High-Sensitivity Cardiac Troponin T and Cognitive Function Over 12 Months After Stroke-Results of the DEMDAS Study.

BACKGROUND: Subclinical myocardial injury in form of hs-cTn (high-sensitivity cardiac troponin)  levels has been associated with cognitive impairment and imaging markers of cerebral small vessel disease (SVD) in population-based and cardiovascular cohorts. Whether hs-cTn is associated with domain-specific cognitive decline and SVD burden in patients with stroke remains unknown. METHODS AND RESULTS: We analyzed patients with acute stroke without premorbid dementia from the prospective multicenter DEMDAS (DZNE [German Center for Neurodegenerative Disease]-Mechanisms of Dementia after Stroke) study. Patients underwent neuropsychological testing 6 and 12 months after the index event. Test results were classified into 5 cognitive domains (language, memory, executive function, attention, and visuospatial function). SVD markers (lacunes, cerebral microbleeds, white matter hyperintensities, and enlarged perivascular spaces) were assessed on cranial magnetic resonance imaging to constitute a global SVD score. We examined the association between hs-cTnT (hs-cTn T levels) and cognitive domains as well as the global SVD score and individual SVD markers, respectively. Measurement of cognitive and SVD-marker analyses were performed in 385 and 466 patients with available hs-cTnT levels, respectively. In analyses adjusted for demographic characteristics, cardiovascular risk factors, and cognitive status at baseline, higher hs-cTnT was negatively associated with the cognitive domains "attention" up to 12 months of follow-up (beta-coefficient, -0.273 [95% CI, -0.436 to -0.109]) and "executive function" after 12 months. Higher hs-cTnT was associated with the global SVD score (adjusted odds ratio, 1.95 [95% CI, 1.27-3.00]) and the white matter hyperintensities and lacune subscores. CONCLUSIONS: In patients with stroke, hs-cTnT is associated with a higher burden of SVD markers and cognitive function in domains linked to vascular cognitive impairment. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01334749.

Associations of C-reactive protein with depressive symptoms over time after mild to moderate ischemic stroke in the PROSCIS-B cohort.

BACKGROUND AND PURPOSE: C-reactive protein serves as a marker of inflammation and is linked to depression in the general population. We aimed to assess whether elevated baseline levels of high-sensitivity C-reactive protein (hs-CRP) are associated with depressive symptoms over time in a prospective cohort of mild-to-moderate first-ever ischemic stroke patients. METHODS: Data were obtained from the Prospective Cohort with Incident Stroke Berlin (NCT01363856). Depressive symptoms were assessed with the Center for Epidemiologic Studies Depression Scale (CES-D) at three annual follow-up points. We assessed the association of elevated levels of hs-CRP with CES-D scores over time via linear mixed models. In a subgroup analysis, we explored an interaction effect with sex. RESULTS: We included 585 ischemic stroke patients with baseline data on CRP levels. The mean age was 67 (13 SD), 39% (n = 226) were female, and the median National Institutes of Health Stroke Scale (NIHSS) was 3 (IQR 1-4). Twenty percent of survivors showed evidence for depressive symptoms one year after stroke with CES-D ≥ 16, 21% at year two, and 17% at year three. Higher log-transformed baseline hs-CRP levels were associated with higher CES-D Scores over time in the adjusted linear mixed model (ß = 1.28; (95% CI 0.22-2.34)). The subgroup analysis revealed an interaction effect of hs-CRP on depressive symptoms in women (ß = 2.33; (95% CI 0.71-3.95)). CONCLUSION: In our cohort with mild-to-moderate first-ever ischemic stroke patients, hs-CRP levels were associated with more depressive symptoms over time, with an interaction effect for the female sex. STUDY REGISTRATION: https://clinicaltrials.gov ; Unique identifier: NCT01363856.

Vasoregulatory Autoantibodies and Clinical Outcome After Ischemic Stroke-PROSCIS-B.

