Long-term cognitive and neurovascular changes after carotid endarterectomy.

BACKGROUND: Carotid endarterectomy (CEA) has been associated with both cognitive decline and improvement, but the underlying neurovascular mechanisms are unclear. The aim of this study was to investigate the relationship between neurovascular indices and cognitive changes after CEA. METHODS: We studied 55 patients with severe (≥70%) symptomatic or asymptomatic carotid stenosis before and six months after CEA. A wide array of neuropsychological tests was arranged in eight cognitive domains and cognitive functions specific to hemisphere ipsilateral to operation. Differences in cognitive performance between patients and 38 matching healthy controls were studied with linear mixed models. Neurovascular functioning and microembolic signals were assessed with transcranial Doppler ultrasound of the middle cerebral artery. Associations between neurovascular indices and cognitive change were assessed with linear regression analyses. RESULTS: On group level, the CEA patients improved more than controls in working memory, whereas no cognitive deterioration was detected. Also on individual level, improvement was most frequently observed in working memory. Worse preoperative cerebrovascular reactivity was related with improvement in cognitive functions of the ipsilateral hemisphere. Low preoperative pulsatility index was associated with improvement in executive functioning and ipsilateral cognitive functions. Poorer preoperative blood flow velocity associated with improvement in complex attention. Microembolic signals were rare. CONCLUSION: The present findings suggest that CEA may have beneficial long-term effects on cognition. These effects may specifically involve patients with impaired preoperative circulatory adaptive mechanisms.

Retinal vessel diameters and microvascular abnormalities in patients with carotid stenosis before and 6 months after carotid endarterectomy: A prospective study.

PURPOSE: To assess retinal findings in patients with severe carotid stenosis (CS) before and after carotid endarterectomy (CEA) compared to those in controls. METHODS: This study is based on 70 patients (male 81%, mean age 69) scheduled for CEA in Helsinki University Hospital and 41 healthy nonmedicated controls (male 76%, mean age 68). Our examinations included fundus photographs. Semi-automated software (Vesselmap, Imedos) served for evaluation of central retinal arterial equivalent (CRAE) and venular equivalent (CRVE), and arterio-venous ratio (AVR) in both eyes. We assessed fundus photographs to subjectively grade microvascular abnormalities in the ipsilateral eyes including focal arteriolar narrowing and irregularities, arteriolar wall reflex, arterio-venous crossing signs and arteriolar and venular tortuosity in the macula. RESULTS: CRAE was similar in the ipsi-and contralateral eyes of our patients, and similar to that of the controls both pre- and postoperatively. Preoperatively, we observed higher CRVE in the patients' ipsilateral than in their contralateral eyes (222 vs. 217 µm, p = 0.009), and likewise higher than in controls' eyes (222 vs. 214 µm, p = 0.024). CRVE decreased postoperatively in the patients' ipsilateral eyes (222 vs. 217 µm, p = 0.037). Among the microvascular abnormalities, arteriolar and venular tortuosity in the macula showed higher grades in the patients than in the controls preoperatively (p = 0.035 and p = 0.043), but not postoperatively (p = 0.15 and p = 0.10). CONCLUSIONS: CRVE decreased after CEA, showing that venules constrict after the mechanical hindrance of blood flow is removed. Higher grades in arteriolar and venular tortuosity in the macula, a potential ocular biomarker of CS, subsided after CEA.

Markers of early vascular aging are not associated with cryptogenic ischemic stroke in the young: A case-control study.

BACKGROUND AND PURPOSE: We aimed to assess the association between covert atherosclerosis, arterial stiffness, and early-onset cryptogenic ischemic stroke (CIS) in a prospective case-control study. METHODS: We enrolled 123 young CIS patients (median age 41 years; 42% women) and 123 age- and sex-matched controls. Carotid intima-media thickness (CIMT), Augmentation Index (AIx), central pulse wave velocity (PWV), and subendocardial viability ratio (SEVR) were compared between patients and controls. Conditional logistic regression was used adjusting for age, systolic blood pressure, diastolic blood pressure, current smoking, total cholesterol/high-density lipoprotein cholesterol (Total-C/HDL-C) ratio, and glycated albumin to assess the independent association between CIMT, arterial stiffness and CIS. RESULTS: Patients with higher CIMT and PWV were older, more often men and they had more frequently well-documented risk factors, lower HDL and higher Total-C/HDL-C ratio compared to other tertiles. In univariate comparisons, we found no differences between patients and controls regarding CIMT, AIx, or PWV. In the entire cohort, patients had a significantly lower SEVR compared to controls (146.3%, interquartile range [IQR] 125.7-170.3 vs. 158.0%, IQR 141.3-181.0, P=0.010). SEVR was lower also in women compared to their controls (132.0%, IQR 119.4-156.1 vs. 158.7%, IQR 142.0-182.8, P=0.001) but no significant difference appeared between male patients and male controls. However, after adjusting for comorbidities and laboratory values these significant differences were lost (odds ratio [OR] 1.52, 95% confidence interval [CI] 0.47-4.91) in the entire cohort and OR 3.89, 95% CI 0.30-50.80 in women). CONCLUSIONS: Higher CIMT and PWV were associated to higher age, male sex, and several well-documented cardiovascular risk factors. However, in this study we could not prove that either covert atherosclerosis or arterial stiffness contribute to pathogenesis of early-onset CIS.

