Predictors of Early Neurological Improvement and Its Relationship to Thrombolysis Treatment and Long-Term Outcome in the WAKE-UP Study.

INTRODUCTION: The aims of this study were to evaluate the relationship of clinical and imaging baseline factors and treatment on the occurrence of early neurological improvement (ENI) in the WAKE-UP trial of MRI-guided intravenous thrombolysis in unknown onset stroke and to examine the association of ENI with long-term favorable outcome in patients treated with intravenous thrombolysis. METHODS: We analyzed data from all patients with at least moderate stroke severity, reflected by an initial National Institutes of Health Stroke Scale (NIHSS) score ≥4 randomized in the WAKE-UP trial. ENI was defined as a decrease in NIHSS of ≥8 or a decline to zero or 1 at 24 h after initial presentation to the hospital. Favorable outcome was defined as a modified Rankin Scale score of 0-1 at 90 days. We performed group comparison and multivariable analysis of baseline factors associated with ENI and performed mediation analysis to evaluate the effect of ENI on the relationship between intravenous thrombolysis and favorable outcome. RESULTS: ENI occurred in 93 out of 384 patients (24.2%) and was more likely to occur in patients who received treatment with alteplase (62.4% vs. 46.0%, p = 0.009), had smaller acute diffusion-weighted imaging lesion volume (5.51 mL vs. 10.9 mL, p ≤ 0.001), and less often large-vessel occlusion on initial MRI (7/93 [12.1%] versus 40/291 [29.9%], p = 0.014). In multivariable analysis, treatment with alteplase (OR 1.97, 95% confidence interval [CI] 0.954-1.100), lower baseline stroke volume (OR 0.965, 95% CI: 0.932-0.994), and shorter time from symptom recognition to treatment (OR 0.994, 95% CI: 0.989-0.999) were independently associated with ENI. Patients with ENI had higher rates of favorable outcome at 90-day follow-up (80.6% vs. 31.3%, p ≤ 0.001). The occurrence of ENI significantly mediated the association of treatment with a good outcome, with ENI at 24 h explaining 39.4% (12.9-96%) of the treatment effect. CONCLUSION: Intravenous alteplase increases the odds of ENI in patients with at least moderate stroke severity, especially when given early. In patients with large-vessel occlusion, ENI is rarely observed without thrombectomy. ENI represents a good surrogate early marker of treatment effect as more than a third of good outcome at 90 days is explained by ENI at 24 h.

Cortical thickness and cognitive performance in asymptomatic unilateral carotid artery stenosis.

BACKGROUND: We investigated changes of cortical thickness and its association with cognitive performance in patients with high-grade carotid artery stenosis without ischemic brain lesions. METHODS: We studied 25 patients with unilateral carotid artery stenosis ≥50% and 25 age-matched controls. All subjects underwent T1-weighted MRI, and cortical thickness was measured in 33 regions of interest in each hemisphere, as well as in brain regions belonging to the vascular territory of the middle cerebral artery (MCA). General linear mixed models were fitted to the dependent variable cortical thickness. Cognitive assessment comprised the Stroop Test and Trail Making Test B. RESULTS: In the linear mixed model, presence of carotid stenosis had no effect on cortical thickness. There was a significant interaction of stenosis and region with a trend towards lower cortical thickness in the MCA region on the side of carotid stenosis. Patients with carotid stenosis performed significantly worse on the Stroop test than controls, but there was no correlation with cortical thickness. CONCLUSION: In patients with carotid stenosis without ischemic brain lesions, neither a clear pattern of reduced cortical thickness nor an association of cortical thickness with cognitive function was observed. Our data do not support the hypothesized association of cortical thinning and cognitive impairment in carotid stenosis.

Kidney dysfunction predicts 90 days mortality after stroke thrombectomy independent of cardiovascular risk factors and chronic kidney disease.