BACKGROUND: Vasoregulatory autoantibodies including autoantibodies targeting G-protein-coupled receptors might play a functional role in vascular diseases. We investigated the impact of vasoregulatory autoantibodies on clinical outcome after ischemic stroke. METHODS AND RESULTS: Data were used from the PROSCIS-B (Prospective Cohort With Incident Stroke-Berlin). Autoantibody-targeting receptors such as angiotensin II type 1 receptor (AT1R), endothelin-1 type A receptor, complement factor-3 and -5 receptors, vascular endothelial growth factor receptor-1 and -2, vascular endothelial growth factor A and factor B were measured. We explored associations of high antibody levels with (1) poor functional outcome defined as modified Rankin Scale >2 or Barthel Index <60 at 1 year after stroke, (2) Barthel Index scores over time using general estimating equations, and (3) secondary vascular events (recurrent stroke, myocardial infarction) or death up to 3 years using Cox proportional hazard models. We included 491 patients with ischemic stroke with data on autoantibody levels and outcome. In models adjusted for demographics and vascular risk factors, high autoantibody concentrations (quartile 4) targeting complement factor C3a receptor, vascular endothelial growth factor receptor-2, and vascular endothelial growth factor B were associated with poor functional outcome at 1 year: (odds ratio, 2.0 [95% CI, 1.1-3.6]; odds ratio, 1.8 [95% CI, 1.1-3.2]; and odds ratio, 2.1 [95% CI, 1.2-3.6], respectively) and with lower Barthel Index scores over 3 years (complement factor C3a receptor: adjusted ß=-3.3 [95% CI, -5.7 to -0.5]; VEGF-B: adjusted ß=-2.4 [95% CI, -4.8 to -0.06]). Patients with high autoantibody levels were not at higher risk for secondary vascular events or death. CONCLUSIONS: High levels of autoantibodies against vascular endothelial growth factor receptor-2, vascular endothelial growth factor B, and complement factor C3a receptor measured are associated with poor functional outcome after stroke but not with recurrent vascular events or death. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01363856.

Depressive symptoms and anti-N-methyl-D-aspartate-receptor GluN1 antibody seropositivity in the PROSpective cohort with incident stroke.

Background: Anti-NMDA-receptor GluN1 antibodies (NMDAR1-abs) are present in an autoimmune encephalitis with severe neuropsychiatric symptoms. We aimed to estimate the impact of serum NMDAR1-abs on depressive symptoms years after first-ever ischemic stroke (IS). Methods: Data were used from the PROSpective Cohort with Incident Stroke-Berlin (PROSCIS-B; NCT01363856). Serum NMDAR1-abs (IgM/IgA/IgG) were measured within 7 days after IS using cell-based assays. We defined seropositivity as titers ≥1:10, thereof low titers as ≤1:100 and high titers as >1:100. We used the Center for Epidemiological Studies-Depression (CES-D) scale to measure depressive symptoms at year one, two and three following IS. We calculated crude and confounder adjusted weighted generalized linear models to quantify the impact of NMDAR1-abs on CES-D assessed at three annual time-points. Results: NMDAR1-abs were measured in 583 PROSCIS-B IS patients (mean age = 67 [SD = 13]; 42%female; median NIHSS = 2 [IQR = 1-4]) of whom 76 (13%; IgM: n = 49/IgA: n = 43/IgG: n = 2) were seropositive, 55 (9%) with low and 21 (4%) with high titers. CES-D regarded over all follow-up time-points was higher in seropositive patients (ßcrude = 2.56 [95%CI = -0.34 to 5.45]; ßadjusted = 2.26 [95%CI = -0.68 to 5.20]) and effects were highest in patients with high titer (low titers: ßcrude = 1.42 [95%CI = -1.79 to 4.62], ßadjusted = 0.53 [95%CI = -2.47 to 3.54]; high titers: ßcrude = 5.85 [95%CI = 0.20 to 11.50]; ßadjusted = 7.20 [95%CI = 0.98 to 13.43]). Conclusion: Patients with serum NMDAR1-abs (predominantly IgM&IgA) suffer more severe depressive symptoms after mild-to-moderate IS compared to NMDAR1-abs seronegative patients.

Associations of clonal hematopoiesis with recurrent vascular events and death in patients with incident ischemic stroke.

Clonal hematopoiesis (CH) is common among older people and is associated with an increased risk of atherosclerosis, inflammation, and shorter overall survival. Age and inflammation are major risk factors for ischemic stroke, yet the association of CH with risk of secondary vascular events and death is unknown. We investigated CH in peripheral blood DNA from 581 patients with first-ever ischemic stroke from the Prospective Cohort With Incident Stroke-Berlin study using error-corrected targeted sequencing. The primary composite end point (CEP) consisted of recurrent stroke, myocardial infarction, and all-cause mortality. A total of 348 somatic mutations with a variant allele frequency ≥1% were identified in 236 of 581 patients (41%). CH was associated with large-artery atherosclerosis stroke (P = .01) and white matter lesion (P < .001). CH-positive patients showed increased levels of proinflammatory cytokines, such as interleukin-6 (IL-6), interferon gamma, high-sensitivity C-reactive protein, and vascular cell adhesion molecule 1. CH-positive patients had a higher risk for the primary CEP (hazard ratio [HR], 1.55; 95% confidence interval [CI], 1.04-2.31; P = .03), which was more pronounced in patients with larger clones. CH clone size remained an independent risk factor (HR, 1.30; 95% CI, 1.04-1.62; P = .022) in multivariable Cox regression. Although our data show that, in particular, larger and TET2- or PPM1D-mutated clones are associated with increased risk of recurrent vascular events and death, this risk is partially mitigated by a common germline variant of the IL-6 receptor (IL-6R p.D358A). The CH mutation profile is accompanied by a proinflammatory profile, opening new avenues for preventive precision medicine approaches to resolve the self-perpetuating cycle of inflammation and clonal expansion.

