.

Background: Cerebral small vessel disease (SVD) is common in older people and causes lacunar stroke and vascular cognitive impairment. Risk factors include old age, hypertension and variants in the genes COL4A1/COL4A2 encoding collagen alpha-1(IV) and alpha-2(IV), here termed collagen-IV, which are core components of the basement membrane. We tested the hypothesis that increased vascular collagen-IV associates with clinical hypertension and with SVD in older persons and with chronic hypertension in young and aged primates and genetically hypertensive rats., Methods: We quantified vascular collagen-IV immunolabeling in small arteries in a cohort of older persons with minimal Alzheimer pathology (N=52; 21F/31M, age 82.8±6.95 years). We also studied archive tissue from young (age range 6.2-8.3 years) and older (17.0-22.7 years) primates ( M mulatta ) and compared chronically hypertensive animals (18 months aortic stenosis) with normotensives. We also compared genetically hypertensive and normotensive rats (aged 10-12 months)., Results: Collagen-IV immunolabeling in cerebral small arteries of older persons was negatively associated with radiological SVD severity (ρ: -0.427, P =0.005) but was not related to history of hypertension. General linear models confirmed the negative association of lower collagen-IV with radiological SVD ( P <0.017), including age as a covariate and either clinical hypertension ( P <0.030) or neuropathological SVD diagnosis ( P <0.022) as fixed factors. Reduced vascular collagen-IV was accompanied by accumulation of fibrillar collagens (types I and III) as indicated by immunogold electron microscopy. In young and aged primates, brain collagen-IV was elevated in older normotensive relative to young normotensive animals ( P =0.029) but was not associated with hypertension. Genetically hypertensive rats did not differ from normotensive rats in terms of arterial collagen-IV., Conclusions: Our cross-species data provide novel insight into sporadic SVD pathogenesis, supporting insufficient (rather than excessive) arterial collagen-IV in SVD, accompanied by matrix remodeling with elevated fibrillar collagen deposition. They also indicate that hypertension, a major risk factor for SVD, does not act by causing accumulation of brain vascular collagen-IV.

Background: The association between frailty and cerebral small vessel disease (CSVD) remains controversial due to the use of different methods to assess frailty, including physical frailty phenotype and frailty scores containing measures of cognition. A frailty index based on laboratory tests (FI-Lab), which assesses frailty by the combination of routine laboratory measures and several vital signs, is independent of cognition and function status. We aimed to evaluate the association of FI-Lab with CSVD., Methods: An observational study was carried out in a hospitalized cohort of older patients with minor ischemic stroke or TIA. The FI-Lab was constructed by 20 routine laboratory tests, plus systolic blood pressure, diastolic blood pressure, and pulse pressure. Manifestations of CSVD including white matter hyperintensity (WMH), silent lacunar infarcts, microbleed, enlarged perivascular spaces (EPVS), as well as deep brain atrophy, were measured on magnetic resonance imaging (MRI). An ordinal score system constructed by WMH, EPVS, silent lacunar infarcts, and microbleed was used to reflect the total burden of CSVD. The associations between FI-lab and CSVD were examined by logistic regression analysis and ordinal regression., Results: A total of 398 patients were recruited from January 2016 to December 2018. The mean FI-Lab value was 0.26 ± 0.11. The prevalence of extensive periventricular WMH, extensive deep WMH, extensive basal ganglia EPVS, extensive centrum semiovale EPVS, silent lacunar infarcts, and deep microbleed was 26.1, 66.6, 68.6, 80.7, 32.9, and 6.5%, respectively. A higher FI-Lab value was associated with increased risks of extensive deep WMH (OR = 1.622; 95% CI, 1.253 ~ 2.100), extensive basal ganglia EPVS (OR = 1.535; 95% CI, 1.187 ~ 1.985), extensive centrum semiovale EPVS (OR = 1.584; 95% CI, 1.167 ~ 2.151), silent lacunar infarcts (OR = 1.273; 95% CI, 1.007 ~ 1.608), and higher total burden of CSVD. These associations remained after the adjustment of potential confounding factors., Conclusion: This study demonstrated that a higher FI-Lab score might be associated with the presence of WMH, EPVS, silent lacunar infarcts, as well as severe total CSVD burden in older patients with minor stroke or TIA. The FI-Lab provides a basis for the prediction of CSVD., (© 2022. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Little is known about the relationship between baseline systolic blood pressure (SBP) and subsequent clinical events in patients with different lesion patterns on diffusion weighted imaging (DWI). We analyzed the Acute Non-disabling Cerebrovascular Events (CHANCE) trial dataset. Patients were categorized into negative DW imaging (no detectable lesions), lacunar infarction (single lesion ≤15 mm) and non-lacunar infarction (single lesion >15 mm or multiple lesions) based on lesion patterns on DWI. The primary outcome was recurrent stroke within 90 days. Cox proportional hazards models were used to assess the association between SBP levels and stroke outcomes in patients with different lesion patterns. A total of 1089 patients were analyzed. We found 258 cases (23.7%) with negative DW imaging, 392 (36.0%) with lacunar infarction and 439 (40.3%) with non-lacunar infarction. Patients with non-lacunar infarction had the highest incidence of stroke at 90-day (P < .001). In non-lacunar infarction group, compared with SBP < 160 mmHg, patients with SBP ≥ 160 mmHg had significantly higher risk of 90-day recurrent stroke (20.3% vs. 10.7%; adjusted hazard ratio 1.81, 95% confidence interval 1.09-3.00). No significant association was found between SBP and clinical outcomes in patients with negative DWI and lacunar stroke groups. The result at 1 year was similar as at 90-day. Therefore, non-lacunar infarction, the most common lesion pattern in CHANCE study, had the highest risk of recurrent stroke and combined vascular events both in 90 days and 1 year. High baseline SBP was significantly associated with increased risk of short- and long-term recurrent strokes in patients with non-lacunar infarction., (© 2022 The Authors. The Journal of Clinical Hypertension published by Wiley Periodicals LLC.)