INTRODUCTION: Kidney dysfunction (KD) is a risk factor for cerebrovascular events and has been shown to have a detrimental effect on outcome after stroke. We evaluated the influence of KD at admission and pre-existing diagnosis of chronic kidney disease (CKD) before thrombectomy for anterior circulation stroke on functional independence and mortality 90 days after stroke in this cross-sectional study. PATIENTS AND METHODS: We included patients with acute ischemic stroke in the anterior circulation treated with thrombectomy at our hospital between June 2015 and May 2022. We analyzed clinical characteristics, laboratory values and pre-existing diagnosis of CKD. KD at admission was defined as glomerular filtration rate (GFR) <60 ml/min/1.73 m2. Outcomes were defined as a modified Rankin Scale Score of 0-2 for functional independence and mortality at 90 days. We fitted multivariate regression analysis to examine the influence of pre-treatment KD and pre-diagnosed CKD on outcome. RESULTS: Nine hundred fifty-three patients were included in this analysis (mean age 73.8 years, 54.2% female). KD was present in 31.8%, and patients with KD were older and more often female, presented more often with comorbidities such as arterial hypertension, diabetes, and atrial fibrillation, and were less often independent before the index stroke. In multivariate analysis adjusted for age, independence before the index stroke, diabetes, hypertension, atrial fibrillation, initial NIHSS, thrombolysis treatment, and recanalization outcome, KD on admission had no significant influence on functional independence 90 days after stroke, but predicted mortality with an odds ratio of 1.80 (95% CI 1.23-2.63, p = 0.003). This influence also persisted when controlling for pre-diagnosed CKD (OR 1.60, 95% CI 1.05-2.43, p = 0.027). DISCUSSION: KD might function as a surrogate parameter for comorbidity burden and thus increased risk of mortality in this cohort. CONCLUSIONS: KD on admission is associated with an 80% higher risk of mortality at 90 days after stroke thrombectomy independent of cardiovascular risk factors and CKD awareness. KD on admission should not exclude patients from thrombectomy but might support prognostic evaluation.

Effect of Comorbidity Burden and Polypharmacy on Poor Functional Outcome in Acute Ischemic Stroke.

PURPOSE: Comorbidities and polypharmacy are risk factors for worse outcome in stroke. However, comorbidities and polypharmacy are mostly studied separately with various approaches to assess them. We aimed to analyze the impact of comorbidity burden and polypharmacy on functional outcome in acute ischemic stroke (AIS) patients undergoing mechanical thrombectomy (MT). METHODS: Acute ischemic stroke patients with large vessel occlusion (LVO) treated with MT from a prospective observational study were analyzed. Relevant comorbidity burden was defined as a Charlson Comorbidity Index (CCI) score ≥ 2, polypharmacy as the intake of ≥ 5 medications at time of stroke onset. Favorable outcome was a score of 0-2 on the modified Rankin scale at 90 days after stroke. The effect of comorbidity burden and polypharmacy on favorable outcome was studied via multivariable regression analysis. RESULTS: Of 903 patients enrolled, 703 AIS patients (mean age 73.4 years, 54.9% female) with anterior circulation LVO were included. A CCI ≥ 2 was present in 226 (32.1%) patients, polypharmacy in 315 (44.8%) patients. Favorable outcome was less frequently achieved in patients with a CCI ≥ 2 (47, 20.8% vs. 172, 36.1%, p < 0.001), and in patients with polypharmacy (69, 21.9% vs. 150, 38.7%, p < 0.001). In multivariable regression analysis including clinical covariates, a CCI ≥ 2 was associated with lower odds of favorable outcome (odds ratio, OR 0.52, 95% confidence interval, 95% CI 0.33-0.82, p = 0.005), while polypharmacy was not (OR 0.81, 95% CI 0.52-1.27, p = 0.362). CONCLUSION: Relevant comorbidity burden and polypharmacy are common in AIS patients with LVO, with comorbidity burden being a risk factor for poor outcome.

Intrinsic functional brain connectivity is resilient to chronic hypoperfusion caused by unilateral carotid artery stenosis.