Cerebral small vessel disease burden and cognitive and functional outcomes after stroke: A multicenter prospective cohort study.

INTRODUCTION: It remains unknown whether the global small vessel disease (SVD) burden predicts post-stroke outcomes. METHODS: In a prospective multicenter study of 666 ischemic and hemorrhagic stroke patients, we quantified magnetic resonance imaging (MRI)-based SVD markers (lacunes, white matter hyperintensities, microbleeds, perivascular spaces) and explored associations with 6- and 12-month cognitive (battery of 15 neuropsychological tests) and functional (modified Rankin scale) outcomes. RESULTS: A global SVD score (range 0-4) was associated with cognitive impairment; worse performance in executive function, attention, language, and visuospatial ability; and worse functional outcome across a 12-month follow-up. Although the global SVD score did not improve prediction, individual SVD markers, assessed across their severity range, improved the calibration, discrimination, and reclassification of predictive models including demographic, clinical, and other imaging factors. DISCUSSION: SVD presence and severity are associated with worse cognitive and functional outcomes 12 months after stroke. Assessing SVD severity may aid prognostication for stroke patients. HIGHLIGHTS: In a multi-center cohort, we explored associations of small vessel disease (SVD) burden with stroke outcomes. SVD burden associates with post-stroke cognitive and functional outcomes. A currently used score of SVD burden does not improve the prediction of poor outcomes. Assessing the severity of SVD lesions adds predictive value beyond known predictors. To add predictive value in assessing SVD in stroke patients, SVD burden scores should integrate lesion severity.

Low ankle-brachial index and cognitive function after stroke-the PROSpective with Incident Stroke Berlin (PROSCIS-B).

Introduction: Low ankle-brachial index (ABI) ≤0. 9 is a marker for generalized atherosclerosis and a risk factor for cognitive decline in the general population. Objective: To evaluate the impact of ABI ≤0.9 on cognitive function up to 3 years after first-ever ischemic stroke. Methods: Data was used from the "PROspective Cohort with Incident Stroke-Berlin" (PROSCIS-B; NCT01363856). ABI was measured at baseline and categorized into normal (1.4-0.9) vs. low (≤0.9). Cognitive function was assessed with the Montreal Cognitive Assessment (MoCA) and the Mini-Mental-State-Examination (MMSE) at baseline and with the Telephone Interview for Cognitive Status-modified (TICS-m) at 1-3 years of follow-up. We performed confounder adjusted generalized linear models (GLM) to calculate relative risks (RR) for cognitive impairment at baseline (MMSE≤26; MoCA≤25) and linear mixed models (LMM) to estimate the impact of low ABI on TICS-m over time. Results: We included 325 patients [mean age: 66 (SD = 13); 38% female, median NIHSS = 2 (IQR = 1-4), ABI≤0.9: 59 (18%)]. Patients with low ABI were at increased risk of cognitive impairment at baseline (adjusted RR for MoCA≤25 = 1.98; 95%-CI:1.24 to 3.16). TICS-m scores were consistently lower over time in patients with low ABI (adjusted ß = -1.96; 95%-CI:-3.55 to -0.37). Independent of ABI, cognitive function did not decline over time (adjusted ß:0.29; 95%-CI:-0.06 to 0.64). Conclusion: In patients with mild to moderate first-ever ischemic stroke, low ABI is associated with reduced cognitive function over a 3-year follow-up. Study Registration: https://clinicaltrials.gov; Unique identifier: NCT01363856.

Serum anti-NMDA-receptor antibodies and cognitive function after ischemic stroke (PROSCIS-B).