Background and Objectives: Although enlarged perivascular spaces (EPVS) have been suggested as an emerging measure of small vessel disease (SVD) in the brain, their association with cognitive impairment is not yet clearly understood. We aimed to examine the relationship between each EPVS in the basal ganglia (BG-EPVS) and centrum semiovale (CSO-EPVS) with cognition in a memory clinic population., Methods: Participants with a diverse cognitive spectrum were recruited from a university hospital memory clinic. They underwent comprehensive clinical and neuropsychological assessments and brain MRI. BG-EPVS and CSO-EPVS were measured on T2-weighted MRI and then dichotomized into low and high degrees for further analyses. Other SVD markers were assessed using validated rating scales., Results: A total of 910 participants were included in this study. A high degree of BG-EPVS was significantly associated with poorer scores on the executive function domain, but not with other cognitive domains, when age, sex, education, MRI scanner type, and cognitive diagnosis were controlled as covariates. However, the association between BG-EPVS and executive function was no longer significant after controlling for other markers of SVD, such as lacunar infarcts and periventricular white matter hyperintensities, as additional covariates. CSO-EPVS did not have a significant relationship with any cognitive scores, regardless of the covariates., Discussion: Our findings from a large memory clinic population suggest that EPVS, regardless of the topographical location, may not be used as a specific SVD marker for cognitive impairment, although an apparent association was observed between a high degree of BG-EPVS and executive dysfunction before controlling other SVD markers that share a common pathophysiologic process with BG-EPVS., (© 2022 American Academy of Neurology.)

Purpose: To report a case of Paracentral acute middle maculopathy (PAMM) caused by severe internal carotid artery (ICA) stenosis and discuss the correlation between PAMM and ICA stenosis., Case Description: A 67-year-old male patient presented with left acute blurred vision for 1 week. The best-corrected visual acuity of the left eye was 0.01. Funduscopic examination showed multiple grayish patches around the left macula. Optical coherence tomography (OCT) demonstrated train-track hyperreflective lesions over the inner nuclear layer of the left eye. Afterwards, he experienced sudden slurred speech with fair comprehension. Magnetic resonance imaging and angiography of the brain demonstrated left lacunar infarction with severe left ICA stenosis. After anticoagulant therapy, his dysarthria and left visual acuity were improved significantly., Conclusions: To our knowledge, PAMM in coincidence with lacunar infarction induced by ICA stenosis is firstly described in the literature. PAMM could be a critical warning of ICA stenosis, and this case can alert ophthalmologists to survey ICA stenosis in patients with PAMM.

Background: Previous genome-wide association studies (GWAS) have identified numerous risk genes for lacunar stroke, but it is challenging to decipher how they confer risk for the disease. We employed an integrative analytical pipeline to efficiently transform genetic associations to identify novel proteins for lacunar stroke., Methods: We systematically integrated lacunar stroke genome-wide association study (GWAS) (N=7338) with human brain proteomes (N=376) to perform proteome-wide association studies (PWAS), Mendelian randomization (MR), and Bayesian colocalization. We also used an independent human brain proteomic dataset (N=152) to annotate the new genes., Results: We found that the protein abundance of seven genes (ICA1L, CAND2, ALDH2, MADD, MRVI1, CSPG4, and PTPN11) in the brain was associated with lacunar stroke. These seven genes were mainly expressed on the surface of glutamatergic neurons, GABAergic neurons, and astrocytes. Three genes (ICA1L, CAND2, ALDH2) were causal in lacunar stroke (P < 0.05/proteins identified for PWAS; posterior probability of hypothesis 4 ≥ 75 % for Bayesian colocalization), and they were linked with lacunar stroke in confirmatory PWAS and independent MR. We also found that ICA1L is related to lacunar stroke at the brain transcriptome level., Conclusions: Our present proteomic findings have identified ICA1L, CAND2, and ALDH2 as compelling genes that may give key hints for future functional research and possible therapeutic targets for lacunar stroke., (© 2022. The Author(s).)