Glutamine synthetase in human carotid plaque macrophages associates with features of plaque vulnerability: An immunohistological study.

BACKGROUND AND AIMS: Glutamine synthetase (GLUL), the sole generator of glutamine, is a metabolic nexus molecule also involved in atherosclerosis. We recently demonstrated a 2.2-fold upregulation of GLUL mRNA in stroke-causing carotid plaques when compared with plaques from asymptomatic patients. Here we compared in the same cohort GLUL mRNA expression with plaque gross morphology, and the colocalization of immunodetectable GLUL protein with histopathological changes and molecular and mechanical mediators linked to plaque development. METHODS: Endarterectomy specimens from 19 asymptomatic and 24 stroke patients were sectioned longitudinally and immunostained for GLUL, CD68, α-smooth muscle actin, iron, heme oxygenase-1 and CD163, and graded semiquantitatively in every 1 mm2. The amounts of cholesterol clefts and erythrocytes were graded. The fibrous cap thickness within each 1 mm2 area was measured. The association between the local pathological findings was analyzed by a hierarchical mixed modelling approach. RESULTS: The previously found correlation between GLUL mRNA and clinical symptomatology was supported by the increased GLUL mRNA in diseased tissue and increased local GLUL immunoreactivity in areas with multiple different atherosclerotic changes. A longer symptom-to-operation time correlated with lower GLUL mRNA (Rs = -0.423, p=0.050) but few outliers had a significantly higher GLUL mRNA levels, which persisted throughout the post-symptomatic period. Plaque ulceration associated with 1.8-fold higher GLUL mRNA (p=0.006). Macrophages were the main GLUL immunoreactive cells. GLUL immunostaining colocalized with erythrocytes, iron, CD163, and heme oxygenase-1. The correlations between local variables were consistent in both asymptomatic and stroke-causing plaques. An inverse correlation was found between the fibrous cap thickness and local GLUL immunoreactivity (p=0.012). Considerable variability in interplaque expression pattern of GLUL was present. CONCLUSIONS: Our results link connect macrophage GLUL expression with carotid plaque features characterizing plaque vulnerability.

Differential Cognitive Functioning and Benefit From Surgery in Patients Undergoing Coronary Artery Bypass Grafting and Carotid Endarterectomy.

Background: Stenosing atherosclerosis in both coronary and carotid arteries can adversely affect cognition. Also their surgical treatments, coronary artery bypass grafting (CABG) and carotid endarterectomy (CEA), are associated with cognitive changes, but the mechanisms of cognitive decline or improvement may not be the same. This study was designed to compare the cognitive profile and outcome in patients undergoing surgical treatment for coronary or carotid disease. Methods: A total of 100 CABG patients and 44 CEA patients were recruited in two previously reported studies. They were subjected to a comprehensive neuropsychological examination prior to surgery and in the acute (3-8 days) and stable (3 months) phase after operation. A group of 17 matched healthy controls were assessed with similar intervals. We used linear mixed models to compare cognitive trajectories within six functional domains between the CABG, CEA and control groups. Postoperative cognitive dysfunction (POCD) and improvement (POCI) were determined with the reliable change index method in comparison with healthy controls. Results: Before surgery, the CEA patients performed worse than CABG patients or healthy controls in the domains of executive functioning and processing speed. The CABG patients exhibited postoperative cognitive dysfunction more often than the CEA patients in most cognitive domains in the acute phase but had regained their performance in the stable phase. The CEA patients showed more marked postoperative improvement in executive functioning than the CABG group in the acute phase, but the difference did not reach significance in the stable phase. Conclusion: Our findings suggest that anterior cerebral dysfunction in CEA patients impairs preoperative cognition more severely than global brain dysfunction in CABG patients. However, CEA may have more beneficial effects on cognition than CABG, specifically in executive functions mainly operated by the prefrontal lobes. In addition, the results underline that POCD is a heterogeneous condition and dependent on type of revascularization surgery.