OBJECTIVE: We aimed to investigate whether serum anti-N-methyl-D-aspartate-receptor GluN1 (previously NR1) antibody (NMDAR1-abs) seropositivity impacts cognitive function (CF) in the long term following ischemic stroke. METHODS: Data were used from the PROSpective Cohort with Incident Stroke-Berlin. NMDAR1-abs (IgM/IgA/IgG) were measured with cell-based assays from serum obtained within 7 days after the first-ever stroke. Seropositivity was defined as titers ≥ 1:10, low titers as ≤ 1:100 and high titers as > 1:100. We assessed CF at 1, 2 and 3 years after stroke with the Telephone Interview for Cognitive Status-modified (TICS-m) and used crude and propensity score adjusted inverse probability weighted generalized linear models to estimate the impact of NMDAR1-abs serostatus on TICS-m. RESULTS: Data on NMDAR1-abs (median day of sampling = 4[IQR = 2-5]) were available in 583/621 PROSCIS-B patients (39% female; median NIHSS = 2[IQR = 1-4]; median MMSE = 28[IQR:26-30]), of whom 76(13%) were seropositive (IgM: n = 48/IgA: n = 43/IgG: n = 2). Any NMDAR1-abs seropositivity had no impact on TICS-m compared to seronegative patients (ßcrude = 0.69[95%CI = - 0.84 to 2.23]; ßadjusted = 0.65[95%CI = - 1.00 to 2.30]). Patients with low titers scored better on TICS-m compared to seronegative patients (ßcrude = 2.33[95%CI = 0.76 to 3.91]; ßadjusted = 2.47[95%CI = 0.75 to 4.19]); in contrast, patients with high titers scored lower on TICS-m (ßcrude =  -2.82[95%CI = - 4.90 to - 0.74], ßadjusted = - 2.96[95%CI = - 5.13 to - 0.80]), compared to seronegative patients. CONCLUSION: In our study, NMDAR1-abs seropositivity did not affect CF over 3 years after a first mild to moderate ischemic stroke. CF differed according to NMDAR1-abs serum titer, with patients with high NMDAR1-abs titers having a less favorable cognitive outcome compared to seronegative patients.

Combined Oral Triglyceride and Glucose Tolerance Test After Acute Ischemic Stroke to Predict Recurrent Vascular Events: The Berlin "Cream&Sugar" Study.

BACKGROUND: Elevated triglyceride and glucose levels are associated with an increased cardiovascular disease risk including ischemic stroke. It is not known whether the response to a combined oral triglyceride and glucose challenge after ischemic stroke improves identification of patients with increased risk for recurrent vascular events. METHODS: The prospective, observational Berlin "Cream&Sugar" study was conducted at 3 different university hospital sites of the Charité-Universitätsmedizin Berlin, Germany, between January 24, 2009 and July 31, 2017. Patients with first-ever ischemic stroke were recruited 3 to 7 days after stroke. An oral triglyceride tolerance test (OTTT) and consecutive blood tests before (t0) as well as 3 (t1), 4 (t2), and 5 hours (t3) after OTTT were performed in fasting patients. An oral glucose tolerance test was performed in all nondiabetic patients 3 hours after the start of OTTT. Outcomes of the study were recurrent fatal or nonfatal stroke as well as a composite vascular end point including stroke, transient ischemic attack, myocardial infarction, coronary revascularization, and cardiovascular death assessed 1 year after stroke. Cox regression models were used to estimate hazard ratios and corresponding 95% CIs between patients with high versus low levels of triglyceride and glucose levels. RESULTS: Overall 755 patients were included; 523 patients completed OTTT and 1-year follow-up. Patients were largely minor strokes patients with a median National Institutes of Health Stroke Scale score of 1 (0-3). Comparing highest versus lowest quartiles of triglyceride levels, neither fasting (adjusted hazard ratiot0, 1.24 [95% CI, 0.45-3.42]) nor postprandial triglyceride levels (adjusted hazard ratiot3, 0.44 [95% CI, 0.16-1.25]) were associated with recurrent stroke. With regard to recurrent vascular events, results were similar for fasting triglycerides (adjusted hazard ratiot0, 1.09 [95% CI, 0.49-2.43]), however, higher postprandial triglyceride levels were significantly associated with a lower risk for recurrent vascular events (adjusted hazard ratiot3, 0.42 [95% CI, 0.18-0.95]). No associations were observed between fasting and post-oral glucose tolerance test blood glucose levels and recurrent vascular risk. All findings were irrespective of the diabetic status of patients. CONCLUSIONS: In this cohort of patients with first-ever' minor ischemic stroke, fasting triglyceride or glucose levels were not associated with recurrent stroke at one year after stroke. However, higher postprandial triglyceride levels were associated with a lower risk of recurrent vascular events which requires further validation in future studies. Overall, our results do not support the routine use of a combined OTTT/oral glucose tolerance test to improve risk prediction for recurrent stroke.