We investigated the pathogenic relationship between cerebral microbleeds and lacunar strokes. Two cases of lacunar strokes in the region of the basal ganglia, a 72-year-old man and a 67-year-old man, were studied; both cases showed cerebral microbleeds in the stroke areas. The cerebral microbleeds were surrounded by oedema, and the oedema faded out over time, suggesting the cerebral microbleeds had developed acutely. The cerebral microbleeds were located at the ventrolateral edge of the lacunar infarctions, and the locations appeared to be at or near the sites of occlusion of the lenticulostriatal branches. Although a cerebral microbleed and a lacunar infarction may be two unrelated events on juxtapositioned vessels, or a cerebral microbleed may be haemorrhagic conversion of an infarction, a cerebral microbleed could cause an occlusion of the arterial branch, leading to lacunar infarction of its supplying territories.

This paper explores the diagnostic value of Hcy combined with the blood pressure variability index in the severity of hypertension complicated with CSVD and its correlation with cognitive function and CysC expression. 200 patients with ischemic small cerebral vessels are selected as the research object. According to the MRI findings, they are divided into 48 cases of white matter lesions (WML), 44 cases of lacunar infarction (LI), 44 cases of enlarged perivascular spaces (EPVs), and 46 cases in the mixed group (referring to two or more types of ischemic cerebrovascular disease on imaging). Different cognitive domains of different types of ischemic cerebrovascular diseases are analyzed. The risk factors of cognitive decline in patients with ischemic cerebrovascular disease are analyzed by univariate analysis and multivariate logistic regression analysis. There is an ancestral correlation between serum Hcy and CSVD, which is an independent risk factor for CSVD., Competing Interests: The authors declare that there are no conflicts of interest regarding the publication of this paper., (Copyright © 2022 Qiaoling Liu et al.)

Atherosclerosis is an important risk factor for cognitive decline. This study aimed to investigate the relationship of ankle-brachial pressure index (ABI) and brachial-ankle pulse wave velocity (baPWV) with cognitive function in patients with lacunar infarction. We included records of consecutive patients with their first-ever acute stroke and a diagnosis of lacunar infarction through magnetic resonance imaging (MRI) from July 1, 2011 to December 31, 2018. We excluded patients diagnosed with dementia, including strategic single-infarct dementia, before or after stroke onset. Moreover, we excluded patients with one or more microbleeds, severe white matter lesions, or severe medial temporal atrophy on MRI. For ABI, we used the lower ankle side and divided the results into ABI < 1.0 and ABI ≥ 1.0. For baPWV, we used the higher ankle side and divided the results into two groups based on the median value of the participants. We analyzed 176 patients with stroke (age 72.5 ± 11.4 years, 67 females). The median score on the Mini-Mental State Examination (MMSE) was 27. The number of patients with ABI < 1.0 was 19 (10.8%). Univariate analysis revealed that the MMSE score was associated with age, body mass index, education, chronic kidney disease, periventricular hyperintensity, and ABI < 1.0 (p < 0.10), but not baPWV. Multivariate analysis revealed that body mass index (p = 0.039) and ABI < 1.0 (p = 0.015) were independently associated with the MMSE score. For patients with lacunar infarction, a lower ABI, but not a higher PWV, was associated with cognitive decline., Competing Interests: The authors have declared that no competing interests exist.

Background: Atrial remodeling is associated with future atrial fibrillation (AF) and stroke. AF has been associated with cognitive impairment and cerebral white matter lesions. We wished to investigate the possible direct association between atrial remodeling and cerebrovascular disease in patients with and without AF documented by implantable loop recorder (ILR)., Methods: Cardiac and cerebral magnetic resonance imaging were acquired in a cross-sectional study, including participants ≥70 years of age with stroke risk factors without known AF. Cerebrovascular disease was visually rated using the Fazekas scale and number of lacunar strokes. Left atrial (LA) and ventricular volumes and function were analyzed. Associations between atrial remodeling and cerebrovascular disease were assessed with logistic regression models. The analyses were stratified according to sinus rhythm or any AF during 3 months of continuous ILR monitoring to account for subclinical AF., Results: Of 200 participants investigated, 87% had a Fazekas score ≥1 and 45% had ≥1 lacunar infarct. Within 3 months of ILR monitoring, AF was detected in 28 (14%) participants. For participants with sinus rhythm (n = 172), lower LA passive emptying fraction was associated with Fazekas score after multivariable adjustment (OR [95% CI]: 0.51 [0.27; 0.86] p = 0.02), and increased LA maximum (OR [95% CI]: 1.38 [1.07; 1.82] p = 0.01) and minimum volumes (OR [95% CI]: 1.48 [1.03; 2.17] p = 0.04) were associated with lacunar infarcts. There were no significant associations in patients with AF., Conclusion: In AF-free patients, as documented by ILR monitoring, we found an independent association between LA passive emptying fraction and Fazekas score and between atrial volumes and lacunar infarcts., (© 2021 S. Karger AG, Basel.)

