Carotid Stenosis, Endarterectomy, and the Brain : Brain microcirculation, diffusion, and cognitive function before and after carotid endarterectomy in patients with a high-grade carotid stenosis

Carotid atherosclerotic disease is a major cause of stroke, but it may remain clinically asymptomatic. The factors that turn the asymptomatic plaque into a symptomatic one are not fully understood, neither are the subtle effects that a high-grade carotid stenosis may have on the brain. The purpose of this study was to evaluate brain microcirculation, diffusion, and cognitive performance in patients with a high-grade stenosis in carotid artery, clinically either symptomatic or asymptomatic, undergoing carotid endarterectomy (CEA). We wanted to find out whether the stenoses are associated with diffusion or perfusion abnormalities of the brain or variation in the cognitive functioning of the patients, and to what extent the potential findings are affected by CEA, and compare the clinically symptomatic and asymptomatic subjects as well as strictly healthy controls. Coagulation and fibrinolytic parameters were compared with the rate microembolic signals (MES) in transcranial Doppler (TCD) and the macroscopic appearance of stenosing plaques in surgery. Patients (n=92) underwent CEA within the study. Blood samples pertaining to coagulation and fibrinolysis were collected before CEA, and the subjects underwent repeated TCD monitoring for MES. A subpopulation (n= 46) underwent MR imaging and repeated neuropsychological examination (preoperative, as well 4 and 100 days after CEA). In MRI, the average apparent diffusion coefficients were higher in the ipsilateral white matter (WM), and altough the interhemispheric difference was abolished by CEA, the levels remained higher than in controls. Symptomatic stenoses were associated with more sluggish perfusion especially in WM, and lower pulsatility of flow in TCD. All patients had poorer cognitive performance than healthy controls. Cognitive functions improved as expected by learning effect despite transient postoperative worsening in a few subjects. Improvement was greater in patients with deepest hypoperfusion, primarily in executive functions. Symptomatic stenoses were associated with higher hematocrit and tissue plasminogen activator antigen levels, as well as higher rate of MES and ulcerated plaques, and better postoperative improvement of vasoreactivity and pulsatility. In light of the findings, carotid stenosis is associated with differences in brain diffusion, perfusion, and cognition. The effect on diffusion in the ipsilateral WM, partially reversible by CEA, may be associated with WM degeneration. Asymptomatic and symptomatic subpopulations differ from each other in terms of hemodynamic adaptation and in their vascular physiological response to removal of stenosis. Although CEA may be associated with a transient cognitive decline, a true improvement of cognitive performance by CEA is possible in patients with the most pronounced perfusion deficits. Mediators of fibrinolysis and unfavourable hemorheology may contribute to the development of a symptomatic disease in patients with a high-grade stenosis.Kaulavaltimoiden ateroskleroottinen ahtautuminen on tärkeä aivohalvauksen syy, mutta enemmistö ahtaumista ei aiheuta halvausta. Syyt, jotka tekevät kaulavaltimoplakista vaarallisen, tunnetaan puutteellisesti, samoin kuin ne mahdolliset muut vaikutukset, joita tiukalla ahtaumalla voi aivojen kannalta olla. Työn tarkoituksena oli tutkia aivojen perfuusiota eli mikroverenkiertoa, solutason diffuusiota ja kognitiivista suoriutumista potilailla, joiden tiukka kaulavaltimoahtauma poistettiin leikkauksella. Tavoitteina oli selvittää, liittyykö kaulavaltimoita ahtauttavaan tautiin aivojen diffuusion, perfuusion tai kognitiivisten toimintojen muutoksia, ja miten leikkaushoito vaikuttaa näihin ja verisuonten reaktiviteettiin, sekä verrata oireisten ja oireettomien löydöksiä keskenään mukaan lukien veren hyytymiseen ja hyytymän liukenemiseen liittyviä tekijöitä. Potilaiden diffuusio- ja kognitiolöydöksiä verrattiin terveiden henkilöiden arvoihin. Potilaiden kognitiivinen suoriutuminen oli kauttaaltaan alempi kuin täysin terveillä ikätovereilla. Ahtauman puoleisessa aivopuoliskossa todettiin magneettikuvauksella toista puolta korkeammat ns. näennäiset diffuusiovakiot aivojen valkeassa aineessa sekä hitaampi aivoperfuusio, ja nämä poikkeamat korjautuivat leikkauksen jälkeen. Diffuusiovakiot jäivät kuitenkin korkeammiksi kuin terveillä ikätovereilla. Neuropsykologinen suoriutuminen parani potilailla toistomittauksissa kuten terveillä, mutta osalla todettiin väliaikainen kognitiivinen heikkenemä heti leikkauksen jälkeen. Kognitiiviset toiminnot kohenivat pit-källä tähtäimellä enemmän niillä, joilla oli näkyvä aivoperfuusion vajaus ennen leikkausta, ja ensisijaisesti muutos tapahtui toiminnanohjauksessa. Näkyvä perfuusiovajaus oli yleisempää oireita aiheuttaneissa ahtaumissa. Oireilleilla oli myös korkeampi punasolujen tilavuusosuus ja kudosplasminogeenin aktivaattorin antigeeni veressä sekä useammin mikroveritulppia kuvaavia ultraäänisignaaleja aivoverenkierrossa kuin oireettomilla. Tulosten valossa tiukka kaulavaltimoahtauma vaikuttaa aivojen diffuusioon, perfuusioon ja kognitiivisiin toimintoihin kliinisistä oireista riippumattakin. Aivojen valkeaan aineeseen aiheutuva diffuusio muutos on samansuuntainen kuin valkean aineen degeneraatiossa, ja muutos korjaantuu osittain ahtauman kirurgisella hoidolla. Oireiset potilaat eroavat oireettomista hemodynamiikaltaan, ja leikkaus hyödyttää heitä enemmän parantuneen hemodynamiikan ja verisuoniston reaktiivisuuden muodossa. Vaikka potilailla on yleisesti alempi kognitiivinen suoritustaso täysin terveisiin verrattuna ja kirurgiseen hoitoon liittyy pieni ohimenevän kognitiivisen haitan riski, jopa kognitiivinen koheneminen on mahdollista potilailla, joiden perfuusiovajaus on suurin. Veren epäedulliset virtausominaisuudet ja fibrinolyysiin liittyvät tekijät saattavat vaikuttaa oireiden ilmaantumiseen näillä potilailla