INTRODUCTION: Chronic cerebral hypoperfusion caused by asymptomatic high-grade stenosis of the internal carotid artery (ICA) has been associated with impaired cognitive function. Only few studies exist on underlying changes of functional connectivity (FC). METHODS: 20 patients with unilateral high-grade ICA stenosis without MRI lesions and 25 aged-match controls underwent resting-state functional MRI (rsfMRI) and neuropsychological assessment. Patients were examined within ten days before and 6-10 weeks after surgical or interventional revascularization of carotid stenosis. We examined mean resting-state FC ipsi- and contralateral to stenosis and network topology using graph-theoretical measures. RESULTS: At baseline, intrahemispheric FC was similar for patients and healthy controls. After revascularization mean FC increased moderately without an effect on network topology. Patients performed worse in TMT B and Stroop test, while performance in global screening tests for dementia (Mini Mental Status Examination, DemTect) were comparable. Test results did not improve after revascularization. CONCLUSION: In our study population, we find no effect of chronic hypoperfusion on FC and global cognitive function, although we observe minor impairments in processing speed and mental flexibility. The subtle increase of FC after revascularization could indicate excessive upregulation after restoration of perfusion. However, it might as well be a coincidental finding due to the limited sample size.

Comprehensive Evaluation of Cerebral Hemodynamics and Oxygen Metabolism in Revascularization of Asymptomatic High-Grade Carotid Stenosis.

INTRODUCTION: Revascularization procedures in carotid artery stenosis have shown a positive effect in the restoration of cerebral oxygen metabolism as assessed by T2' (T2 prime) imaging as well as capillary homeostasis by measurement of capillary transit time heterogeneity (CTH); however, data in patients with asymptomatic carotid stenosis without manifest brain lesions are scarce. PATIENTS AND METHODS: The effect of revascularization on the hemodynamic profile and capillary homeostasis was evaluated in 13 patients with asymptomatic high-grade carotid stenosis without ischemic brain lesions using dynamic susceptibility contrast perfusion imaging and oxygenation-sensitive T2' mapping before and 6-8 weeks after revascularization by endarterectomy or stenting. The cognitive performance at both timepoints was further assessed. RESULTS: Perfusion impairment at baseline was accompanied by an increased CTH (p = 0.008) in areas with a time to peak delay ≥ 2 s in the affected hemisphere compared to contralateral regions. Carotid intervention improved the overall moderate hemodynamic impairment at baseline by leading to an increase in normalized cerebral blood flow (p = 0.017) and a decrease in mean transit time (p = 0.027), oxygen extraction capacity (OEC) (p = 0.033) and CTH (p = 0.048). The T2' values remained unchanged. CONCLUSION: This study presents novel evidence of a state of altered microvascular function in patients with high-grade carotid artery stenosis in the absence of ischemic brain lesions, which shows sustained normalization after revascularization procedures.

Higher comorbidity burden is associated with lower self-reported quality of life after stroke.

Introduction: This study assesses the association of comorbidity burden and polypharmacy with self-reported quality of life after stroke. Patients and methods: We performed a post-hoc analysis of a prospective, single-center, observational study of outcome evaluation by patient-reported outcome measures in stroke clinical practice. Consecutive patients with acute ischemic stroke (AIS) were enrolled and self-reported health-related quality of life (HrQoL) was assessed 90 days after acute stroke using the Patient-reported Outcomes Measurement Information System 10-Question Short-Form (PROMIS-10). Comorbidities at baseline were assessed by the Charlson Comorbidity Index (CCI). Polypharmacy was defined as medication intake of ≥5 at baseline. We used linear regression analysis to study the association of CCI, polypharmacy and other clinical covariates with HrQoL after stroke. Results: Of 781 patients (median age 76 years, 48.4% female) enrolled, 30.2% had a CCI Score ≥2, and 31.5% presented with polypharmacy. At follow up, 71 (9.1%) had died. In 409 (52.4%) reached for outcome evaluation, Global Physical Health T-Score was 43.8 ± 10 and Global Mental Health T-Score was 43.5 ± 8.76, indicating lower HrQoL than the average population. A CCI Score ≥2, higher NIHSS Score, female sex, dependency on others for dressing, toileting and mobility before index stroke, atrial fibrillation and hypertension were independent predictors of worse physical and mental health outcomes, while polypharmacy was not. Conclusion: In patients with AIS, high comorbidity burden and polypharmacy are frequent. Comorbidity burden at admission is independently associated with worse self-reported physical and mental health three months after stroke.

Higher white matter hyperintensity lesion load is associated with reduced long-range functional connectivity.