Flicker-induced retinal vascular dilation in ipsi- and contralateral eyes of patients with carotid stenosis before and after carotid endarterectomy: a prospective study.

PURPOSE: Retinal vascular function was assessed in patients with carotid stenosis (CS) before and six months after carotid endarterectomy (CEA) and in controls at a six-month interval. METHODS: We studied 68 patients (81% male, mean age 69) and 41 healthy non-medicated controls (77%, 68) from March 2015 to December 2018. Our ophthalmological examination included flicker-induced arteriolar and venular measurements with a Dynamic Vessel Analyser in both eyes. RESULTS: At baseline, flicker-induced arteriolar and venular dilation was reduced in the ipsilateral eyes of the patients compared with dilation in the controls (arteriolar 1.0% versus 2.6%, p = 0.001 and venular 2.2% versus 2.8%, p = 0.049). These differences subsided after CEA. In patients' ipsilateral eyes, flicker-induced arteriolar dilation was borderline postoperatively (preoperative 1.0% versus postoperative 1.6%, p = 0.06), whereas venular dilation increased (2.2% versus 2.8%, p = 0.025). We found various tentative associations with the change in flicker-induced dilations after CEA, but not with the preoperative dilations. CONCLUSIONS: Postoperative recovery of the reduced flicker-induced arteriolar and venular dilatation in the ipsilateral eye shows that, after CEA, the activity-dependent vascular reactivity of haemodynamically compromised retinal tissue can improve.

Ocular signs of carotid stenosis in ipsi- and contralateral eyes before and after carotid endarterectomy: a prospective study.

PURPOSE: We describe hypoperfusion-related and embolic ocular signs of carotid stenosis (CS) before and six months after carotid endarterectomy (CEA) in a CS population. METHODS: We enrolled prospectively 70 CEA patients (81% male, mean age 69) and 41 non-medicated control subjects (76%, 68), from March 2015 to December 2018, assessing intraocular pressure (IOP), best-corrected visual acuity (BCVA) in logMAR units and performing a bio-microscopy examination. RESULTS: Main index symptoms included amaurosis fugax (Afx) (29, 41%) and hemispheric TIA (17, 24%), and 17 (24%) were asymptomatic. Of the 70, 17 patients (24%, 95% CI 16-36) showed ocular signs of CS. Of four embolic (Hollenhorst plaques) findings, one small macular plaque disappeared postoperatively. Four had hypoperfusion, that is ocular ischaemic syndrome (OIS), requiring panretinal photocoagulation: one for multiple mid-peripheral haemorrhages, two for iris neovascularization and one for neovascular glaucoma (NVG); only the NVG proved irreversible. Nine (de novo in three) showed mild OIS, that is only few mid-peripheral haemorrhages, ranging pre- /postoperatively in ipsilateral eyes from one to eleven (median two)/ one to two (median one), and in contralateral eyes from three to nine (median five)/ one to six (median three). Pre- and postoperative median BCVA was 0 or better, and mean IOP was normal, except in the NVG patient. Temporary visual impairment from 0 to 0.3 occurred in one eye soon after CEA due to ocular hyperperfusion causing macular oedema. CONCLUSIONS: Ocular signs of CS are common in CEA patients, ranging from few mid-peripheral haemorrhages to irreversible NVG. Clinicians should be aware of these signs in detecting CS.

Sonothrombolysis in Patients With Acute Ischemic Stroke With Large Vessel Occlusion: An Individual Patient Data Meta-Analysis.