Objective: Cerebral small vessel disease (CSVD) and chronic kidney disease (CKD) may be part of a multisystem small-vessel disorder. Since the kidney and brain share unique susceptibilities to vascular injury, kidney impairment may be predictive of the presence and severity of CSVD. This study explored the relationship between CSVD and CKD. Methods: Between December 2015 and December 2017 (follow-up 10-20 months) 52 patients with chronic nephritis and CKD were classified into a progressive group ( n  = 17) and stable group ( n  = 35). Age, gender, hypertension, diabetes and smoking were matched between groups. CSVD features of both groups, including enlarged Virchow-Robin spaces (VRS), white matter lesions (WML), lacunar infarcts (LI), and cerebral microbleeds (CMB) were evaluated by magnetic resonance (MR) imaging. Results: WML and CMB in the progressive group were exacerbated at follow-up compared to initial exam ( p  = 0.004 and 0.041, respectively). There was no significant change in VRS, WML, LI, or CMB in the stable group at follow-up compared to initial exam. CMB were significantly different between the progressive group and stable group at follow-up.etimtaed Glomerular filtration rate (eGFR) was significantly correlated with VRS, WML, and CMB at follow-up ( p  = 0.037, 0.041, and 0.009, respectively). Conclusions: Patients with progressive CKD have a higher prevalence and severity of CSVD, which correlates with deterioration of renal function as assessed by decreased eGFR. Thus EGFR may also be of value in the prediction of cerebral small vessel disease.

Internuclear Ophthalmoplegia (INO) is an inability of the ipsilateral adduction with a contralateral horizontal abducting saccade on attempted gaze to the contra-lesion side. Injury to the medial longitudinal fasciculus (MLF) will obstruct the signalling pathway between the ipsilateral abducens nucleus and the contralateral medial rectus muscle. Infarction accounts for 38% of INO cases with mostly being unilateral (87%), followed by demyelination (34%), which mostly being bilateral (73%). Lacunar infarct is the most common ischemic stroke. INO can be easily missed due to its subtle presentation with no complaints from the patients. A full cranial nerves assessment, includes the extraocular muscles movement, is important. Ischemic and demyelinating INO typically recover. We present here of a case of INO following right lacunar infarct in a 72-year-old Malay woman. She had hypertensive crisis due to missed medications. Her blood pressure was well controlled throughout the hospital admission and finally she was discharged home with continuation of care at her primary facility.

[Figure: see text].

Background: Lacunar infarction (LI) is the mild type in the classification of ischemic stroke, mostly occurs in the middle-aged and elderly, with mild hemiplegia and partial sensory disorder as the main manifestations. In the treatment of LI, acupuncture is often regarded as dominant therapy in the convalescence period. However, acupuncture for treatment of LI in the recovery period lacks high-quality reports and evidence-based medical evidence. Thus, we aim to evaluate the curative effect and safety of acupuncture for LI objectively., Methods: Pubmed, Cochrane Library, Web of Science, EBSCO, Springer, China National Knowledge Infrastructure, Chinese Scientific and Technical Journals Database (VIP), Wan-fang Database, Chinese Biomedical Literature Database, Chinese Science Citation Database, and other electronic databases will be retrieved from the inception to May, 2021. Randomized controlled trials related to this subject will be searched. The inclusion criteria are established and a detailed literature search strategy is designed through discussion. Article retrieval, screening, excluding repetitive studies, assessment of quality, and data processing will be conducted by 2 reviewers independently using EndNote (X9) and Review Manager (5.3.5). The outcome measures include primary outcome measures (total effective rate, National Institute of Health Stroke Scale score, and Fugl-Meyer Assessment score), secondary outcome measures (blood pressure, plasma glucose, and blood lipid), and safety outcome measures. We will perform a meta-analysis, descriptive analysis, and subgroup analysis based on data conditions., Results: The study of total effective rate, National Institute of Health Stroke Scale score, Fugl-Meyer Assessment score, blood pressure, plasma glucose, blood lipid, and adverse effects will provide evidenced outcome for high-quality synthesis and descriptive analysis., Conclusion: This systematic review will kindly provide evidence of whether acupuncture is an effective and safe intervention for LI in the recovery period., Inplasy Registration Number: INPLASY202150060 (DOI:10.37766/inplasy2021.5.0060)., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.)