Prior Intravenous Stroke Thrombolysis Does Not Increase Complications of Carotid Endarterectomy

Background and Purpose Carotid endarterectomy (CEA) is recommended within 14 days after carotid artery stroke to prevent recurrence. However, the optimal timing of CEA after intravenous thrombolysis (IVT) remains unclear. We studied the safety of CEA after IVT while taking into account both stroke recurrence and CEA-related complications. Methods Patients who underwent IVT followed by CEA in Helsinki University Hospital 2005 to 2016 were withdrawn from prospectively collected registers. The incidence of stroke recurrence during the time between IVT and CEA, peri/postoperative stroke, hyperperfusion syndrome or drug-resistant high blood pressure, and 3-month outcome measured by modified Rankin Scale was recorded. Stroke patients treated with CEA without preceding IVT were used as controls. Results Altogether 128 CEAs with preceding IVT and 777 CEAs for stroke without IVT were identified. The median time from IVT to CEA was 9 days (range, 0-349 days; interquartile range, 16). Seven patients (5.5%) underwent CEA within 24 hours, 20 (15.6%) within 48 hours and 87 (68.0%) within 2 weeks from IVT. Stroke recurrence in IVT-CEA patients was 5.5% at median 4 days after IVT (range, 0-8 days). Outcome from CEAs performed within 48 hours from IVT did not differ from CEAs performed later with respect to peri/postoperative ischemic strokes (5.0% and 3.7%), hemorrhagic strokes (5.0% and 1.9%), neck hematomas (5.0% and 8.3%), myocardial infarctions (0.0% and 0.9%), or 3-month modified Rankin Scale. There was a tendency toward higher incidence of hyperperfusion syndrome in the patients operated within 48 hours from IVT (20.0% versus 6.5%; P=0.070). The CEA-related stroke rate was similar to that of the operation without thrombolysis. Only smoking was significantly associated with peri/postoperative stroke (odds ratio, 21.82; 95% confidence interval, 1.08-439.58). Conclusions Time between IVT and CEA was not associated with CEA-related complications. The high rate of stroke recurrence during the waiting time for CEA underscores the importance of shortening surgery delays.Peer reviewe

Active lifestyle as a reflection of cognitive reserve : The Modified Cognitive Reserve Scale

Cognitive reserve (CR) refers to individual differences in cognitive processing that can protect from and compensate for functional decline related to ageing or brain pathology. The CR theory postulates that attaining an active and cognitively stimulating lifestyle can accumulate CR. The Cognitive Reserve Scale (CRS) is a questionnaire that measures lifelong attainment in leisure activities. This cross-sectional study aimed to examine the usefulness, validity and reliability of a modified Finnish translation of the CRS, the Modified Cognitive Reserve Scale (mCRS). The mCRS consists of 20 questions concerning studying and information seeking, hobbies and social relationships during three age phases: young adulthood (18-35 years), adulthood (36-64 years) and late adulthood (>= 65 years). A group of 69 neurologically healthy adults aged 26-78 filled the mCRS and completed a neuropsychological test battery. We examined the internal consistency of the mCRS and associations between the mCRS, demographical variables and cognitive performance. The mCRS was normally distributed and showed satisfactory internal consistency (Cronbach's alpha 0.81). It was significantly associated with occupation (ԑ(2) = 0.14) and education (rho = 0.51) but not with age or gender. There were significant associations between the mCRS and verbal reasoning (rho = .306), visual reasoning (r = .319), learning (r = .293) and inhibition (rho = -.368). Our study suggests that the mCRS is a reliable and valid method to assess lifelong leisure activity. The mCRS is related to other factors that enhance CR, occupation and education, and associated with cognitive performance of healthy adults. It provides an easily administrable means to assess lifelong attainment in stimulating leisure activities.Peer reviewe

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.Peer reviewe

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 similar to 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.Peer reviewe

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.Peer reviewe

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

Sonotrombolisis; Endovascular; Cambio de equilibrio clínicoSonothrombolysis; Endovascular; Equipoise shiftSonotrombolisis; Endovascular; Canvi d'equilibri clínicBackground: 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

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

BackgroundStenosing 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. MethodsA 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. ResultsBefore 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. ConclusionOur 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.Peer reviewe

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 ( Results At baseline, patients had thinner mean SFCT than control subjects in both eyes (ipsilateral, 222 versus 257 mu m and contralateral, 217 versus 258 mu m, p 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.Peer reviewe

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.Peer reviewe