BACKGROUND AND PURPOSE: Evidence about the utility of ultrasound-enhanced thrombolysis (sonothrombolysis) in patients with acute ischemic stroke (AIS) is conflicting. We aimed to evaluate the safety and efficacy of sonothrombolysis in patients with AIS with large vessel occlusion, by analyzing individual patient data of available randomized-controlled clinical trials. METHODS: We included all available randomized-controlled clinical trials comparing sonothrombolysis with or without addition of microspheres (treatment group) to intravenous thrombolysis alone (control group) in patients with AIS with large vessel occlusion. The primary outcome measure was the rate of complete recanalization at 1 to 36 hours following intravenous thrombolysis initiation. We present crude odds ratios (ORs) and ORs adjusted for the predefined variables of age, sex, baseline stroke severity, systolic blood pressure, and onset-to-treatment time. RESULTS: We included 7 randomized controlled clinical trials that enrolled 1102 patients with AIS. A total of 138 and 134 confirmed large vessel occlusion patients were randomized to treatment and control groups respectively. Patients randomized to sonothrombolysis had increased odds of complete recanalization compared with patients receiving intravenous thrombolysis alone (40.3% versus 22.4%; OR, 2.17 [95% CI, 1.03-4.54]; adjusted OR, 2.33 [95% CI, 1.02-5.34]). The likelihood of symptomatic intracranial hemorrhage was not significantly different between the 2 groups (7.3% versus 3.7%; OR, 2.03 [95% CI, 0.68-6.11]; adjusted OR, 2.55 [95% CI, 0.76-8.52]). No differences in the likelihood of asymptomatic intracranial hemorrhage, 3-month favorable functional and 3-month functional independence were documented. CONCLUSIONS: Sonothrombolysis was associated with a nearly 2-fold increase in the odds of complete recanalization compared with intravenous thrombolysis alone in patients with AIS with large vessel occlusions. Further study of the safety and efficacy of sonothrombolysis is warranted.

Endothelial Dysfunction is Associated With Early-Onset Cryptogenic Ischemic Stroke in Men and With Increasing Age.

Background The aim of this study was to assess the association between endothelial function and early-onset cryptogenic ischemic stroke (CIS), with subgroup analyses stratified by sex and age groups. Methods and Results We prospectively enrolled 136 consecutive patients aged 18 to 49 years (median age, 41 years; 44% women) with a recent CIS and 136 age- and sex-matched (±5 years) stroke-free controls. Endothelial function was measured with an EndoPAT 2000 device and analyzed as tertiles of natural logarithm of reactive hyperemia index with lower values reflecting dysfunction. We used conditional logistic regression adjusting for age, education, hypertension, diabetes mellitus, dyslipidemia, current smoking, heavy drinking, obesity, and diet score to assess the independent association between endothelial function and CIS. Patients in the lowest tertile of natural logarithm of reactive hyperemia index were more often men and they more frequently had a history of dyslipidemia; they were also more often obese, had a lower diet score, and lower high-density lipoprotein cholesterol. In the entire cohort, we found no association in patients with endothelial function and CIS compared with stroke-free controls. In sex- and age-specific analyses, endothelial dysfunction was associated with CIS in men (adjusted odds ratio [OR], 3.50 for lowest versus highest natural logarithm of reactive hyperemia index tertile; 95% CI, 1.22-10.07) and in patients ≥41 years (OR, 5.78; 95% CI, 1.52-21.95). These associations remained significant when dyslipidemia was replaced with the ratio of total to high-density lipoprotein cholesterol. Conclusions Endothelial dysfunction appears to be an independent player in early-onset CIS in men and patients approaching middle age.

Warfarin Treatment Is Associated to Increased Internal Carotid Artery Calcification.

Background: Long-term treatment with the vitamin K antagonist warfarin is widely used for the prevention of venous thrombosis and thromboembolism. However, vitamin K antagonists may promote arterial calcification, a phenomenon that has been previously studied in coronary and peripheral arteries, but not in extracranial carotid arteries. In this observational cohort study, we investigated whether warfarin treatment is associated with calcification of atherosclerotic carotid arteries. Methods: Overall, 500 consecutive patients underwent carotid endarterectomy, 82 of whom had received long-term warfarin therapy. The extent of calcification was assessed with preoperative computed tomography angiography, and both macroscopic morphological grading and microscopic histological examination of each excised carotid plaque were performed after carotid endarterectomy. Results: Compared with non-users, warfarin users had significantly more computed tomography angiography-detectable vascular calcification in the common carotid arteries (odds ratio 2.64, 95% confidence interval 1.51-4.63, P < 0.001) and even more calcification in the internal carotid arteries near the bifurcation (odds ratio 18.27, 95% confidence interval 2.53-2323, P < 0.001). Histological analysis revealed that the intramural calcified area in plaques from warfarin users was significantly larger than in plaques from non-users (95% confidence interval 3.36-13.56, P = 0.0018). Conclusions: Long-lasting warfarin anticoagulation associated with increased calcification of carotid atherosclerotic plaques, particularly in locations known to be the predilection sites of stroke-causing plaques. The clinical significance of this novel finding warrants further investigations.

Blood pressure excursions in acute ischemic stroke patients treated with intravenous thrombolysis.