Context: Lacunar strokes and diabetes are risk factors for cognitive dysfunction. Elucidating modifiable risk factors for cognitive dysfunction has great public health implications. One factor may be glycemic status, as measured by glycated hemoglobin (A1c)., Objective: The aim of this study was to assess the relationship between A1c and cognitive function in lacunar stroke patients with diabetes., Methods: The effect of baseline and follow-up A1c on the baseline and the change in Cognitive Assessment Screening Instrument (CASI) score over time among participants with a median of 2 cognitive assessments (range, 1-5) was examined in 942 individuals with diabetes and a lacunar stroke who participated in the Secondary Prevention of Small Subcortical Strokes (SPS3) trial (ClinicalTrials.gov No. NCT00059306)., Results: Every 1% higher baseline A1c was associated with a 0.06 lower standardized CASI z score (95% CI, -0.101 to -0.018). Higher baseline A1c values were associated with lower CASI z scores over time (P for interaction = .037). A 1% increase in A1c over time corresponded with a CASI score decrease of 0.021 (95% CI, -0.0043 to -0.038) during follow-up. All these remained statistically significant after adjustment for age, sex, education, race, depression, hypertension, hyperlipidemia, body mass index, cardiovascular disease, obstructive sleep apnea, diabetic retinopathy, nephropathy insulin use, and white-matter abnormalities., Conclusion: This analysis of lacunar stroke patients with diabetes demonstrates a relationship between A1c and change in cognitive scores over time. Intervention studies are needed to delineate whether better glucose control could slow the rate of cognitive decline in this high-risk population., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

We conducted a cross-sectional study to characterize the relationship between total and modified small vessel disease (SVD) score with vascular cognitive impairment (VCI). Patients (n = 157) between the ages of 50 and 85 years old who had suffered their first lacunar infarction were analyzed prospectively. Brain magnetic resonance imaging was performed to identify SVD manifestations, which were used to calculate total or modified SVD scores. Neuropsychological assessments measured cognitive function. Spearman correlation analysis demonstrated that the total and modified SVD scores were associated with overall cognition as well as with function in the executive and visuospatial domains. The associations remained significant in linear regression after adjusting for age, sex, education and vascular risk factors. Binary logistic regression and chi-squared trend tests revealed that VCI risk increased significantly with SVD burden based on the modified SVD score. Subsequent chi-squared testing demonstrated that the VCI rate was significantly higher in patients with a modified SVD score of 5-6 than in patients without any SVD burden. Our results suggest that both the total and modified SVD scores show a negative association with cognitive function, but the modified SVD score may be better at identifying patients at high VCI risk.

Stroke is the leading cause of long-term, severe disability worldwide. Immediately after the stroke, endogenous inflammatory processes are upregulated, leading to the local neuroinflammation and the potentiation of brain tissue destruction. The innate immune response is triggered as early as 24 h post-brain ischemia, followed by adaptive immunity activation. Together these immune cells produce many inflammatory mediators, i.e., cytokines, growth factors, and chemokines. Our study examines the immune response components in the early stage of deep brain lacunar infarct in the rat brain, highly relevant to the clinical scenario. The lesion was induced by stereotactic injection of ouabain into the adult rat striatum. Ouabain is a Na/K ATPase pump inhibitor that causes excitotoxicity and brings metabolic and structural changes in the cells leading to focal brain injury. We have shown a surge of neurodegenerative changes in the peri-infarct area in the first days after brain injury. Immunohistochemical analysis revealed early microglial activation and the gradual infiltration of immune cells with a significant increase of CD4 + and CD8 + T lymphocytes in the ipsilateral hemisphere. In our studies, we identified the higher level of pro-inflammatory cytokines, i.e., interleukin-1α, interleukin-1β, tumor necrosis factor-α, and interferon-γ, but a lower level of anti-inflammatory cytokines, i.e., interleukin-10 and transforming growth factor-β2 in the injured brain than in normal rats. Concomitantly focal brain injury showed a significant increase in the level of chemokines, i.e., monocyte chemoattractant protein-1 and CC motif chemokine ligand 5 compared to control. Our findings provide new insights into an early inflammatory reaction in our model of the deep-brain lacunar infarct. The results of this study may highlight future stroke immunotherapies for targeting the acute immune response accompanied by the insult., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: Patients with poststroke cognitive impairment appear to be at higher risk of recurrent stroke and death. However, whether cognitive impairment after lacunar stroke is associated with recurrent stroke and death remains unclear. We assessed whether global or domain-specific cognitive impairment after lacunar stroke is associated with recurrent stroke and death., Methods: We considered patients from the Secondary Prevention of Small Subcortical Strokes (SPS3) trial with a baseline cognitive exam administered in English by certified SPS3 personnel, 14-180 days after qualifying lacunar stroke. We considered a baseline score of ≤86 on the Cognitive Assessment Screening Instrument to indicate global cognitive impairment, <10 on the Clock Drawing on Command test to indicate executive function impairment, and domain-specific summary scores in the lowest quartile to indicate memory and nonmemory impairment. We used Cox proportional hazards models to estimate the association between poststroke cognitive impairment and subsequent risk of recurrent stroke and death., Results: The study included 1,528 participants with a median enrollment time of 62 days after qualifying stroke. During a mean follow-up of 3.9 years, 11.4% of participants had recurrent stroke and 8.2% died. In the fully adjusted models, memory impairment was independently associated with an increased risk of recurrent stroke (hazard ratio, 1.48; 95% confidence interval [95% CI]: 1.04-2.09) and death (hazard ratio, 1.87; 95% CI: 1.25-2.79). Global impairment (hazard ratio, 1.66; 95% CI: 1.06-2.59) and nonmemory impairment (hazard ratio, 1.74; 95% CI: 1.14-2.67) were associated with an increased risk of death., Discussion/conclusion: After lacunar stroke, memory impairment was an independent predictor of recurrent stroke and death, while global and nonmemory impairment were associated with death. Cognitive screening in lacunar stroke may help identify populations at higher risk of recurrent stroke and death., (© 2021 S. Karger AG, Basel.)