Cerebral small vessel disease is a common disease in the older population and is recognized as a major risk factor for cognitive decline and stroke. Small vessel disease is considered a global brain disease impacting the integrity of neuronal networks resulting in disturbances of structural and functional connectivity. A core feature of cerebral small vessel disease commonly present on neuroimaging is white matter hyperintensities. We studied high-resolution resting-state EEG, leveraging source reconstruction methods, in 35 participants with varying degree of white matter hyperintensities without clinically evident cognitive impairment in an observational study. In patients with increasing white matter lesion load, global theta power was increased independently of age. Whole-brain functional connectivity revealed a disrupted network confined to the alpha band in participants with higher white matter hyperintensities lesion load. The decrease of functional connectivity was evident in long-range connections, mostly originating or terminating in the frontal lobe. Cognitive testing revealed no global cognitive impairment; however, some participants revealed deficits of executive functions that were related to larger white matter hyperintensities lesion load. In summary, participants without clinical signs of mild cognitive impairment or dementia showed oscillatory changes that were significantly related to white matter lesion load. Hence, oscillatory neuronal network changes due to white matter lesions might act as biomarker prior to clinically relevant behavioural impairment.

Normalization of reduced functional connectivity after revascularization of asymptomatic carotid stenosis.

Internal carotid artery stenosis is a risk factor for ischemic stroke. Even in the absence of visible structural brain changes, patients with asymptomatic stenosis are prone to cognitive impairment. On a neuronal level, it was suggested that stenosis may lead to disturbed functional brain connectivity. If so, carotid revascularization should have an effect on hypothesized brain network disturbances. We studied functional connectivity in a motor network by resting-state electroencephalography in 12 patients with high grade asymptomatic carotid stenosis before and after interventional or surgical revascularization as compared to 23 controls. In patients with stenosis, functional connectivity of neural oscillations was significantly decreased prior and improved returning to normal connectivity after revascularization. In a subgroup of patients, also studied by contrast perfusion magnetic resonance imaging, reduced connectivity was associated with decreased regional brain perfusion reflected by increased mean transit time in the middle cerebral artery borderzone. Cognitive testing revealed only minor differences between patients and controls. In summary, we identified oscillatory connectivity changes in patients with asymptomatic carotid stenosis correlating with regional hypoperfusion, which both normalized after revascularization. Hence, electrophysiological changes might be a reversible precursor preceding macroscopic structural brain damage and behavioral impairment in patients with asymptomatic carotid stenosis.

Dynamics of brain perfusion and cognitive performance in revascularization of carotid artery stenosis.

INTRODUCTION: There is evidence suggesting a detrimental effect of asymptomatic carotid artery stenosis on cognitive function even in the absence of ischemic cerebral lesions. Hypoperfusion has been suggested as pathophysiological mechanism causing cognitive impairment. We aimed to assess cognitive performance and cerebral perfusion changes in patients with carotid artery stenosis without ischemic lesions by arterial spin labeling (ASL) and contrast enhanced (CE) perfusion MRI before and after revascularization therapy. METHODS: 17 asymptomatic patients with unilateral high-grade (≥70%) carotid artery stenosis without evidence of structural brain lesions underwent ASL and CE perfusion MRI and cognitive testing (MMSE, DemTect, Clock-Drawing Test, Trail-Making Test, Stroop Test) before and 6-8 weeks after revascularization therapy by endarterectomy or stenting. Multiparametric perfusion maps (ASL: cerebral blood flow (ASL-CBF), bolus arrival time (ASL-BAT); CE: cerebral blood flow (CE-CBF), mean transit time (CE-MTT), cerebral blood volume (CE-CBV)) were calculated and analyzed by vascular territory. Relative perfusion values were calculated. RESULTS: Multivariate analysis revealed a significant impact of revascularization therapy on all perfusion measures analyzed. At baseline post-hoc testing showed significant hypoperfusion in MCA borderzones as assessed by ASL-CBF, ASL-BAT, CE-MTT and CE-CBV. All perfusion alterations normalized after revascularization. We did not observe any significant correlation of cognitive test results with perfusion parameters. There was no significant change in cognitive performance after revascularization. CONCLUSION: We found evidence of traceable perfusion alterations in patients with high grade carotid artery stenosis in the absence of structural brain lesions, which proved fully reversible after revascularization therapy. In this cohort of asymptomatic patients we did not observe an association of hypoperfusion with cognitive performance.