OBJECTIVE: To investigate the association of blood pressure BP excursions, defined as greater than 185 SBP or greater than 105 DBP, with the probability of intracranial hemorrhage (ICH) and worse functional outcomes in patients with acute ischemic stroke (AIS) treated with tissue plasminogen activator (tPA). METHODS: We performed a post hoc analysis of the CLOTBUST-ER trial. Serial BP measurements were conducted using automated cuff recording according to the recommended BP protocol guidelines for tPA administration. The outcomes were prespecified efficacy and safety endpoints of CLOTBUST-ER. RESULTS: The mean number of serial BP recordings per patient was 37. Of the 674 patients, 227 (34%) had at least one BP excursion (>185/105 mmHg) during the first 24 h following tPA-bolus. The majority of BP excursions (46%) occurred within the first 75 min from tPA-bolus. Patients with at least one BP excursion in the first 24 h following tPA bolus had significantly lower rates of independent functional outcome at 90 days (31 vs. 40.1%, P = 0.028). The total number of BP excursions was associated with decreased odds of 24-h clinical recovery (OR = 0.88, 95% CI:0.80-0.96), 24-h neurological improvement (OR = 0.87, 95% CI: 0.81-0.94), 7-day functional improvement (common OR = 0.92, 95% CI: 0.87-0.97), 90-day functional improvement (common OR = 0.94, 95% CI: 0.88-0.98) and 90-day independent functional outcome (OR = 0.90, 95% CI: 0.82-0.98) in analyses adjusted for potential confounders. DBP excursions were independently associated with increased odds of any intracranial hemorrhage (OR = 1.26, 95% CI: 1.04-1.53). CONCLUSION: BP excursions above guideline thresholds during the first 24 h following tPA administration for AIS are common and are independently associated with adverse clinical outcomes.

Subfoveal choroidal thickness in ipsi- and contralateral eyes of patients with carotid stenosis before and after carotid endarterectomy: a prospective study.

PURPOSE: To compare subfoveal choroidal thickness (SFCT) and associated clinical variables in patients with carotid stenosis (CS) before and 6 months after carotid endarterectomy (CEA). METHODS: The prospective non-randomized Helsinki Carotid Endarterectomy Study - Brain and Eye Sub-sTudy included seventy patients (81% male, mean age 69 years) and 40 control subjects (77% male, 68 years), from March 2015 to December 2018. Ophthalmological examination included SFCT measured with enhanced-depth imaging-optical coherence tomography. Carotid stenosis (CS) was more severe (≥70% stenosis in 92%) ipsilateral to the CEA than contralaterally (<50% stenosis in 74%; p < 0.001). RESULTS: At baseline, patients had thinner mean SFCT than control subjects in both eyes (ipsilateral, 222 versus 257 µm and contralateral, 217 versus 258 µm, p ≤ 0.005). At follow-up, SFCT did not change in ipsi- and contralateral eyes compared to baseline in patients (p = 0.68 and p = 0.77), or in control subjects (p = 0.59 and p = 0.79). Patients with coronary artery disease had thinner mean SFCT versus those without it in ipsilateral eyes before CEA (200 versus 233 µm, p = 0.027). In ipsilateral eyes of patients before CEA, thinner SFCT and ocular signs of CS, plaque and hypoperfusion related findings combined, were associated (p = 0.036), and the best-corrected visual acuity, measured in logMAR, increased with increasing SFCT (r = -0.25; p = 0.046). CONCLUSIONS: Subfoveal choroidal thickness (SFCT) is thinner in patients with CS without association between SFCT and the grade of CS. Unchanged SFCT after CEA suggests, that choroidal vessels in severe CS are unable to react to increased blood flow. Bilaterally thin SFCT could be considered as yet another sign of CS.

Predictive Factors for Pre-operative Recurrence of Cerebrovascular Symptoms in Symptomatic Carotid Stenosis.