Oligodendrocyte precursor cells (OPCs) are glial cells that differentiate into oligodendrocytes and myelinate axons. The number of OPCs is reportedly increased in brain lesions in some demyelinating diseases and during ischemia; however, these cells also secrete cytokines and elicit both protective and deleterious effects in response to brain injury. The mechanism regulating the behaviors of OPCs in physiological and pathological conditions must be elucidated to control these cells and to treat demyelinating diseases. Here, we focused on transient receptor potential melastatin 3 (TRPM3), a Ca 2+ -permeable channel that is activated by the neurosteroid pregnenolone sulfate (PS) and body temperature. Trpm3 + /Pdgfra + OPCs were detected in the cerebral cortex (CTX) and corpus callosum (CC) of P4 and adult rats by in situ hybridization. Trpm3 expression was detected in primary cultured rat OPCs and was increased by treatment with tumor necrosis factor α (TNFα). Application of PS (30-100 µM) increased the Ca 2+ concentration in OPCs and this effect was inhibited by co-treatment with the TRP channel blocker Gd 3+ (100 µM) or the TRPM3 inhibitor isosakuranetin (10 µM). Stimulation of TRPM3 with PS (50 µM) did not affect the differentiation or migration of OPCs. The number of Trpm3 + OPCs was markedly increased in demyelinated lesions in an endothelin-1 (ET-1)-induced ischemic rat model. In conclusion, TRPM3 is functionally expressed in OPCs in vivo and in vitro and is upregulated in inflammatory conditions such as ischemic insults and TNFα treatment, implying that TRPM3 is involved in the regulation of specific behaviors of OPCs in pathological conditions.

Background: Diabetes mellitus increases stroke risk 1.5 to 3 fold, particularly ischemic stroke. There is limited literature on the impact of diabetes on stroke patients in Saudi Arabia., Objectives: Determine the association of diabetes on the presentation, subtypes, in-hospital complications and outcomes of ischemic stroke and transient ischemic attacks (TIA)., Design: IRB approved, retrospective chart review., Setting: Tertiary care center., Patients and Methods: All adult patients with ischemic stroke or TIA aged 18 years or older admitted from January 2016 to December 2017 were included., Main Outcome Measures: Stroke severity at presentation, stroke-related complications, discharge disposition and discharge modified Rankin Scale (mRS) in relation to diabetes., Sample Size: 802 patients., Results: Among 802 cases, 584 (72.8%) had diabetes; the majority (63.1%) were males. The mean age was younger in the non-diabetic stroke group (54.6 [15.5] years vs. 63.3 [9.9], P <.001). Hypertension (83.6% vs 49.1%, P <.001), dyslipidemia (38.9% vs. 28.9%, P =.009), prior stroke (27.7% vs. 19.3% P =.014), and ischemic heart disease (20.4% vs. 7.8%, P <.001) were more common in diabetic patients whereas smoking was more common (19.3% vs. 11.1%, P =.003) in the non-diabetic patients. The commonest subtype of stroke was large artery disease followed by small vessel disease. Both were more common in diabetic vs. non-diabetic patients (55.8% vs. 44%, P =.003), and (16.6% vs. 11%, P =.05) respectively. Diabetic stroke patients were more likely to have lacunar stroke (16.4% versus 9.2%, P =.009). TIAs occurred more commonly in the non-diabetic group (26.1% vs. 13.7%, P <.001). Non-diabetic patients had a better outcome (mRS score of 0-2) at discharge (62.4% vs. 45.9%, P =.002)., Conclusions: Almost three-fourth stroke patients were diabetic in our cohort. Diabetic stroke patients were older, had multiple vascular comorbid conditions, presented late to the hospital, and were likely to have more disability at the time of discharge. Large vessel atherosclerosis as well as lacunar infarctions were more common in diabetic stroke patients., Limitations: Missing data about time of presentation in few patients, missing modified Rankin Scale score at discharge., Conflict of Interest: None.