High-Sensitivity Cardiac Troponin T and Recurrent Vascular Events After First Ischemic Stroke.

Background Recent evidence suggests cardiac troponin levels to be a marker of increased vascular risk. We aimed to assess whether levels of high-sensitivity cardiac troponin T (hs-cTnT) are associated with recurrent vascular events and death in patients with first-ever, mild to moderate ischemic stroke. Methods and Results We used data from the PROSCIS-B (Prospective Cohort With Incident Stroke Berlin) study. We computed Cox proportional hazards regression analyses to assess the association between hs-cTnT levels upon study entry (Roche Elecsys, upper reference limit, 14 ng/L) and the primary outcome (composite of recurrent stroke, myocardial infarction, and all-cause death). A total of 562 patients were analyzed (mean age, 67 years [SD 13]; 38.6% women; median National Institutes of Health Stroke Scale=2; hs-cTnT above upper reference limit, 39.2%). During a mean follow-up of 3 years, the primary outcome occurred in 89 patients (15.8%), including 40 (7.1%) recurrent strokes, 4 (0.7%) myocardial infarctions, and 51 (9.1%) events of all-cause death. The primary outcome occurred more often in patients with hs-cTnT above the upper reference limit (27.3% versus 10.2%; adjusted hazard ratio, 2.0; 95% CI, 1.3-3.3), with a dose-response relationship when the highest and lowest hs-cTnT quartiles were compared (15.2 versus 1.8 events per 100 person-years; adjusted hazard ratio, 4.8; 95% CI, 1.9-11.8). This association remained consistent in sensitivity analyses, which included age matching and stratification for sex. Conclusions Hs-cTnT is dose-dependently associated with an increased risk of recurrent vascular events and death within 3 years after first-ever, mild to moderate ischemic stroke. These findings support further studies of the utility of hs-cTnT for individualized risk stratification after stroke. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT01363856.

Coagulation factor XII, XI, and VIII activity levels and secondary events after first ischemic stroke.

BACKGROUND: Though risk for recurrent vascular events is high following ischemic stroke, little knowledge about risk factors for secondary events post-stroke exists. OBJECTIVES: Coagulation factors XII, XI, and VIII (FXII, FXI, and FVIII) have been implicated in first thrombotic events, and our aim was to estimate their effects on vascular outcomes within 3 years after first stroke. PATIENTS/METHODS: In the Prospective Cohort with Incident Stroke Berlin (PROSCIS-B) study, we followed participants aged 18 and older for 3 years after first mild to moderate ischemic stroke event or until occurrence of recurrent stroke, myocardial infarction, or all-cause mortality. We compared high coagulation factor activity levels to normal and low levels and also analyzed activities as continuous variables. We used Cox proportional hazards models adjusted for age, sex, and cardiovascular risk factors to estimate hazard ratios (HRs) for the combined endpoint. RESULTS: In total, 94 events occurred in 576 included participants, resulting in an absolute rate of 6.6 events per 100 person-years. After confounding adjustment, high FVIII activity showed the strongest relationship with the combined endpoint (HR = 2.05, 95% confidence interval [CI] 1.28-3.29). High FXI activity was also associated with a higher hazard (HR = 1.80, 95% CI 1.09-2.98), though high FXII activity was not (HR = 0.86, 95% CI 0.49-1.51). Continuous analyses yielded similar results. CONCLUSIONS: In our study of mild to moderate ischemic stroke patients, high activity levels of FXI and FVIII but not FXII were associated with worse vascular outcomes in the 3-year period after first ischemic stroke.

High-Sensitivity Cardiac Troponin T and Cognitive Function in Patients With Ischemic Stroke.