OBJECTIVE: Across stroke subtypes, carotid artery stroke carries the highest risk of recurrence. Despite initiation of best medical therapy (BMT), some patients suffer recurrent neurological events before undergoing carotid endarterectomy (CEA). The aim was to identify clinical predictors of early recurrent events in patients with symptomatic carotid stenosis (sCS) awaiting CEA on modern BMT. METHODS: The Helsinki Carotid Endarterectomy Study 2 (HeCES2) is a cross sectional, longitudinal, prospective, and consecutive cohort study, which enrolled 500 symptomatic or asymptomatic patients with carotid stenosis scheduled for CEA in a tertiary stroke centre. Symptomatic patients were included for this analysis (n = 324). RESULTS: Of all 324 patients with sCS, 39 (12%) had a recurrent cerebrovascular event at a median of six days after the index symptom: four had an ischaemic stroke (1.2%), 16 a hemispheric transient ischaemic attack (TIA; 4.9%), and 19 amaurosis fugax (AFX; 5.9%). The recurrence rate was 4.0 % (n = 13) within 48 h and 9.9% (n = 32) within two weeks. None of the patients (n = 108) presenting with ocular symptoms (AFX or retinal artery occlusion) suffered recurrent hemispheric TIA or stroke. In Cox regression analysis, comorbid hypertension (hazard ratio [HR] 6.58, 95% confidence interval [CI] 1.33-32.47), hemispheric TIA as the index symptom (HR 3.42, 95% CI 1.70-6.90), the number of prior attacks (HR 1.12, 95% CI 1.08-1.15), and high low density lipoprotein/high density lipoprotein ratio (HR 1.51, 95% CI 1.09-2.11) were independently associated with an increased risk of recurrent event, while a history of major cardiovascular event (HR 0.33, 95% CI 0.11-0.96) and high serum fibrinogen level (HR 0.59, 95% CI 0.41-0.86) were associated with a decreased risk. CONCLUSION: More than every tenth patient with sCS experienced an early recurrent cerebrovascular event prior to scheduled CEA, despite optimal medication. However, stroke recurrence was lower than in earlier observational studies, which could be explained by improved care pathways, more aggressive medication, and expedited CEA. All recurrent strokes occurred in patients initially presenting with minor stroke.

Postoperative cognitive change after cardiac surgery predicts long-term cognitive outcome.

OBJECTIVES: Postoperative cognitive dysfunction (POCD) is a common consequence of coronary artery bypass grafting. However, domain-specific associations between postoperative changes and long-term performance are poorly known. The aim of this study was to investigate whether domain-specific cognitive changes after cardiac surgery predict long-term cognitive outcome. MATERIALS AND METHODS: We assessed 100 patients (86 men, mean age 60) before coronary artery bypass grafting, with re-examinations after one week, three months, and a mean of 6.7 years. The extensive neuropsychological test battery was organized into seven functional cognitive domains. Cognitive decline and improvement were defined with the reliable change index derived from 17 matching healthy controls. Analyses were adjusted for baseline cognitive performance, age, gender, education and cardiovascular risks factors. RESULTS: On group level, one week after surgery 71% patients showed cognitive decline and 9% improvement in any functional domain, as compared to preoperative results. Three months postsurgery, decline was observed in 47% and improvement in 25% of patients. Executive functioning was the most sensitive domain to both decline and improvement. Postoperative dysfunction predicted long-term cognitive deterioration six years after operation, particularly in the domain of executive functioning. CONCLUSIONS: POCD after coronary artery bypass grafting is an essential risk factor for long-term deterioration and an indication for neuropsychological follow-up. Assessment of change in executive functioning after coronary artery bypass grafting may help to identify patients at risk for unfavorable long-term outcome.

Cognitive Dysfunction and Mortality After Carotid Endarterectomy.

Background: Carotid endarterectomy (CEA) has been associated with both postoperative cognitive dysfunction (POCD) and improvement (POCI). However, the prognostic significance of postoperative cognitive changes related to CEA is largely unknown. The aim of this study was to examine the associations between postoperative cognitive changes after CEA and long-term survival. Methods: We studied 43 patients 1 day before CEA as well as 4 days and 3 months after surgery with an extensive neuropsychological test array, and followed them for up to 14 years. POCD and POCI relative to baseline were determined with the reliable change index derived from 17 healthy controls. Associations between POCD/POCI and mortality within the patient group were studied with Cox regression analyses adjusted for confounders. Results: POCD in any functional domain was evident in 28% of patients 4 days after surgery and in 33% of patients 3 months after surgery. POCI was shown in 23% of patients at 4 days and in 44% of patients at 3 months. POCD at 3 months was associated with higher long-term mortality (hazard ratio 5.0, 95% CI 1.8-13.9, p = 0.002) compared with patients with no cognitive decline. Conclusions: Our findings suggest that POCD in a stable phase, 3 months after CEA predicts premature death. Evaluation of postoperative cognitive changes is essential, and POCD in a stable phase after CEA should prompt scrutiny of underlying factors and better adherence to therapies to prevent recurrences and to promote early intervention in imminent deterioration.

Endovascular equipoise shift in a phase III randomized clinical trial of sonothrombolysis for acute ischemic stroke.