Background and Purpose: Previous studies have revealed a relationship between chronic kidney disease (CKD) and white matter hyperintensities (WMH). However, studies on the WMH and CKD in acute stroke patients are rare, and the conclusion is consistent. Our study aimed to investigate the relationship between the severity of WMH and CKD in acute lacunar infarction patients., Methods: Consecutive acute lacunar infarction patients were recruited in this cross-sectional study. All patients were divided into two groups according to the severity of periventricular WMH (PVWMH) and deep WMH (DWMH). We dichotomized the severity of WMH (PVWMH and DWMH, separately) into mild group (Fazekas scores 0-1) and moderate-severe group (Fazekas scores 2-3). Estimated glomerular filtration rate (eGFR), proteinuria, vascular risk factors, and clinical features were compared between these two groups. Multivariable logistic regression analysis was used to investigate the association between the severity of WMH and risk factors., Results: A total of 993 acute lacunar infarction patients aged 25-95 years were enrolled. The proportions of participants presenting moderate-severe group PVWMH and DWMH were 46.6% and 38.6%, respectively. Patients with moderate-severe PVWMH had higher age (P < 0.001) and higher incidence of stroke history (P < 0.001) than those in mild group. The level of serum creatinine and the presence of CKD were significantly higher while the eGFR was significantly lower in patients with moderate-severe PVWMH than those with mild PVWMH. Patients with moderate-severe DWMH (n = 383) also had higher age (P < 0.001) and often had a history of stroke (P < 0.001). But the association between the severity of DWMH and eGFR was not found. Multivariable logistic regression analyses showed stage 2 CKD and stage 3 CKD were independently associated with moderate-severe PVWMH, but not DWMH., Conclusions: Our study demonstrates that CKD was independently associated with moderate-severe PVWMH in patients with acute lacunar infarction, but not DWMH. PVWMH and DWMH may have distinct pathophysiology.

Associations between cognitive decline and cerebral microbleeds (CMBs) have received increasing attention. An association between CMB distribution (deep or lobar) and cognitive decline has been reported, but these findings are controversial. We investigated the association between magnetic resonance imaging (MRI) findings, including CMBs, and cognitive function in patients with first-ever lacunar infarction. We retrospectively included consecutive patients admitted with first-ever lacunar infarction identified by MRI from July 1, 2011, to December 31, 2018. We excluded patients diagnosed with dementia, including strategic single-infarct dementia, before or after the onset of stroke. The Mini-Mental State Examination (MMSE) was performed within 3 days of admission. We searched the records of 273 patients (age 72.0 ± 11.2 years, 95 females). The median MMSE score was 27 (interquartile range 25.5-29). In a univariate analysis, the MMSE score was associated with age, body mass index (BMI), education, dyslipidemia, chronic kidney disease (CKD), periventricular hyperintensity, medial temporal atrophy, lobar CMBs, and mixed CMBs (p < 0.20). The lacunar infarction location was not associated with the MMSE score. In a multivariate analysis of these factors, lobar CMBs (p < 0.001) and mixed CMBs (p = 0.008) were independently associated with the MMSE score. Lobar CMBs were associated with cognitive impairment.

Purpose: Lacunar infarcts are thought to result from occlusion of small penetrating arteries due to microatheroma and lipohyalinosis, pathognomonic for cerebral small vessel disease (CSVD). Concurrent embolic ischemic lesions indicate a different stroke mechanism. The purpose of this study was to examine the clinical characteristics and outcome of patients with lacunar infarcts and concurrent embolic infarcts on diffusion-weighted imaging (DWI)., Methods: All patients screened for the WAKE-UP trial (ClinicalTrials.gov number, NCT01525290) were reviewed for acute lacunar infarcts and concurrent embolic lesions on baseline DWI. Clinical characteristics and outcome were compared between lacunar infarct patients with and without concurrent embolic lesions., Results: Of 244 patients with an acute lacunar infarct, 20 (8.2%) had concurrent acute embolic infarcts. Compared to patients with a lacunar infarct only, patients with concurrent embolic infarcts were older (mean age 69 years vs. 63 years; p = 0.031), more severely affected (median National Institutes of Health Stroke Scale [NIHSS] score 5 vs. 4; p = 0.046), and-among those randomized-had worse functional outcome at 90 days (median modified Rankin Scale [mRS] 3 vs. 1; p = 0.011)., Conclusion: Approximately 8% of lacunar infarct patients show concurrent embolic lesions suggesting a stroke etiology other than CSVD. These patients are more severely affected and have a worse functional outcome illustrating the need for a thorough diagnostic work-up of possible embolic sources even in patients with an imaging-defined diagnosis of lacunar infarcts.