Background and Purpose- Our study aim was to assess whether high-sensitivity cardiac troponin T (hs-cTnT), a specific biomarker for myocardial injury, is associated with cognitive function in patients after mild-to-moderate first-ever ischemic stroke. Methods- We used data from PROSCIS-B (Prospective Cohort With Incident Stroke Berlin). Cognitive function was assessed by Mini-Mental-State-Examination at baseline, and Telephone Interview for Cognitive Status-modified after 1 to 3 years of follow-up. Patients were categorized according to hs-cTnT quartiles. We performed generalized linear regression to calculate risk ratios of cognitive impairment (Mini-Mental-State-Examination <27; Telephone Interview for Cognitive Status-modified <32). Association of hs-cTnT with cognitive function over time was estimated using a linear mixed model. Results- We included 555 patients (mean age, 67 years, 62% male, median National Institutes of Health Stroke Scale 2 [interquartile range, 1-5], hs-cTnT above upper reference limit 40%, baseline cognitive impairment 28%). Baseline Mini-Mental-State-Examination score and rate of cognitive impairment were lower in patients in the highest versus lowest hs-cTnT quartile (median Mini-Mental-State-Examination 27 versus 29, and 15.3% versus 43.0%, adjusted risk ratio, 1.76 [95% CI, 1.07-2.90], respectively). If anything, cognition seemed to improve in all groups, yet Telephone Interview for Cognitive Status-modified scores were consistently lower in patients within the highest versus lowest hs-cTnT quartile (adjusted ß, -1.33 [95% CI, -2.65 to -0.02]), without difference in the rate of change over time. Conclusions- In patients with mild-to-moderate first-ever ischemic stroke without dementia, higher hs-cTnT was associated with higher prevalence of cognitive impairment at baseline and lower Telephone Interview for Cognitive Status-modified during 3-year follow-up. Registration- URL: https://www.clinicaltrials.gov; Unique identifier: NCT01363856.

Serum Anti-NMDA (N-Methyl-D-Aspartate)-Receptor Antibodies and Long-Term Clinical Outcome After Stroke (PROSCIS-B).

Background and Purpose- NMDAR1-abs (anti-N-Methyl-D-Aspartate receptor GluN1 antibodies), predominantly known in the context of autoimmune encephalitis, have been observed in serum of healthy individuals. A previous study found smaller stroke magnetic resonance imaging lesion growth in seropositive patients, suggesting a neuroprotective effect of these antibodies. The impact of NMDAR1-abs seropositivity on long-term functional outcome and recurrent vascular events and death after first-ever stroke remains unclear. Methods- Data from the Prospective Cohort with Incident Stroke-Berlin were used. NMDAR1-abs (ie, IgM, IgA, and IgG) were measured in serum within 7 days after first stroke. Outcomes of interest included modified Rankin Scale at one year and the time-to-event of a combined end point (recurrent stroke, myocardial infarction, and all-cause mortality) within 3 years. We calculated odds ratios from adjusted partial proportional odds models and subsequently compared outcome of patients with low titers (1:10; 1:32; and 1:100), and high titers (1:320; 1:1000) to seronegative patients. Furthermore, we estimated hazard ratios for a secondary vascular event or death in NMDAR1-abs seropositive compared to seronegative patients in models adjusted for confounders. Results- The analyses included 583 patients with antibody measurements (39% female, median National Institutes of Health Stroke Scale:2, IQR:1-4), and NMDAR1-abs were observed in 76 (13%) patients. NMDAR1-abs seroprevalence was not associated with functional outcome (odds ratio=1.27; 95% CI, 0.77-2.09); sub-group analyses, however, showed worse outcome in patients with high titers (odds ratio=3.47; 95% CI, 1.54-7.80). Seropositive patients had an increased risk for a secondary vascular event or death (hazard ratios =1.83, 95% CI, 1.10-3.05). Conclusions- In our study, NMDAR1-abs seropositivity was not associated with functional outcome at one year after stroke, however, high titers (≥1:320) were associated with poor functional outcome. Furthermore, NMDAR1-abs seropositivity was associated with increased cardiovascular risk within 3 years after first stroke, independently from other risk factors. Clinical Trial Registration- URL: https://www.clinicaltrials.gov. Unique identifier: NCT01363856.

The Montreal Cognitive Assessment (MoCA) in a population-based sample of Turkish migrants living in Germany.

OBJECTIVES: Data on cognitive testing in migrants in Germany are scarce. We aimed to evaluate the Montreal Cognitive Assessment (MoCA) in Turkish migrants in Berlin and its association with demographics and health-related variables. METHOD: For this cross-sectional study, a random sample of persons with Turkish names was drawn from the registration-office. Cognitive function was assessed using the MoCA; 0 = worst, 30 = best total score. Multivariable linear regression models were calculated to determine associated factors with the total MoCA-score. RESULTS: In our analyses we included 282 participants (50% female), mean age 42.3 ± 11.9 years (mean ± standard deviation (SD)). The mean ± SD MoCA score was 23.3 ± 4.3. In the multivariable analysis, higher education (ß = 2.68; p < 0.001), and chosing the German version of the MoCA (ß = -1.13; p = 0.026), were associated with higher MoCA-scores, whereas higher age (ß = -0.08; p = 0.002) was associated with lower MoCA scores. CONCLUSION: In our study, a higher educational level, lower age, and German as the preferred test language (as compared to Turkish) were positively associated with the cognitive performance of Berliners with Turkish roots. To examine neurocognitive health of migrants, longitudinal population-based and clinical cohort studies that specifically compare migrants and their descendants with the original population of their home countries are required.