BACKGROUND: Results of our recently published phase III randomized clinical trial of ultrasound-enhanced thrombolysis (sonothrombolysis) using an operator-independent, high frequency ultrasound device revealed heterogeneity of patient recruitment among centers. METHODS: We performed a post hoc analysis after excluding subjects that were recruited at centers reporting a decline in the balance of randomization between sonothrombolysis and concurrent endovascular trials. RESULTS: From a total of 676 participants randomized in the CLOTBUST-ER trial we identified 52 patients from 7 centers with perceived equipoise shift in favor of endovascular treatment. Post hoc sensitivity analysis in the intention-to-treat population adjusted for age, National Institutes of Health Scale score at baseline, time from stroke onset to tPA bolus and baseline serum glucose showed a significant (p < 0.01) interaction of perceived endovascular equipoise shift on the association between sonothrombolysis and 3 month functional outcome [adjusted common odds ratio (cOR) in centers with perceived endovascular equipoise shift: 0.22, 95% CI 0.06-0.75; p = 0.02; adjusted cOR for centers without endovascular equipoise shift: 1.20, 95% CI 0.89-1.62; p = 0.24)]. After excluding centers with perceived endovascular equipoise shift, patients randomized to sonothrombolysis had higher odds of 3 month functional independence (mRS scores 0-2) compared with patients treated with tPA only (adjusted OR: 1.53; 95% CI 1.01-2.31; p = 0.04). CONCLUSION: Our experience in CLOTBUST-ER indicates that increasing implementation of endovascular therapies across major academic stroke centers raises significant challenges for clinical trials aiming to test noninterventional or adjuvant reperfusion strategies.

Magnetic Nanoparticles in Human Cervical Skin.

Magnetic iron oxide nanoparticles, magnetite/maghemite, have been identified in human tissues, including the brain, meninges, heart, liver, and spleen. As these nanoparticles may play a role in the pathogenesis of neurodegenerative diseases, a pilot study explored the occurrence of these particles in the cervical (neck) skin of 10 patients with Parkinson's disease and 10 healthy controls. Magnetometry and transmission electron microscopy analyses revealed magnetite/maghemite nanoparticles in the skin samples of every study participant. Regarding magnetite/maghemite concentrations of the single-domain particles, no significant between-group difference was emerged. In low-temperature magnetic measurement, a magnetic anomaly at ~50 K was evident mainly in the dermal samples of the Parkinson group. This anomaly was larger than the effect related to the magnetic ordering of molecular oxygen. The temperature range of the anomaly, and the size-range of magnetite/maghemite, both refute the idea of magnetic ordering of any iron phase other than magnetite. We propose that the explanation for the finding is interaction between clusters of superparamagnetic and single-domain-sized nanoparticles. The source and significance of these particles remains speculative.

The Efficacy of Carotid Surgery by Subgroups: The Concept of Stroke Prevention Potential.

OBJECTIVE: Considering carotid endarterectomy (CEA), reporting treatment delay, symptom status, and surgical complication rates separately gives an incomplete picture of efficacy; therefore, the aim was to combine these factors and develop a reporting standard that better describes the number of potentially prevented strokes. With a real life cohort and theoretical inclusion scenarios, the aim was to explore the stroke prevention potential of different carotid practices. METHODS: Landmark studies for symptomatic and asymptomatic patients were revisited. By using published estimates of treatment effect, a simplified calculator was designed to assess the five year stroke prevention rate per 1000 CEAs (stroke prevention potential [SPP], range 0-478), including the presence and recentness of symptoms, sex, increasing stenosis severity, and complication rates. Patients operated on for carotid stenosis at Helsinki University Hospital (HUH) between 2008 and 2016 were collected from a vascular registry (HUSVASC) and categorised according to the model. The local annual complication rate was re-evaluated and added to the model. The HUH patient cohort was incorporated into the SPP model, and changes over time analysed. Finally, theoretical changes in patient selection were compared in order to explore the theoretical impact of patient selection and shortening of the delay. RESULTS: Fifteen hundred and five symptomatic and 356 asymptomatic carotid stenoses were operated on with stroke plus death rates of 3.6% and 0.3%, respectively. The proportion of CEAs performed within two weeks of the index event increased over the follow up period, being 77% in 2016. The SPP increased from 123 in 2008 to 229 in 2016. Theoretically, 350 ischaemic strokes were prevented in the period 2008-16, with 1861 CEAs. CONCLUSIONS: National and international comparison of different CEA series is irrelevant if the inclusion criteria are not considered. A calculator that is easy to apply to large scale high quality registered data was developed and tested. SPP was found to increase over time, which is a probable sign of improved patient selection and an increased number of strokes prevented by the CEAs performed.