Background: Cerebral small vessel disease (CSVD) is a well-known cause of vascular dementia, a leading medical morbidity in the aging population. Obstructive sleep apnea (OSA) has been validated as a cardiovascular risk factor. However, the relationship between these two clinical syndromes is not well established. We aimed to assess the association between OSA and CSVD., Methods: Databases were searched from inception through May 2019. Studies that reported incidence or odd ratios of CSVD in patients with OSA were included. Effect estimates from the individual studies were extracted and combined using random-effect, generic inverse variance method of DerSimonian and Laird., Results: A total of 14 observational studies comprising of 4335 patients were included into the analysis. Compared to patients without OSA, patients with OSA were significantly associated with CSVD magnetic resonance imaging (MRI) findings of white matter hyperintensity (WMH) and asymptomatic lacunar infarction (ALI) with a pooled OR of 2.31 (95% confidence interval [CI], 1.46-3.66, I 2  = 79%) and 1.78 (95% CI, 1.06-3.01, I 2  = 41%), respectively. However, there was no significant association between OSA and findings of cerebral microbleeds (CMBs), with a pooled odds ratio (OR) of 2.15 (95% CI, 0.64-7.29, I 2  = 55%)., Conclusions: Our study demonstrated the association between OSA and CSVD MRI findings of white matter hyperintensity (WMH) and asymptomatic lacunar infarction (ALI) when compared to patients without OSA. The absence of an association of CMBs findings with OSA could be due either by a lower sensitivity of neuroimaging techniques utilized to detect CMBs or a potentially different pathogenesis of CMBs., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: The link between arterial stiffness and mild cognitive impairment (MCI) is receiving increasing attention, and the goal of this study was to explore the relationship among the ankle brachial index (ABI), brachial-ankle pulse wave velocity (Ba-PWV), and MCI in patients with acute lacunar infarction (ALI)., Methods: A total of 103 hospitalized patients with ALI were divided into a non-MCI group (n = 41) and an MCI group (n = 62) according to their Montreal Cognitive Assessment (MoCA) scores. A binary logistic regression model was used to assess the association among ABI, Ba-PWV, and MCI after adjusting for confounding factors. Spearman correlation was utilized to analyse the correlations between ABI, Ba-PWV, and MoCA total scores and sub-scores in ALI patients., Results: Participants with cognitive impairment had significantly higher Ba-PWV and lower ABI than those with normal cognition. Correlation analysis suggested that Ba-PWV (r = -0.854, p < 0.05) and ABI (r = 0.734, p < 0.05) were correlated with MoCA total scores; of all MoCA sub-scores, visuospatial/executive function was the most strongly correlated with the vascular variables. In the binary logistic regression analysis, Ba-PWV (odds ratio [OR] = 4.507, 95% confidence interval [CI] = 2.152-9.441) and ABI (OR = 1.124, 95% CI = 1.015-1.254) were significantly associated with MCI, even after adjusting for lipoprotein (a) and systolic and diastolic blood pressure., Conclusion: The present study suggested that a higher Ba-PWV and a lower ABI were independent risk factors for MCI in patients with ALI., (© 2020 S. Karger AG, Basel.)

Background: Cerebral small vessel disease (SVD) lesions on MRI are common in patients with cognitive impairment. It has been suggested that cerebral hypoperfusion is involved in the etiology of these lesions., Objective: The aim of the study was to determine the relationship between cerebral blood flow (CBF) and SVD burden in patients referred to a memory clinic with SVD on MRI., Method: We included 132 memory clinic patients (mean age 73 ± 10, 56% male) with SVD on MRI. We excluded patients with large non-lacunar cortical infarcts. Global CBF (mL/min per 100 mL of brain tissue) was derived from 2-dimensional phase-contrast MRI focused on the internal carotid arteries and the basilar artery. SVD burden was defined as the sum of (each 1 point): white matter hyperintensities (WMHs) Fazekas 1 or more, lacunes, microbleeds (MBs), or enlarged perivascular spaces (PVS) presence, and each SVD feature separately. Linear regression analyses were performed to study the association between CBF and SVD burden, age- and sex-adjusted., Results: Median SVD burden score was 2, 36.4% of patients had MBs, 35.6% lacunar infarcts, 48.4% intermediate to severe enlarged PVS, and 57.6% a WMH Fazekas score 2 or more. Median WMH volume was 21.4 mL (25% quartile: 9.6 mL, 75% quartile: 32.5 mL). Mean CBF ± SD was 44.0 ± 11.9 mL/min per 100 mL brain. There was no relation between CBF and overall SVD burden (CBF difference per burden score point [95% CI]: -0.5 [-2.4; 1.4] mL/min/100 mL brain, p = 0.9). CBF did also not differ according to presence or absence or an high burden of any of the individual SVD features. Moreover, there was no significant relation between WMH volume and CBF (CBF difference per ml increase in WMH [95% CI] -0.6 [-1.5; 0.3] mL/min/100 mL brain p = 0.2)., Conclusion: Global CBF was not related to overall SVD burden or with individual SVD features in this memory clinic cohort, indicating that in this setting these lesions were not primarily due to cerebral hypoperfusion., (© 2020 The Author(s) Published by S. Karger AG, Basel.)