Posterior reversible encephalopathy syndrome.

PURPOSE OF REVIEW: Posterior reversible encephalopathy syndrome (PRES) is a clinicoradiological syndrome characterized by acute cerebral endotheliopathy with consecutive disruption of the blood-brain barrier and vasogenic edema. Since its first description in 1996, PRES is increasingly recognized. However, many aspects of this syndrome with its wide spectrum of clinical and radiological features are still incompletely understood. In this review, possible pathophysiological mechanisms, approaches to diagnosis, recent study results on outcome, and future directions of research are described. RECENT FINDINGS: Clinical manifestations of PRES include seizures, headache, visual disturbances, altered mental state, and more rarely hemiparesis or aphasia. Vasogenic edema predominantly occurs in the parieto-occipital region, but lesions affecting formerly called 'atypical' regions such as frontal lobe, cerebellum, or basal ganglia are common. If treated early and adequately, that is by removal of the underlying cause, PRES has a favorable prognosis, but neurological residual symptoms and even mortality can occur, particularly in patients with complications such as intracranial hemorrhage. SUMMARY: In summary, validated diagnostic criteria and algorithms are warranted to standardize the diagnosis of PRES. This is essential for further research and future prospective studies that should investigate risk factors for unfavorable outcome and identify the roles of imaging features, clinical symptoms, and other biomarkers in predicting outcome.

Gut Microbiota-Dependent Trimethylamine N-Oxide Predicts Risk of Cardiovascular Events in Patients With Stroke and Is Related to Proinflammatory Monocytes.

Objective- Gut microbiota-dependent metabolites, in particular trimethylamine N-oxide (TMAO), have recently been reported to promote atherosclerosis and thrombosis. Here, we examined for the first time the relation of TMAO and the risk of incident cardiovascular events in patients with recent first-ever ischemic stroke in 2 independent prospective cohorts. Moreover, the link between TMAO and proinflammatory monocytes as a potential contributing factor for cardiovascular risk in stroke patients was studied. Approach and Results- In a first study (n=78), higher TMAO plasma levels were linked with an increased risk of incident cardiovascular events including myocardial infarction, recurrent stroke, and cardiovascular death (fourth quartile versus first quartile; hazard ratio, 2.31; 95% CI, 1.25-4.23; P<0.01). In the second independent validation cohort (n=593), high TMAO levels again heralded marked increased risk of adverse cardiovascular events (fourth quartile versus first quartile; hazard ratio, 5.0; 95% CI, 1.7-14.8; P<0.01), and also after adjustments for cardiovascular risk factors including hypertension, diabetes mellitus, LDL (low-density lipoprotein) cholesterol, and estimated glomerular filtration rate (hazard ratio, 3.3; 95% CI, 1.2-10.9; P=0.04). A significant correlation was also found between TMAO levels and percentage of proinflammatory intermediate CD14++CD16+ monocytes ( r=0.70; P<0.01). Moreover, in mice fed a diet enriched with choline to increase TMAO synthesis, levels of proinflammatory murine Ly6Chigh monocytes were higher than in the chow-fed control group (choline: 9.2±0.5×103 per mL versus control: 6.5±0.5×103 per mL; P<0.01). This increase was abolished in mice with depleted gut microbiota (choline+antibiotics: 5.4±0.7×103 per mL; P<0.001 versus choline). Conclusions- The present study demonstrates for the first time a graded relation between TMAO levels and the risk of subsequent cardiovascular events in patients with recent prior ischemic stroke. Our data support the notion that TMAO-related increase of proinflammatory monocytes may add to elevated cardiovascular risk of patients with increased TMAO levels.

Lipoprotein(a) Levels and Recurrent Vascular Events After First Ischemic Stroke.