Safety and efficacy of sonothrombolysis for acute ischaemic stroke: a multicentre, double-blind, phase 3, randomised controlled trial.

BACKGROUND: Pulsed-wave ultrasound increases the exposure of an intracranial thrombus to alteplase (recombinant tissue plasminogen activator), potentially facilitating early reperfusion. We aimed to ascertain if a novel operator-independent transcranial ultrasound device delivering low-power high-frequency ultrasound could improve functional outcome in patients treated with alteplase after acute ischaemic stroke. METHODS: We did a multicentre, double-blind, phase 3, randomised controlled trial (CLOTBUST-ER) at 76 medical centres in 14 countries. We included patients with acute ischaemic stroke (National Institutes of Health Stroke Scale score ≥10) who received intravenous thrombolysis (alteplase bolus) within 3 h of symptom onset in North America and within 4·5 h of symptom onset in all other countries. Participants were randomly allocated (1:1) via an interactive web response system to either active ultrasound (2 MHz pulsed-wave ultrasound for 120 min [sonothrombolysis]; intervention group) or sham ultrasound (control group). Ultrasound was delivered using an operator-independent device, which had to be activated within 30 min of the alteplase bolus. Participants, investigators, and those assessing outcomes were unaware of group assignments. The primary outcome was improvement in the modified Rankin Scale score at 90 days in patients enrolled within 3 h of symptom onset, assessed in the intention-to-treat population as a common odds ratio (cOR) using ordinal logistic regression shift analysis. This trial is registered with ClinicalTrials.gov, number NCT01098981. The trial was stopped early by the funder after the second interim analysis because of futility. FINDINGS: Between August, 2013, and April, 2015, 335 patients were randomly allocated to the intervention group and 341 patients to the control group. Compared with the control group, the adjusted cOR for an improvement in modified Rankin Scale score at 90 days in the intervention group was 1·05 (95% CI 0·77-1·45; p=0·74). 51 (16%) of 317 patients in the intervention group and 44 (13%) of 329 patients in the control group died (unadjusted OR 1·24, 95% CI 0·80-1·92; p=0·37) and 83 (26%) and 79 (24%), respectively, had serious adverse events (1·12, 0·79-1·60; p=0·53). INTERPRETATION: Sonothrombolysis delivered by an operator-independent device to patients treated with alteplase after acute ischaemic stroke was feasible and most likely safe, but no clinical benefit was seen at 90 days. Sonothrombolysis could be further investigated either in randomised trials undertaken in stroke centres that are dependent on patient transfer for endovascular reperfusion therapies or in countries where these treatments cannot yet be offered as the standard of care. FUNDING: Cerevast Therapeutics.

Morphology and histology of silent and symptom-causing atherosclerotic carotid plaques - Rationale and design of the Helsinki Carotid Endarterectomy Study 2 (the HeCES2).

INTRODUCTION: Every fifth ischemic stroke is caused by thromboembolism originating from an atherosclerotic carotid artery plaque. While prevention is the most cost-effective stroke therapy, antiplatelet and cholesterol-lowering drugs have a ceiling effect in their efficacy. Therefore, discovery of novel pathophysiologic targets are needed to improve the primary and secondary prevention of stroke. This article provides a detailed study design and protocol of HeCES2, an observational prospective cohort study with the objective to investigate the pathophysiology of carotid atherosclerosis. MATERIALS AND METHODS: Recruitment and carotid endarterectomies of the study patients with carotid atherosclerosis were performed from October 2012 to September 2015. After brain and carotid artery imaging, endarterectomised carotid plaques (CPs) and blood samples were collected from 500 patients for detailed biochemical and molecular analyses. Findings to date: We developed a morphological grading for macroscopic characteristics within CPs. The dominant macroscopic CP characteristics were: smoothness 62%, ulceration 61%, intraplaque hemorrhage 60%, atheromatous gruel 59%, luminal coral-type calcification 34%, abundant (44%) and moderate (39%) intramural calcification, and symptom-causing "hot spot" area 53%. Future plans: By combining clinically oriented and basic biomedical research, this large-scale study attempts to untangle the pathophysiological perplexities of human carotid atherosclerosis. Key Messages This article is a rationale and design of the HeCES2 study that is an observational prospective cohort study with the objective to investigate the pathophysiology of carotid atherosclerosis. The HeCES2 study strives to develop diagnostic algorithms including radiologic imaging to identify carotid atherosclerosis patients who warrant surgical treatment. In addition, the study aims at finding out new tools for clinical risk stratification as well as novel molecular targets for drug development.