BACKGROUND AND PURPOSE: The association of elevated lipoprotein(a) (Lp(a)) levels and the incidence of cardiovascular disease, especially coronary heart disease and ischemic stroke, is well established. However, evidence on the association between Lp(a) levels and residual vascular risk in stroke survivors is lacking. We aimed to elucidate the risk for recurrent cardiovascular and cerebrovascular events in the patients with first-ever ischemic stroke with elevated Lp(a). METHODS: All patients with acute ischemic stroke who participated in the prospective Berlin C&S study (Cream & Sugar) between January 2009 and August 2014 with available 12-month follow-up data and stored blood samples were eligible for inclusion. Lp(a) levels were determined in serum samples using an isoform-insensitive nephelometry assay. We assessed the risk for the composite vascular end point of ischemic stroke, transient ischemic attack, myocardial infarction, nonelective coronary revascularization, and cardiovascular death with elevated Lp(a) defined as >30 mg/dL using Cox regression analyses. RESULTS: Of 465 C&S study participants, 250 patients were included into this substudy with a median National Institutes of Health Stroke Scale score of 2 (1-4). Twenty-six patients (10%) experienced a recurrent vascular event during follow-up. Among patients with normal Lp(a) levels, 11 of 157 subjects (7%) experienced an event at a median time of 161 days (interquartile range, 19-196 days), whereas in patients with elevated Lp(a) levels, 15 of 93 subjects (16%) experienced an event at a median time of 48 days (interquartile range, 9-194 days; P=0.026). The risk for a recurrent event was significantly higher in patients with elevated Lp(a) levels after adjustment for potential confounders (hazard ratio, 2.60; 95% confidence interval, 1.19-5.67; P=0.016). CONCLUSIONS: Elevated Lp(a) levels are associated with a higher risk for combined vascular event recurrence in patients with acute, first-ever ischemic stroke. This finding should be validated in larger, multicenter trials. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01378468.

Stromal Cell-Derived Factor-1 Alpha Is Decreased in Women With Migraine With Aura.

BACKGROUND: Endothelial dysfunction may contribute to the pathophysiology of migraine with aura. Stromal cell-derived factor-1 alpha (SDF-1α) is involved in the maintenance of endothelial integrity via mobilization of vascular stem cells. OBJECTIVES: We sought to determine whether SDF-1α levels are decreased in women with MA. METHODS: In this post hoc analysis of a case-cohort study, levels of SDF-1α were determined by enzyme-linked immunosorbent assay. Endothelial function was assessed using peripheral arterial tonometry. Arterial stiffness was assessed by fingertip tonometry derived and heart-rate-adjusted augmentation index (AI). RESULTS: Twenty-eight women with MA and 27 age-matched healthy women were included in this study. Levels of SDF-1α were significantly lower in women with MA compared to age- and risk factor-matched healthy women (1763 ± 281 vs 2013 ± 263 pg/mL, P = 0.006). SDF-1α levels were positively correlated with AI in healthy women (r = 0.49, P = 0.009), but not in women with MA (r = 0.05, P = 0.78). SDF-1α levels were negatively correlated with CD144-positive endothelial microparticles (EMP; r = -0.31, P = .02), and activated CD62E-positive EMP (r = -0.35, P = .01). CONCLUSION: Levels of SDF-1α are decreased in women with MA and are associated with EMPs as a surrogate marker of endothelial dysfunction. This might contribute to the pathophysiology and vascular risk in MA, but evidence from larger prospective studies is warranted.

Spectrum of cerebral spinal fluid findings in patients with posterior reversible encephalopathy syndrome.

The purpose of this study is to characterize the spectrum of cerebrospinal fluid (CSF) findings in patients with posterior reversible encephalopathy syndrome (PRES)and determine its associations with severity of edema. In this retrospective cross-sectional study electronic medical reports were screened for patients with PRES. Clinical and laboratory data closest to onset of clinical symptoms were collected. Neuroimaging reports from all patients were categorized according to the presence of vasogenic edema,cytotoxic edema and contrast enhancement. From Jan 1999to Feb 2015, 87 patients with PRES and CSF findings were included. Mean total protein levels were 793 ± 929 mg/l. Median cell counts were 2/µl (IQR 1-4). Eight patients had cell counts[6/µl with a maximum of 41/µl. In 31 patients with extended CSF analysis, mean CSF/serum albuminquotient (QAlb) was 10.1 (IQR 6-17.3). An elevated QAlb (age-adjusted) was found in 74 % of these 31 patients. PRES patients with severe edema had higher mean total protein levels in CSF (mean difference = 407 mg/l; 95 %CI 187-628). Significant correlations were found for edema severity with levels of CSF protein (r = 0.48, p<0.001) as well with QAlb (r = 0.44, p = 0.013). This study shows that total protein in CSF and QAlb are elevated and correlate with severity of edema in PRES patients, whereas pleocytosis was rare in our cohort. This supports the theory that PRES is caused by a dysfunctional blood brain barrier.